NZ787301A

NZ787301A - Bromodomain inhibitors

Info

Publication number: NZ787301A
Application number: NZ787301A
Authority: NZ
Inventors: Dachun Liu; Le Wang; Keith F Mcdaniel; Steven D Fidanze; George S Sheppard; Lisa A Hasvold; John PRATT; Michael Schrimpf; Bing Li
Original assignee: Abbvie Inc
Filing date: 2017-04-14
Publication date: 2022-04-29

Abstract

The present invention provides for compounds of formula (I) wherein R1, R2, R3, R4, R6, X1, and X2 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising compounds of formula (I).

Description

BROMODOMAIN INHIBITORS CROSS REFERENCE The present ation is a divisional of New Zealand patent application no. 745741, which was the national phase entry of , the entire specifications of which are incorporated herein by reference.

BACKGROUND Bromodomains refer to conserved protein structural folds which bind to N-acetylated lysine residues that are found in some proteins. The BET family of bromodomain containing proteins comprises four s (BRD2, BRD3, BRD4 and BRDt). Each member of the BET family s two bromodomains to recognize N-acetylated lysine residues typically, but not exclusively those found on transcription s (Shi, J., et al. Cancer Cell 25(2): 210-225 (2014)) or on the amino-terminal tails of histone proteins. ing from the N-terminal end of each BET protein the tandem bromodomains are typically labelled g Domain I (BDI) and Binding Domain II (BDII). These interactions modulate gene expression by recruiting transcription factors to specific genome locations within chromatin. For example, histonebound BRD4 recruits the transcription factor P-TEFb to promoters, resulting in the expression of a subset of genes ed in cell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967- 976 (2008)). BRD2 and BRD3 also function as riptional regulators of growth promoting genes (LeRoy et al., Mol. Cell 30: 51-60 (2008)). BET family members were recently established as being important for the maintenance of several cancer types (Zuber et al., Nature 478: 524-528 (2011); Mertz et al; Proc. Nat’l. Acad. Sci. 108: 16669-16674 (2011); Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478: 529-533 ). BET family members have also been implicated in mediating acute inflammatory responses through the canonical NF-KB pathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) resulting in the upregulation of genes associated with the production of cytokines (Nicodeme et al., Nature 468: 1119-1123, (2010)). Suppression of cytokine induction by BET bromodomain inhibitors has been shown to be an effective approach to treat inflammation-mediated kidney disease in an animal model (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)). BRD2 function has been linked to pre-disposition for dyslipidemia or improper regulation of adipogenesis, ed inflammatory profiles and increased susceptibility to autoimmune diseases (Denis, Discovery ne 10: 489-499 (2010)). The human immunodeficiency virus utilizes BRD4 to initiate ription of viral RNA from stably integrated viral DNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomain inhibitors have also been shown to reactivate HIV transcription in models of latent T cell ion and latent monocyte infection (Banerjee, et al, J. Leukocyte Biol. doi:10.1189/jlb.0312165). BRDt has an important role in togenesis that is blocked by BET bromodomain inhibitors (Matzuk, et al., Cell 150: 673-684 (2012)).

Thus, compounds that inhibit the binding of BET family bromodomains to their cognate acetylated lysine proteins are being pursued for the treatment of cancer, inﬂammatory diseases, kidney diseases, diseases involving metabolism or fat accumulation, and some viral infections, as well as for providing a method for male contraception. Accordingly, there is an ongoing medical need to develop new drugs to treat these indications.

SUMMARY In one aspect the present ion provides for compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, CD2CD3, C1-C6 alkyl, C1-C6 haloalkyl, a C3-C6 cycloalkyl, a phenyl, or a -6 membered clic heteroaryl, wherein the C3-C6 cycloalkyl, the phenyl, and the 5-6 membered monocyclic heteroaryl are each optionally substituted with l, 2, 3, or 4 independently selected RX groups, R2 is Gza, C1-C6 haloalkyl, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of G2b and —OH, G2a is a phenyl or a C3-C6 monocyclic cycloalkyl, wherein each G2a is optionally substituted with l, 2, 3, or 4 independently selected RX groups, G2b is phenyl optionally tuted with l, 2, 3, or 4 independently selected RX 2O groups, R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a C3-C6 monocyclic cycloalkyl wherein the C3-C6 monocyclic cycloalkyl is optionally substituted with l, 2, 3, or 4 ndently selected RX groups, or R2 and R3, together with the carbon atom to which they are attached, form a C3-C6 monocyclic cycloalkyl, a C4-C6 monocyclic cycloalkenyl, or a 4-6 membered clic heterocycle, n the C3-C6 monocyclic cycloalkyl, the C4-C6 clic cycloalkenyl, and the 4-6 ed monocyclic heterocycle are each ally substituted with l, 2, 3, or 4 independently selected RX groups, R4 is phenyl, nyl, a C3-C6 monocyclic lkyl, or a C4-C6 monocyclic lkenyl, wherein each R4 is ally substituted with l, 2, 3, or 4 independently selected Ry groups, or R4 is a (a) R4d Oi R4C Y/ R4b R4a and R4b are each independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R4C and R4d are each independently hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -S(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), or —(C1-C6 alkylenyl)-OH, Y is C(R4e) or N, wherein R46 is hydrogen, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl, Rx, at each occurrence, is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl, Ry, at each occurrence, is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C6 alkyl), -O(C1-C6 haloalkyl), or —(C1-C6 alkylenyl)-OH, X1 and X2 are C(RS), or one of X1 and X2 is N and the other is C(RS), R5, at each occurrence, is independently hydrogen or halogen, and R6 is hydrogen, halogen, -CN, C1-C6 kyl, or C1-C6 alkyl.

In another aspect, the present invention provides for methods for treating or preventing disorders that are ameliorated by inhibition of BET. Such methods comprise of administering to the subject a therapeutically effective amount of a compound of a (I), alone, or in combination with a pharmaceutically acceptable carrier.

Some of the methods are directed to treating or ting an inﬂammatory disease or cancer or AIDS. id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5" id="p-5"

[0005] In another aspect, the present invention relates to methods of treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a ceutically acceptable salt f, to a subject in need thereof. In certain embodiments, the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic ia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic cytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal , craniopharyngioma, enocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), nal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, ial thrombocythemia, Ewing’s tumor, f1brosarcoma, follicular ma, germ cell testicular cancer, glioma, glioblastoma, rcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, e itive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and dgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid ancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, lastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, atic cancer, papillary adenocarcinomas, papillary oma, pinealoma, polycythemia vera, prostate , rectal cancer, renal cell oma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and as), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, d cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine cancer, and Wilms’ tumor. In certain embodiments, the methods further comprise stering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is selected from the group consisting of bine, bortezomib, and 5- azacitidine.

In another aspect, the present invention relates to methods of treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, itis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inﬂammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, y biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, , systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I es, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention s to s of ng a chronic kidney disease or condition in a subject comprising stering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or ion is selected from the group consisting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus tis, IgA nephropathy, focal segmental glomerulosclerosis, membranous ulonephritis, minimal change disease, polycystic kidney e, and tubular interstitial nephritis. In certain embodiments, the methods r se administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treating an acute kidney injury or disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I), or a ceutically acceptable salt thereof, to a t in need thereof, wherein said acute kidney injury or disease or condition is selected from the group consisting of: ia-reperfusion induced kidney disease, cardiac and major surgery induced kidney disease, percutaneous coronary intervention induced kidney disease, radio-contrast agent induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney disease, and drug toxicity induced kidney disease. In certain embodiments, the methods further comprise administering a eutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention s to s of treating AIDS in a subject comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In 3O certain embodiments, the methods further comprise stering a therapeutically effective amount of at least one additional therapeutic agent.

In r aspect, the present invention relates to methods of treating obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, or diabetic neuropathy in a t comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In n embodiments, the methods further comprise administering a therapeutically ive amount of at least one additional eutic agent.

In another aspect, the present invention relates to methods of ting conception by inhibiting togenesis in a subject comprising administering a eutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12"

[0012] A further aspect of the invention provides the use of a compound of formula (I), alone or in combination with at least one additional therapeutic agent, in the manufacture of a medicament for treating or preventing ions and disorders disclosed herein, with or without a pharmaceutically acceptable carrier.

Pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, alone or in combination with at lease one onal therapeutic agent, are also provided.

DETAILED DESCRIPTION Disclosed herein are compounds of formula (I) wherein R1, R2, R3, R4, R6, X1, and X2 are deﬁned above in the y of the Invention and below in the Detailed Description. Further, compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

Compounds disclosed herein may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its tion at another occurrence. Further, combinations of tuents are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a on e. a. ions It is noted that, as used in this speciﬁcation and the intended claims, the singular form (L 77 (L a, an," and "the" include plural referents unless the context clearly dictates otherwise.

Thus, for example, reference to "a compound" includes a single compound as well as one or more of the same or different compounds, reference to "a pharmaceutically able carrier" means a single pharmaceutically acceptable r as well as one or more pharmaceutically acceptable carriers, and the like. id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17" id="p-17"

[0017] As used in the speciﬁcation and the ed claims, unless speciﬁed to the contrary, the following terms have the g indicated: The term "alkyl" as used herein, means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is ted by the preﬁx "CK-Cy", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-C6 alkyl" means an alkyl substituent containing from 1 to 6 carbon atoms and "C1-C3 alkyl" means an alkyl substituent containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, l-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3- dimethylbutyl, l,l-dimethylpropyl, l,2-dimethylpropyl, 2,2-dimethylpropyl, l-methylpropyl, 2-methylpropyl, l-ethylpropyl, and 1,2,2-trimethylpropyl. The terms "alkyl," "C1-C6 alkyl," and "C1-C3 alkyl" used herein are tituted, unless otherwise indicated.

The term "alkylene" or enyl" means a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of l to 10 carbon atoms or of l to 6 carbon atoms (C1-C6 alkylenyl) or of l to 4 carbon atoms (C1-C4 alkylenyl) or of l to 3 carbon atoms (C1-C3 alkylenyl) or of 2 to 6 carbon atoms (C2-C6 alkylenyl). Examples of C1- C6 alkylenyl include, but are not limited to, -CH2-, -CH2CH2-, -C((CH3)2)-CH2CH2CH2- and -CH2CH(CH3)CH2-.

, -C((CH3)2)-CH2CH2, -CH2CH2CH2CH2-, The term "C3-C6 cycloalkyl" as used herein, means a hydrocarbon ring radical 3O containing 3-6 carbon atoms, zero heteroatom, and zero double bond. The C3-C6 cycloalkyl group may be a single-ring (monocyclic) or have two rings (bicyclic). C3-C6 monocyclic cycloalkyls means cyclopropyl, cyclobutyl, cyclopentyl, and exyl. The rings within the bicyclic cycloalkyl groups are in a bridged ation. In a bridged cycloalkyl, the rings share at least two non-adjacent atoms. An example of a bridged C3-C6 lkyl is o[l.l.l]pentanyl.

The term "C4-C6 monocyclic cycloalkenyl" as used , means a monocyclic hydrocarbon ring radical containing 4-6 carbon atoms, zero heteroatom, and one or two double bonds. Examples of C4-C6 monocyclic cycloalkenyl groups are cyclobutenyl, entenyl, cyclohexenyl, and cycloheptyl.

The term "halo" or "halogen" as used herein, means Cl, Br, I, and F.

The term "haloalkyl" as used herein, means an alkyl group, as deﬁned , in which one, two, three, four, ﬁve, or six hydrogen atoms are replaced by halogen. The term "C1-C6 haloalkyl" means a C1-C6 alkyl group, as deﬁned herein, in which one, two, three, four, ﬁve, or six hydrogen atoms are replaced by halogen. The term "C1-C3 haloalkyl" means a C1-C3 alkyl group, as deﬁned herein, in which one, two, three, four, or ﬁve hydrogen atoms are replaced by halogen. Examples of haloalkyl include, but are not limited to, chloromethyl, 2-ﬁuoroethyl, 2,2-diﬁuoroethyl, ﬁuoromethyl, l,l,l-trifluoromethylpropanyl, 2,2,2- trifluoroethyl, triﬁuoromethyl, diﬁuoromethyl, pentaﬁuoroethyl, 2-chloroﬁuoropentyl, and l, l, l -triﬁuoromethylpropanyl.

The term "4-6 membered monocyclic heterocycle" is a four-, ﬁve- or six-membered hydrocarbon ring wherein at least one carbon atom is replaced by heteroatom independently selected from the group consisting of O, N, and S. A four-membered monocyclic heterocycle contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. Examples of four-membered monocyclic heterocycles e, but not limited to, azetidinyl and oxetanyl. A ﬁve-membered monocyclic heterocycle contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of ﬁve-membered monocyclic cycles include those containing in the ring: 10,1 S,lN,2N,3N,l Sanle, lS,and2N, lOanle,orlOand2N. Non limiting examples of 5-membered monocyclic heterocyclic groups include l,3-dioxolanyl, tetrahydrofuranyl, ofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2- inyl, 3-pyrrolinyl, thiazolinyl, and lidinyl. A six-membered clic cycle contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of six-membered monocyclic heterocycles include those containing in the ring: 1 O, 2 O, l S, 2 S, l N, 2 N, 3 N, l S, l 0, anle, 1 Sanle, l Sand2N, 1 Sand 1 O, l Sand20, l Oanle, and l .

Examples of six-membered monocyclic heterocycles include tetrahydropyranyl, dihydropyranyl, dioxanyl, l,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl, piperidinyl, tetrahydropyridinyl, ydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl. The nitrogen and sulfur atoms in the heterocycle rings may optionally be oxidized (e. g. l, l-dioxidotetrahydrothienyl, l,l-dioxido-l,2-thiazolidinyl, l,l- dioxidothiomorpholinyl) and the nitrogen atoms may optionally be mized.

The term "5-6 membered monocyclic heteroaryl" is a f1ve- or six-membered hydrocarbon ring wherein at least one carbon atom is replaced by atom independently selected from the group consisting of O, N, and S. The five-membered ring contains two double bonds. The five ed ring may contain one heteroatom selected from O or S, or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms.

Examples of 5-6 membered monocyclic heteroaryl include, but are not limited to, l, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, l,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, l,3-thiazolyl, thienyl, triazolyl, and triazinyl. The nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be quartemized.

The phenyl, the C3-C6 cycloalkyls, the C3-C6 monocyclic cycloalkyls, the C4-C6 cycloalkenyls, the 4-6 membered monocyclic heterocycles, and the 5-6 membered monocyclic heteroaryls, including the exemplary rings, are optionally tuted unless otherwise ted, and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.

The term oatom" as used herein, means a nitrogen, oxygen, and sulfur.

The term "radiolabel" means a compound of the invention in which at least one of the atoms is a radioactive atom or a ctive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta les, or positrons. es of such radioactive atoms include, but are not limited to, 3H (tritium), 14C, 11C, 15O, 18F, 35 S, 123I, and 125I.

A moiety is described as "substituted" when a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the moiety. Thus, for example, a substituted 3O heterocycle moiety is a cycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be recognized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless ise stated).

If a moiety is described as being "optionally substituted," the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either (1) not sub stituted, or (2) tuted by up to that particular number of drogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted with up to 3 non- hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has tutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be ally substituted with up to one non-hydrogen radical. To illustrate r, if an amino nitrogen is described as being optionally substituted with up to 2 drogen radicals, then a primary amino en will be optionally substituted with up to 2 non- hydrogen radicals, whereas a secondary amino nitrogen will be optionally tuted with up to only 1 non-hydrogen l. id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31" id="p-31"

[0031] The terms "treat", "treating", and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. In certain ments, "treat," ing," and "treatment" refer to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treat77 (L 7 treating", and "treatment" refer to modulating the disease or disorder, either physically (for example, 2O stabilization of a discernible symptom), physiologically (for example, stabilization of a physical parameter), or both. In a further embodiment, "treat", "treating", and "treatment" refer to slowing the progression of the disease or disorder.

The terms nt", "preventing", and "prevention" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used , "prevent77 (4 , preventing" and "prevention" also include delaying the onset of a disease and/or its ant symptoms and reducing a subject's risk of acquiring or developing a disease or disorder.

The phrase "therapeutically effective " means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to 3O alleviate to some extent one or more of the symptoms of the condition or er being treated when administered alone or in conjunction with another therapeutic agent for treatment in a particular subject or subject population. The "therapeutically effective " may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject to be treated. For example in a human or other mammal, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or lent foreign agency, for the ular disease and subject being treated.

The term "subject" is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and the like. In one embodiment, the subject is a human. The terms "human,77 (4patient," and "subject" are used interchangeably herein.

The term ‘at least one additional therapeutic agent’ means one to four therapeutic agents other than the compounds of the invention. In one embodiment it means one to three additional therapeutic agents. In further embodiments it means one or two additional therapeutic agents. In a yet further embodiment it means one additional therapeutic agent. In a yet further embodiment it means two additional therapeutic agents. In a yet further embodiment it means three additional therapeutic . b. Compounds Compounds of the invention have the general formula (I) as described above.

Particular values of variable groups in nds of formula (I) are as follows. Such values may be used where appropriate with any of the other values, deﬁnitions, claims or embodiments deﬁned hereinbefore or hereinafter. 2O [0038] In certain embodiments, R1 is hydrogen.

In certain embodiments, R1 is CD2CD3, C1-C6 alkyl, C1-C6 haloalkyl, or a C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R1 is CD2CD3, C1-C6 alkyl, C1-C6 haloalkyl, cyclopropyl, or bicyclo[l . l . l]pentanyl, n the cyclopropyl and the bicyclo[l . l . l]pentanyl are each optionally tuted with l, 2, 3, or 4 independently ed RX groups.

In certain embodiments, R1 is CD2CD3.

In certain embodiments, R1 is C1-C6 alkyl or C1-C6 haloalkyl. In some such embodiments, R1 is CH3, , C(CH3)3, or C(CH3)2CF3. 3O [0043] In certain embodiments, R1 is C1-C6 alkyl. In some such embodiments, R1 is CH3, CH2CH3, or 3. In some further ments, R1 is CH3 or . In some further embodiments, R1 is CH3. In some r embodiments, R1 is CH2CH3.

In certain embodiments, R1 is C1-C6 haloalkyl. In some such embodiments, R1 is C(CH3)2CF3.

In certain ments, R1 is a C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups. In some such embodiments, the C3-C6 cycloalkyl is ropyl or bicyclo[l . l . l]pentanyl, wherein the cyclopropyl and the bicyclo[l.l.l]pentanyl are each optionally substituted with l, 2, 3, or 4 independently selected RX groups. In some further ments, the C3-C6 cycloalkyl is cyclopropyl wherein the cyclopropyl is optionally substituted with l, 2, 3, or 4 independently ed RX groups. In some further ments, the C3-C6 cycloalkyl is bicyclo[l . l . l]pentanyl wherein the bicyclo[l . l . l]pentanyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups. id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46" id="p-46"

[0046] In certain embodiments, R1 is a phenyl or a 5-6 membered monocyclic heteroaryl, wherein the phenyl and the 5-6 membered monocyclic heteroaryl are each ally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R2 is phenyl, cyclopropyl, cyclopentyl, C1-C6 kyl, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of G2b and —OH, and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In n embodiments, R2 is Gza. In some such ments, G2a is phenyl, cyclopropyl, or cyclopentyl, wherein each G2a is optionally substituted with l, 2, 3, or 4 ndently selected RX groups. In some such ments, G2a is phenyl, wherein the 2O phenyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R2 is C1-C6 haloalkyl or C1-C6 alkyl n the C1-C6 alkyl is ally substituted with one substituent selected from the group consisting of G2b and -OH. In some such embodiments, R2 is C1-C6 haloalkyl, C1-C6 alkyl, -CH2- phenyl, -CH2CH2-phenyl, CHzOH, or CHZCHZOH, wherein the phenyl moiety of -CH2- phenyl and -CH2CH2-phenyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R2 is -CH2-phenyl or -CH2CH2-phenyl, wherein the phenyl moiety of -CH2-phenyl and -CH2CH2-phenyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups. 3O [0051] In certain ments, R2 is C1-C6 haloalkyl or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one —OH. In some such embodiments, R2 is CF3, CHZF, CH3, CH2CH3, C(H)(CH3)2, C(CH3)(H)CH2CH3, CH2C(H)(CH3)2, CHZOH, or CHZCHZOH.

In certain embodiments, R2 is C1-C6 haloalkyl. In some such embodiments, R2 is CF3 or CHZF.

In certain embodiments, R2 is C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one —OH. In some such embodiments, R2 is CH3, CH2CH3, C(H)(CH3)2, C(CH3)(H)CH2CH3, CH2C(H)(CH3)2, CHZOH, or CH2CH20H.

In certain embodiments, R2 is C1-C6 alkyl. In some such embodiments, R2 is CH3, CH2CH3, C(H)(CH3)2, C(CH3)(H)CH2CH3, or CH2C(H)(CH3)2. In some such embodiments, R2 is CH3.

In certain embodiments, R2 is C1-C6 alkyl which is substituted with one -OH. In some such embodiments, R2 is CHZOH or CHZCHZOH.

In certain embodiments, R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a C3-C6 monocyclic lkyl wherein the C3-C6 monocyclic cycloalkyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R3 is a C3-C6 monocyclic cycloalkyl wherein the C3-C6 clic cycloalkyl is ally tuted with l, 2, 3, or 4 independently selected RX groups. In some such embodiments, R3 is cyclopropyl wherein the cyclopropyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R3 is C1-C6 haloalkyl or C1-C6 alkyl. In some such embodiments, R3 is CF3, CH3, or CH2CH3. 2O [0060] In certain embodiments, R3 is C1-C6 kyl. In some such ments, R3 is CF3.

In certain embodiments, R3 is C1-C6 alkyl. In some such embodiments, R3 is CH3 or CH2CH3. In some such embodiments, R3 is CH3.

In certain embodiments, R2 and R3, together with the carbon atom to which they are attached, form a C3-C6 clic cycloalkyl, a C4-C6 monocyclic lkenyl, or a 4-6 membered monocyclic heterocycle, wherein the C3-C6 monocyclic cycloalkyl, the C4-C6 monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R2 and R3, er with the carbon atom to which they are attached, is a cyclobutyl, a cyclopentyl, a cyclopentenyl, or an oxetanyl, wherein the 3O cyclobutyl, the cyclopentyl, the cyclopentenyl, and the oxetanyl are each optionally substituted with l, 2, 3, or 4 independently selected RX groups.

In certain embodiments, R4 is , pyridinyl, C3-C6 monocyclic lkyl, or C4- C6 monocyclic cycloalkenyl, n each R4 is optionally substituted with l, 2, 3, or 4 independently selected Ry groups.

In certain embodiments, R4 is phenyl, entenyl, or cyclohexenyl, n each R4 is optionally substituted with l, 2, 3, or 4 independently selected Ry groups.

In certain embodiments, R4 is formula (a) R4d \ Cg R40 Y/ R4b In certain embodiments, R4a is halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R4a is F, Cl, C1-C3 alkyl, or C1-C3 haloalkyl. In some such ments, R4a is F, Cl, CH3, CF3, or CHFz.

In certain embodiments, R4a is C1-C3 alkyl. In some such embodiments, R4a is CH3. id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69"

[0069] In certain embodiments, R4b is halogen or C1-C6 alkyl. In some such embodiments, R4b is C1 or C1-C3 alkyl. In some such embodiments, R4b is C1 or CH3.

In certain embodiments, R4b is C1-C3 alkyl. In some such embodiments, R4b is CH3.

In n embodiments, R4C is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -S(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), or 6 alkylenyl)-OH. id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72"

[0072] In certain embodiments, R4C is hydrogen, halogen, -CN, -S(C1-C6 alkyl), -S(O)2(C1-C6 , or —(C1-C6 alkylenyl)-OH.

In certain embodiments, R4C is hydrogen, F, Cl, Br, -CN, -SCH3, -S(O)2CH3, or -C(CH3)2-OH.

In n embodiments, R4C is hydrogen or halogen. In some such embodiments, the halogen is F, C1, or Br. In some such embodiments, the halogen is F.

In certain embodiments, R4C is halogen. In some such embodiments, the halogen is F, C1, or Br. In some such embodiments, the halogen is F.

In certain embodiments, R4C is F.

In certain ments, R4d is hydrogen or halogen. In some such embodiments, the halogen is F or C1.

In certain embodiments, R4d is hydrogen.

In certain embodiments, Y is C(R4e) or N, wherein R46 is hydrogen.

In certain embodiments, Y is N.

In certain ments, Y is C(R4e). In some such embodiments, R46 is hydrogen or 3O halogen. In some such embodiments, R46 is hydrogen.

In certain embodiments, R6 is hydrogen or halogen. In some such ments, the halogen is F.

In certain embodiments, R6 is hydrogen.

In certain embodiments, R6 is halogen. In some such embodiments, the halogen is F.

Various embodiments of substituents R1, R2, R3, R4, R4a, R4b, R4C, R4d, R46, R5, R6, X1, X2, and Y have been discussed above. These substituents embodiments can be combined to form various embodiments of compounds of formula (I). All embodiments of compounds of formula (I), formed by combining the substituent embodiments discussed above are within the scope of ant’s invention, and some illustrative embodiments of the nds of formula (I) are provided below.

In one embodiment, the invention is directed to compounds of formula (I), n R2 is phenyl, cyclopropyl, entyl, C1-C6 haloalkyl, or C1-C6 alkyl wherein the C1- C6 alkyl is optionally substituted with one tuent selected from the group consisting of G2b and —OH, and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with l, 2, 3, or 4 independently selected RX groups, and R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with l, 2, 3, or 4 independently selected RX .

In one embodiment, the invention is directed to compounds of formula (I), wherein 2O R2 is C1-C6 haloalkyl or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one —OH, and R3 is 01—06 haloalkyl or 01—06 alkyl.

In one embodiment, the invention is directed to compounds of formula (I), n R2 is C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one —OH, and R3 is C1-C6 alkyl.

In one embodiment, the invention is directed to compounds of formula (I), wherein R2 is C1-C6 alkyl, and R3 is C1-C6 alkyl. In some such embodiment, R2 is CH3, and R3 is In one embodiment, the invention is ed to compounds of formula (I), wherein 3O R4 is formula (a), wherein R4a is n, C1-C6 alkyl, or crc6 haloalkyl, R4b is halogen or C1-C6 alkyl, R4d is hydrogen or halogen, and Y is C(R4e) or N, wherein R46 is hydrogen.

In one embodiment, the invention is directed to compounds of formula (I); n R4 is formula (a); n R4a is halogen, C1-C6 alkyl; or crc6 haloalkyl; R4b is halogen or C1-C6 alkyl; R4C is hydrogen or halogen; R4d is en or n; and Y is C(R4e) or N; wherein R46 is hydrogen.

In some such embodiments; R4C is hydrogen or F. In some such embodiments; R4C is F. In some such embodiments; R4C is hydrogen. id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92" id="p-92"

[0092] In one embodiment; the invention is directed to compounds of a (I); wherein R4 is formula (a); wherein R4a is 01—03 alkyl; R4b is C1-C3 alkyl; R4C is hydrogen or halogen; R4d is hydrogen; and Y is C(R4e) wherein R46 is hydrogen.

In some such embodiments; R4C is hydrogen or F. In some such embodiments; R4C is F. In some such embodiments; R4C is hydrogen.

In one embodiment; the invention is directed to nds of formula (I); wherein X1 is N or C(RS); X2 is C(RS); and R5 is hydrogen.

In one embodiment; the invention is directed to compounds of formula (I); n X1 and X2 are C(RS); and R5 is hydrogen.

In one embodiment; the invention is directed to compounds of formula (I); wherein X1 is N; X2 is C(RS); and R5 is hydrogen. id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96" id="p-96"

[0096] In one embodiment; the invention is ed to compounds of formula (I); wherein X1 is C(RS); X2 is N; and R5 is hydrogen.

In one embodiment; the invention is directed to compounds of formula (I); wherein X1 is N or C(RS); x2 is C(RS); 3O R5 is hydrogen; and R2 and R3; together with the carbon atom to which they are attached; form a C3-C6 monocyclic cycloalkyl; a C4-C6 monocyclic cycloalkenyl; or a 4-6 membered monocyclic heterocycle; wherein the C3-C6 monocyclic cycloalkyl; the C4-C6 monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each ally substituted with l, 2, 3, or 4 independently selected RX groups.

In some such embodiments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such ments, X1 is N, X2 is C(RS), and R5 is hydrogen. id="p-98" id="p-98" id="p-98" id="p-98" id="p-98" id="p-98" id="p-98" id="p-98" id="p-98" id="p-98" id="p-98" id="p-98" id="p-98"

[0098] In one embodiment, the invention is directed to compounds of a (I), wherein X1 is N or C(RS), x2 is C(RS), R5 is hydrogen, R2 and R3, er with the carbon atom to which they are attached, form a C3-C6 monocyclic cycloalkyl, a C4-C6 monocyclic lkenyl, or a 4-6 membered monocyclic heterocycle, wherein the C3-C6 monocyclic cycloalkyl, the C4-C6 monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with l, 2, 3, or 4 independently selected RX groups, R4 is formula (a), wherein R4a is halogen, Ci—C6 alkyl, or crc6 haloalkyl, R4b is halogen or C1-C6 alkyl, R4d is hydrogen or halogen, and Y is C(R4e) or N, wherein R46 is hydrogen, and R6 is hydrogen or halogen. 2O In some such embodiments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such embodiments, X1 is N, X2 is C(RS), and R5 is en.

In one embodiment, the invention is directed to compounds of formula (I), wherein X1 is N or C(RS), x2 is C(RS), R5 is hydrogen, R1 is C1-C6 alkyl, or R1 is C3-C6 cycloalkyl optionally substituted with l, 2, 3, or 4 independently selected RX groups, R2 and R3, together with the carbon atom to which they are attached, form a C3-C6 monocyclic cycloalkyl, a C4-C6 monocyclic cycloalkenyl, or a 4-6 membered 3O monocyclic heterocycle, wherein the C3-C6 monocyclic cycloalkyl, the C4-C6 monocyclic cycloalkenyl, and the 4-6 ed monocyclic heterocycle are each ally substituted with l, 2, 3, or 4 independently ed RX groups, R4 is formula (a), wherein R4a is 01—03 alkyl, R4b is C1-C3 alkyl; R4C is hydrogen or halogen; R4d is hydrogen; and Y is ; wherein R46 is hydrogen; and R6 is hydrogen.

In some such embodiments; X1 and X2 are C(RS); and R5 is hydrogen.

In some such embodiments; X1 is N; X2 is C(RS); and R5 is hydrogen.

In some such embodiments; R1 is C1-C6 alkyl.

In some such embodiments; R1 is optionally substituted cyclopropyl. id="p-100" id="p-100" id="p-100" id="p-100" id="p-100" id="p-100" id="p-100" id="p-100" id="p-100" id="p-100" id="p-100" id="p-100" id="p-100"

[00100] In one embodiment; the invention is directed to compounds of formula (I); wherein X1 is N or C(RS); x2 is C(RS); R5 is hydrogen; R2 is phenyl; cyclopropyl; cyclopentyl; C1-C6 haloalkyl; or C1-C6 alkyl wherein the C1- C6 alkyl is optionally substituted with one substituent ed from the group consisting of G2b and —OH; and wherein the phenyl; the cyclopropyl; and the cyclopentyl are each optionally substituted with l; 2; 3; or 4 independently selected RX groups; and R3 is C1-C6 haloalkyl; C1-C6 alkyl; or a cyclopropyl wherein the cyclopropyl is optionally substituted with l; 2; 3; or 4 ndently ed RX groups.

In some such embodiments; X1 and X2 are C(RS); and R5 is hydrogen.

In some such embodiments; X1 is N; X2 is C(RS); and R5 is hydrogen.

In one ment; the invention is directed to compounds of formula (I); wherein X1 is N or C(RS); x2 is C(RS); R5 is en; R2 is phenyl; cyclopropyl; cyclopentyl; C1-C6 haloalkyl; or C1-C6 alkyl wherein the C1- C6 alkyl is optionally substituted with one substituent selected from the group consisting of G2b and —OH; and wherein the phenyl; the ropyl; and the 3O cyclopentyl are each optionally substituted with l; 2; 3; or 4 independently selected RX groups; R3 is C1-C6 haloalkyl; C1-C6 alkyl; or a cyclopropyl wherein the cyclopropyl is optionally substituted with l; 2; 3; or 4 ndently selected RX groups; R4 is phenyl, pyridinyl, a C3-C6 monocyclic cycloalkyl, or a C4-C6 monocyclic cycloalkenyl, wherein each R4 is optionally substituted with l, 2, 3, or 4 independently selected Ry groups, and R6 is hydrogen.

In some such embodiments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such embodiments, X1 is N, X2 is C(RS), and R5 is hydrogen.

In one embodiment, the invention is directed to nds of formula (I), wherein X1 is N or C(RS), x2 is C(RS), R5 is hydrogen, R2 is C1-C6 alkyl wherein the C1-C6 alkyl is ally substituted with one —OH, R3 is C1-C6 alkyl, R4 is phenyl, pyridinyl, a C3-C6 monocyclic lkyl, or a C4-C6 monocyclic cycloalkenyl, wherein each R4 is optionally substituted with l, 2, 3, or 4 independently selected Ry groups, and R6 is hydrogen.

In some such embodiments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such embodiments, X1 is N, X2 is C(RS), and R5 is hydrogen.

In one embodiment, the invention is directed to compounds of formula (I), wherein 2O X1 is C(RS), X2 is C(RS), R5 is hydrogen, R1, R2, and R3 are C1-C6 alkyl, R4 is phenyl, pyridinyl, a C3-C6 monocyclic cycloalkyl, or a C4-C6 monocyclic lkenyl, wherein each R4 is optionally substituted with l, 2, 3, or 4 independently selected Ry groups, and R6 is en.

In one embodiment, the invention is directed to compounds of formula (I), wherein X1 is N or C(RS), 3O x2 is C(RS), R5 is hydrogen, R2 is phenyl, cyclopropyl, cyclopentyl, C1-C6 haloalkyl, or C1-C6 alkyl wherein the C1- C6 alkyl is ally substituted with one substituent ed from the group consisting of G2b and —OH, and wherein the , the cyclopropyl, and the cyclopentyl are each optionally substituted with l, 2, 3, or 4 independently selected RX groups, R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a cyclopropyl wherein the cyclopropyl is optionally tuted with l, 2, 3, or 4 independently selected RX groups, R4 is formula (a), and R6 is hydrogen or halogen.

In some such embodiments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such embodiments, X1 is N, X2 is C(RS), and R5 is hydrogen.

In one embodiment, the invention is directed to compounds of formula (I), wherein X1 is N or C(RS), x2 is C(RS), R5 is hydrogen, R2 is phenyl, cyclopropyl, cyclopentyl, C1-C6 haloalkyl, or C1-C6 alkyl wherein the C1- C6 alkyl is optionally substituted with one substituent selected from the group consisting of G2b and —OH, and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with l, 2, 3, or 4 ndently selected RX groups, R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a cyclopropyl wherein the ropyl is optionally substituted with l, 2, 3, or 4 independently ed RX groups, 2O R4 is formula (a), wherein R4a is halogen, C1-C6 alkyl, or crc6 haloalkyl, R4b is halogen or C1-C6 alkyl, R4d is hydrogen or halogen, and Y is C(R4e) or N, wherein R46 is hydrogen, and R6 is hydrogen or halogen.

In some such embodiments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such embodiments, X1 is N, X2 is C(RS), and R5 is hydrogen.

In one embodiment, the ion is ed to compounds of formula (I), n X1 is N or C(RS), 3O x2 is C(RS), R5 is hydrogen, R2 is phenyl, cyclopropyl, cyclopentyl, C1-C6 haloalkyl, or C1-C6 alkyl wherein the C1- C6 alkyl is optionally substituted with one substituent ed from the group consisting of G2b and —OH, and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with l, 2, 3, or 4 independently selected RX groups, R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups, R4 is formula (a), wherein R4a is 01—03 alkyl, R4b is C1-C3 alkyl, R4C is hydrogen or halogen, R4d is hydrogen, and Y is C(R4e) or N, wherein R46 is hydrogen, and R6 is en or halogen.

In some such ments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such embodiments, X1 is N, X2 is C(RS), and R5 is hydrogen.

In one embodiment, the ion is directed to compounds of formula (I), wherein X1 is N or C(RS), x2 is C(RS), R5 is hydrogen, R2 is C1-C6 haloalkyl or C1-C6 alkyl wherein the C1-C6 alkyl is ally substituted with one —OH, R3 is C1-C6 haloalkyl or C1-C6 alkyl, R4 is formula (a), wherein R4a is 01—03 alkyl, R4b is C1-C3 alkyl, R4C is en or halogen, R4d is hydrogen, and Y is C(R4e) or N, wherein R46 is hydrogen, and R6 is hydrogen or halogen.

In some such embodiments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such embodiments, X1 is N, X2 is C(RS), and R5 is hydrogen. id="p-108" id="p-108" id="p-108" id="p-108" id="p-108" id="p-108" id="p-108" id="p-108" id="p-108" id="p-108" id="p-108" id="p-108" id="p-108"

[00108] In one embodiment, the invention is directed to nds of formula (I), wherein X1 is N or C(RS), x2 is C(RS), R5 is hydrogen, R1 is C1-C6 alkyl or cyclopropyl which is optionally substituted with l, 2, 3, or 4 independently selected RX groups, R2 and R3 are C1-C6 alkyl, R4 is a (a), wherein R" is 01—03 alkyl, R4b is C1-C3 alkyl, R4C is hydrogen or halogen, R4d is hydrogen, and Y is C(R4e) wherein R46 is hydrogen, and R6 is hydrogen or halogen.

In some such embodiments, X1 and X2 are C(RS), and R5 is hydrogen.

In some such embodiments, X1 is N, X2 is C(RS), and R5 is hydrogen.

In one embodiment, the invention is directed to compounds of a (I), wherein X1 is C(RS), x2 is C(RS), R5 is en, R1 is cyclopropyl which is optionally substituted with l, 2, 3, or 4 ndently selected RX groups, R2 and R3 are C1-C6 alkyl, 2O R4 is formula (a), wherein R" is 01—03 alkyl, R4b is C1-C3 alkyl, R4C is hydrogen or halogen, R4d is hydrogen, and Y is C(R4e) wherein R46 is hydrogen, and R6 is hydrogen.

In some such embodiments, R4C is halogen. In some such embodiments, R4C is F.

In one embodiment, the invention is directed to compounds of formula (I), wherein X1 is N or C(RS), 3O x2 is C(RS), R5 is hydrogen, R1, R2 and R3 are C1-C6 alkyl, R4 is a (a), wherein R" is 01—03 alkyl, R4b is C1-C3 alkyl; R4C is hydrogen or halogen; R4d is hydrogen; and Y is C(R4e) n R46 is hydrogen; and R6 is hydrogen or halogen.

In some such embodiments; X1 and X2 are C(RS); and R5 is hydrogen.

In some such embodiments; X1 is N; X2 is C(RS); and R5 is hydrogen.

In one ment; the invention is directed to compounds of formula (I); wherein X1 is C(RS); X2 is C(RS); R5 is en; R1; R2 and R3 are C1-C6 alkyl; R4 is formula (a); wherein R4a is 01—03 alkyl; R4b is ci—c3 alkyl; R4C is halogen; R4d is hydrogen; and Y is C(R4e) wherein R46 is en; and R6 is hydrogen.

In some such embodiments; R4C is F.

In one embodiment; the ion is directed to a process for preparing compound of formula (A) wherein the process comprises bromination of compound of formula (B) wherein PG1 is a nitrogen protecting group; and R105 is C1-C6 alkyl. id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113" id="p-113"

[00113] In certain embodiments; PG1 is selected from the group consisting of p- toluenesulfonyl; benzyl; and 2-(trimethylsilyl)ethoxymethyl. In certain embodiments; PG1 is p-toluenesulfonyl.

In certain embodiments; R105 is ethyl.

Compound (B) may be brominated using a brominating agent and in the presence of an acid. In certain embodiments; the brominating agent may include; for example; bromine or osuccinimide. In certain embodiments; the brominating agent is N- bromosuccinimide. Examples of the acid may include acetic acid and p-toluenesulfonic acid.

In certain ments, the acid is p-toluenesulfonic acid. In certain embodiments, compound (B) is brominated using N—bromosuccinimide and p-toluenesulfonic acid.

] In certain embodiments, compound (B) may be brominated with or without the presence of a solvent. In n embodiments, the bromination is conducted in the presence of a solvent. Solvents may include, for example, tetrahydrofuran, N,N—dimethylformamide, N,N—dimethylacetamide, N—methyl-pyrrolidone, dimethyl sulfoxide, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, cyclopentyl methyl ether, toluene, benzene, lerl-amyl alcohol, tert- butyl alcohol, yltetrahydrofuran, ethyl acetate, isopropyl acetate, anisole, triﬂuorotoluene, and any other suitable solvent and combinations thereof. In certain embodiments, the solvent is tetrahydrofuran. In certain embodiments, the solvent is acetonitrile.

In certain embodiments, compound (B) may be brominated without the presence of a solvent, for example, compound (B) may be reacted with e in neat acetic acid to e nd (A).

In certain ments, compound (B) may be brominated at a temperature from about 20 0C to about 50 0C. In certain embodiments, nd (B) is brominated at a temperature of about 20 0C to about 25 0C. In certain embodiments, compound (B) is brominated at a temperature of about 25 0C. id="p-119" id="p-119" id="p-119" id="p-119" id="p-119" id="p-119" id="p-119" id="p-119" id="p-119" id="p-119" id="p-119" id="p-119" id="p-119"

[00119] In an ment, compound (B) is reacted with N—bromosuccinimide in the presence of p-toluenesulfonic acid to give compound (A).

In an embodiment, compound (B) is reacted with N—bromosuccinimide in the presence of enesulfonic acid and tetrahydrofuran to give compound (A).

In an ment, compound (B) is reacted with N—bromosuccinimide in the presence of p-toluenesulfonic acid and acetonitrile to give compound (A).

In an embodiment, compound (B) is reacted with N—bromosuccinimide in the presence of acetic acid to give compound (A).

In an embodiment, compound (B) is reacted with N—bromosuccinimide in the presence of p-toluenesulfonic acid and tetrahydrofuran at about 25 0C to give compound (A). id="p-124" id="p-124" id="p-124" id="p-124" id="p-124" id="p-124" id="p-124" id="p-124" id="p-124" id="p-124" id="p-124" id="p-124" id="p-124"

[00124] In an embodiment, compound (B) is reacted with N—bromosuccinimide in the presence of p-toluenesulfonic acid and acetonitrile at about 25 0C to give nd (A).

Compound of the invention are named by using Name 2015 naming algorithm by Advanced Chemical Development or Struct=Name naming algorithm as part of CHEMDRAW® ULTRA v. 12.02.1076.

Compounds of the invention may exist as stereoisomers wherein tric or chiral centers are present. These stereoisomers are "R" or "5" depending on the conﬁguration of substituents around the chiral carbon atom. The terms "R" and "5" used herein are conﬁgurations as deﬁned in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates various stereoisomers and es thereof and these are speciﬁcally included within the scope of this invention. Stereoisomers include enantiomers and reomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution nown to those of ordinary skill in the art. These methods of resolution are exempliﬁed by (1) attachment of a mixture of enantiomers to a chiral ary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the lly pure product from the auxiliary as described in Fumiss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientiﬁc & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of l enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods. nds of the invention may exist as cis or trans isomers, wherein sub stituents on a ring may attached in such a manner that they are on the same side of the ring (cis) relative to each other, or on opposite sides of the ring relative to each other (trans). For example, utane may be t in the cis or trans conﬁguration, and may be t as a single isomer or a mixture of the cis and trans isomers. Individual cis or trans isomers of compounds of the invention may be ed synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by puriﬁcation of mixtures of the cis and trans isomers. Such methods are well-known to those of ordinary skill in the art, and may include separation of s by recrystallization or chromatography.

It should be understood that the compounds of the invention may possess tautomeric 3O forms, as well as geometric s, and that these also constitute an aspect of the invention.

The present sure includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are ed by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of en, such as 2H and 3H, , such as 11C, 13C and 14C, chlorine, such as 36Cl, ﬂuorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32F, and sulphur, such as 358. Certain isotopically-labelled compounds of a (I), for e, those incorporating a radioactive e, are useful in drug and/or substrate tissue distribution studies. The ctive isotopes tritium, 2'. e. 3H, and carbon-l4, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, zle. 2H, may afford certain eutic advantages resulting from greater lic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. tution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Thus, the formula drawings within this specification can represent only one of the possible tautomeric, geometric, or stereoisomeric forms. It is to be understood that the invention encompasses any tautomeric, geometric, or stereoisomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric, geometric, or isomeric form utilized within the formula drawings.

Exemplary compounds of formula (I) e, but are not limited to: 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl]—N—ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-I]pyridinecarboxamide, 4- [2-(2, 6-dimethylphenoxy)-5 -(3 -hydroxypentan-3 -yl)py1i din-3 -yl]-N-ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide, 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro-lH-pyrrolo[2,3-c]py1idinecarboxamide, 4- [2-(2, 6-dimethylphenoxy)-5 -(l -hydroxycyclopent-3 -enyl)pyridin-3 -yl ] -N-ethyl- 3O 6-methyloxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide, 4- [2-(2, 6-dimethylphenoxy)-5 -(l -hydroxycyclopent-3 -enyl)phenyl]-N-ethyl methyloxo-6,7-dihydro- rolo[2,3-c]pyridinecarboxamide, 4-[2-(2,6-dimethylphenoxy)(l -hydroxycyclopentyl)py1idin-3 -yl]—N—ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide, 4- [2-(2, thy1phenoxy)(1-hydroxypheny1propy1)pyridin-3 -y1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 4-[2-(2,6-dimethy1phenoxy)(2-hydroxybutanyl)pyridin-3 -y1]-N-ethy1methy1- 7-0X0-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; 4-{2-(2,6-dimethy1phenoxy)[1-(4-ﬂuorophenyl)—1-hydroxypropy1]pyridin-3 -y1}-N— ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dimethy1phenoxy)(3 -hydroxymethy1hexan-3 -y1)pyn'din-3 -y1]-N-ethy1- y1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[5-(1-cyclopenty1-1 -hydroxypropy1)—2-(2,6-dimethylphenoxy)pyridin-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[5-(1 -cyclopropy1-1 -hydroxypropyl)(2,6-dimethy1phenoxy)pyﬁdin-3 -y1]-N- ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dimethy1phenoxy)(3 -hydroxymethy1hexan-3 -y1)pyn'din-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4- [2-(2, thy1phenoxy)-5 -(3 -hydroxypheny1pentan-3 -y1)pyridin-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-{2-(2,6-dimethy1phenoxy)[1-(4-ﬂuorophenyl)hydroxybutanyl]pyridin-3 - yl }-N-ethy1methy1oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(2,6-dimethylphenoxy)(1 -hydroxyphenylethy1)pyn'din-3 -y1]-N-ethy1 oxo—6,7-dihydro- 1H-py1Tolo[2,3 idinecarboxamide; 4-{2-(2,6-dimethylphenoxy)[1-(4-ﬂuoropheny1)—1-hydroxyethyl]pyﬁdin-3 -y1}-N— 6-methy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dimethylphenoxy)(2-hydroxymethylpentan-Z-y1)pyn'din-3 -y1]-N- ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dimethylphenoxy)(2-hydroxy-3 -methy1butanyl)pyﬁdin-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[2-(2,6-dimethylphenoxy)(2-hydroxy-3 -methy1pentan-Z-yl)pyﬁdin-3 -y1]-N- ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dimethy1phenoxy)(2-hydroxyphenylbutany1)pyridin-3 -y1]-N-ethy1- 3O 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 idinecarboxamide; 4-{2-(2,6-dimethy1phenoxy)[1-(4-ﬂuorophenyl)hydroxypropany1]pyn'din-3 - yl }-N-ethy1methy1oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-{5-[cyclopropyl(4-ﬂuoropheny1)hydroxymethyl](2,6-dimethy1phenoxy)pyﬁdiny1}-N—ethy1methy1oxo—6,7-dihydro—1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; 4- { 5 -[cyclopenty1(cyclopropyl)hydroxymethyl](2,6-dimethy1phenoxy)pyridin-3 - yl }-N-ethy1methy1oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4- { 5 clopropy1(hydroxy)methyl](2,6-dimethy1phenoxy)pyridin-3 -y1 } -N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[5-(1 -cyclopropy1-1 -hydroxymethy1propy1)(2,6-dimethy1phenoxy)pyridin-3 - yl]-N—ethy1methy1oxo—6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide; 4-[5-(1 -cyclopropy1-1 -hydroxymethylbutyl)(2,6-dimethy1phenoxy)pyridin-3 - yl]-N—ethy1methy1oxo—6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide; 1 { ydroxypropany1)[2-methy1 (triﬂuoromethyl)phenoxy]pheny1}methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(2-hydroxypropan-Z-yl)pyridin-3 -y1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 4-[2-(2-ch1oromethy1phenoxy)—5-(2-hydroxypropany1)pheny1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-lerl-butyl[2-(2-ch1oro—6-methylphenoxy)(2-hydroxypropany1)pheny1] methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-lerl-butyl[2-(2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl]methy1- 7-0X0-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; N—lerl-butyl[2',4'—diﬂuoro(2-hydroxypropany1)[1,1'—bipheny1]—2-y1]—6- methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N—(2,2-diﬂuoro—1-methy1cyclopropyl)[2-(2,6-dimethylphenoxy)(2- hydroxypropan-Z-y1)pyﬁdin-3 -y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyn'dine carboxamide; 1[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropany1)pheny1] methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-lerZ-butyl[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)pheny1]- y1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-Zerl-butyl[2-(2-ch1oromethylphenoxy)(2-hydroxypropany1)pyridin-3 - 3O y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 idine-Z-carboxamide; 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(2-hydroxypropany1)pyridin-3 -y1]methy1 oxo—N—(l, 1,1-tn'ﬂuoro—2-methy1propanyl)-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(2-hydroxypropan-Z-yl)pyridin-3 -y1]-N-(2,2- diﬂuoro-l -methy1cyclopropy1)methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 'dine amide; 4-{2-[2,6-dimethy1(methy1sulfanyl)phenoxy]—5-(2-hydroxypropany1)phenyl } -N— ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(2-hydroxypropan-Z-yl)pheny1]methy1oxo— N—(l,1,1-tﬁﬂuoromethy1propanyl)-6,7-dihydro—1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-[2-(2-ch1oromethy1phenoxy)—5-(2-hydroxypropany1)pheny1]-N-(2,2-diﬂuoro- 1-methy1cyclopropy1)methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyﬁdine-Z-carboxamide; N-ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropanyl)pyridin-3 -y1]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; -buty1[2-(4-ﬂuoro—2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridiny1]methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; N-lerl-buty1{ 5 -(2-hydroxypropany1)[2-methy1 (triﬂuoromethyl)phenoxy]pyridin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 - c]pyridinecarboxamide; 4- { 5-(2-hydroxypropanyl)[2-methy1(tﬁﬂuoromethy1)phenoxy]pyridin-3 -y1}- 6-methy1oxo—N—(1,1,1-triﬂuoromethy1propanyl)-6,7-dihydro—1H—pyrrolo[2,3 - c]pyridinecarboxamide; -diﬂuoromethy1cyclopropy1){ 5-(2-hydroxypropany1)[2-methyl (triﬂuoromethyl)phenoxy]pyridin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 - c]pyridinecarboxamide; 1 { 5-(2-hydroxypropany1)[2-methy1 (triﬂuoromethyl)phenoxy]pyridin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 - c]]pyn'dinecarboxamide; 4-[2-(2-ch1oroﬂuoro—6-methy1phenoxy)(2-hydroxypropany1)pheny1]-N—ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1[2-(2,6-dimethylphenoxy)(2-hydroxypropany1)pyridin-3 -y1] 3O methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropan yl)pyn'din-3 -y1]methy1oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropany1)pyn'din-3 -y1]-N- 6-methy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; N-lerl-buty1[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropan y1)pheny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; N-lerl-buty1{ 5 -(2-hydroxypropany1)[2-methy1 (triﬂuoromethyl)phenoxy]pheny1}methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl]methy1 oxo—N—(l, 1,1-tn'ﬂuoro—2-methy1propanyl)-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridin-3 -y1] methyloxo—N—(1,1,1-triﬂuoro-Z-methylpropanyl)-6,7-dihydro—1H—pyrrolo[2,3 - c]pyridinecarboxamide; 4-[2-(2-ch1oroﬂuoro—6-methy1phenoxy)(2-hydroxypropany1)pheny1] methyloxo—N—(1,1,1-triﬂuoro-Z-methylpropanyl)-6,7-dihydro—1H—pyrrolo[2,3 - c]pyridinecarboxamide; 4-[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropany1)pyn'din-3 -y1] methyloxo—N—(1,1,1-triﬂuoro-Z-methylpropanyl)-6,7-dihydro—1H—pyrrolo[2,3 - dinecarboxamide; 4-[2-(2-chloroﬂuoromethy1phenoxy)(2-hydroxypropany1)pheny1]-N—(2,2- diﬂuoro-l -methy1cyclopropy1)methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N—(2,2-diﬂuoro—1-methy1cyclopropy1)[2-(4-ﬂuoro—2,6-dimethy1phenoxy)(2- hydroxypropan-Z-y1)pheny1]methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N—(2,2-diﬂuoro—1-methy1cyclopropy1)[2-(4-ﬂuoro—2,6-dimethy1phenoxy)(2- ypropan-Z-y1)pyﬁdin-3 -y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyn'dine carboxamide; 4-[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropany1)pyn'din-3 -y1]-N- (2,2-diﬂuoro— 1 -methyl cyclopropyl)methy1oxo-6,7-dihydro— 1H-py1Tolo[2, 3 idine- 2-carboxamide; 3O N-(bicyclo[ 1 . 1.1]pentany1)[2-(2-ch1oromethy1phenoxy)(2-hydroxypropan- 2-y1)pyridin-3 -y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyn'dine-Z-carboxamide; 2,6-dimethylphenoxy)ﬂuoro(2-hydroxypropany1)phenyl]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-ethy1[4-ﬂuoro—2-(4-ﬂuoro—2,6-dimethylphenoxy)(2-hydroxypropan y1)pheny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide, 4-[5-(1 ydroxypropany1)—2-(2,6-dimethy1phenoxy)phenyl]-N—ethy1methy1- 7-0X0-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide, 4-[5-(2,4-dihydroxybutany1)(2,6-dimethy1phenoxy)pheny1]-N—ethy1methyl oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide, 4-{5-[(2R)-1,2-dihydroxypropanyl](2,6-dimethy1phenoxy)phenyl}-N—ethy1 methyloxo—6,7-dihydro- Tolo[2,3 -c]pyridinecarboxamide, 4-{5-[(25)—1,2-dihydroxypropanyl](2,6-dimethy1phenoxy)pheny1}-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, 4-{2-[2-(diﬂuoromethy1)methy1phenoxy](2-hydroxypropany1)phenyl } -N— ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide, N—ZerZ-butyl{2-[2-(diﬂuoromethyl)methy1phenoxy](2-hydroxypropan ny1 } hy1oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide, 4-[2-(4-bromo—2,6-dimethylphenoxy)(2-hydroxypropanyl)pheny1]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, 4-cyano—2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, 4-{2-[(2,4-dimethylpyn'din-3 -y1)oxy](2-hydroxypropany1)phenyl}-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, yclo[1.1.1]pentany1)[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2- hydroxypropan-Z-y1)pheny1]methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide, N-lerl-buty1[3 -(2,6-dimethylphenoxy)(2-hydroxypropan-Z-yl)pyridin-Z-yl] methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, 4-[3 -(2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridiny1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, N—ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)( 1 -ﬂuorohydroxypropan yl)pyn'din-3 -y1]methy1oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide, 3O N—ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(1,1,1-tn'ﬂuoro—Z-hydroxypropan-Z- yl)pyn'din-3 -y1]methy1oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide, N—ethyl[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(1, 1,1,3 ,3 ,3 -hexaﬂuoro—2- hydroxypropan-Z-y1)pyﬁdin-3 -y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyn'dine carboxamide, N-ethy1[2-(2-ﬂuoromethy1phenoxy)(2-hydroxypropany1)pheny1] methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-(d5)ethyl[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)pheny1]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N—ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)( 1 -ﬂuorohydroxypropan y1)pheny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(4-ch1ore-2,6-dimethy1phenoxy)(2-hydroxypropanyl)pheny1]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 idinecarboxamide; N-ethy1 { 5-(2-hydroxypropany1)[4-(methanesulfony1)-2,6- dimethylphenoxy]pheny1 }methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N—ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(1,1,1-tn'ﬂuoro—Z-hydroxypropan-Z- ny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 dine-Z-carboxamide; N-ZerZ-butyl[2-(4-ﬂuoro-2,6-dimethy1phenoxy)( 1 hydroxypropan-Z- ny1]methy1oxo—6,7-dihydro—1H-pyrrolo[2,3 -c]pyn'dine-Z-carboxamide; 4-[2-(4-ch1ore-2,6-dimethy1phenoxy)(1-ﬂuoro—2-hydroxypropany1)phenyl]-N— ethylmethy1oxo—6,7-dihydro—1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,4-diﬂuoropheny1)(2-hydroxypropanyl)pyn'din-3 -y1]-N-ethy1methy1 oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; N-lerl-buty1{ 5 -(2-hydroxypropany1)[4-(methanesulfony1)-2,6- ylphenoxy]pheny1 }methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N-ethy1[2-(3 -ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropany1)pyridin-3 -y1]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1{ 5 -(2-hydroxypropany1)[4-(methanesulfony1)-2,6- dimethylphenoxy]pyﬁdin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N-ethy1 { 5-(2-hydroxypropany1)[4-(methanesulfony1)-2,6- dimethylphenoxy]pyﬁdin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine 3O carboxamide; 4-[2-(4-ch1ore-2,6-dimethy1phenoxy)(2-hydroxypropanyl)pyridin-3 -y1]—N—ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1[2-(4-chloro-2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridiny1]methy1oxo—6,7-dihydro-1H-pyrrolo[2,3 -c]pyn'dine-Z-carboxamide; N-ethy1[3 -(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropanyl)pyridiny1]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1[3 -(4-ﬂuoro—2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridin- 2-yl]methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 'dinecarboxamide; 4-{2-[2-(diﬂuoromethy1)ﬂuoromethy1phenoxy](2-hydroxypropan y1)pheny1}-N—ethy1methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(3 -ch1ore-2,6-dimethy1phenoxy)(2-hydroxypropanyl)phenyl]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N—lerl-buty1[2-(2,6-dichloroﬂuorophenoxy)(2-hydroxypropanyl)pyridin-3 - y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dichloroﬂuor0phenoxy)(2-hydroxypropanyl)pyridin-3 -y1]—N—ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[2-(4-ch1ore-2,6-dimethy1phenoxy)(1 -ﬂuorohydroxypropany1)pyridin-3 - yl]-N—ethy1methy1oxo—6,7-dihydro- rolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1[2-(4-ch1ore-2,6-dimethy1phenoxy)(1 -ﬂuorohydroxypropan yl)pyn'din-3 -y1]methy1oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide; N-ethy1[2-(3 -ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl] methyloxo—6,7-dihydro- Tolo[2,3 -c]pyridinecarboxamide; 4-[2-(2,6-dimethy1phenoxy)(2-hydroxymethylpentan-Z-y1)phenyl]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 idinecarboxamide; N—lerl-buty1[2-(2,6-dimethylphenoxy)(2-hydroxymethy1pentan-Z-y1)phenyl]- y1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N—ethy1{5-(2-hydroxypropany1)[4-(2-hydroxypropanyl)-2,6- dimethylphenoxy]pheny1 }methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N-lerl-buty1{ 5 -(2-hydroxypropany1)[4-(2-hydroxypropanyl)-2,6- dimethylphenoxy]pheny1 }methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 'dine carboxamide; 4-[2-(3 -chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -y1]—N—ethy1- 3O 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-ethy1[4-(2-hydroxypropany1)-4'-(triﬂuoromethoxy)[ 1 1 '-bipheny1]—2-y1]—6- methyloxo—6,7-dihydro- Tolo[2,3 -c]pyridinecarboxamide; 4-[4',4'-diﬂuoro—4-(2-hydroxypropanyl)[2',3 ',4', 5'—tetrahydro[1,1'—bipheny1]]—2-y1]— N-ethy1methy1oxo—6,7-dihydro— 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(4-fluoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyl oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; N-ethyl[4-(2-hydroxypropanyl)-4'-methyl [2'3 ',4', 5'—tetrahydro[ l l '-biphenyl]]— 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3 -c]pyn'dinecarboxamide; 4- [2-(cyclopent- l -en-l -yl)—5 -(2-hydroxypropanyl)phenyl]-N—ethylmethyl oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(2-chloro—6-methylphenoxy)—5 -(l ,2-dihydroxypropanyl)phenyl]-N—ethyl methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-lerl-butyl[2-(2-chloro—6-methylphenoxy)( l ,2-dihydroxypropan-Z-yl)phenyl]- 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3 idinecarboxamide; 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo-6,7- dihydro-1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; N-ZerZ-butyl[2-(2-chloroﬂuoromethylphenoxy)(l ,2-dihydroxypropan yl)phenyl]methyloxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(2-chloroﬂuoro—6-methylphenoxy)( l ydroxypropanyl)phenyl]-N— ethylmethyloxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N,6-dimethyl- 7-oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyn'dinecarboxamide; N-cyclopropyl[2-(4-ﬂuoro—2,6-dimethylphenoxy)(2-hydroxypropan yl)phenyl]methyloxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; N-ethyl[2-(4-fluoro-2,6-dimethylphenoxy)( l -hydroxycyclobutyl)phenyl] methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 idinecarboxamide; and N-ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(3 -hydroxyoxetan-3 -yl)phenyl]—6- oxo—6,7-dihydro- Tolo[2,3 -c]pyridine-Z-carboxamide. id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132" id="p-132"

[00132] Examples of formula (I) also include: N-ethyl { 5-(2-hydroxypropanyl)[4-(2-hydroxypropanyl)-2,6- dimethylphenoxy]pyﬁdin-3 -yl } methyloxo-6,7-dihydro-1H-pyrrolo[2,3 -c]pyn'dine carboxamide; N-lerl-butyl{ 5 -(2-hydroxypropanyl)[4-(2-hydroxypropanyl)-2,6- 3O ylphenoxy]pyﬁdin-3 -yl } methyloxo-6,7-dihydro-1H-pyrrolo[2,3 -c]pyn'dine carboxamide; 4-{5-(1,2-dihydroxypropanyl)[2-methyl(tﬁﬂuoromethyl)phenoxy]phenyl}-N— ethylmethyloxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; N—lerl-butyl{5-(l,2-dihydroxypropanyl)[2-methyl (triﬂuoromethyl)phenoxy]phenyl}methyloxo-6,7-dihydro-lH-pyrrolo[2,3-c]py1idine carboxamide, 4-[5-(2,5-dihydroxypentanyl)(4-ﬂuoro-2,6-dimethylphenoxy)phenyl]-N—ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide, and N—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(4-hydroxyoxanyl)phenyl] methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide.

Compounds of formula (I) may be used in the form of pharmaceutically acceptable salts. The phrase "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue ty, irritation, allergic response and the like and are commensurate with a reasonable beneﬁt/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge et al. J.

Pharmaceutical Sciences, 1977, 66: l-l9. id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135" id="p-135"

[00135] Compounds of formula (I) may contain either a basic or an acidic functionality, or both, and may be ted to a pharmaceutically acceptable salt, when desired, by using a suitable acid or base. The salts may be prepared in situ during the ﬁnal isolation and puriﬁcation of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate, e, alginate, e, aspartate, benzoate, benzenesulfonate, ate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, lfate, heptanoate, hexanoate, te, hydrochloride, hydrobromide, hydroiodide, oxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.

Also, the basic nitrogen-containing groups can be nized with such agents as lower alkyl s such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides, l sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, 3O arylalkyl halides like benzyl and phenethyl bromides and . Water or oil-soluble or dispersible products are thereby ed. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.

Basic addition salts may be prepared in situ during the ﬁnal isolation and puriﬁcation of compounds of this invention by reacting a carboxylic acid-containing moiety with a le base such as, but not d to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including um, ethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other examples of organic amines useful for the ion of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, zine and the like.

] The term "pharmaceutically acceptable prodrug" or "prodrug"as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable beneﬁt/risk ratio, and effective for their intended use. id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139"

[00139] The present ion contemplates compounds of formula (1) formed by synthetic means or formed by in vivo biotransfonnation of a prodrug.

Compounds bed herein may exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the ion. c. General Synthesis ] The compounds described herein, including nds of general formula (I) and speciﬁc examples, may be prepared, for example, through the reaction routes depicted in s 1-9. The variables X1, X2, R1, R2, R3, R4, R5, R6, R4a, R4b, R4C, RM, and Y used in 3O the following schemes have the meanings as set forth in the summary and ed description sections unless ise noted.

Abbreviations used in the descriptions of the schemes and the speciﬁc examples have the following meanings: DMF for N,N—dimethylformamide, DMSO for dimethyl sulfoxide, psi for pounds per square inch, HPLC for high mance liquid chromatography, and SFC for Supercritical Fluid Chromatography.

Scheme 1 O l-l R102 N + I HN_R1 X1~ OH R4 R101 R6 R2 R3 NWOH (1) (2) R6 R2 R3 id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143" id="p-143"

[00143] Compounds of general formula (I) may be prepared by reaction of boronic acids or a derivative thereof (e.g., a l ester) of formula (1) wherein R101 is boronic acid or a derivative thereof (e.g., a pinacol ester) with compounds of formula (2), wherein R102 is halo (Cl, Br, or I) or triﬂate, under Suzuki coupling ions (N. Miyama and A. Suzuki, Chem.

Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148). For example, the coupling reaction may be conducted in the ce of a palladium catalyst and a base, and optionally in the ce of a ligand, and in a suitable solvent at elevated temperature (about 60 0C to about 150 oC). The reaction may be facilitated by microwave irradiation. Examples of the palladium catalyst include, but are not d to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) ride, and palladium(II)acetate. Examples of suitable bases that may be employed include, but not limited to, carbonates or phosphates of sodium, ium, and cesium, and cesium ﬂuoride. Examples of suitable ligands include, but are not limited to, l,3,5,7-tetramethylphenyl-2,4,8-t1ioxaphosphaadamante, 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), and l,l'- 2O bis(diphenylphosphanyl) ferrocene. Non-limiting examples of suitable solvent e methanol, ethanol, dimethoxyethane, N,N—dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, e, and water, or a mixture thereof.

Similar transformation may be ted for compounds of formula (1) wherein R101 is halo (Cl, Br, or I) or triﬂate and compounds of formula (2) wherein R102 is boronic acid or a derivative thereof (e.g., a pinacol ester).

Scheme 2 halo R101 (10) (1) Compounds of formula (1) may be prepared using l synthetic route as shown in Scheme 2. Treatment of compounds of formula (3) wherein halo is Br, C1, or I, with 1,1- dimethoxy-N,N—dimethylmethanamine at elevated temperature (for example, at about 60 0C to about 100 0C), in the absence or presence of a base, and in a solvent such as, but not limited to, N,N—dimethylformamide, provide compounds of formula (4). Examples of bases that may be employed include, but not limited to, lithium or sodium methanolate. tic hydrogenation of (4) in the presence of a catalyst such as, but not limited to, Nickel and under hydrogen atmosphere (about 30 psi) and in a solvent such as, but not limited to, ethyl acetate, at about room temperature generally affords compounds of a (5).

Protection of the nitrogen atom with protecting group (PG) such as, but not d to, benzyl, p-tolunesulfonyl, and (trimethylsilyl)ethoxy)methyl group may be derived from reaction with an appropriate halide, in the presence of a strong base such as, but not limited to, sodium hydride, to provide compounds of a (6). sion of (6) to (7) may be achieved by reaction with alkyl carbonochloridate in the presence of a base such as, but not limited to, lithium diisopropylamide. Treatment of (7) with an acid such as, but not limited to, hydrochloric acid or hydrobromic acid and in a solvent such as, but not limited to, dioxane or water, at about 40 0C to about 100 oC, provides compounds of formula (8).

] Alkylation of (8) with methyl iodide, in the presence of a base such as, but not limited to, sodium hydride, cesium carbonate, or potassium carbonate, and in a solvent such as, but not limited to, N,N—dimethylformamide or dimethylsulfoxide at a temperature of about 0 0C to about 50 oC provides compounds of formula (9). ysis of esters (9) provides acids of formula (1).

Acids of formula (10) may be transformed to the appropriate acid chloride by treatment with oxalyl chloride in the presence of catalytic amount of N,N—dimethylformamide at about room temperature, and in a suitable solvent such as, but not limited to, ydrofuran or dichloromethane. The resulting acid chloride may be converted to amides of formula (1) wherein R101 is halo by treatment with an amine of formula RINHz in a solvent such as, but not limited to, tetrahydrofuran, N,N—dimethylformamide, or dichloromethane at a temperature from about room temperature to about 50 oC, optionally in the ce of a base such as, but not limited to, triethylamine, N,N—diisopropylethylamine, or potassium ate, and optionally in the presence of a catalyst such as 4-dimethylaminopy1idine.

Alternatively, acids of a (10) may be reacted with the amine of formula RINHZ in a solvent such as, but not limited to, tetrahydrofuran or N,N—dimethylformamide in the presence of a coupling reagent such as l,l ’-carbonyldiimidazole (CD1), bis(2-oxo oxazolidinyl)phosphinic chloride ), cyclohexylcarbodiimide (DCC), polymer supported l,3-dicyclohexylcarbodiimide C), O-(7-azabenzotriazol-l-yl)-N,N,N’,N’- tetramethyluronium hexaﬂuorophosphate , or O-benzotriazol-l-yl-N,N,N’,N’- tetramethyluronium tetraﬂuoroborate (TBTU), in the presence or absence of a coupling auxiliary such as, but not limited to, oxyazabenzotriazole (HOAT) or 1- hydroxybenzotriazole hydrate (HOBT). The reaction may be lly conducted in the presence or absence of a base such as, but not limited to, N—methyl morpholine, triethylamine, or N,N—diisopropylethylamine.

Treatment of the compounds of formula (1) wherein R101 is halo with 4,4,4',4',5,5,5',5'—octamethyl-2,2'-bi(l,3,2-dioxaborolane) generally affords compounds of formula (1) wherein R101 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl. In general, the sion may be facilitated by a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), or palladium(II)acetate, an optional ligand such as, but not limited to, 2-dicyclohexylphosphino- 3O 2’,4’,6’-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos), orl,l'- bis( diphenylphosphanyl) ferrocene, and a base such as, but not limited to, carbonates, acetates, or phosphates.of , potassium, and cesium, and cesium ﬂuoride. Non-limiting examples of suitable ts include methanol, dimethoxyethane, N,N—dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, and water, or a mixture thereof.

Scheme 3 R103 = -O-a|ky| or R3 O H \N N O I / R4a \ R4d HN—R1 / \ O / x2 .— R4C / I Y R4b MWOH R6 R2 R3 Compounds of general formula (I) wherein R4 is formula (a) may also be prepared by the route shown in Scheme 3. Reaction of formula (1) wherein R101 is boronic acid or a derivative thereof (e.g., a pinacol ester) with nds of formula (11), n R104 is halo (Cl, Br, or I) or triﬂate, under Suzuki ng conditions (N. Miyama and A. Suzuki, Chem.

Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148), as described above, to provide compounds of formula (12). Compounds of a (13) may be ed by displacement of the ﬂuorine atom of the intermediates (12) with an appropriate alcohol (12a).

Displacement of the e atom may be accomplished in a solvent such as, but not limited to, dimethylsulfoxide, dimethylformamide, dioxane, or tetrahydrofuran and in the presence of a base such as, but not limited to, carbonate of cesium, potassium, or sodium, or sodium e, and at a temperature from about 40 0C to about 120 oC. Compounds of formula (14) n R2 and R3 are different may be prepared by reaction of compounds of a (13) wherein R103 = R3 with a Grignard reagent of formula RZMgX in a solvent such as tetrahydrofuran, diether ether, or dioxane at about ambient temperatures. Compounds of formula (14) wherein R2 and R3 are the same may be prepared by reaction of compounds of formula (13) wherein R103 = Oalkyl with greater than two equivalents of a Grignard reagent of formula RZMgX in a solvent such as tetrahydrofuran, diether ether, or dioxane at about ambient temperatures.

Scheme 4 HN—R1 F, CI\%\X2 F, 0%)(2 B(OR)2 (la) | —> | x1, R103 x1. OH —, R6 o R6 R2 R3 (15) (16) H \N IN 0 A HN—R1 XLI)\ Scheme 5 / x2 0 X1IJYOH \N N O 0 o / PG PG R6 RZR3 \ O-alkyl \N N O \N N 0 (2a) R4 I —> I / —> / / X2 \ \ I O-alkyl O-alkyl X1 ‘ OH halo B(OR)2 R6 R2 R3 (7) (20) (21) o o H H \N N o \N N o | / | \ / HN—R1 \ R4 R4 / X2 / X2 X1, OH R6 R2 R3 R6 R2 R3 (1) (22) ] Compounds of general formula (I) may also be ed according to Scheme 5.

Treatment of the compounds of formula (7) with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- orolane) under cross-coupling conditions as described in Scheme 2 generally affords compounds of formula (20). Reaction of compounds of formula (20) with compounds of formula (2a) under Suzuki coupling conditions (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148), as described in Scheme 1, provides compounds of formula (21). Hydrolysis of the ester of compounds of formula (21), along with itant removal of the protecting group (PG) provides compounds of formula (22).

Conversion of the acids (22) to the corresponding amides of formula (I) may be achieved with reaction conditions as outlined in Scheme 2.

Scheme 6 Br, I Br, I Br, I Br, I F, 0%)(2 F, 0%)(2 4 ' ' R\%\X2 R\%\X24 | | | | x1. OH x1. 0\ x1. 0\ X1. OH alkyl alkyl R6 o R6 o R6 o R6 R2 R3 (23) (15a) / (24) (2a) Br, I Br, I Br, I R%X2 R%X2 R4 —> I —> MWOH X1WN\o X19968 R6 I (25) (26) (27) Compounds of general formula (2a) may be prepared as described in Scheme 7.

Compounds of formula (23) may be esterifled under general conditions known to one skilled in the art to provide nds of formula (15a). Compounds of formula (24) wherein R4 is a (a) may be prepared by cement of the C1 or F atom of the intermediates (15a) with an alcohol as described in Scheme 3. Suzuki coupling of (15a) with an appropriate boronic acid or esters (or derivatives thereof) as bed in Scheme 1. Reaction of (24) with about two equivalents of Grignard reagent of formula R3MgX provides compounds of 2O formula (2a) wherein R2 and R3 are the same.

Hydrolysis of esters (24) provides acids of formula (25), which may be treated with N,O-dimethylhydroxylamine in a solvent such as, but not limited to, tetrahydrofuran or N,N— dimethylformamide in the presence of a ng reagent such as 1,1’-carbonyldiimidazole (CDI), bis(2-oxooxazolidinyl)phosphinic chloride (BOPCl), cyclohexylcarbodiimide (DCC), polymer supported 1,3-dicyclohexylcarbodiimide (PS-DCC), O-(7-azabenzot1iazol yl)-N,N,N’,N’-tetramethyluronium hexaﬂuorophosphate (HATU), or O-benzotriazol-l-yl- N,N,N’,N’-tetramethyluronium uoroborate (TBTU), in the presence or absence of a coupling auxiliary such as, but not limited to, l-hydroxyazabenzotriazole (HOAT) or 1- hydroxybenzotriazole hydrate (HOBT), to provide compounds of formula (26). Reaction of compounds of formula (26) with a rd reagent of formula R3MgX in a solvent such as tetrahydrofuran, diether ether, or dioxane at about ambient temperatures provides compounds of formula (27). Reaction of compounds of formula (27) with a Grignard reagent of formula R2MgX in a solvent such as tetrahydrofuran, diether ether, or dioxane at about ambient temperatures provides compounds of general a (2a).

Scheme 7 N02 N02 NH2 Br, I \l)(2 R\%\IX24 R\%\I)(24 R\%\I)(24 X1Wc O\ X1Wc O\ X OH alkyl alkyl 1"4 O\ X 4 alkyl 1W R6 o R6 o R6 o R6 R2 R3 (27) (28) (29) (2a) Alternatively, compounds of general formula (2a) may be prepared as described in Scheme 7. Conversion of (27) to compounds (28) may be achieved using reaction conditions as described in Scheme 4. ion of the nitro group of compounds of formula (28) provides amines of formula (29). Compounds of general formula (2a) may be ed from compounds (29) under Sandmeyer conditions.

Scheme 8 Br,| Br,| Br" R\%\X24 R\%\X24 R4 I —> X1WR3 —> \%\IX2 3 R3 X1‘ R 6 6 R6 R o R (27) (30) (31) Alternatively, compounds of general formula (2a) wherein R2 is -CH20H may be 2O prepared as described in Scheme 8. Reaction of compounds of formula (27) with a Wittig reagent such as methyltriphenylphosphonium bromide in a solvent such as but not limited to tetrahydrofuran or dioxane in the ce of a base, such as but not limited to n-butyllithium or sodium e at temperatures ranging from about -20 °C to ambient temperature, provides compounds of formula (3 O). ion of compounds of formula (3 O) with reagents such as but not d to potassium hexacyanoferrate (III) and potassium osmate e in a solvent ation such as but not limited to water and tert-butanol in the presence of a base such as but not limited to potassium carbonate or sodium carbonate, provides compounds of formula (31).

Scheme 9 0 PG 0 PG \ [\i O | \ / Oalkyl _.

\ / Oalkyl (32) (7) id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157" id="p-157"

[00157] Intermediates (7) may also be prepared as bed in Scheme 9 by halogenation of compounds (32). The reaction may be conducted in the presence of a halogenating agent such as, but not limited to, N—bromosuccinimide, succinimide, or N—chlorosuccinimide, an acid such as, but not limited to, p-toluenesulofonic acid, and a solvent such as, but not limited to, tetrahydrofuran and acetonitrile. id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158"

[00158] It can be appreciated that the synthetic schemes and speciﬁc examples as illustrated in the tic examples section are illustrative and are not to be read as limiting the scope of the invention as it is deﬁned in the appended claims. All alternatives, modiﬁcations, and equivalents of the synthetic methods and speciﬁc examples are included within the scope of the claims. id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159" id="p-159"

[00159] Optimum reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used.

Unless otherwise speciﬁed, solvents, temperatures and other reaction conditions can be readily selected by one of ordinary skill in the art. Speciﬁc procedures are provided in the Synthetic es section. Reactions can be worked up in the conventional manner, e. g. by eliminating the t from the residue and further puriﬁed according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise bed, the starting materials and ts are either commercially ble or can be prepared by one d in the art from cially available materials using methods described in the chemical literature. id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160" id="p-160"

[00160] Routine experimentations, including riate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that can not be compatible with the reaction conditions, and deprotection at a le point in the reaction sequence of the method are included in the scope of the invention. le protecting groups and the methods for protecting and deprotecting 3O different substituents using such suitable protecting groups are well known to those skilled in the art, examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by s analogous to those described in the synthetic schemes described hereinabove and in speciﬁc examples.

Starting materials, if not commercially available, can be prepared by procedures selected from standard c chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the tic examples section. id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162" id="p-162"

[00162] When an optically active form of a compound is ed, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution). id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163" id="p-163"

[00163] Similarly, when a pure geometric isomer of a compound is ed, it can be prepared by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric s of the compound or intermediates using a standard ure such as chromatographic tion. d. Pharmaceutical Compositions id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164" id="p-164"

[00164] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such composition may be ed in a manner well known in the ceutical art and comprise a therapeutically ive amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, alone or or in ation with at least one additional therapeutic agent, together with a pharmaceutically acceptable carrier. The phrase "pharmaceutical composition" refers to a composition suitable for administration in medical or veterinary use.

The pharmaceutical compositions that comprise a compound of formula (I), alone or or in combination with at least one additional therapeutic agent, may be administered to the subjects orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, 3O topically (as by s, ointments or , bucally or as an oral or nasal spray. The term "parenterally" as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous, and intraarticular injection and infusion.

The term "pharmaceutically acceptable r" as used herein, means a non-toxic, inert solid, semi-solid or liquid flller, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as ceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose, starches such as, but not limited to, corn starch and potato starch, cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, ed tragacanth, malt, gelatin, talc, excipients such as, but not limited to, cocoa butter and suppository waxes, oils such as, but not limited to, peanut oil, cottonseed oil, safﬂower oil, sesame oil, olive oil, corn oil and soybean oil, glycols, such a propylene glycol, esters such as, but not limited to, ethyl oleate and ethyl e, agar, ing agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and ate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, ng and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection se pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile able solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles e water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. Proper ﬂuidity can be ined, for example, by the use of g materials such as in, by the maintenance of the required particle size in the case of sions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting , emulsifying agents and dispersing agents. tion of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic 3O agents such as sugars, sodium chloride and the like. ged absorption of the able pharmaceutical form can be brought about by the inclusion of agents, which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, d absorption of a parenterally-administered drug form may be accomplished by ving or ding the drug in an oil vehicle.

Injectable depot forms may be made by forming microencapsule es of the drug in biodegradable rs such as polylactide-polyglycolide. Depending upon the ratio of drug to r and the nature of the particular r employed, the rate of drug e can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot able formulations are also prepared by entrapping the drug in liposomes or microemulsions which are ible with body s.

The injectable formulations may be sterilized, for example, by ﬁltration through a bacterial-retaining ﬁlter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In certain embodiments, solid dosage forms may contain from 1% to 95% (w/w) of a compound of formula I. In certain embodiments, the compound of formula I may be present in the solid dosage form in a range of from 5% to 70% (w/w). In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) flllers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, e and , c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as parafﬁn, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case 3O of capsules, tablets and pills, the dosage form may also se buffering agents.

The pharmaceutical composition may be a unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted s, es, and powders in vials or ampules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w/w) of a unit dose, ing to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

The dose to be administered to a subject may be determined by the efﬁcacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the subject to be treated. The size of the dose also will be determined by the nce, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a ular subject. In determining the effective amount of the compound to be administered in the treatment or prophylaxis of the disorder being treated, the physician can evaluate factors such as the circulating plasma levels of the nd, compound toxicities, and/or the progression of the disease, etc. In general, the dose equivalent of a nd is from about 1 ug/kg to 100 mg/kg for a typical t.

For administration, compounds of the a (I) may be administered at a rate determined by factors that can include, but are not limited to, the LD50 of the compound, the pharmacokinetic proﬁle of the compound, contraindicated drugs, and the side-effects of the compound at s trations, as applied to the mass and overall health of the subject.

Administration can be accomplished via single or divided doses.

] The nds utilized in the pharmaceutical method of the invention may be administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily. In certain embodiments, the daily dose range is from about 0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varied depending upon the requirements of the subject, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Treatment may be initiated with smaller dosages, which are less than the optimum dose of the compound.

Thereafter, the dosage is increased by small increments until the m effect under circumstances is reached. For ience, the total daily dosage may be divided and administered in portions during the day, if desired.

Solid compositions of a similar type may also be employed as flllers in soft and hard- fllled gelatin capsules using such rs as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills and es may be prepared with coatings and shells such as enteric gs and other gs well-known in the pharmaceutical ating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric nces and waxes.

The active nds may also be in encapsulated form, if appropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active nds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for e, water or other solvents, solubilizing agents and emulsiﬁers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, tylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Besides inert ts, the oral itions may also include adjuvants such as wetting , emulsifying and suspending agents, sweetening, ﬂavoring and perfuming agents. id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182" id="p-182"

[00182] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, um metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds of this ion with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds of formula (I) may also be administered in the form of liposomes. 3O Liposomes generally may be d from phospholipids or other lipid substances.

Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, logically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may contain, in addition to a compound of formula (I), stabilizers, preservatives, ents and the like. Examples of lipids include, but are not limited to, natural and synthetic phospholipids and atidyl cholines (lecithins), used separately or together.

Methods to form liposomes have been described, see example, Prescott, Ed, s in Cell y, Volume XIV, Academic Press, New York, NY. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound described herein include powders, sprays, ointments and inhalants. The active compound may be mixed under sterile conditions with a ceutically able carrier and any needed preservatives, buffers or lants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this ion. e. Methods of Use The compounds of formula (I), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered to a subject suffering from a bromodomain- mediated disorder or condition. The term "administering" refers to the method of contacting a compound with a subject. Thus, the compounds of formula (I) may be administered by injection, that is, enously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, parentally, or intraperitoneally. Also, the compounds described herein may be stered by inhalation, for example, asally. Additionally, the compounds of formula (I) may be administered transdermally, lly, via implantation, and transdermaly.

In n embodiments, the compounds of the formula (I) may be delivered orally. The compounds may also be delivered rectally, bucally, intravaginally, ocularly, ly, or by insufﬂation. Bromodomain-mediated disorders and conditions may be treated prophylactically, acutely, and chronically using compounds of formula (1), depending on the nature of the disorder or condition. Typically, the host or subject in each of these methods is human, although other mammals may also beneﬁt from the administration of a compound of formula (I).

A domain-mediated disorder or condition" is characterized by the participation of one or more bromodomains (e.g., BRD4) in the inception, manifestation of 3O one or more symptoms or disease markers, severity, or progression of a disorder or condition.

Accordingly, the invention provides a method for treating cancer, including, but not limited to ic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic oma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, c myelocytic locytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial oma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, ﬂbrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, osarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, , colon, lung, s, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, enous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary arcinomas, papillary carcinoma, oma, themia vera, prostate cancer, rectal cancer, renal cell carcinoma, blastoma, rhabdomyosarcoma, a, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, ular tumors, uterine cancer and Wilms’ tumor. The method ses the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a preferred embodiment thereof, with or without a pharmaceutically acceptable carrier.

The invention further provides a method for treating inﬂammatory diseases, inﬂammatory conditions, and mune diseases, including, but not limited to: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, 's disease, bullous 3O skin diseases, chronic obstructive ary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inﬂammatory bowel disease, ki disease, lupus nephritis, multiple sclerosis, myocarditis,myositis, tis, organ transplant rejection, osteoarthritis, atitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, toid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's tis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis. The method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a compound of a (I) or a preferred embodiment thereof, with or without a pharmaceutically acceptable carrier.

The invention further provides a method for ng diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental ulosclerosis, membranous ulonephritis, minimal change disease, polycystic kidney disease, or tubular interstitial nephritis. The method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a preferred embodiment thereof, with or without a pharmaceutically acceptable carrier.

The invention r provides a method for ng acute kidney injury or e or condition, wherein said acute kidney injury or disease or condition is selected from the group consisting of: ischemia-reperfusion induced kidney disease, cardiac and major surgery induced kidney disease, percutaneous coronary intervention d kidney e, radio- contrast agent induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney e, and drug toxicity induced kidney disease. The method ses the step of administering to a subject in need thereof a therapeutically effective amount of a nd of formula (I) or a preferred embodiment thereof, with or without a ceutically acceptable carrier.

The invention further provides a method for treating chronic kidney disease or condition, wherein said e or condition is ed from the group consisting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus tis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubular interstitial tis. The method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a preferred embodiment thereof, with or without a pharmaceutically acceptable carrier. 3O [00193] The invention further provides a method for treating AIDS. The method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a preferred embodiment thereof, with or without a pharmaceutically acceptable carrier.

In another ment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in ne.

In a particular ment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in the treatment of es or disorders as described herein above.

One embodiment is directed to the use of a compound according to formula (I), or a pharmaceutically acceptable salt thereof in the preparation of a medicament. The medicament optionally can comprise at least one additional therapeutic agent. In some embodiments the medicament is for use in the treatment of diseases and disorders as described herein above.

This ion is also directed to the use of a nd according to formula (I), or a pharmaceutically acceptable salt thereof in the cture of a medicament for the treatment of the diseases and disorders as described herein above. The medicament optionally can comprise at least one additional therapeutic agent. id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197" id="p-197"

[00197] The compounds of formula (I) may be administered as the sole active agent or it may be co-administered with other therapeutic agents, including other compounds that demonstrate the same or a similar therapeutic activity and that are determined to be safe and eff1cacious for such ed administration. The term "co-administered" means the administration of two or more different therapeutic agents or treatments (e.g., radiation treatment) that are administered to a subject in a single pharmaceutical composition or in separate pharmaceutical compositions. Thus inistration involves administration at the same time of a single pharmaceutical composition comprising two or more different therapeutic agents or administration of two or more different compositions to the same subject at the same or different times. id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198" id="p-198"

[00198] The nds of the invention may be co-administered with a therapeutically effective amount of at least one additional therapeutic agent to treat cancer, where examples of the therapeutic agents include, such as radiation, alkylating agents, angiogenesis inhibitors, antibodies, tabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoters (for example, Bcl-XL, Bcl-w and Bﬂ-l) inhibitors, activators of death 3O receptor y, Bcr-Abl kinase inhibitors, BiTE (Bi-Speciﬁc T cell Engager) antibodies, antibody drug conjugates, biologic se modif1ers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (dual variable domain antibodies), leukemia viral ne homolog ) or tors, growth factor inhibitors, heat shock protein (HSP)-9O inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of tors of apoptosis proteins (IAPs), intercalating otics, kinase tors, kinesin tors, Jak2 tors, ian target of rapamycin inhibitors, microRNA’s, mitogen-activated extracellular signal-regulated kinase inhibitors, alent binding proteins, non-steroidal anti-inﬂammatory drugs (NSAle), poly ADP (adenosine phate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (bromodomain) tors, proteosome inhibitors, purine analogs, dine analogs, receptor ne kinase inhibitors, etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), omerase inhibitors, ubiquitin ligase inhibitors, and the like, and in combination with at least one of these agents .

BiTE antibodies are bi-speciﬁc antibodies that direct T-cells to attack cancer cells by simultaneously g the two cells. The T-cell then attacks the target cancer cell.

Examples of BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and the like. Without being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule ents, which include perforin and granzyme B. In this regard, Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B. These data suggest that inhibition of Bcl-2 could enhance the cytotoxic effects elicited by T-cells when targeted to cancer cells (V.R. Sutton, D.L. Vaux and J.A. Trapani, J. ofImmunology 1997, 158 (12), 5783) SiRNAs are molecules having endogenous RNA bases or chemically modiﬁed nucleotides. The modiﬁcations do not abolish cellular ty, but rather impart increased stability and/or increased cellular potency. Examples of chemical modiﬁcations include phosphorothioate groups, 2'—deoxynucleotide, 2'—OCH3-containing ribonucleotides, 2'—F- ribonucleotides, 2'—methoxyethyl ribonucleotides, combinations thereof and the like. The siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends angs). The overhang of 1-2 3O nucleotides can be present on the sense and/or the antisense strand, as well as present on the '— and/ or the 3'—ends of a given strand.

Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent g proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies. The term "multispeciﬁc binding n" means a binding protein capable of binding two or more related or unrelated targets. Dual le domain (DVD) binding proteins are tetravalent or alent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecif1c (i.e., capable of binding one antigen) or multispecif1c (i.e., e of binding two or more antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in n binding per antigen binding site. Multispecif1c DVDs include DVD binding proteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents e altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, uone, cannustine (BCNU), chlorambucil, CLORETAZINE® (laromustine, VNP 40lOlM), hosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N—oxide, ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamide and the like.

Angiogenesis inhibitors include endothelial-specif1c receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor Z) inhibitors, matrix metalloproteinase-2 (MMP-Z) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin s, vascular endothelial growth factor receptor tyrosine kinase ) inhibitors and the like. id="p-204" id="p-204" id="p-204" id="p-204" id="p-204" id="p-204" id="p-204" id="p-204" id="p-204" id="p-204" id="p-204" id="p-204" id="p-204"

[00204] Antimetabolites include ALIMTA® (pemetrexed disodium, 14, MTA), -azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine ate, cytosine arabinoside, decitabine, deferoxamine, doxiﬂuridine, hine, EICAR (5-ethynyl-l-B -D-ribofuranosylimidazole carboxamide), enocitabine, ethnylcytidine, ﬂudarabine, 5-ﬂuorouracil alone or in 3O combination with leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN®(melphalan), topurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-l, tiazofurin, tegafur, TS-l, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN—8054, VX-680, Aurora A-speciﬁc kinase inhibitors, Aurora B-speciﬁc kinase inhibitors and pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-lOl ((-)gossypol), NSE® (G3 139 or oblimersen (Bcltargeting antisense oligonucleotide)), lPI-l94, lPI-565, N—(4-(4-((4'- chloro( l , l '-biphenyl)yl)methyl)piperazin- l -yl)benzoyl)(((lR)-3 -(dimethylamino)— l - ((phenylsulfanyl)methyl)propyl)amino)-3 -nitrobenzenesulfonamide) (ABT-73 7), N—(4-(4-((2- (4-chlorophenyl)—5 , 5 -dimethyl- l hexenyl)methyl)piperazin- l -yl)benzoyl)—4- (((lR)—3-(morpholinyl)-l-((phenylsulfanyl)methyl)propyl)amino)—3- ((triﬂuoromethyl)sulfonyl)benzenesulfonamide (ABT-263), GX-O7O (obatoclaX) and the like.

] Bcr-Abl kinase inhibitors e DASATINIB® (EMS-354825), C® (imatinib) and the like.

CDK inhibitors include AZD-543 8, BMI—lO40, EMS-032, BMS-3 87, CVT-2584, ﬂavopyridol, GPC-286l99, MC S-5A, 991, FHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like. cox—2 inhibitors include 3, A® (etoricoxib), BEXTRA® (valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, yl(3,4-dimethylphenyl)-l-(4- 2O sulfamoylphenyl-lH-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, 8-2474, T-6l4, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, GFR immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® (geﬁtinib), TARCEVA® (erlotinib or 4), TP-3 8, EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP7l4, CI—lO33 (canertinib), HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-l65, 016 (ionafarnib), GW-282974, 9, PI—l66, dHER2 (HER2 vaccine), AFC-8024 (HER-2 vaccine), anti-HER/2neu iﬁc antibody, B7.her2IgG3, AS HER2 3O trifunctional ﬁc antibodies, mAB AR-209, mAB 2B-l and the like.

Histone deacetylase inhibitors include depsipeptide, 4, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.

HSP-9O inhibitors include l7-AAG—nab, l7-AAG, CNF- l O l , CNF- l O l O, CNF-2024, l7-DMAG, geldanamycin, lPI-504, KOS-953, MYCOGRAB® (human recombinant antibody to HSP-90), NCS-683664, l, PU-3, radicicol, SNX-2112, STA-9090 09 and the like.

] Inhibitors of inhibitors of apoptosis proteins include HGSlO29, GDC-0145, GDC- 0152, LCL-161, LBW-242 and the like.

] Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CRVcMMAE, PSMA-ADC, MEDI—547, SGN-19Am SGN-35, SGN—75 and the like Activators of death receptor pathway include TRAIL, dies or other agents that target TRAIL or death receptors (e.g., DR4 and DRS) such as Apomab, conatumumab, ETR2-ST01, GDC0145, umumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab. n inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520, CENPE inhibitors such as GSK923295A and the like.

] JAK-2 tors include CEP-701 (lesaurtinib), X14019 and INCB018424 and the like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like. mTOR inhibitors include 73, CCI—779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORCl/TORC2 inhibitors, including PI—103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inﬂammatory drugs include AMIGESIC® late), DOLOBID® (diﬂunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE® (naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like. id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223" id="p-223"

[00223] PDGFR inhibitors include C-451, , CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), latin, picoplatin and the like. ike kinase inhibitors include BI—2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, 658, PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, ABE-788, ANGIOZYMETM (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA)), aXitinib (AG-13736), AZD-217l, CP-547,632, , MACUGEN (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034),vata1anib (PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMATM (vandetanib, ZD-6474), GAIOl, ofatumumab, ABT-806 (mAb-806), ErbB3 speciﬁc antibodies, BSG2 speciﬁc antibodies, DLL4 speciﬁc antibodies and C-met speciﬁc antibodies, and the like.

Antibiotics include intercalating otics bicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, S® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, ozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, de, amsacrine, becatecarin, belotecan, BN—80915, CAMPTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine), diﬂomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN—3 8, taﬂuposide, topotecan and the like.

Antibodies include N® (bevacizumab), CD40-speciﬁc antibodies, chTNT- l/B, denosumab, ERBITUX® (cetuXimab), HUlVIAX-CD4® imumab), IGFlR-speciﬁc antibodies, lintuzumab, PANOREX® olomab), RENCAREX® (WX G250), N® imab), ticilimumab, trastuzimab, CD20 antibodies types I and II and the like.

] Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN® (exemestane), arzoxifene, CASODEX® utamide), CETROTIDE® (cetroreliX), degareliX, deslorelin, DESOPAN® (trilostane), thasone, DROGENIL® (ﬂutamide), EVISTA® (raloxifene), AFEMATM (fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA® (letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol), RENAGEL® (sevelamer carbonate), xifene, leuprolide acetate, MEGACE® (megesterol), M113EPREX® (mifepristone), NILANDRONTM (nilutamide), NOLVADEX® (tamoxifen 3O citrate), PLENAXISTM (abarelix), prednisone, IA® (ﬁnasteride), rilostane, SUPREFACT® elin), AR® (luteinizing e releasing hormone (LHRH)), VANTAS® (Histrelin implant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin, goserelin) and the like.

] Deltoids and retinoids include citol (EB1089, ), lexacalcitrol (KH1060), fenretinide, IN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436, 81, AG- 014699, 1, BGP-15, INC-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI—OOSZ, PR-l7l and the like. id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237" id="p-237"

[00237] Examples of immunologicals include interferons and other immune-enhancing agents.

Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-la, VIUNE® (interferon gamma-lb) or eron gamma-nl, combinations thereof and the like. Other agents include ALFAFERONE®,(1FN-oc), BAM-002 (oxidized glutathione), BEROMUN® (tasonennin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, YTE® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, O CTLA-4), melanoma e, mitumomab, molgramostim, MYLOTARGTM (gemtuzumab ozogamicin), NEUPOGEN®(f11grastim), OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFGl), PROVENGE® (sipuleucel-T), sargaramostim, sizofllan, teceleukin, THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, Lorus Pharmaceuticals), Z-lOO (Speciﬁc Substance of Maruyama (SSM)), WF-lO (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (9OY-Ibritumomab tiuxetan) and the like. id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238" id="p-238"

[00238] Biological response modiﬁers are agents that modify defense isms of living organisms or ical responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizoﬁran, picibanil PF- 3512676 (CpG—8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), ne arabinoside, 3O doxiﬂuridine, FLUDARA® (ﬂudarabine), 5-FU (5-ﬂuorouracil), ﬂoxuridine, GEMZAR® (gemcitabine), TOMUDEX® rexed), TROXATYLTM (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI—NETHOL® (mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862), N—(2-((4- hydroxyphenyl)amino)py1idinyl)methoxybenzenesulfonamide, ixabepilone (BMS 247550), axel, TAXOTERE® (docetaxel), PNUlOO94O (109881), patupilone, XRP-9881 (larotaxel), vinﬂunine, ZK-EPO (synthetic epothilone) and the like.

] Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like.

] Compounds of this invention may also be used as radiosensitizers that enhance the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.

Additionally, compounds of formula (I) may be combined with other chemotherapeutic agents such as ABRAXANETM (ABI—OO7), ABT-lOO (famesyl transferase inhibitor), ADVEXIN® V-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly Izpoly C12U, a synthetic RNA), APTOSYN® (exisulind), ® (pamidronic acid), arglabin, L-asparaginase, atamestane (l-methyl-3,l7-dione-androsta-l,4- diene), AVAGE® (tazarotene), 62 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC® (cancer vaccine), CELEUK® leukin), CEPLENE® mine dihydrochloride), CERVARIX® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide), H: ADRIAMYCIN® (hydroxydoxorubicin), O: Vincristine (ONCOVIN®), P: prednisone), CYPATTM (cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor) or TranleD-107RTM (diphtheria toxins), dacarbazine, dactinomycin, 5,6- dimethylxanthenoneacetic acid (DMXAA), eniluracil, EVIZONTM (squalamine lactate), DIMERICINE® (T4N5 me lotion), discodermolide, DX-8951f (exatecan mesylate), aurin, EPO906 ilone B), GARDASIL® (quadrivalent human papillomavirus (Types 6, ll, 16, 18) recombinant e), VHVIUNE®, GENASENSE®, GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin, 3O hydroxycarbamide, ibandronic acid, l, lL-l3-PE3 8, IL-l3-PE38QQR (cintredekin besudotox), IL- 1 3 -pseudomonas in, eron-0t, interferon-y, JUNOVANTM or MEPACTTM (mifamurtide), lonafarnib, 5,lO-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT®(AE-94l), NEUTREXIN® (trimetrexate glucuronate), ® (pentostatin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® oma vaccine treatment), ONCOVAX® (IL-2 Vaccine), ORATHECINTM (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb (murine monoclonal antibody), paclitaxel, PANDIMEXTM (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), argase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), SORIATANE® etin), staurosporine (Streptomyces staurospores), talabostat (PTlOO), TARGRETIN® otene), TAXOPREXIN® (DHA-paclitaxel), TELCYTA® (canfosfamide, ), temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, OPE® (STn- KLH), thymitaq (2-amino-3,4-dihydromethyloxo(4-py1idylthio)quinazoline dihydrochloride), TNFERADETM (adenovector: DNA carrier containing the gene for tumor necrosis factor-0t), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), drine, TRISENOX® (arsenic de), VIRULIZIN®, ukrain (derivative of ids from the greater celandine plant), vitaXin (anti-alphavbeta3 antibody), XCYTRIN® (motexaﬁn gadolinium), XINLAYTM (atrasentan), XYOTAXTM (paclitaxel poliglumeX), YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA® (zolendronic acid), zorubicin and the like.

The compounds of the ion may also be co-administered with a therapeutically effective amount of at least one additional therapeutic agents to treat an inﬂammatory disease or condition, or autoimmune disease, where examples of the agents include, such as methotrexate, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/ hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, ine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, eral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, opium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate l, leﬂunomide, NSAle, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which 3O interfere with signalling by proinﬂammatory cytokines such as TNFOL or lL-l (e.g., NIK, IKK, p38 or MAP kinase inhibitors), lL-lB converting enzyme inhibitors, T-cell signalling inhibitors such as kinase inhibitors, oproteinase inhibitors, sulfasalazine, 6- mercaptopurines, angiotensin converting enzyme inhibitors, soluble ne receptors and derivatives thereof (e. g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (etanercept) and p55TNFRIgG (Lenercept), , le-lRII, le-6R), antiinﬂammatory cytokines (e. g. IL-4, IL-10, IL-1 1, lL-l3 and TGFB), celecoxib, folic acid, hydroxychloroquine e, rofecoxib, etanercept, inﬂiximab, naproxen, oxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, n, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, zin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium, solone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, mab, lL-l TRAP, MRA, CTLA4-IG, 1L-18 BP, anti-1L-12, L15, BIRB-796, SCIO-469, , AMG— 548, VX-740, Roﬂumilast, IC-485, 1, SlPl agonists (such as FTY720), PKC family inhibitors (such as Ruboxistaurin or 1) and Mesopram. In certain ments, combinations e methotrexate or leﬂunomide and in moderate or severe rheumatoid tis cases, cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for atory bowel disease with which a compound of formula (I) may be co-administered include the following: budenoside, epidermal growth factor, corticosteroids, cyclosporin, sulfasalazine, aminosalicylates, 6- mercaptopurine, azathioprine, metronidazole, lipoxygenase inhibitors, mesalamine, olsalazine, balsalazide, antioxidants, thromboxane inhibitors, lL-l receptor antagonists, anti- IL-lB monoclonal antibodies, L-6 monoclonal antibodies, growth factors, elastase inhibitors, pyridinyl-imidazole compounds, antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, lL-l, IL-2, IL-6, IL-7, 1L-8, 1L-12, 1L-15, IL—16, 1L-23, EMAP-II, GM-CSF, FGF, and PDGF, cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands, methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leﬂunomide, NSAle, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase 3O inhibitors, adenosine agonists, antithrombotic agents, ment inhibitors, adrenergic agents, agents which interfere with signalling by proinﬂammatory cytokines such as TNFOL or IL-1 (e. g. NIK, IKK, or MAP kinase inhibitors), IL-lB converting enzyme inhibitors, TNFOL converting enzyme inhibitors, T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors; sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin ting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e. g. soluble p55 or p75 INF receptors, le-lRI, sIL-lRII, sIL-6R) and antiinflammatory cytokines (e. g.

IL-4, lL-lO, lL-l l, IL-13 and TGFB). Preferred es of therapeutic agents for s disease with which a compound of formula (I) may be combined include the following: INF nists, for example, anti-TNF antibodies, D2E7 (adalimumab), CA2 (inﬂiximab), CDP 57l, TNFR—Ig constructs, (p751NFRIgG(etanercept) and p55TNFRIgG (LENERCEPTTM) tors and PDE4 inhibitors. A compound of formula (I) may be combined with corticosteroids, for example, budenoside and dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine, and agents which interfere with synthesis or action of proinﬂammatory cytokines such as IL-1, for example, lL-lB ting enzyme inhibitors and lL-lra, T cell ing inhibitors, for example, tyrosine kinase tors, 6-mercaptopurine, lL-l l, mesalamine, prednisone, azathioprine, mercaptopurine, infliximab, methylprednisolone sodium succinate, diphenoxylate/atrop sulfate, loperamide hydrochloride, methotrexate, zole, folate, ciprofloxacin/dextrose-water, hydrocodone bitartrate/apap, tetracycline hydrochloride, fluocinonide, metronidazole, thimerosal/boric acid, cholestyramine/sucrose, ciproﬂoxacin hydrochloride, hyoscyamine sulfate, meperidine hydrochloride, midazolam hydrochloride, oxycodone HCl/acetaminophen, promethazine hydrochloride, sodium phosphate, sulfamethoxazole/trimethoprim, celecoxib, polycarbophil, yphene napsylate, hydrocortisone, itamins, balsalazide disodium, codeine phosphate/apap, colesevelam HCl, cyanocobalamin, folic acid, levofloxacin, methylprednisolone, natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound of formula (I) may be co-administered include the following: corticosteroids, solone, methylprednisolone, azathioprine, hosphamide, cyclosporine, methotrexate, 4-aminopyridine, tizanidine, interferon-B la (AVONEX®, Biogen), interferon- Blb (BETASERON®, Chiron/Berlex), interferon oc-n3) (Interferon Sciences/Fujimoto), interferon-0L (Alfa Wassermann/J&J), interferon BIA-1F o/Inhale Therapeutics), Peginterferon 0L 2b /Schering-Plough), Copolymer l (Cop-l, COPAXONE®, Teva 3O Pharmaceutical Industries, Inc), hyperbaric oxygen, intravenous immunoglobulin, cladribine, antibodies to or antagonists of other human cytokines or growth factors and their receptors, for example, TNF, LT, lL-l, 1L-2, IL-6, IL-7, IL-8, 1L-12, 1L-23, 1L-15, IL-16, I, GM-CSF, FGF, and PDGF. A compound of formula (I) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound of formula (I) may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leﬂunomide, an SlPl agonist, NSAle, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine ts, antithrombotic agents, complement inhibitors, adrenergic agents, agents which ere with signalling by proinﬂammatory cytokines such as TNFOL or lL-l (e.g., NIK, IKK, p38 or MAP kinase inhibitors), lL-lB converting enzyme tors, TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, alazine, oprine, 6-mercaptopurines, angiotensin converting enzyme tors, soluble cytokine receptors and denvatives thereof (e. g. soluble p55 or p75 TNF receptors, sIL-lRI, I, s1L-6R) and antiinﬂammatory cytokines (e.g. 1L-4, lL-lO, lL-l3 and TGFB).

A compound of formula (I) may also be co-administered with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, oc-immunokine NNSO3, AER-215062, AnergiX.MS, ine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THCCBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap l258 (RDP-l258), sTNF-Rl, talampanel, teriﬂunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for example, TR-l403 5, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma antagonists and 1L-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a compound of a (I) may be co-administered include the following: ibuprofen, enac, misoprostol, naproxen, cam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, and anti-TNF antibodies, D2E7 (HUMIRA®), CA2 (inﬂiximab), CDP 57l, g ucts, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (LENERCEPT®).

Non-limiting examples of therapeutic agents for asthma with which a compound of fonnula (I) may be inistered include the following: rol, salmeterol/ﬂuticasone, montelukast , ﬂuticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate, tnamcinolone acetonide, beclomethasone ionate, opium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zaf1rlukast, formoterol te, inﬂuenza Virus vaccine, amoxicillin rate, ﬂunisolide, allergy injection, cromolyn , fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, inhaler assist device, nesin, dexamethasone sodium phosphate, moxiﬂoxacin HCl, doxycycline hyclate, guaifenesin/d-methorphan, p-ephedrine/cod/chlorphenir, gatiﬂoxacin, cetirizine hydrochloride, sone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine, zil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, L-l3 antibody, and metaproterenol sulfate.

Non-limiting examples of therapeutic agents for COPD with which a compound of formula (I) may be co-administered include the following: albuterol e/ipratropium, ipratropium bromide, salmeterol/ﬂuticasone, albuterol, salmeterol xinafoate, ﬂuticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, ukast , budesonide, formoterol fumarate, triamcinolone ide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, ﬂunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zaf1rlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, drine/cod/chlorphenir, erol acetate, p- ephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-fonnoterol, TgAAT, cilomilast and roﬂumilast.

Non-limiting examples of therapeutic agents for psoriasis with which a compound of formula (I) may be co-administered include the ing: calcipotriene, clobetasol propionate, inolone acetonide, halobetasol propionate, tazarotene, methotrexate, ﬂuocinonide, betamethasone diprop augmented, ﬂuocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, ine/ﬂuocinolone, hydrocortisone valerate, ﬂurandrenolide, urea, betamethasone, clobetasol propionate/emoll, ﬂuticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diﬂorasone diacetate, 3O etanercept folate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, metasone, am, ent, ﬂuocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis with which a compound of formula (I) may be co-administered include the following: methotrexate, etanercept, rofecoxib, xib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium, iazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), and umab.

Examples of therapeutic agents for SLE (Lupus) with which a compound of formula (I) may be co-administered include the following: NSAIDS, for e, diclofenac, en, ibuprofen, piroxicam, indomethacin, COX2 inhibitors, for example, xib, rofecoxib, valdecoxib, anti-malarials, for example, hydroxychloroquine, steroids, for example, prednisone, prednisolone, budenoside, thasone, cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate, inhibitors of PDE4 or purine synthesis inhibitor, for e Cellcept®. A compound of formula (I) may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, zine, ® and agents which ere with sis, tion or action of proinﬂammatory cytokines such as IL-1, for example, caspase inhibitors like lL-l B converting enzyme inhibitors and IL- lra. A compound of formula (I) may also be used with T cell signaling inhibitors, for example, tyrosine kinase tors, or molecules that target T cell tion les, for example, CTLAIgG or anti-B7 family antibodies, D-l family antibodies. A compound of formula (I) can be combined with lL-ll or anti-cytokine dies, for example, fonotolizumab (anti-lFNg antibody), or anti-receptor receptor antibodies, for example, anti-lL-6 receptor antibody and antibodies to B-cell surface molecules. A compound of formula (I) may also be used with LJP 394 (abetimus), agents that deplete or 3O vate B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 (adalimumab), CA2 (inﬂiximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (etanercept) and p55TNFRIgG (LENERCEPTTM).

The compounds of the invention can also be co-administered with a therapeutically effective amount of at least one additional therapeutic agents used in the tion or ent of AIDS, where examples of the agents include, HIV reverse transcriptase inhibitors, HIV protease inhibitors, immunomodulators, and other retroviral drugs. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir, adefovir, didanosine, dipivoxil delavirdine, efavirenz, lamivudine, nevirapine, stavudine zalcitabine, and dine. Examples of protease inhibitors include, but are not limited to, amprenavir, indinavir, lopinavir, nelf1navir, ritonavir, and saquinavir.

The following Examples may be used for illustrative purposes and should not be deemed to narrow the scope of the invention. f. Examples All reagents were of commercial grade and were used as received without further purification, unless ise stated. Commercially ble anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Chemical shifts (6) for 1H NMR spectra were ed in parts per million (ppm) relative to tetramethylsilane (8 0.00) or the appropriate residual solvent peak, i.e. CHC13 (8 7.27), as internal nce. Multiplicities were given as singlet (s), doublet (d), t (t), quartet (q), plet (quin), let (m) and broad (br).

Example 1 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)py1idin-3 -yl]-N-ethylmethyloxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide Method A for the preparation of ethyl 4-bromomethyloxo-l-tosyl-6,7-dihydro-1H- pyrrolo| 2, 3 -c |pyridinecarboxylate: Example la (E)—2-(5-bromomethoxynitropyridinyl)-N,N-dimethylethenamine 5-Bromomethoxymethylnitropyridine (15.0 g, 60.7 mmol) was dissolved in ylfonnamide (300 mL), and lithium methanolate (6.07 mL, 6.07 mmol, l M) was added. The reaction mixture was heated at 100 0C. To this mixture was added 1, l- oxy-N,N—dimethylmethanamine (64.5 mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95 0C for 16 hours. The reaction mixture was cooled to ambient temperature and water was added carefully (300 mL, exothermic). The resulting precipitate was collected by vacuum filtration, washed with water, and dried to e the title compound (13.9 g, 45.9 mmol, 76 % yield).

Example 1b 4-bromomethoxy-1H—pyrrolo[2,3-c]pyridine Example 1a (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added to Ra-Ni 2800 (pre-washed with ethanol) water slurry (6.9 g, 118 mmol) in a stainless steel pressure bottle and stirred for 30 minutes at 30 psi of H2 and ambient temperature. The reaction mixture was ﬁltered, and concentrated. The residue was triturated with dichloromethane, and the solid ﬁltered to provide the title compound (5.82 g). The mother liquor was concentrated and the residue triturated again with romethane and ﬁltered to provide an additional 1.63 g ofthe title compound. Total yield = 7.45 g, 72 % yield.

Example 1c 4-bromomethoxytosyl-1H—pyrrolo[2,3-c]pyridine A solution of Example 1b (7.42 g, 32.7 mmol) in dimethylformamide (235 mL) was stirred at ambient temperature. To this solution was added sodium hydride (1.18 g, 1.96 g of 60 % dispersion in oil, 49.0 mmol), and the reaction mixture was stirred for 10 minutes. P- toluenesulfonyl de (9.35 g, 49.0 mmol) was then added n-wise, and the mixture was stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was quenched with water. The resulting beige solid was collected by vacuum ﬁltration on a Buchner funnel, and washed with water. The solid was collected and dried in a vacuum oven at 50 0C to provide 12.4 g (100 %) ofthe title nd.

Example 1d ethyl 4-bromomethoxytosyl- 1H-pyrrolo[2,3 -c]pyridinecarboxylate To a solution of Example 1c (12 g, 31.5 mmol) in tetrahydrofuran (150 mL) was added lithium diisopropylamide (24.3 mL, 47.2 mmol) drop wise at -70 oC. The mixture was d at -70 0C to - 50 0C for 45 s, followed by drop wise addition of ethyl carbonochloridate (5.12 g, 47.2 mmol). After 1.5 hours, the on mixture was quenched with saturated aqueous um chloride solution, the organic layer was separated, and the aqueous phase was extracted with ethyl acetate (3 x 300 mL). The combined organic layers was dried over anhydrous sodium e, d, and concentrated under reduced pressure.

The crude product was triturated with dichloromethane and methanol (1:10) to provide the title compound (13 g, 91% yield).

Example 1e ethyl 4-bromooxotosyl-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxylate To a mixture of Example 1d (29 g, 64.0 mmol) and sodium iodide (14.38 g, 96 mmol) in acetonitrile (400 mL), chlorotrimethylsilane (10.43 g, 96 mmol) was added se at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 hour.

Water (0.576 g, 32.0 mmol) was added dropwise to the reaction mixture and the mixture was stirred at 65 0C for 3 hours. The reaction mixture was cooled to ambient temperature and d. The precipitate was dissolved in dichloromethane, ﬁltered, and trated to provide a solid which was triturated with petroleum ether and dichloromethane to provide the title compound (32 g, 97 %).

Example 1f ethyl 4-bromomethyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3 -c]pyridinecarboxylate To a solution of Example 1e (18.72 g, 42.6 mmol) in anhydrous dimethylformamide (200 mL) was added cesium carbonate (16.66 g, 51.1 mmol), followed by the dropwise addition of iodomethane (3.20 mL, 51.1 mmol). The reaction mixture was stirred for 72 hours at ambient temperature. Water was added to the reaction e (500 mL) and the itate was ﬁltered off, washed with water, and dried overnight in a vacuum oven at 55 0C to provide 17.9 g (93%) of the title compound.

Method B for the preparation of ethyl 4-bromomethyloxotosyl-6,7-dihydro-1H— p_yrrolo| 2, 3 -c |pyridinecarboxylate: Example 1f-i N—(2,2-dimethoxyethyl)-N-methyl-1H-pyrrolecarboxamide A solution of 1H—pyrrolecarboxylic acid (50.0 g, 450 mmol) in 500 mL of tetrahydrofuran was cooled to -5 to -8 OC, followed by the on of 2,2-dimethoxy-N— methylethanamine (64.4 g, 540 mmol) and diisopropylethylamine (171 mL, 128 mmol). The reaction mixture was stirred at this temperature, while propylphosphonic anhydride (315 g, 495 mmol) was added dropwise over 20 minutes. After the addition, the reaction mixture was warmed to 23 0C over 15 minutes. The reaction mixture was stirred for 1 hour at t temperature, and then heated to 40 0C. After 18 hours at 40 0C, the reaction mixture was cooled in an ice bath and diluted with 1000 mL of water and 500 mL of ethyl e.

The organic layer was separated. The aqueous layer was back extracted three times with 250 mL of ethyl acetate. The combined ethyl acetate layers were washed with 250 mL of water and 250 mL of brine. The resulting organic layer was reduced under house high vacuum with a jacket ature of 30-40 0C. After the volume was reduced by 50% to 850 mL, an additional 850 mL of heptane was added and the distillation continued under house high vacuum with a jacket ature of 30-40 0C. Heptane (550 mL) was distilled off and the reaction mixture was cooled to 15 oC. The product began to precipitate and then 500 mL of heptane was added to generate a slurry, which was heated to 30-40 0C to remove all the solids that adhered to the vessel wall. The slurry was cooled to 25 0C. An additional 500 mL of heptane was added to thin out the slurry. The slurry was cooled in an ice bath and ﬁltered at 0 0C. The solid was y washed with heptane, and then dried in the vacuum oven at 40 0C ght to give the title compound (63.6 g, 70.1% yield) as a ﬂuffy, white solid.

Example 1f-ii 6-methyl-1H—pyrrolo[2,3-c]pyridin-7(6H)—one id="p-265" id="p-265" id="p-265" id="p-265" id="p-265" id="p-265" id="p-265" id="p-265" id="p-265" id="p-265" id="p-265" id="p-265" id="p-265"

[00265] To Example 1f-i (50 g, 236 mmol) in 500 mL of tetrahydrofuran, was added p- toluenesulfonic acid drate (8.96 g, 47.1 mmol) and the reaction mixture was stirred at 60 0C for 5 hours. After this time, the reaction mixture was stirred for 12 hours, and allowed to cool to 23 0C. During this time, the product began to itate from the reaction mixture.

A solution of sodium bicarbonate (0.2 N, 500 mL) was added, and the reaction mixture was ted with 250 mL of ethyl acetate. The organic layer was separated, and the aqueous layer was back-extracted three times with 188 mL of ethyl acetate. The combined c layers were washed with brine (188 mL). The resulting organic layer was dried with anhydrous magnesium sulfate, ﬁltered through a 0.45 micron ﬁlter, and the organic layer was reduced to 850 mL under vacuum with a jacket temperature of 40 0C. After this time, 500 mL of heptane was added slowly over 10 minutes at 25 0C. A slurry formed, which was cooled to 10 0C and stirred at this temperature for 14 hours. The resulting solid was ﬁltered, washed with heptane, and dried in the vacuum oven at 50 0C to yield the title compound (27.9 g, 80% yield) as a tan solid.

Example 1f-iii 6-methyltosyl-1H—pyrrolo[2,3-c]pyridin-7(6H)-one A ed 3000 mL round bottom ﬂask was ﬂushed with nitrogen and charged with Example 1f-ii (121 g, 817 mmol). Tetrahydrofuran (1200 mL) was added and the reaction mixture was cooled to -8 0C. A tetrahydrofuran on of lithium bis(trimethylsilyl)amide (1M, 1022 mL, 1022 mmol) was added to the resulting suspension at a rate that maintained an internal reaction temperature below 10 oC. The solution was cooled to -8 oC and stirred for 1 hour. After this time, p-toluenesulfonyl chloride (238 g, 1225 mmol) was added in several portions. Once the internal ature of the reaction mixture was stabilized, the contents of the ﬂask were allowed to warm to 20 0C, at which point the product began to precipitate. The reaction e was stirred for 2 hours, and held for an additional 14 hour. After this time, heptane (600 mL) was added and the reaction mixture was distilled to a total volume of approximately 1200 mL. The solution was cooled to 0 oC, and the precipitated solid was ﬁltered in a 2L ﬁlter funnel with a medium-pore frit. The ted solid was then slurried in 1200 mL of water and re-ﬁltered. Additional slurry was generated using the solid and 1200 mL of methanol. After stirring the slurry for 15 minutes the solid was ﬁltered and dried at 0C to give the title compound (215 g, 86% yield) as an off-white solid.

Example lf-iv ethyl 6-methyloxo- l -tosyl-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxylate ] To a 500 mL three-neck round bottom ﬂask was added Example lf-iii (10.0 g, 33.1 mmol). The ﬂask was ﬁt with a thermocouple and purged with nitrogen. After 30 minutes the ﬂask was sealed with septa, and a nitrogen inlet. The solid was then suspended in 70 mL of tetrahydrofuran. The off-white sion was stirred and cooled to -15 0C. After holding at this temperature for 2 minutes, n-butyllithium in hexanes (2.5 M, 13.0 ml, 32.5 mmol) was added at a rate to in the temperature at +/- 5 0C, which gave a light brown suspension.

After on, the on mixture was stirred for 5 minutes, and then cooled to -55 0C.

After holding at this temperature for 1 minute, ethyl carbonochloridate (4.6 ml, 50.7 mmol) was added at a rate to maintain the ature +/- 10 0C. After complete addition, the reaction mixture was stirred for 5 minutes and then the cold bath was removed. The reaction mixture was stirred for an additional 180 minutes or until the reaction mixture warmed to 0C. After this time, the reaction mixture was quenched with 50 mL of water and added to a separatory funnel with about 100 mL of additional water. Ethyl acetate was then added (200 mL) and the layers were separated. The aqueous layer was then extracted 2 X 100 mL with ethyl acetate. After removal of the ethyl acetate, the crude dark brown solid was slurried in 100 mL of acetonitrile, which produced a tan precipitate. The solid was collected, washed with 20 mL of acetonitrile, and dried. The acetonitrile ﬁltrate was distilled until precipitation began once again. The tan solid was collected by ﬁltration, washed with acetonitrile (1 x 20 mL), and dried. The ted solids were combined to give the title compound (6.94 g, 57% yield) as a tan solid.

Example 1f ethyl omethyloxo- l -tosyl-6,7-dihydro-1H-pyrrolo[2,3 -c]pyridinecarboxylate A 250 mL round-bottom ﬂask was charged with a stir bar and Example lf-iv (3.00 g, 8.02 mmol). To the ﬂask was added 100 mL of tetrahydrofuran, and the reaction mixture was stirred until complete dissolution (about 1 minute). To the stirring reaction mixture was added p-tolunesulfonic acid e (0.763 g, 4.01 mmol), followed by N—bromosuccinimide (1.455 g, 8.17 mmol). The reaction mixture was d at 23 0C for 12.5 hours. After this time, the tetrahydrofuran was removed on a rotary evaporator, leaving a yellow residue. The residue was suspended in 200 proof ethanol (75 mL), and stirred as a slurry for 80 minutes.

The slurry was ﬁltered and washed with ethanol (200 proof, 1 X 50 mL), to provide the title compound (3.06 g, 84% yield) as an off-white solid.

Example 1 g 4-bromo-N-ethylmethyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]py1idinecarboxamide ] To a solution of e 1f (10 g, 22.06 mmol) and 2 M ethanamine in tetrahydrofuran (90 mL, 180 mmol) at 20 0C was added 8 % wt% magnesium methanolate (88 mL, 66.7 mmol) in methanol. The reaction mixture was heated at 55 0C for 15 hours with the system sealed. Then the mixture was cooled to ambient temperature and diluted with 0.5 N HCl (800 mL), stirred for 5 minutes, and ﬁltered. The solid was washed with ice water and dried to provide 6.8 g (98 %) of the title compound.

Example 1h N-ethylmethyloxo(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide A 1 L three-necked round bottom ﬂask was d with dried potassium acetate (17.18 g, 175 mmol), Example 1g (17.4 g, 58.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (29.6 g, 117 mmol), (2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.837 g, 2.335 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.113 g, 2.335 mmol), and placed under en. Degassed anhydrous 2-methyl tetrahydrofuran (500 mL) was added and the e was heated at 75 oC overnight. The mixture was cooled to ambient temperature, diluted with water and ethyl acetate and the ic mixture was stirred for about one hour with 1.2 g. (3.0 equiv. based on moles of palladium) of ammonium pyrrolidine dithiocarbamate. The mixture was ﬁltered through a plug of Diatomaceous earth with ethyl acetate and 10 % methanol/ethyl acetate washes. The ﬁltrate was diluted further with ethyl acetate and brine, the layers separated, and the organic layer washed with water and brine, dried with anhydrous sodium sulfate, d, and concentrated. The crude product was triturated with 300 mL of 20 % ethyl acetate/heptane. The dried solids provided 17.4g (86 %) of the title compound.

Example 1i -bromo(2,6-dimethylphenoxy)nicotinic acid A solution of 5-bromochloronicotinic acid (12 g, 50.8 mmol), 2,6-dimethylphenol (7.44 g, 60.9 mmol) and cesium carbonate (49.6 g, 152 mmol) in dimethyl sulfoxide (100 mL) was heated at 100 0C for 40 hours, cooled to ambient temperature, and poured into 500 mL of ice water. The pH was adjusted to a constant pH of 2 by careful addition of 12 M HCl. The aqueous mixture was extracted with ethyl acetate (3 X 200 mL). The combined organics were washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, treated with decolorizing charcoal, ﬁltered, and concentrated. The crude material was adsorbed on silica gel and chromatographed on a 330g silica dge, eluting with 10-70 % 3 :1 ethyl e/ethanol: es to provide 10.74 g (66 %) of the title compound.

Example 1j -bromo(2,6-dimethylphenoxy)-N-methoxy-N-methylnicotinamide A on of Example 1i (8.5 g, 26.4 mmol), N1-((ethylimino)methylene)-N3,N3 - dimethylpropane-1,3-diamine hydrochloride (6.05 g, 31.6 mmol), 1H—benzo[d][1,2,3]triazol- 1-ol hydrate (5.12 g, 33.4 mmol), N,O-dimethylhydroxylamine hydrochloride (5.21 g, 53.4 mmol) and 4-methylmorpholine (10 mL, 91 mmol) in dichloromethane (130 mL) was stirred at 25 0C for 3 hours. The mixture was washed into a separatory funnel with 50 mL of dichloromethane, extracted with water, washed with aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by chromatography (silica gel, 0-50 % ethyl acetate in heptane) to provide the title nd (8.56 g, 89 %).

Example 1k romo(2,6-dimethylphenoxy)pyridin-3 -yl)ethanone A solution of e 1j (1.51 g, 4.13 mmol) in tetrahydrofuran (30 mL) was treated with a solution of methylmagnesium de (3.0 M on in tetrahydrofuran, 1.8 mL, .40 mmol) and stirred at 25 0C for 90 minutes. The solution was poured into aqueous ammonium chloride and extracted into ethyl acetate (100 mL), dried over anhydrous sodium sulfate, ﬁltered, and trated. The residue was puriﬁed by chromatography (silica gel, 0-100 % ethyl acetate in heptane) to provide 0.875 g (66 %) of the title compound.

Example 11 2-(5-bromo(2,6-dimethylphenoxy)pyridin-3 -yl)propanol A solution of Example 1k (0.239 g, 0.746 mmol) in tetrahydrofuran (5 mL) was treated with a on of methylmagnesium chloride (3.0 M solution in tetrahydrofuran, 0.4 mL, 1.2 mmol) and stirred at 25 0C for 3.5 hours. The solution was poured into aqueous ammonium chloride and extracted into ethyl acetate (60 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by chromatography (silica gel, 0-100 % ethyl e in e) to provide 0.195 g (78 %) of the title compound.

Example 1m 4-(2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl)-N-ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 1h (222 mg, 0.643 mmol), Example 11 (195 mg, 0.580 mmol), potassium phosphate (363 mg, 1.710 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.7 mg, 0.018 mmol) and 1,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamantane (18.3 mg, 0.063 mmol) were ed and sparged with nitrogen for 15 minutes, ed by addition of a degassed mixture of ydrofuran (4.80 mL)/ water (1.20 mL). The mixture was heated at 60 0C for 3 hours. The mixture was diluted with 20 mL of ethyl acetate, washed with saturated aqueous sodium chloride, dried with anhydrous sodium e, ﬁltered and evaporated. The residues were puriﬁed by reverse phase HPLC (C18, CH3CN/water (0.1 % triﬂuoroacetic acid), 0-100 % gradient) to e the title compound as a triﬂuoroacetic acid salt. 1H NMR (400 MHz, DMSO-dg) 5 12.31 (bs, 1H), 8.35 (t, J = 5.3 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.45 (s, 1H), 7.06 (m, 1H), 7.01 (m, 1H), 6.88 (d, J = 2.1 Hz, 1H), 3.61 (s, 3H), 3.28 (m, 2H), 1.99 (s, 6H), 1.48 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H).

MS (ESI+) m/z 475.2 (M+H)+.

Example 2 4- [2-(2, 6-dimethylphenoxy)-5 -(3 -hydroxypentan-3 -yl)pyri din-3 -yl]-N-ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 2 was prepared according to the procedure used for the preparation of Example 7, substituting ethyl magnesium bromide for phenyl magnesium bromide. 1H NMR (400 MHz, DMSO-d6) 5 7.97 (d, J: 2.4 Hz, 1H), 7.83 (d, J: 2.4 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J: 1.9 Hz, 1H), 7.03 — 6.99 (m, 1H), 6.91 (s, 1H), 3.61 (s, 3H), 3.28 (t, J: 7.2 Hz, 2H), 1.96 (s, 6H), 1.76 (dh, J: 13.8, 7.1 Hz, 4H), 1.12 (t, J: 7.2 Hz, 3H), 0.71 (t, J = 7.3 Hz, 6H). MS (ESI+) m/z 503 (M+H)+. e 3 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N—ethylmethyloxo-6,7- dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 3a 3-bromo(2,6-dimethylphenoxy)benzoic acid A mixture of methyl 3-bromoﬂuorobenzoate (10.80 g, 46.3 mmol), 2,6- dimethylphenol (6.24 g, 51.1 mmol) and cesium carbonate (16.6 g, 50.9 mmol) in dimethyl sulfoxide (95 mL) was heated at 190 0C for 20 hours. The mixture was allowed to cool, then poured into 400 mL of brine, acidiﬁed with HCl and ted with 500 mL of ethyl acetate.

The organic extracts were washed with brine and dried over ous magnesium sulfate.

After ﬁltration the crude material was adsorbed on silica gel and chromatographed on a 220 g silica cartridge eluting with 10-70 % 3:1 ethyl acetate/ethanolzheptanes to provide 13.54g (91 %) of the title nd.

Example 3b 3-bromo(2,6-dimethylphenoxy)-N-methoxy-N—methylbenzamide Example 3b was prepared according to the procedure used for the preparation of Example 1j, substituting Example 3a for Example 1i.

Example 3c 1-(3 -bromo(2,6-dimethylphenoxy)phenyl)ethanone Method A To a mixture of Example 3b (1.19 g, 3.27 mmol) in tetrahydrofuran (24 mL) was added by syringe methylmagnesium chloride (3.0 M solution in ydrofuran, 1.4 mL, 4.20 mmol) and the mixture was d at ambient temperature. After 90 minutes, the solution was poured into saturated aqueous ammonium de and extracted into ethyl acetate (100 mL). The organics were dried over anhydrous sodium sulfate, ﬁltered, and concentrated under d pressure. The residue was purified by ﬂash chromatography (silica gel, 0- 100% ethyl acetate/heptane) to provide the title compound (0.631 g, 61% .

Method B: id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280" id="p-280"

[00280] A mixture of potassium carbonate (4.78 g, 34.6 mmol) 2,6-dimethylphenol (2.96 g, 24.19 mmol) 1-(3-bromoﬂuorophenyl)ethanone (5 g, 23.04 mmol) in dimethylacetamide (50 mL) was stirred at 80 0C for 1.5 hours. After cooling to ambient temperature, water (40 mL) was added. The e was extracted with ethyl acetate, and the combined organic phase was washed with water, brine, and concentrated to provide the title compound (7.1 g, 22.24 mmol, 97 % yield).

Example 3d 2-(3 -bromo(2,6-dimethylphenoxy)phenyl)propanol Method A: To a solution of Example 3c (0.365 g, 1.144 mmol) in tetrahydrofuran (10.00 mL) was added by syringe methylmagnesium chloride (3.0 M solution in tetrahydrofuran, 1 mL, 3.00 mmol), and the mixture was stirred at ambient temperature. After 3.5 hours, the solution was partitioned between saturated aqueous ammonium chloride (50 mL) and ethyl e (75 mL). The organics were dried over anhydrous sodium sulfate, ﬁltered, and concentrated under reduced pressure. The residue was puriﬁed by ﬂash chromatography (silica gel, 0- 100% ethyl acetate/heptane) to provide the title compound (0.247g, 64% yield).

Method B: To a solution of 2,6-dimethylphenol (11.53 g, 94 mmol) and methyl 3-bromo ﬁuorobenzoate (20 g, 86 mmol) in yl sulfoxide (80 mL) was added cesium carbonate (41.9 g, 129 mmol). The mixture was stirred at 80 0C under nitrogen for 2 hours, cooled, diluted with 200 mL of water, and stirred for 10 minutes. The e was transferred to a separatory funnel and extracted 4 x 200 mL with methyl tert-butyl ether. The organic extracts were combined, dried over anhydrous sodium e, ﬁltered and concentrated. Puriﬁcation by chromatography (silica, 0-10 % ethyl acetate in es) provided methyl 3-bromo (2,6-dimethylphenoxy)benzoate as an oil that ﬁed upon ng (25.7 g, 82%). To a solution of this material (11.08 g, 33.1 mmol) in tetrahydrofuran (165 mL) under nitrogen at 23 0C was added magesium bromide (33.1 mL, 99 mmol, 3.0 M in diethyl ether) in a drop wise manner. The reaction was exothermic. The on mixture was stirred for 1 hour allowing the internal temperature to cool to about ambient temperature. The mixture was poured into cold 5 % aqueous ammonium chloride and partitioned with 400 mL diethyl ether.

The organic layer was washed with ted aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. Puriﬁcation by chromatography (silica, 0-25 % ethyl acetate in heptanes) afforded the title compound (9.0 g, 81%).

Example 3e 4-(2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl)-N-ethylmethyloxo-6,7- dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 3e was prepared according to the procedure used for the preparation of e 1m, substituting Example 3d for Example 11. 1H NMR (400 MHz, DMSO-dg) 5 12.21 (bds, 1H), 8.34 (t, J = 5.4 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.34 (s, 1H), 7.31 (dd, J = 8.6, 2.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.04 (m, 1H), 6.86 (d, J = 2.1 Hz, 1H), 6.28 (d, J = 8.6 Hz, 1H), 3.60 (s, 3H), 3.28 (m 2H), 2.02 (s, 6H), 1.44 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H).

MS (ESI+) m/z 474.2 (M+H)+.

Example 4 4- [2-(2, 6-dimethylphenoxy)-5 -(l -hydroxycyclopent-3 -enyl)pyridin-3 -yl ] -N-ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide Example 4a l-(5-bromo(2,6-dimethylphenoxy)pyridin-3 -yl)buten-l-one id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284" id="p-284"

[00284] Example 4a was prepared according to the procedure used for the preparation of Example 1k, substituting allylmagnesium chloride for methylmagnesium chloride.

Example 4b 4-(5-bromo(2,6-dimethylphenoxy)pyridinyl)hepta-l,6-dienol e 4b was prepared according to the procedure used for the preparation of Example 11, substituting Example 4a for Example 1k, and tuting allylmagnesium chloride for methylmagnesium chloride.

Example 4c l-(5-bromo(2,6-dimethylphenoxy)py1idinyl)cyclopentenol A ﬂask with stir bar was charged with (l,3-bis(2,4,6-trimethylphenyl) imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)- ruthenium (21.5 mg, 0.025 mmol), sealed with a septum and swept with en. A solution of Example 4b (176 mg, 0.453 mmol) in degassed 1,2-dichloroethane (4.5 mL) was added to the reaction vessel. The solution was d at t temperature for 3 hours, trated, and the residue was taken up in 4 mL dichloromethane, ﬁltered through a syringe ﬁlter, and chromatographed (silica gel, 0-100% ethyl acetate/heptanes) to provide 0.138g (85%) of the title compound.

Example 4d 4-(2-(2,6-dimethylphenoxy)-5 -(l xycyclopent-3 -enyl)pyridin-3 -yl)—N—ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287" id="p-287"

[00287] The triﬂuoroacetic acid salt of e 4d was ed according to the procedure used for the preparation of Example 1m, substituting Example 4c for Example 11. 1H NMR (400 MHz, DMSO-dg) 5 12.31 (d, J = 2.4 Hz, 1H), 8.34 (t, J = 5.3 Hz, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.46 (s, 1H), 7.06 (m, 2H), 7.00 (dd, J = 8.6, 6.0 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 5.75 (s, 1H), 3.61 (s, 3H), 3.27 (m, 2H), 2.86 — 2.61 (m, 4H), 1.99 (s, 3O 6H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 499.2 (M+H)+.

Example 5 4- [2-(2, 6-dimethylphenoxy)-5 -(l -hydroxycyclopent-3 -enyl)phenyl]-N—ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 5a l-(5-bromo(2,6-dimethylphenoxy)pyridin-3 -yl)buten-l-one ] Example 5a was prepared according to Method A of Example 3c, substituting agnesium chloride for methylmagnesium chloride. 4-(3 (2,6-dimethylphenoxy)phenyl)hepta-1,6-dienol ] Example 5b was prepared according to Method A of Example 3d, substituting Example 5a for Example 3c, and substituting allylmagnesium chloride for methylmagnesium chloride.

Example 5c l-(5-bromo(2,6-dimethylphenoxy)py1idinyl)cyclopentenol Example 5c was ed according to the procedure used for the preparation of Example 4c, substituting Example 5b for Example 4b.

Example 5d 4-(2-(2,6-dimethylphenoxy)-5 -(l -hydroxycyclopent-3 -enyl)phenyl)-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 5d was prepared according to the procedure used for the preparation of Example 1m, substituting Example 5c for Example 11. 1H NMR (400 MHz, DMSO-dg) 5 12.22 (bs, 1H), 8.34 (m, 1H), 7.48 (m, 1H), 7.35 (s, 1H), 7.28 (dd, J = 8.5, 2.3 Hz, 1H), 7.18 - 6.97 (m, 2H), 6.88 (m, 1H), 6.31 (d, J = 8.6 Hz, 1H), 5.73 (s, 2H), 3.60 (s, 3H), 3.26 (m, 2H), 2.75 (d, J = 16.2 Hz, 2H), 2.56 (d, J =16.2 Hz, 2H), 2.03 (s, 6H), 1.12 (td, J = 7.3, 1.9 Hz, 3H). MS (ESI+) m/z 498.1 (M+H)+.

Example 6 4-[2-(2,6-dimethylphenoxy)-5 -( l -hydroxycyclopentyl)pyridin-3 -yl]-N—ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292" id="p-292"

[00292] Example 4d (48 mg, 0.096 mmol) and tetrahydrofuran (10 mL) were added to 5 % Pd/C (wet JM#9) (9 mg, 0.038 mmol) in a 50 mL pressure bottle and shaken for 30 minutes at 30 psi of hydrogen, and at ambient temperature. The mixture was ﬁltered, and concentrated. The residues were d by reverse phase HPLC (C18, CH3CN/water (0.1 % triﬂuoroacetic acid), 0-100 % gradient) to provide the title compound as a triﬂuoroacetic acid 3O salt. 1H NMR (400 MHz, g) 6 12.31 (d, J = 2.4 Hz, 1H), 8.34 (t, J = 5.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.45 (s, 1H), 7.11 - 6.93 (m, 2H), 6.88 (d, J = 2.1 Hz, 1H), 3.61 (s, 3H), 3.27 (m,2H), 1.99 (s, 6H), 1.97 - 1.68 (m, 8H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 501.2 (M+H)+.

Example 7 4-[2-(2,6-dimethylphenoxy)(1-hydroxyphenylpropyl)pyridin-3 -yl]-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide A 4 mL vial was charged with Example 1j (75 mg, 0.20 mmol) in tetrahydrofuran (1 .5mL) and treated with phenyl magnesium bromide, 1.0 M solution in tetrahydrofuran (0.3 mL, 0.3 mmol) and the mixture stirred at t temperature for 3 hours. After 3 hours, aqueous ammonium de was added and the intermediate ketone was extracted with dichloromethane using a phase separator. The organic layer was trated. The resulting residue was ved in tetrahydrofuran (1.5 mL) and treated with ethyl magnesium bromide (3.0 M solution in tetrahydrofuran, 0.1 mL, 0.32 mmol) and allowed to stir at ambient temperature for 3 hours. After 3 hours, aqueous ammonium chloride was added to the reaction mixture and the intermediate tertiary alcohol was extracted with romethane using a phase separator. After tion and solvent l, the crude al was combined with Example 1h (9 mg, 0.027 mmol), potassium phosphate (20 mg, 0.027 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.75 mg, .82 umol) and 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphoadamantane (0.70 mg, 0.0025 mmol). The mixture was purged with nitrogen for 15 minutes and ved in a degassed mixture of 0.5 mL tetrahydrofuran and 0.1 mL of water. This mixture was heated at 60 0C for 3 hours, ﬁltered through diatom aceous earth, and concentrated under reduced pressure. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and puriﬁed by reverse phase HPLC HPLC on a Phenomenex Luna C8(2) 5 pm 100A AXIA column (30 mm X 150 mm) with a gradient of acetonitrile (A) and 0.1% roacetic acid in water (B), at a ﬂow rate of 50 mL/min (005 min 5 % A, 0.5-8.5 min linear gradient 5-100 % A, 8.7-10.7 min 100 % A, 10.7 -11.0 min linear gradient 100-5 % A) to provide the title compound as a triﬂuoroacetic acid salt (3.8 mg, 21% . 1H NMR (400 MHz, DMSO-d6) 5 8.06 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.50 — 7.43 (m, 2H), 7.39 (s, 1H), 7.31 (dd, J: 8.4, 7.1 Hz, 2H), 7.22 — 7.17 (m, 1H), 7.06 (s, 1H), 7.04 — 6.99 (m, 2H), 6.81 (s, 1H), 3.59 (s, 3H), 3.28 (t, J: 7.2 Hz, 2H), 2.28 (q, J = 7.3 Hz, 2H), 1.94 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 551 (M+H)+.

Example 8 4-[2-(2,6-dimethylphenoxy)(2-hydroxybutanyl)py1idin-3 -yl]-N-ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 8 was prepared according to the procedure used for the preparation of Example 7, substituting methyl magnesium bromide for phenyl magnesium bromide. 1H NMR (500 MHz, DMSO-d6) 5 8.05 (d, J: 2.4 Hz, 1H), 7.91 (s, 1H), 7.08 (d, J: 7.4 Hz, 2H), 7.03 (dd, J: 8.4, 6.3 Hz, 1H), 3.64 (s, 3H), 3.30 (q, J: 7.2 Hz, 2H), 2.00 (s, 6H), 1.75 (dt, J: 8.9, 6.7 Hz, 2H), 1.48 (s, 3H), 1.13 (d, J: 7.2 Hz, 3H), 0.76 (t, J: 7.3 Hz, 3H). MS (ESI+) m/z 489 (M+H)+.

Example 9 4- { 2-(2, 6-dimethylphenoxy)-5 -[1-(4-fluorophenyl)hydroxypropyl]pyridin-3 -yl } -N—ethyl- 6-methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 9 was prepared according to the procedure used for the preparation of Example 7, substituting 4-ﬂuorophenyl ium bromide for phenyl magnesium bromide. 1H NMR (400 MHz, DMSO-d6) 5 8.07 (d, J: 2.5 Hz, 1H), 7.85 (d, J: 2.4 Hz, 1H), 7.51 (dd, J: 8.9, 5.5 Hz, 2H), 7.41 (s, 1H), 7.13 (t, J: 8.9 Hz, 2H), 7.05 (s, 1H), 7.03 (s, 1H), 6.81 (s, 1H), 3.60 (s, 3H), 3.28 (q, J: 7.2 Hz, 2H), 2.28 (d, J: 7.4 Hz, 2H), 1.96 (s, 6H), 1.13 (t, J: 7.2 Hz, 3H), 0.78 (t, J: 7.1 Hz, 3H). MS (ESI+) m/z 569 (M+H)+.

Example 10 4-[2-(2,6-dimethylphenoxy)(3 -hydroxymethylhexanyl)py1idinyl]-N—ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of e 10 was ed according to the ure used for the preparation of Example 7, substituting 2-methylpropyl magnesium bromide for phenyl magnesium bromide. 1H NMR (400 MHz, DMSO-d6) 5 7.98 (d, J = 2.4 Hz, 1H), 7.84 (d, J: 2.4 Hz, 1H), 7.39 (s, 1H), 7.10 — 6.98 (m, 3H), 6.86 (s, 1H), 3.61 (s, 3H), 3.27 (q, J: 7.3 Hz, 2H), 1.96 (s, 6H), 1.75 (ddd, J: 25.4, 14.0, 6.6 Hz, 3H), 1.68 — 1.50 (m, 2H), 1.12 (t, J: 7.2 Hz, 3H), 0.85 (d, J: 6.5 Hz, 3H), 0.68 (t, J: 7.3 Hz, 3H), 0.62 (d, J: 6.5 Hz, 3H). MS (ESI+) m/z 531 (M+H)+.

Example 11 4-[5 -( 1 -cyclopentylhydroxypropyl)(2,6-dimethylphenoxy)py1idin-3 -yl]-N—ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 11 was prepared ing to the ure used for the preparation of Example 7, substituting cyclopentyl magnesium bromide for phenyl magnesium bromide. 1H NMR (400 MHz, DMSO-d6) 5 8.00 (d, J: 2.3 Hz, 1H), 7.86 (d, J: 2.4 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J: 7.2 Hz, 2H), 7.04 — 6.97 (m, 1H), 6.88 (s, 1H), 3.62 (s, 3H), 3.28 (q, J: 7.2 Hz, 2H), 2.40 — 2.27 (m, 1H), 1.97 (s, 6H), 1.80 (dd, J: 11.5, 7.1 Hz, 1H), 1.65 (m, 1H), 1.47 (d, J: 33.2 Hz, 3H), 1.27 — 1.20 (m, 1H), 1.13 (t, J: 7.2 Hz, 3H), 0.66 (t, J: 7.3 Hz, 3H). MS (ESI+) m/z 543 (M+H)+.

Example 12 4-[5 -( 1 -cyclopropylhydroxypropyl)(2, 6-dimethylphenoxy)pyridin-3 -yl]-N—ethyl methyloxo-6,7-dihydro- lH—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 12 was prepared ing to the procedure used for the preparation of Example 7, substituting cyclopropyl magnesium bromide for phenyl magnesium e. 1H NMR (400 MHz, DMSO-d6) 5 8.07 (d, J: 2.4 Hz, 1H), 7.91 (d, J: 2.4 Hz, 1H), 7.43 (s, 1H), 7.11 — 6.98 (m, 3H), 6.90 (s, 1H), 3.61 (s, 3H), 3.27 (q, J: 7.2 Hz, 2H), 1.97 (s, 6H), 1.83 (dh, J: 21.1, 7.3 Hz,2H), 1.33 — 1.25 (m, 1H), 1.12 (t, J: 7.2 Hz, 3H), 0.76 (q, J: 7.4, 6.9 Hz, 3H), 0.43 (ddt, J: 43.3, 9.1, 4.9 Hz, 2H), 0.31 — 0.21 (m, 2H). MS (ESI+) m/z 515 .

Example 13 4- [2-(2, 6-dimethylphenoxy)-5 -(3 -hydroxymethylhexan-3 -yl)py1idin-3 -yl]-N—ethyl methyloxo-6,7-dihydro- lH—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 13 was prepared according to the procedure used for the preparation of Example 7, substituting 2-butyl magnesium bromide for phenyl magnesium bromide. 1H NMR (400 MHz, DMSO-d6) 8 7.96 (d, J: 2.3 Hz, 1H), 7.85 — 7.81 (m, 1H), 7.42 (d, J: 1.9 Hz, 1H), 7.07 (d, J: 7.1 Hz, 2H), 7.04 — 6.98 (m, 1H), 6.88 (d, J: 1.4 Hz, 1H), 3.62 (s, 3H), 3.28 (q, J: 7.2 Hz, 2H), 1.97 (s, 6H), 1.88 — 1.74 (m, 1H), 1.65 (d, J: 8.2 Hz, 1H), 1.35 (s, 1H), 1.13 (t, J: 7.2 Hz, 3H), 0.90 — 0.82 (m, 3H), 0.79 (t, J: 7.1 Hz, 2H), 0.68 (dd, J: 14.7, 7.4 Hz, 3H). MS (ESI+) m/z 531 .

Example 14 4- [2-(2, 6-dimethylphenoxy)-5 -(3 -hydroxyphenylpentan-3 -yl)pyridin-3 -yl]-N—ethyl methyloxo-6,7-dihydro- lH—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 14 was prepared according to the procedure used for the ation of Example 7, substituting ylethyl magnesium bromide for phenyl magnesium e. 1H NMR (400 MHz, DMSO-d6) 5 8.06 (s, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 7.26 — 7.18 (m, 2H), 7.15 — 7.10 (m, 3H), 7.07 (d, J: 1.8 Hz, 2H), 7.03 — 6.98 (m, 1H), 6.89 (s, 1H), 3.63 (s, 3H), 3.28 (q, J: 7.3 Hz, 2H), 2.65 (dq, J: 12.4, 7.6, 6.5 Hz, 1H), 2.36 — 2.25 (m, 1H), 2.11 — 2.02 (m, 1H), 1.97 (s, 6H), 1.81 (dt, J: 13.6, 6.8 Hz, 2H), 1.11 (t, J: 7.2 Hz, 3H), 0.73 (t, J: 7.3 Hz, 3H). MS (ESI+) m/z 579 (M+H)+.

Example 15 4- { 2-(2,6-dimethylphenoxy)[1-(4-ﬂuorophenyl)hydroxybutanyl]pyridin-3 -yl } -N— ethylmethyloxo-6,7-dihydro- lH—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 15 was prepared according to the procedure used for the preparation of Example 7, substituting 4-ﬂuorobenzyl magnesium bromide for phenyl magnesium bromide. 1H NMR (400 MHz, DMSO-d6) 5 7.80 (d, J: 2.4 Hz, 1H), 7.67 (d, J: 2.4 Hz, 1H), 7.24 (s, 1H), 7.09 — 6.93 (m, 7H), 6.81 (s, 1H), 3.60 (s, 3H), 3.29 (t, J: 7.2 Hz, 2H), 2.99 (q, J: 13.5 Hz, 2H), 1.94 (s, 7H), 1.78 (dt, J: 14.2, 7.2 Hz, 1H), 1.12 (t, J = 7.2 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 514 (M+H)+. Ms (ESI+) 583m/z (M+H)+.

Example 16 4- [2-(2, 6-dimethylphenoxy)-5 -(1 -hydroxy- l -phenylethyl)py1idin-3 -yl]-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 16 was prepared according to the procedure used for the preparation of e 7, substituting methyl magnesium bromide for ethyl magnesium bromide. 1H NMR (500 MHz, DMSO-d6) 5 8.08 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.50 (d, J: 7.5 Hz, 2H), 7.43 (s, 1H), 7.34 (t, J: 7.6 Hz, 2H), 7.22 (t, J: 7.3 Hz, 1H), 7.07 (d, J: 7.3 Hz, 2H), 7.02 (dd, J: 8.5, 6.1 Hz, 1H), 6.86 (s, 1H), 3.62 (s, 3H), 3.30 (q, J: 7.3 Hz, 2H), 2.04 (s, 1H), 1.98 (s, 5H), 1.91 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 536.9 .

Example 17 4- { -dimethylphenoxy)-5 -[ l -(4-ﬂuorophenyl)- l -hydroxyethyl]pyridin-3 -yl } -N-ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 17 was prepared according to the procedure 2O used for the ation of Example 7, substituting 4-ﬂuorophenyl magnesium bromide for phenyl ium bromide, and tuting methyl magnesium bromide for ethyl magnesium bromide. 1H NMR (500 MHz, DMSO-d6) 5 8.07 (d, J: 2.5 Hz, 1H), 7.87 (d, J: 2.4 Hz, 1H), 7.55 — 7.50 (m, 2H), 7.44 (s, 1H), 7.14 (t, J: 8.9 Hz, 2H), 7.07 (d, J: 6.7 Hz, 2H), 7.02 (dd, J: 8.5, 6.1 Hz, 1H), 6.85 (s, 1H), 3.62 (s, 3H), 3.30 (q, J: 7.3 Hz, 2H), 2.04 (s, 1H), 1.98 (s, 5H), 1.90 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 555.7 (M+H)+.

Example 18 4-[2-(2,6-dimethylphenoxy)(2-hydroxymethylpentanyl)py1idinyl]-N—ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 18 was prepared according to the procedure 3O used for the preparation of Example 7, substituting 2-methyll-propyl ium bromide for phenyl magnesium bromide, and substituting methyl magnesium bromide for ethyl magnesium bromide. 1H NMR (500 MHz, DMSO-d6) 5 8.07 (d, J: 2.4 Hz, 1H), 7.92 (d, J: 2.5 Hz, 1H), 7.44 (s, 1H), 7.08 (d, J: 7.4 Hz, 2H), 7.04 — 7.00 (m, 1H), 6.91 (s, 1H), 3.64 (s, 3H), 3.30 (q, J: 7.2 Hz, 2H), 1.99 (s, 6H), 1.71 — 1.57 (m, 3H), 1.50 (s, 3H), 1.14 (t, J: 7.2 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.70 (d, J = 6.6 Hz, 3H). MS (ESI+) m/z 517 (M+H)+.

Example 19 4-[2-(2,6-dimethylphenoxy)(2-hydroxy-3 -methylbutanyl)py1idinyl]-N-ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 19 was prepared according to the procedure used for the preparation of Example 7, substituting isopropyl magnesium bromide for phenyl magnesium bromide, and substituting methyl magnesium bromide for ethyl magnesium bromide. 1H NMR (500 MHz, DMSO-d6) 5 8.07 (d, J = 2.5 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.55 — 7.50 (m, 2H), 5 7.09 (d, J: 7.4 Hz, 2H), 7.04 — 6.99 (m, 1H), 3.64 (s, 3H), ), 6.9 (s, 1H) 3.30 (q, J: 7.2 Hz, 2H), 1.99 (s, 6H), 1.91 (hept, J: 6.8 Hz, 1H), 1.47 (s, 3H), 1.18 — 1.09 (m, 3H), 0.84 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H). MS (ESI+) m/z 503 (M+H)+.

Example 20 4-[2-(2,6-dimethylphenoxy)(2-hydroxy-3 -methylpentanyl)py1idinyl]-N—ethyl oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 20 was prepared according to the procedure used for the preparation of Example 7, substituting 2-butyl magnesium bromide for phenyl magnesium bromide, and substituting methyl ium bromide for ethyl magnesium bromide. 1H NMR (500 MHz, 6) 5 8.02 (s, 1H), 7.89 (s, 1H), 7.45 (s, 1H), 7.08 (d, 2O 2H), 7.04 — 7.00 (m, 1H), 6.9 (s, 1H), 3.64 (s, 3H), 3.29 (t, J: 7.3 Hz, 2H), 1.99 (s, 6H), 1.59 — 1.53 (m, 1H), 1.47 (d, J: 11.7 Hz, 3H), 1.14 (d, J: 7.2 Hz, 2H), 0.83 — 0.75 (m, 5H). MS (ESI+) m/z 517 (M+H)+.

Example 21 2,6-dimethylphenoxy)(2-hydroxyphenylbutanyl)py1idinyl]-N-ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 21 was prepared according to the procedure used for the preparation of Example 7, tuting 2-phenylethyl magnesium bromide for phenyl magnesium e, and substituting methyl magnesium bromide for ethyl ium bromide. 1H NMR (500 MHz, DMSO-d6) 5 8.13 (d, J: 2.4 Hz, 1H), 7.96 (d, J: 3O 2.4 Hz, 1H), 7.44 (s, 1H), 7.26 — 7.21 (m, 2H), 7.17 — 7.12 (m, 3H), 7.08 (d, J: 7.9 Hz, 2H), 7.03 (dd, J = 8.4, 6.3 Hz, 1H), 6.94 (s, 1H), 3.64 (s, 3H), 3.29 (q, J = 7.3 Hz, 2H), 2.65 (ddd, J: 13.6, 11.0, 6.0 Hz, 1H), 2.41 (ddd, J: 13.4, 11.0, 5.6 Hz, 1H), 2.07 — 2.03 (m, 1H), 2.00 (s, 6H), 1.56 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 565 (M+H)+.

Example 22 4- { 2-(2,6-dimethylphenoxy)[1-(4-ﬂuorophenyl)hydroxypropanyl]pyridin-3 -yl } -N— ethylmethyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The roacetic acid salt of Example 22 was prepared according to the procedure used for the preparation of Example 7, substituting 4-ﬂuorobenzyl magnesium bromide for phenyl magnesium bromide, and substituting methyl magnesium bromide for ethyl magnesium bromide. 1H NMR (500 MHz, DMSO-d6) 8 7.88 (s, 1H), 7.77 (d, J: 2.4 Hz, 1H), 7.31 (s, 1H), 7.08 (d, J: 7.4 Hz, 2H), 7.04 — 6.96 (m, 5H), 6.88 (s, 1H), 3.63 (s, 3H), 3.30 (q, J: 7.3 Hz, 2H), 3.03 — 2.93 (m, 2H), 1.98 (s, 6H), 1.53 (s, 3H), 1.15 (t, J: 7.2 Hz, 3H). MS (ESI+) m/z 568.9 .

Example 23 4- { 5 -[cyclopropyl(4-ﬂuorophenyl)hydroxymethyl](2,6-dimethylphenoxy)py1idin-3 -yl } -N— ethylmethyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 23 was prepared ing to the procedure used for the preparation of Example 7, substituting 4-ﬂuorophenyl magnesium bromide for phenyl magnesium bromide, and substituting cyclopropyl magnesium bromide for ethyl magnesium bromide. 1H NMR (400 MHz, ne-d5) 5 8.46 (s, 1H), 8.31 (d, J: 2.4 Hz, 1H), 7.88 (s, 1H), 7.77 — 7.70 (m, 2H), 7.11 — 6.98 (m, 6H), 3.59 (s, 3H), 3.58 — 3.51 (m, 2H), 2.15 (s, 7H), 1.81 (tt, J: 8.2, 5.4 Hz, 1H), 1.20 (t, J: 7.2 Hz, 3H), 0.90 — 0.75 (m, 2H), 0.62 (dtdd, J: 26.5, 9.1, 5.3, 3.7 Hz, 2H). MS (ESI+) m/z 581 (M+H)+.

Example 24 4- { 5 -[cyclopentyl (cyclopropyl)hydroxymethyl](2,6-dimethylphenoxy)pyridin-3 -yl } -N— ethylmethyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 24 was prepared according to the ure used for the preparation of Example 7, substituting cyclopentyl magnesium bromide for phenyl magnesium bromide, and substituting cyclopropyl magnesium bromide for ethyl magnesium bromide. 1H NMR (400 MHz, Pyridine-d5) 5 8.47 (d, J: 2.5 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J: 1.1 Hz, 1H), 7.08 — 7.03 (m, 2H), 7.03 — 6.96 (m,1H), 3.65 (s, 3H), 3.55 (td, J: 7.2, 5.6 Hz, 2H), 2.64 (h, J: 9.0, 8.6 Hz, 1H), 2.17 (s, 6H), 1.85 (dt, J: 9.6, 6.6 Hz, 2H), 1.75 — 1.40 (m, 7H), 1.18 (t, J: 7.2 Hz, 3H), 0.88 (ddd, J: 9.1, 5.4, 3.7 Hz, 1H), 0.57 — 0.31 (m, 3H). MS (ESI+) m/z 555 (M+H)+.

Example 25 4- { 5 -[dicyclopropyl(hydroxy)methyl](2,6-dimethylphenoxy)pyridin-3 -yl }-N-ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 25 was ed according to the ure used for the preparation of Example 7, substituting cyclopropyl magnesium bromide for phenyl ium bromide, and substituting cyclopropyl magnesium bromide for ethyl magnesium bromide 1H NMR (400 MHz, Pyridine-d5) 5 8.58 (s, 1H), 8.48 (d, J: 0.7 Hz, 1H), 7.42 (s, 2H), 7.23 (d, J: 2.6 Hz, 1H), 7.06 (d, J: 10.3 Hz, 2H), 7.03 — 6.98 (m, 1H), 3.65 (d, J: 10.0 Hz, 3H), 3.59 — 3.51 (m, 2H), 2.16 (d, J: 3.2 Hz,6H), 1.43 — 1.29 (m, 1H), 1.19 (t, J: 7.2 Hz, 3H), 0.88 — 0.78 (m, 2H), 0.72 (dtd, J: 9.5, 5.5, 3.9 Hz, 2H), 0.54 (ddd, J = 9.4, 7.4, 4.6 Hz, 2H), 0.42 (tdd, J = 9.1, 5.6, 3.9 Hz, 2H). MS (ESI+) m/z 527 (M+H)+.

Example 26 4-[5 -( l -cyclopropyl- l xymethylpropyl)(2,6-dimethylphenoxy)pyridin-3 -yl]—N— ethylmethyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 26 was prepared according to the ure used for the preparation of Example 7, tuting isopropyl magnesium bromide for phenyl magnesium bromide, and substituting cyclopropyl magnesium bromide for ethyl magnesium bromide. 1H NMR (400 MHz, Pyridine-d5) 5 8.45 (d, J = 2.5 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J: 1.2 Hz, 1H), 7.06 (s, 1H), 7.01 (d, J: 5.9 Hz, 1H), 3.64 (s, 3H), 3.59 — 3.50 (m, 2H), 2.17 (s, 6H), 1.50 — 1.40 (m, 1H), 1.20 — 1.13 (t, 3H), 1.12 (d, 3H), 1.06 (d, J: 6.8 Hz, 3H), O.98-O.90(m,1H), 0.58 — 0.50 (m, 1H), 0.50 — 0.43 (m, 1H), 04-038 (m, 1H). MS (ESI+) m/z 529 (M+H)+. 2O Example 27 4- [5 -(l -cyclopropyl - l -hydroxymethylbutyl)(2, 6-dimethylphenoxy)pyridin-3 -yl]—N— ethylmethyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide The roacetic acid salt of Example 27 was prepared according to the procedure used for the preparation of Example 7, substituting 2-butyl magnesium bromide for phenyl magnesium bromide, and substituting cyclopropyl magnesium bromide for ethyl magnesium bromide. 1H NMR (400 MHz, Pyridine-d5) 5 8.47 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 7.42 (s, 1H), 7.23 (s, 1H), 7.07 (d, J = 7.0 Hz, 2H), 7.05 — 6.95 (m, 1H), 3.64 (s, 2H), 3.57 — 3.50 (m, 2H), 2.17 (s, 7H), 2.06 (td, J: 6.9, 3.6 Hz, 2H), 1.58 — 1.39 (m, 1H), 1.32 — 1.19 (m, 2H), 1.17 (d, J: 7.2 Hz, 3H), 1.10 (dd, J: 12.8, 6.9 Hz, 3H), 0.98 — 0.87 (m, 4H), 3O 0.61 — 0.43 (m, 2H), 0.43 — 0.34 (m, 1H). MS (ESI+) m/z 543 (M+H)+.

N-ethyl{ 5-(2-hydroxypropanyl)[2-methyl(t1iﬂuoromethyl)phenoxy]phenyl } methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide Example 28a 2-(benzyloxy)methyl-3 -(triﬂuoromethyl)benzene Phenylmethanol (3.24 g, 30.0 mmol) in ylpyrrolidinone (25 mL) was treated with 60% sodium e in oil (2.40 g, 60.0 mmol). The reaction mixture was stirred at ambient temperature for 10 s. To this solution was added 2-ﬂuoromethyl (triﬂuoromethyl)benzene (1.781 g, 10 mmol). The reaction mixture was stirred at 100 0C for 4 hours. After cooling, the reaction e was partitioned between water and ethyl acetate.

The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, separated, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography on silica eluting with 5% ethyl acetate in heptanes to e the title compound (1.56 g, 5.86 mmol, 58.6 % yield) as a colorless oil.

Example 28b 2-methyl(triﬂuoromethyl)phenol Example 28a (1.1 g, 4.13 mmol) and methanol (25 mL) were added to 20% Pd(OH)2 on carbon (wet, 0.22g, 0.16 mmol) in a 50 mL pressure bottle and stirred for 3 hours at 30 psi of hydrogen and at 50 0C. After cooling, the solid was removed by ﬁltration. The ﬁltrate was concentrated under reduced pressure to provide the title compound (0.35 g, 1.987 mmol, 48%).

Example 28c methyl o(2-methyl(t1iﬂuoromethyl)phenoxy)benzoate A e of methyl 3-bromoﬂuorobenzoate (0.280 g, 1.2 mmol), e 28b (0.211 g, 1.200 mmol), and cesium carbonate (0.391 g, 1.200 mmol) in dimethyl sulfoxide (5 mL) was heated at 110 oC overnight. After g, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, separated, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated. The residue was d by ﬂash chromatography on silica eluting with 20% ethyl acetate in heptanes to provide the title compound (0.08 g, 0.206 mmol, 17.1 % yield).

Example 28d 2-(3 -bromo(2-methyl(triﬂuoromethyl)phenoxy)phenyl)propanol Example 28c (0.08 g, 0.206 mmol) in ydrofuran (5 mL) was treated with methylmagnesium chloride (0.685 mL, 2.056 mmol) at 0 oC. The reaction mixture was stirred at ambient ature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride, and partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl e three times. The combined organic layers were washed with brine, ted, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated.

The residue was puriﬁed by ﬂash chromatography (silica eluting, 20 % ethyl acetate in heptanes) to provide the title compound (0.056 g, 0.144 mmol, 70.0 % yield).

Example 28e N-ethyl{ 5-(2-hydroxypropanyl)[2-methyl(t1iﬂuoromethyl)phenoxy]phenyl } oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide A mixture of Example 1h (0.069 g, 0.2 mmol), Example 28d (0.078 g, 0.200 mmol), tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.020 mmol), and cesium ﬂuoride (0.091 g, 0.600 mmol) in 1,2-dimethoxyethane (1 mL) and methanol (0.500 mL) was heated at 120 0C for 40 minutes in a microwave reactor. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, separated, dried over anhydrous ium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 5 % methanol in ethyl acetate) to provide the crude t, which was then puriﬁed by reverse phase Preparative HPLC (C18 column, CH3CN/water (0.1 % triﬂuoroacetic acid), 20-80 % gradient) to provide the title nd (0.039 g, 0.074 mmol, 37.0 % yield). 1H NMR (500 MHz, DMSO-dg) 5 12.25 (d, J = 2.4 Hz, 1H), 8.35 (t, J = 5.3 Hz, 1H), 7.72 — 7.53 (m, 3H), 7.42 — 7.21 (m, 3H), 6.81 (d, J = 2.2 Hz, 1H), 6.33 (d, J = 8.7 Hz, 1H), 3.60 (s, 3H), 3.27 (qdd, J = 7.2, 4.9, 2.4 Hz, 2H), 1.94 (s, 3H), 1.45 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 528.1 (M+H)+.

Example 29 4-[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl]—N—ethylmethyl - 7-oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 29a methyl 5-bromo(2-chloromethylphenoxy)nicotinate A mixture of 2-chloromethylphenol (1.195 g, 8.38 mmol), methyl 5-bromo nicotinate (2g, 7.98 mmol), and cesium carbonate (2.60 g, 7.98 mmol) in anhydrous dimethyl sulfoxide (20 mL) was stirred at 80 0C for 1.5 hours. After cooling to ambient ature, water (40 mL) was added to the mixture, and the precipitated product was collected by ﬁltration and dried to provide the title nd (2.6 g, 7.29 mmol, 91 % yield) as off-white solid.

Example 29b 2-(5-bromo(2-chloromethylphenoxy)py1idinyl)propanol To a solution of Example 29a (1 g, 2.80 mmol) in anhydrous tetrahydrofuran (10 mL) at 0 0C was added 1 M methylmagnesium bromide (14.02 mmol) in tetrahydrofuran dropwise, and the mixture was stirred at room temperature for 16 hours. The on mixture was quenched with saturated aqueous ammonium chloride (20 mL) carefully, and extracted with ethyl acetate (20 mL x 3). The ed organic phase was washed with brine (20 mL), dried over ous sodium e, d, and concentrated to dryness to provide the title compound (1 g, 2.80 mmol, 100 % yield).

Example 29c 4-(2-(2-chloromethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl)-N—ethylmethyl - 7-oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 29c was prepared according to the procedure used for the preparation of Example 1m, substituting Example 29b for Example 11. 1H NMR (400 MHz, DMSO-d6) 5 12.30 (s, 1H), 8.36 (t, J: 5.4 Hz, 1H), 8.11 (d, J: 2.4 Hz, 1H), 7.99 (d, J: 2.4 Hz, 1H), 7.49 (s, 1H), 7.35 (dd, J: 7.9, 1.6 Hz, 1H), 7.31 — 7.21 (m, 1H), 7.16 (t, J: 7.8 Hz, 1H), 6.96 (s, 1H), 5.23 (s, 1H), 3.61 (s, 3H), 3.28 (td, J = 7.2, 5.3 Hz, 2H), 2.09 (s, 3H), 1.49 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 495.2 (M+H)+.

Example 30 4-[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)phenyl]-N—ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide 2O Example 30a methyl 3-bromo(2-chloromethylphenoxy)benzoate A mixture of cesium carbonate (839 mg, 2.57 mmol), 2-chloromethylphenol (294 mg, 2.060 mmol), and methyl 3-bromoﬂuorobenzoate (400 mg, 1.716 mmol) in dimethyl sulfoxide (5 mL) was stirred at 100 0C for 1 hour under nitrogen. After cooling to ambient temperature, water (50 mL) was added. The resulting mixture was ted with ethyl acetate (50 mL) twice. The organic layers were combined and dried over anhydrous sodium sulfate. After ﬁltration and solvent removal the crude material was puriﬁed by ﬂash chromatographed (silica gel, 0-50 % ethyl acetate/petroleum ether) to provide the title compound (400 mg, 65.5 % yield). 3O Example 30b 2-(3 -bromo(2-chloromethylphenoxy)phenyl)propanol e 30b was prepared according to the procedure used for the preparation of Example 29b, substituting Example 30a for e 29a.

Example 30c 4-[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)phenyl]-N—ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 30c was prepared according to the procedure used for the preparation of Example 1m, substituting Example 30b for Example 11. 1H NMR (300 MHz, DMSO-d6) 5 12.23 (s, 1H), 8.34 (bs, 1H), 7.53 (d, J: 2.4 Hz, 1H), 7.45 — 7.25 (m, 4H), 7.19 (t, J: 7.8 Hz, 1H), 6.91 (s, 1H), 6.30 (d, J: 8.6 Hz, 1H), 5.01 (s, 1H), 3.59 (s, 3H), 3.30 — 3.21 (m, 2H), 2.08 (s, 3H), 1.44 (s, 6H), 1.11 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 494.2 (M+H)+.

Example 31 —butyl[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide A e of Example 30b (95 mg, 0.268 mmol), sodium carbonate (85 mg, 0.804 mmol), tris(dibenzylideneacetone)dipalladium(0) (24.5 mg, 0.027 mmol), Example 32c (100 mg, 0.268 mmol), and 1,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamantane (9.40 mg, 0.032 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL).The e was heated at 60 0C for 3 hours under nitrogen. The mixture was cooled to ambient temperature and ﬁltered and the ﬁltrate was extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, d, and ated. The crude residue was dissolved in dimethyl sulfoxide and puriﬁed by preparative-HPLC (Column:Waters HSS C18, 21*50 mm, 1 .8 pm, Mobile Phase A:water/10 mmol NH4HC03, Mobile Phase B: itrile, Flow rate: 25 mL/min, gradient:25 % B to 50 % B in 5 min, hold 0.5 min, 254 nm) to provide the title compound (18.9 mg, 0.036 mmol, 13.5 % . 1H NMR (300 MHz, DMSO-d6) 5 12.36 (s, 1H), 7.86 (s, 1H), 7.54 (d, J: 2.3 Hz, 1H), 7.41 (d, J: 7.0 Hz, 1H), 7.37 (s, 1H), 7.31 (m, 2H), 7.19 (t, J: 7.8 Hz, 1H), 6.91 (d, J: 2.1 Hz, 1H), 6.29 (d, J: 8.6 Hz, 1H), 5.01 (s, 1H), 3.60 (s, 3H), 2.08 (s, 3H), 1.44 (s, 6H), 1.36 (s, 9H). MS (ESI+) m/z 522.2 (M+H)+.

Example 32 N—lerl—butyl[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 32a 4-bromomethyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]py1idinecarboxylic acid A 500 mL round bottom ﬂask was charged with Example 1f (7.9 g, 17.43 mmol) and dioxane (100 mL). To this solution was added 2M NaOH (34.9 mL, 69.7 mmol), and the reaction mixture was heated at 80 0C for 2 hours. After cooling, the reaction mixture was diluted with HCl (0.1 N) to pH 2. IN HCl was then added dropwise to lower the pH to about 1. The resulting mixture was stirred vigorously for about one hour. The mixture was ﬁltered and the resulting solid was washed with water and dried to e the title compound (4.44 g, 94 % yield).

Example 32b 4-bromo-N-(tert-butyl)methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridine amide To a slurry of Example 32a (2.98 g, 11.0 mmol) in dichloromethane (30 mL) was added 4 drops of dimethylformamide followed by the addition of oxalyl chloride (1.93 mL, 22.0 mmol). The mixture was stirred at ambient temperature for 3 hours and concentrated. To the residue were added tetrahydrofuran (30 mL) and 2-methylpropanamine (3.47 mL, 33.0 mmol) and the mixture stirred at ambient temperature for 1 hour. The mixture was ioned with ethyl acetate and water. The organic layer was washed with saturated s sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated. The resulting residue was triturated with ethyl acetate/heptanes (1:1) to provide the title nd (3.35 g, 10.27 mmol, 93 %). e 32c t-butyl)methyloxo(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-6,7-dihydro- 1H—pyrrolo[2,3-c]pyridinecarboxamide A e of anhydrous potassium acetate (26.6 g, 271 mmol), Example 32b (29.5 g, 90 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (45.9 g, 181 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (2.85 g, 3.62 mmol), and 2-dicyclohexylphosphino-2',4',6'— triisopropylbiphenyl (1.725 g, 3.62 mmol) was degassed under a stream of nitrogen. To this mixture was added degassed anhydrous 2-methyl ydrofuran (1 L). The resulting yellow slurry was heated at 80 oC overnight. The reaction mixture was cooled to ambient temperature and then diluted with water (500 mL) and ethyl acetate (500 mL) and stirred for 90 minutes with 1.8 g. (3.0 equivalents based on moles of palladium) of ammonium pyrrolidine dithiocarbamate. The resulting mixture was ﬁltered through diatomaceous earth and the dia‘tomaceous earth pad was rinsed with ethyl acetate. The ﬁltrate was washed with brine. The organic layer was mixed with about 20 g. SiliaMetS Thiol® (a thiol attached on silica via an alkyl chain, a palladium scavenger from Silicycle), and this mixture was stirred for about one hour. The mixture was dried over anhydrous sodium sulfate, ﬁltered, and concentrated under reduced pressure. The residue was puriﬁed on a Grace Reveleris X2 MPLC using a Teledyne-Isco RediSep Rf Gold 750 g. silica gel column, eluting with 50 % to 60 % to 70 % to 80 % ethyl acetate/heptane to provide the title compound. This material was sonicated in 250 mL of 20 % ethyl e/heptane. The solid was collected by ion, washed with 20% ethyl e/heptane, and dried to provide the title compound (17.6 g, 52% yield).

Example 32d N—lerl—butyl[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide A stream of nitrogen gas was blown over a mixture of Example 32c (15.0 g, 40.2 mmol), Example 3d (16.2 g, 48.2 mmol), 7-tetramethylphenyl-2,4,8-trioxa phosphaadamantane (1.175 g, 4.02 mmol), potassium phosphate (21.33 g, 100 mmol), and tris(dibenzylideneacetone)dipalladium (1.104 g, 1.206 mmol) for one hour. In the meantime, in a 1 L. ﬂask were mixed anhydrous dioxane (300 mL) and water (75 mL). This solution was degassed for one hour by bubbling nitrogen through it. After one hour, the solvents were transferred via cannula into the mixture of degassed solids. As the solvents were added an exotherm was ed and the temperature rose from 20.5 0C to 32.0 0C. When the reaction mixture was sufﬁciently mixed, it was heated at 80 0C for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate and water. The mixture was stirred for one hour with about 600 mg. (3.0 equivalents. based on moles of ium) of ammonium pyrrolidine dithiocarbamate. The resulting mixture was ﬁltered h aceous earth. The dia‘tomaceous earth pad was washed with ethyl acetate. The resulting ﬁltrate was poured into a separatory funnel and the mixture diluted further with ethyl acetate and brine. The organic layer was washed with water (2X) and brine. The organic layer was dried with anhydrous sodium sulfate, ﬁltered, and trated under reduced pressure. The residue was puriﬁed on a Grace Reveleris X2 MPLC using a Teledyne Isco RediSep Rf Gold 330 g. silica gel column eluting with 70 % to 80 % to 90 % ethyl acetate/heptanes to 100 % ethyl e. The resulting pure material was dissolved with heating in ethanol, concentrated under reduced pressure, and dried to produce the title compound (18.0 g, 89% yield). 1H NMR (501 MHz, DMSO-d6) 5 12.34 (s, 1H), 7.85 (s, 1H), 7.52 (d, J: 2.3 Hz, 1H), 7.33 (s, 1H), 7.28 (dd, J: 8.6, 2.4 Hz, 1H), 7.10 (d, J: 7.8 Hz, 2H), 7.03 (dd, J: 8.3, 6.6 Hz, 1H), 6.85 (s, 1H), 6.26 (d, J: 8.6 Hz, 1H), 4.97 (s, 1H), 3.59 (s, 3H), 2.00 (s, 6H), 1.42 (s, 6H), 1.35 (s, 9H). MS (ESI+) m/z 502.1 (M+H)+.

Example 33 N—Zerl—butyl[2',4'-diﬂuoro(2-hydroxypropanyl)[1,1'-biphenyl]yl]—6-methyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 33a methyl 2',4'—diﬁuoronitro-[1,1'-biphenyl]carboxylate A mixture of methyl 4-bromonitrobenzoate (750 mg, 2.88 mmol), (2,4- diﬂuorophenyl)boronic acid (683 mg, 4.33 mmol), tetrakis(triphenylphosphine)palladium(0) (333 mg, 0.288 mmol), and sodium carbonate (611 mg, 5.77 mmol) were combined in dioxane (15 mL) and water(4 mL), sparged with nitrogen gas for 10 minutes, and heated at 90 0C under nitrogen for 2 hours. The mixture was cooled to ambient ature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with diatomaceous earth, ﬁltered, and concentrated. The residue was puriﬁed by chromatography a gel, 0- 100 % ethyl acetate in eum ether) to provide the title compound (510 mg, 1.739 mmol, 60.3 % yield).

Example 33b methyl 2-amino-2',4'-diﬁuoro-[1,1'-biphenyl]carboxylate ] Example 33a (450 mg, 1.535 mmol), zinc (1003 mg, 15.35 mmol) and a hydrochloride (821 mg, 15.35 mmol) were combined in tetrahydrofuran (4 mL), methanol (1 mL) and water (1 mL) with vigorous stirring at 26 0C for 3 hours. The mixture was ﬁltered through a plug of diatomaceous earth to remove solids. The plug was rinsed repeatedly with methanol and tetrahydrofuran. The e was trated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (anhydrous sodium sulfate), ﬁltered, and trated to provide the title compound (380 mg, 1.444 mmol, 94 % yield).

Example 33c methyl 2',4'-diﬁuoroiodo-[1,1'-biphenyl]carboxylate id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331" id="p-331"

[00331] A solution of Example 33b (200 mg, 0.760 mmol)in 1,4-dioxane (10 mL) at 0 CC was treated with concentrated HCl (27.7 mg, 0.760 mmol) and stirred for 15 minutes and then treated with a solution of sodium nitrite (62.9 mg, 0.912 mmol) in water (2 mL). The mixture was stirred for 1 hour at 0 oC, d with a solution of potassium iodide (252 mg, 1.52 mmol) in water (2 mL) and stirred for 1 hour at ambient temperature. The reaction mixture was ioned between ethyl acetate and water. The organic layer was washed with saturated sodium thiosulfate, water, and brine, dried (anhydrous magnesium sulfate), ﬁltered, and concentrated. The residue was puriﬁed by tography on silica gel (hexane) to provide the title compound (300 mg, 0.642 mmol, 84 % yield).

Example 33d 2-(2',4'-diﬂuoroiodo-[1,1'-biphenyl]yl)propanol A mixture of Example 33c (100 mg, 0.267 mmol) in tetrahydrofuran (10 mL) was stirred at -10 0C. To this solution was slowly added methylmagnesium bromide (0.356 mL, 1.069 mmol). The reaction mixture was stirred at 25 oC overnight. The mixture was diluted with ethyl ether, washed with 20 mL water ), and brine. The organic layer was dried over anhydrous sodium sulfate, ﬁltered, and concentrated under reduced pressure. The residue was puriﬁed by silica gel chromatography (petroleum ether/ ethyl acetate = 33/1) to provide the title compound (50 mg, 0.134 mmol, 50.0 % yield).

Example 33e N—Zerl—butyl[2',4'-diﬂuoro(2-hydroxypropanyl)[1,1'-biphenyl]yl]methyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 33e was prepared according to the procedure used for the preparation of Example 32d, substituting Example 33d for Example 3d. 1H NMR (400 MHz, Methanol-d4) 7.67 (d, J: 2.0 Hz, 1H), 7.62 (dd, J: 8.0, 2.1 Hz, 1H), 7.41 (d, J: 8.1 Hz, 1H), 7.30 — 7.21 (m, 1H), 6.86 (s, 1H), 6.86 — 6.77 (m, 2H), 6.69 (s, 1H), 3.53 (s, 3H), 1.63 (s, 6H), 1.45 (s, 9H). Ms (ESI+) m/z 494.2 (M+H)+.

N-(2,2-diﬂuoromethylcyclopropyl)[2-(2,6-dimethylphenoxy)-5 -(2-hydroxypropan yl)py1idinyl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 34a 4-bromomethyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]py1idinecarbonyl chloride e 32a (1.0 g, 3.69 mmol) in dichloromethane (18.45 mL) under nitrogen was treated with N,N—dimethylfonnamide (0.057 mL, 0.738 mmol) followed by dropwise addition of oxalyl ride (0.969 mL, 11.07 mmol). The reaction mixture was stirred under en at ambient temperature for 3 hours and concentrated. The residue was azeotroped three more times with 1:1 dichloromethane/toluene to provide the title compound (1.06 g, 99%) that was used without puriﬁcation.

Example 34b 4-bromo-N-(2,2-diﬂuoromethylcyclopropyl)methyloxo-6,7-dihydro-1H—pyrrolo[2,3- c]pyridinecarboxamide A mixture of Example 34a (1.06 g, 3.69 mmol) and 2,2-diﬂuoro methylcyclopropanamine hloride (0.636 g, 4.43 mmol) in tetrahydrofuran (24.59 mL) under en was treated dropwise with N—ethyl-N—isopropylpropanamine (6.44 mL, 36.9 mmol). The reaction e was stirred under nitrogen at ambient temperature for 18 hours.

The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, d, and concentrated. ation by trituration (2:1 dichloromethane/heptanes) provided the title compound (0.688 g, 52 %).

Example 34c N—(2,2-diﬁuoromethylcyclopropyl)—6-methyloxo(4,4,5,5-tetramethyl-1,3,2- orolanyl)-6,7-dihydro-1H—pyrrolo[2,3-c]py1idinecarboxamide Dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]yl)phosphine (0.109 g, 0.229 mmol), potassium acetate (0.750 g, 7.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol), Example 34b (0.688 g, 1.910 mmol) and 4,4,4',4',5,5,5',5'—octamethyl- 2,2'-bi(1,3,2-dioxaborolane) (1.455 g, 5.73 mmol) were combined in dioxane (9.55 mL) and sparged with argon for 15 minutes. The mixture was then heated under nitrogen for 18 hours at 80 oC, cooled, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), treated with 3-mercaptopropyl functionalized silica gel, ﬁltered, and trated. Puriﬁcation by chromatography (silica gel, 20-100 % ethyl acetate in heptanes) provided the crude desired product. Trituration in a minimal volume of 9:1 heptanes/diethyl ether provided the title compound (0.362 g, 46 %).

Example 34d N-(2,2-diﬁuoromethylcyclopropyl)—4-[2-(2,6-dimethylphenoxy)-5 -(2-hydroxypropan yl)py1idinyl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide e 34c (0.06 g, 0.147 mmol), Example 11 (0.059 g, 0.177 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.05 mg, 4.42 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (4.31 mg, 0.015 mmol) and sodium ate (0.062 g, 0.589 mmol) were ed and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 tetrahydrofuran/water (1.0 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 3 hours under argon at 60 oC, , and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium de, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, ﬁltered and concentrated. Puriﬁcation by reverse phase HPLC (C18, CH3CN/water (0.1 % roacetic acid), 0-100 %) provided the title compound (0.066 g, 83 %). 1H NMR (400 MHz, DMSO- d6) 12.38 (d, J = 2.1 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.43 (s, 1H), 7.07 — 6.89 (m, 4H), 3.59 (s, 3H), 1.96 (s, 6H), 1.72 — 1.54 (m, 2H), 1.46 (s, 6H), 1.43 (d, J = 2.5 Hz, 3H). MS (ESI+) m/z 537 [M+H]+.

Example 35 N—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 35a 4-ﬂuoro-2,6-dimethylphenol A on of 2-bromoﬂuoro-1,3-dimethylbenzene (25 g, 123 mmol) in tetrahydrofuran (300 mL) was cooled to -78 OC and n-butyllithium (59.1 mL, 148 mmol) was added dropwise at a rate to keep the internal temperature at or below -75 oC. The mixture was stirred for 2 hours and then trimethylborate (16.51 mL, 148 mmol) was added and the mixture d for 3 hours at -78 0C, then warmed to ambient ature. After 4 hours, the e was cooled to -10 oC and a precooled solution ofNaOH (7.39 g, 185 mmol) and % hydrogen peroxide (201 mL, 1970 mmol) was added. Once the addition was te the mixture was allowed to warm to ambient temperature overnight. The pH of the mixture was adjusted to pH 1 with 2M HCl. 400 mL of ethyl ether and 200 mL of water were added and the layers were separated. The aqueous layer was extracted with 3 x 200 mL of ether, and the combined organic layers were washed with saturated NaHC03 and saturated NaSzOg, then stirred with a saturated aqueous NaSzOs solution (200 mL) for 15 minutes. The organic 2O phase was dried with anhydrous magnesium sulfate, ﬁltered, and concentrated. The residues were taken up in 1/1 diethyl ether/pentane and ﬂushed through a silica plug. Concentration of the ﬁltrate provided 11.47g (67%) of the title compound.

Example 35b methyl 3-bromo(4-ﬁuoro-2,6-dimethylphenoxy)benzoate id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339" id="p-339"

[00339] To a solution of Example 35a (1.86 g, 13.27 mmol) and methyl 3-bromo ﬁuorobenzoate (2.099 mL, 14.20 mmol) in dimethyl sulfoxide (14 mL) was added cesium carbonate (6.49 g, 19.91 mmol). The mixture was heated at 80 0C for 2 hours, cooled, and diluted with water (100 mL), then extracted with methyl tert-butyl ether (200 mL). The aqueous phase was extracted with additional portions (2 x 100 mL) of methyl tert—butyl ether. 3O The combined organics were dried over ous sodium sulfate, ﬁltered, and concentrated.

The crude al was puriﬁed by chromatography (silica gel, eluting with 0-25 % ethyl e/heptanes) to provide 4.56g (97%) of the title compound. e 35c 2-(3 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)propanol A ﬂask containing a solution of Example 35b (2.49 g, 7.05 mmol) in tetrahydrofuran (28.0 mL) was placed in a water bath, and then treated with 3 M methylmagnesium bromide in tetrahydrofuran (7.0 mL, 21.00 mmol). After 30 minutes, the mixture was ed by addition of 100 mL of s ammonium chloride and partitioned with 100 mL of diethyl ether. The organics were washed with water and dried over anhydrous sodium sulfate. After ﬁltration and solvent removal, the crude material was chromatographed (silica cartridge, 0- 100 % ethyl e/heptanes) to provide 2.056 g (83 %) of the title compound. e 35d N-ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Method A: A mixture of Example 35c, Example 1h (0.280 g, 0.810 mmol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (0.021 g, 0.073 mmol), tris(dibenzylideneacetone)dipalladium(0) (4) (0.017 g, 0.019 mmol), and potassium phosphate (0.331 g, 1.557 mmol) in dioxane (4 mL) and water (1 mL) was degassed and back-ﬁlled with nitrogen six times. The reaction mixture was heated at 60 0C for 12 hours.

The reaction e was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash column chromatography on silica gel eluting with 5 % methanol in ethyl acetate. The crude product was further puriﬁed by reverse phase ative HPLC (C18, CH3CN/water (0.1 % triﬂuoroacetic acid), 20-80 % nt). The desired fractions were combined and freeze-dried to provide the title compound (0.14 g, 0.285 mmol, 45.7 % yield). 1H NMR (400 MHz, g) 5 12.20 (s, 1H), 8.32 (t, J = 5.3 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.46 — 7.21 (m, 2H), 6.96 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 2.3 Hz, 1H), 6.29 (d, J = 8.6 Hz, 1H), 3.58 (s, 3H), 3.24 (dt, J = 12.6, 6.2 Hz, 2H), 2.00 (s, 6H), 1.42 (s, 6H), 1.10 (t, J = 7.2 Hz, 2H). MS (ESI+) m/z 492.2 (M+H)+.

Method B: m: Preparation of ethyl 4-(2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropan nyl)methyloxotosyl-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxyl ate A three-neck ﬂask was charged with a stir bar, and ﬁt with a thermocouple and reﬂux condenser. To the ﬂask was added bis(pinacolato)diboron (27.0 g, 106 mmol), tris(dibenzylideneacetone)dipalladium(0) (605 mg, 0.661 mmol), 7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (465 mg, 1.591 mmol), Example 1f prepared from Method B (38.832 g, 86 mmol), and potassium acetate (17.67 g, 180 mmol). The ﬂask containing the solids was purged with nitrogen for 30 minutes and a separate ﬂask containing 350 mL of tetrahydrofuran was sparged for 30 minutes. After this time, the three-neck ﬂask was stoppered and 350 mL of the sparged tetrahydrofuran was transferred to the solids using a cannula. The reaction e was then stirred and heated to 60 0C until the reaction was judged complete by HPLC (22 hours). After this time, the reaction e was ﬁltered through a pad of diatomaceous earth, and collected in a bottom ﬂask. The diatomaceous earth pad was washed with tetrahydrofuran (l X 50 mL) and added to the reaction. The reaction mixture was then sparged with en for 30 minutes. In a separate ﬂask, tribasic potassium phosphate (52.0 g, 548 mmol) was dissolved in water (50 mL) and the solution was sparged with nitrogen for 30 minutes. After this time, the ﬂask containing the reaction mixture was open (under high ﬂow of en) and Example 35c (28.8 g, 82 mmol) was added as a solid. Immediately following the addition, the phosphate and water solution was added via cannula. The reaction mixture was then heated at 60 0C for 2 hours or until complete consumption of Example 35C was ed. The volatile components were then removed on a rotary evaporator. To the remaining mixture was added 300 mL of ethyl acetate to completely ve the crude residue. The aqueous and organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 250 mL). The c layers were combined and washed with 5% cysteine/8% sodium bicarbonate (2 x 100 mL).

The organic and aqueous layers were seperated and the organic component was removed on a rotary evaporator leaving a yellow/light brown solid. The solid was dissolved in methyl tert- butyl ether (450 mL) to give a yellow solution and 900 mL of heptane was added to promote itation. The off-white solid was d and washed quickly with 200 mL of heptane.

The e was concentrated until itation began again. The solid was again ﬁltered and washed. A ﬁnal amount of solvent was removed from the second ﬁltrate, and a precipitate began to form. Cooling the ﬁltrate, followed by ﬁltration and washing of the solid with heptane, gave a third and ﬁnal batch of the title compound (41.69 g, 75%).

M: Preparation of 4-(2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropan yl)phenyl)methyloxo-6,7-dihydro-lH-pyrrolo[2,3-c]py1idinecarboxylic acid id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343" id="p-343"

[00343] A 24 mL dram vial was charged with a stir bar and ethyl 4-ﬂuoro-2,6- dimethylphenoxy)(2-hydroxypropanyl)phenyl)methyloxo- l -tosyl-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxylate (140 mg, 0.216 mmol). The solid was dissolved in 3 mL of tetrahydrofuran and aqueous potassium hydroxide (4.45 M, 0.60 mL, 2.67 mmol) was added. The mixture was stirred at 60 0C for 22 hours. To the vial was added 10 mL of ethyl acetate. The reaction mixture was transferred to a separatory funnel and shaken. The organic and aqueous layers were separated. The aqueous layer was extracted with additional ethyl acetate (2 X 10 mL). The aqueous layer was then adjusted to pH = 3 using 1 M HCl, and ted with ethyl acetate (3 x 10 mL). The ethyl acetate fractions ted after pH adjustment were combined and distilled from the reaction using a rotary evaporator to provide the title compound (80 mg, 80% yield). m: Preparation ofN—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropan yl)phenyl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]py1idinecarboxamide A 50 mL round-bottom ﬂask was d with a stir bar and 4-(2-(4-ﬂuoro-2,6- dimethylphenoxy)(2-hydroxypropanyl)phenyl)methyloxo-6,7-dihydro- 1H- pyrrolo[2,3-c]pyridinecarboxylic acid (80 mg, 0.388 mmol). The ﬂask was flushed with nitrogen, and 3.8 mL of anhydrous N,N—dimethylforamide was added. The light yellow solution was stirred as HATU (1-[bis(dimethylamino)methylene]-1H—1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexaﬂuorophosphate,166 mg, 0.437 mmol) was added in one portion as a solid. The bright yellow reaction mixture was stirred for 10 minutes. After this time, ethanamine (0.40 ml, 0.800 mmol) was added and the reaction mixture was stirred an additional 20 minutes before diisopropylethylamine (0.20 ml, 1.145 mmol) was added. After 12 hours, 20 mL of water was added to the reaction mixture causing precipitation of the product as a white solid. The solid was washed quickly with additional water (2 x 10 mL) and dried to provide the title nd (70 mg, 83% yield).

Example 36 N—ZerZ-butyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 36 was prepared ing to the procedure used for the preparation of e 32d, tuting e 35c for Example 3d. 1H NMR (400 MHz, DMSO-dg) 5 12.35 (d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.41 — 7.25 (m, 2H), 6.99 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 2.3 Hz, 1H), 6.31 (d, J = 8.6 Hz, 1H), 3.61 (s, 3H), 2.02 (s, 6H), 1.44 (s, 6H), 1.37 (s, 9H). MS (ESI+) m/z 520.1 (M+H)+.

Example 37 N—lerl—butyl[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)py1idinyl]—6- oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 32c (45 mg, 0.12 mmol), Example 29b (47 mg, 0.13 mmol), sodium carbonate (46 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.3 mg, 3.6 umol) and 1 3 5 7-tetramethylphenyl-2,4,8-trioxaphosphaadamantane (3.2 mg, 11 umol) were 7 7 7 combined in a microwave tube and purged with nitrogen for 15 minutes. The mixture of tetrahydrofuran (2 mL) and water (0.5 mL) was purged with nitrogen for 15 minutes and transferred to the microwave tube. The reaction mixture was heated at 60 0C for 3 hours, cooled and partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, treated with 3- mercaptopropyl functionalized silica gel, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 20-40 % 3 :l ethyl acetate/ethanol in es) to provide the title nd (56 mg, 89 %). 1H NMR (500 MHz, DMSO-d6) 5 12.41 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.46 (s, 1H), 7.35 — 7.31 (m, 1H), 7.25 — 7.22 (m, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 2.1 Hz, 1H), 5.19 (s, 1H), 3.59 (s, 3H), 2.07 (s, 3H), 1.46 (s, 6H), 1.35 (s, 9H). MS (ESI+) m/z 523 (M+H)+.

Example 38 4-[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)py1idinyl]methyloxo-N— (l , l , l -triﬂuoromethylpropanyl)-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide Example 38a 4-bromomethyloxo-N—(l , l, l -t1iﬂuoromethylpropanyl)-6,7-dihydro- 1H- pyrrolo[2,3-c]pyridinecarboxamide Example 38a (1.04 g, 74 %) was prepared according to the procedure used for the preparation of Example 34b, substituting l, l,l-triﬂuoromethylpropanamine for 2,2- diﬂuoro- l -methylcyclopropanamine hydrochloride.

Example 38b 6-methyloxo(4,4,5, 5-tetramethyl- l ,3 ,2-dioxaborolanyl)—N—(l , l, l -triﬂuoro methylpropanyl)-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide ] Example 38b (0.404 g, 60 %) was prepared according to the procedure used for the ation of e 34c, substituting Example 38a for Example 34b.

Example 38c 2-chloromethylphenoxy)(2-hydroxypropanyl)py1idinyl]methyloxo-N— (l , l , l -triﬂuoromethylpropanyl)-6,7-dihydro- 1H-pyrrolo[2,3 idinecarboxamide ] Example 38c (48 mg, 83 %) was prepared according to the procedure used for the preparation of Example 37, substituting Example 38b for Example 32c. 1H NMR (400 MHz, DMSO-d6) 5 12.54 (s, 1H), 8.11 — 8.06 (m, 2H), 7.97 (d, J: 2.3 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J: 7.9 Hz, 1H), 7.23 (d, J: 7.2 Hz, 1H), 7.13 (t, J: 7.8 Hz, 1H), 7.05 (s, 1H), 5.19 (s, 1H), 3.60 (s, 3H), 2.07 (s, 3H), 1.59 (s, 6H), 1.46 (s, 6H). MS (ESI+) m/z 577 (M+H)+.

Example 39 100100 4-[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)py1idin-3 -yl]-N-(2,2-diﬂuoro methylcyclopropyl)methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide ] Example 39 (48 mg, 86 %) was prepared according to the procedure used for the preparation of Example 37, substituting Example 34c for Example 32c. 1H NMR (500 MHz, DMSO-d6) 6 12.39 (s, 1H), 8.76 (s, 1H), 8.09 (d, J: 2.4 Hz, 1H), 7.95 (d, J: 2.4 Hz, 1H), 7.45 (s, 1H), 7.35 — 7.29 (m, 1H), 7.25 — 7.21 (m, 1H), 7.13 (t, J: 7.8 Hz, 1H), 6.98 (d, J: 1.7 Hz, 1H), 5.19 (s, 1H), 3.59 (s, 3H), 2.06 (s, 3H), 1.71 — 1.55 (m, 2H), 1.46 (s, 6H), 1.43 (s, 3H). MS (ESI+) m/z 557 (M+H)+.

Example 40 4- { 2-[2,6-dimethyl(methylsulfanyl)phenoxy] (2-hydroxypropanyl)phenyl } -N-ethyl- yloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 40 was isolated as a byproduct from the preparation of Example 35. 1H NMR (400 MHz, DMSO-dg) 6 12.21 (d, J = 2.2 Hz, 1H), 8.33 (t, J = 5.4 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.9 Hz, 2H), 7.02 (s, 2H), 6.84 (d, J = 2.2 Hz, 1H), 6.31 (d, J = 8.7 Hz, 1H), 3.60 (s, 3H), 3.26 (qd, J = 7.2, 5.2 Hz, 2H), 2.45 (s, 3H), 1.99 (s, 6H), 1.44 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 520.1 (M+H)+.

Example 41 4-[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo-N- (1 , 1 , 1 -triﬂuoromethylpropanyl)-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352" id="p-352"

[00352] Example 41 (44 mg, 76%) was prepared ing to the procedure used for the preparation of Example 37, substituting Example 38b for Example 32c, and tuting Example 30b for Example 29b. 1H NMR (400 MHz, DMSO-d6) 5 12.45 (s, 1H), 8.07 (s, 1H), 7.53 (d, J: 1.7 Hz, 1H), 7.43 — 7.35 (m, 2H), 7.34 — 7.25 (m, 2H), 7.17 (t, J: 7.8 Hz,1H), 7.02 (s, 1H), 6.28 (d, J: 8.6 Hz, 1H), 4.98 (s, 1H), 3.59 (s, 3H), 2.07 (s, 3H), 1.59 (s, 6H), 1.42 (s, 6H). Ms (ESI+) m/z 576 .

Example 42 4-[2-(2-chloromethylphenoxy)(2-hydroxypropanyl)phenyl]-N—(2,2-diﬂuoro methylcyclopropyl)methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 42 (45 mg, 81%) was prepared according to the procedure used for the preparation of Example 34d, substituting Example 30b for Example 11. 1H NMR (400 MHz, 6) 6 12.29 (s, 1H), 8.75 (s, 1H), 7.52 (d, J: 2.3 Hz, 1H), 7.39 (dd, J: 7.9, 1.0 Hz, 1H), 7.35 (s, 1H), 7.31 (dd, J: 8.6, 2.4 Hz, 1H), 7.28 (d, J: 6.9 Hz, 1H), 7.17 (t, J: 7.8 Hz, 1H), 6.95 (d, J: 1.7 Hz, 1H), 6.29 (d, J: 8.6 Hz, 1H), 4.98 (s, 1H), 3.58 (s, 3H), 2.06 (s, 3H), 1.71 — 1.52 (m, 2H), 1.43 (s, 9H). MS (ESI+) m/z 556 (M+H)+. 101101 Example 43 N—ethyl[2-(4-fluoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 43a methyl 5-bromo(4-ﬂuoro-2,6-dimethylphenoxy)nicotinate Example 43a was prepared according to the procedure used for the preparation of Example 28c, substituting Example 35a for Example 28b, and tuting methyl 5-bromo- 6-chloronicotinate for methyl 3-bromofluorobenzoate respectively.

Example 43b 2-(5-bromo(4-fluoro-2,6-dimethylphenoxy)pyridinyl)propanol Example 43b was prepared according to the procedure used for the ation of Example 28d, tuting Example 43a for Example 28c. e 43c N—ethyl[2-(4-fluoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 43c was prepared according to the procedure used for the ation of Example 1m, substituting Example 43b for Example 11. 1H NMR (400 MHz, DMSO-dg) 5 12.31 (d, J = 2.2 Hz, 1H), 8.34 (t, J = 5.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.44 (s, 1H), 6.92 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 2.2 Hz, 1H), 3.61 (s, 3H), 3.27 2O (qd, J = 7.3, 5.2 Hz, 2H), 1.99 (s, 6H), 1.48 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 493.2 .

Example 44 N—ZerZ-butyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357" id="p-357"

[00357] Example 44 was prepared according to the procedure used for the ation of Example 1m, substituting Example 43b for Example 11, and substituting Example 32c for Example 1h, respectively. 1H NMR (400 MHz, DMSO-d6) 5 12.43 (d, J: 2.4 Hz, 1H), 8.10 (d, J: 2.4 Hz, 1H), 7.96 (d, J: 2.4 Hz, 1H), 7.87 (s, 1H), 7.44 (s, 1H), 6.98 — 6.82 (m, 3H), 3.61 (s, 3H), 1.99 (s, 6H), 1.48 (s, 6H), 1.37 (s, 9H). MS (ESI+) m/z 521.2 (M+H)+.

Example 45 N—lerl-butyl{5-(2-hydroxypropanyl)[2-methyl(t1iﬂuoromethyl)phenoxy]pyridin- 3-yl}methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide Example 45a 2-(benzyloxy)methyl-3 -(triﬂuoromethyl)benzene 102102 A 3-neck, oven-dried and nitrogen-ﬂushed 250 mL round-bottom ﬂask was charged with 60% sodium hydride (8.98 g, 225 mmol). The ﬂask was equipped with a reﬂux condenser and a temperature probe and the system was degassed with nitrogen for 30 minutes. 1-methylpyrrolidinone (150 mL) was added, and the suspension was cooled in an ice- water bath (to internal temp = 4 oC). Benzyl alcohol (17.4 mL, 168 mmol) was added dropwise over about 5 minutes. The reaction mixture was warmed to ambient temperature for about 30 minutes. A solution of omethyl(triﬂuoromethyl)benzene (20.0 g, 112 mmol) in toluene (30 mL) was added. The reaction e was stirred at ambient temperature for about 5 minutes, then heated at 60 0C for 16 hours, cooled in an ice bath, carefully quenched with isopropyl alcohol (25 mL), diluted with water, and extracted with ethyl acetate four times. The combined organic layers were dried with anhydrous sodium e, ﬁltered, and evaporated. The residue was puriﬁed by ﬂash tography (silica gel, 0-5% ethyl acetate in heptanes) to provide the title compound (27.6 g, 92%).

Example 45b yl(triﬂuoromethyl)phenol To a solution of Example 45a (35.3 g, 133 mmol) in methanol (200 mL) in a 500 mL stainless steel pressure bottle was added Pd(OH)2/C (wet, 20 %, 6.60 g, 10.2 % wt, 4.79 mmol). The reaction e was shaken at 50 0C for 3 hours under 30 psi of hydrogen, ﬁltered, and concentrated to e the title nd (22.9 g, 98 %). 2O Example 45c methyl 5-bromo(2-methyl(triﬂuoromethyl)phenoxy)nicotinate Methyl 5-bromochloronicotinate (9.90 g, 39.5 mmol), Example 45b (8.70 g, 49.4 mmol) and cesium carbonate (25.8 g, 79.0 mmol) were ed in dimethyl sulfoxide (100 mL). The reaction mixture was heated at 100 0C for 2 hours, cooled, diluted with water, and extracted with ethyl e three times. The ed organic layers were washed with saturated s sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 0-10 % ethyl acetate in heptane) to provide the title compound (11.9 g, 77 %).

Example 45d 2-(5-bromo(2-methyl(t1iﬂuoromethyl)phenoxy)pyridinyl)propanol To a solution of Example 45c (11.9 g, 30.6 mmol) in tetrahydrofuran (300 mL) was added 3M methylmagnesium chloride in tetrahydrofuran (30.6 mL, 92.0 mmol) dropwise over 20 minutes at -74 oC. The reaction mixture was stirred in the cold bath which was thawed overnight, cooled in an ice-water bath, quenched by the careful addition of water, 103103 diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with anhydrous sodium sulfate, ﬁltered, and concentrated. The e was puriﬁed by ﬂash chromatography (silica gel, 0-25 % ethyl acetate in heptane) to provide the title compound (6.1 g, 51 %).

Example 45e N-Zerl-butyl{5-(2-hydroxypropanyl)[2-methyl(triﬂuoromethyl)phenoxy]pyridin- 3-yl}methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide e 45e was prepared according to the procedure used for the preparation of Example 37, substituting Example 45d for Example 29b. Puriﬁcation by ﬂash chromatography (silica gel, 2-4 % methanol in dichloromethane) ed the title compound (57 mg, 85 %).1H NMR (400 MHz, DMSO-d6) 5 12.44 (s, 1H), 8.07 (d, J: 2.4 Hz, 1H), 7.98 (d, J: 2.4 Hz, 1H), 7.84 (s, 1H), 7.55 (dd, J: 7.7, 3.0 Hz, 2H), 7.38 (s, 1H), 7.31 (t, J: 7.7 Hz, 1H), 6.79 (d, J: 1.7 Hz, 1H), 5.19 (s, 1H), 3.56 (s, 3H), 1.97 (s, 3H), 1.44 (s, 6H), 1.34 (s, 9H). MS (ESI+) m/z 557 (M+H)+.

Example 46 4- { 5 -(2-hydroxypropanyl)[2-methyl(t1iﬂuoromethyl)phenoxy]pyridin-3 -yl } methyloxo-N-(1,1,1-triﬂuoromethylpropanyl)-6,7-dihydro-1H—pyrrolo[2,3 - c]pyridinecarboxamide Example 46 was ed according to the procedure used for the preparation of 2O Example 37, substituting Example 38b for Example 32c, and substituting Example 45d for Example 29b. Puriﬁcation by ﬂash chromatography (silica gel, 2-4 % methanol in dichloromethane) ed the title compound (61 mg, 83%). 1H NMR (400 MHz, DMSO- d6) 5 12.56 (s, 1H), 8.09 — 8.06 (m, 2H), 7.98 (d, J: 2.4 Hz, 1H), 7.55 (dd, J: 7.7, 3.2 Hz, 2H), 7.39 (s, 1H), 7.30 (t, J: 7.7 Hz, 1H), 6.89 (d, J: 1.7 Hz, 1H), 5.18 (s, 1H), 3.56 (s, 3H), 1.97 (s, 3H), 1.58 (s, 6H), 1.44 (s, 6H). MS (ESI+) m/z 611 (M+H)+.

Example 47 N-(2,2-diﬂuoromethyl cyclopropyl){ 5 -(2-hydroxypropanyl) hyl (triﬂuoromethyl)phenoxy]pyridin-3 -yl } methyloxo-6,7-dihydro- 1H-pyrrolo[2, 3 - c]pyridinecarboxamide id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364" id="p-364"

[00364] Example 47 was prepared according to the procedure used for the preparation of Example 37, substituting Example 34c for Example 32c and tuting Example 45d for Example 29b. Puriﬁcation by ﬂash tography (silica gel, 2-4% methanol in dichloromethane) provided the title nd (53 mg, 75%). 1H NMR (400 MHz, DMSO-d6) 12.39 (s, 1H), 8.76 (s, 1H), 8.08 (d, J: 2.4 Hz, 1H), 7.97 (d, J: 2.4 Hz, 1H), 7.55 (dd, J: 104104 7.7, 3.1 Hz, 2H), 7.37 (s, 1H), 7.30 (t, J: 7.7 Hz, 1H), 6.85 (s, 1H), 5.18 (s, 1H), 3.55 (s, 3H), 1.97 (d, J: 3.9 Hz, 3H), 1.70 — 1.53 (m, 2H), 1.45 (s, 6H), 1.42 (s, 3H). MS (ESI+) m/z 591 (M+H)+.

Example 48 N—ethyl{5-(2-hydroxypropanyl)[2-methyl(t1iﬂuoromethyl)phenoxy]pyridin-3 -yl}- 6-methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 48 was prepared according to the procedure used for the preparation of Example 1m, substituting e 45d for Example 11. 1H NMR (400 MHz, Methanol-d4) 5 8.12 (s, 2H), 7.54 (dd, J = 16.8, 7.7 Hz, 2H), 7.48 (s, 1H), 7.31 (t, J = 7.7 Hz, 1H), 6.97 (s, 1H), 3.70 (s, 3H), 3.41 (q, J = 7.3 Hz, 2H), 2.02 (s, 3H), 1.60 (s, 6H), 1.23 (t, J = 7.2 Hz, 3H).

MS (ESI+) m/z 529.2 (M+H)+.

Example 49 4-[2-(2-chloroﬂuoromethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 49a methyl 3-bromo(2-chloroﬂuoromethylphenoxy)benzoate Example 49a was ed according to the procedure used for the preparation of Example 35b, substituting 2-chloroﬂuoromethylphenol for Example 35a.

Example 49b 2-(3 -bromo(2-chloroﬂuoromethylphenoxy)phenyl)propanol Example 49b was prepared according to the procedure used for the preparation of Example 35c, substituting Example 49a for Example 35b.

Example 49c 4-[2-(2-chloroﬂuoromethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 49c was prepared ing to the ure used for the preparation of Example 1m, tuting Example 49b for Example 11. 1H NMR (400 MHz, Methanol-d4) 5 7.55 (d, J: 2.4 Hz, 1H), 7.31 (s, 1H), 7.26 (dd, J: 8.7, 2.4 Hz, 1H), 7.08 (dd, J: 8.1, 3.1 Hz, 1H), 6.94 (dd, J: 8.9, 3.0 Hz, 1H), 6.91 (s, 1H), 6.33 (d, J: 8.6 Hz, 1H), 3.62 (s, 3H), 3.31 (q, J: 7.2 Hz, 2H), 2.01 (s, 3H), 1.47 (s, 6H), 1.12 (t, J: 7.2 Hz, 3H). MS (ESI+) m/z 512.2 (M+H)+.

N—lerl—butyl[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)py1idin-3 -yl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide 105105 The triﬂuoroacetic acid salt of Example 50 was prepared according to the procedure used for the preparation of Example 1m, substituting Example 32c for Example 1h. 1H NMR (400 MHz, DMSO-dg) 6 12.44 (s, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.87 (s, 1H), 7.44 (s, 1H), 7.05 (d, J = 7.1 Hz, 2H), 7.02 - 6.96 (m, 1H), 6.87 (d, J = 2.0 Hz, 1H), 3.60 (s, 3H), 1.98 (s, 6H), 1.46 (s, 6H), 1.35 (s, 9H). MS (ESI+) m/z 512.2 (M+H)+.

Example 51 N-ZerZ-butyl[2-(2-chloroﬂuoromethylphenoxy)-5 -(2-hydroxypropanyl)pyridin-3 - yl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 51a methyl 5-bromo(2-chloroﬂuoromethylphenoxy)nicotinate Example 51a was prepared according to the procedure used for the preparation of Example 35b, substituting methyl ochloronicotinate for methyl 3-bromo ﬂuorobenzoate, and substituting 2-chloroﬂuoromethylphenol for Example 35a.

Example 51b 2-(5-bromo(2-chloroﬂuoromethylphenoxy)py1idinyl)propanol Example 51b was prepared according to the procedure used for the preparation of Example 35c, substituting Example 51a for Example 35b.

Example 51c N-ZerZ-butyl[2-(2-chloroﬂuoromethylphenoxy)-5 -(2-hydroxypropanyl)pyridin-3 - 2O yl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 51c was prepared according to the procedure used for the preparation of Example 37, substituting Example 51b for Example 29b. 1H NMR (400 MHz, ol-d4) 6 8.03 (d, J: 2.3 Hz, 1H), 7.97 (d, J: 2.4 Hz, 1H), 7.38 (s, 1H), 7.04 (dd, J: 8.2, 3.0 Hz, 1H), 6.96 (s, 1H), 6.91 (dd, J: 8.9, 3.0 Hz, 1H), 3.62 (s, 3H), 2.02 (s, 3H), 1.50 (s, 6H), 1.36 (s, 9H). MS (ESI+) m/z 541.2 .

Example 52 4-[2-(2-chloroﬂuoromethylphenoxy)(2-hydroxypropanyl)pyridinyl]-N-ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 52 was ed according to the procedure used for the preparation of Example 1m, substituting Example 51b for e 11. 1H NMR (400 MHz, DMSO-dg) 6 12.30 (s, 1H), 8.32 (t, J = 5.4 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.45 (s, 1H), 7.33 (dd, J = 8.3, 3.0 Hz, 1H), 7.17 (dd, J = 9.3, 3.0 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 3.59 (s, 3H), 3.25 (td, J = 7.3, 5.4 Hz, 2H), 2.07 (s, 3H), 1.47 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 513.2 (M+H)+. 106106 Example 53 N—ZerZ-butyl[2-(2-chloroﬂuoromethylphenoxy)(2-hydroxypropanyl)phenyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 53 was prepared according to the ure used for the preparation of Example 37, substituting Example 49b for Example 29b. 1H NMR (400 MHz, Methanol-d4) 7.63 (d, J = 2.4 Hz, 1H), 7.41 = 8.1, 3.0Hz, 1H), 7.06 - 7.32 (m, 2H), 7.17 (dd, J - 6.99 (m, 2H), 6.41 (d, J = 8.6 Hz, 1H), 3.71 (s, 3H), 2.09 (s, 3H), 1.56 (s, 6H), 1.44 (s,9H). MS (ESI+) m/z 540.2 (M+H)+.

Example 54 N-lerl-butyl{ 5 -(2-hydroxypropanyl)[2-methyl(triﬂuoromethyl)phenoxy]phenyl } - 6-methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 54 was prepared according to the procedure used for the preparation of Example 37, substituting Example 28d for Example 29b. 1H NMR (400 MHz, DMSO-dg) 5 12.37 (s, 1H), 7.84 (s, 1H), 7.64 - 7.58 (m, 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.31 (dd, J = 8.6, 2.4 Hz, 1H), 7.28 (s, 1H), 6.78 (d, J = 1.7 Hz, 1H), 6.31 (d, J = 8.6 Hz, 1H), 5.01 (s, 1H), 3.57 (s, 3H), 1.92 (s, 3H), 1.43 (s, 6H), 1.36 (s, 9H). MS (ESI+) m/z 556.4 (M+H)+.

Example 55 4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo-N- (1 , 1 , 1 -triﬂuoromethylpropanyl)-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide Example 55 was ed ing to the ure used for the preparation of Example 35d, substituting Example 38b for Example 1h. 1H NMR (400 MHz, Methanol-d4) d 7.61 (d, J = 2.4 Hz, 1H), 7.45 7.25 (m, 2H), 7.06 (s, 1H), 6.83 (d, J = 8.9 Hz, 2H), 6.39 (d, J = 8.6 Hz, 1H), 3.72 (s, 3H), 2.05 (s, 6H), 1.67 (s, 6H), 1.55 (s, 6H). MS (ESI+) m/z 574.2 (M+H)+.

Example 56 4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl]methyl oxo-N-(1 1 oromethylpropanyl)-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine carboxamide id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377" id="p-377"

[00377] A mixture of Example 43b (80 mg, 0.226 mmol), Example 38b (106 mg, 0.248 mmol), tris(dibenzylideneacetone)dipalladium(0) (7.65 mg, 8.36 umol), potassium phosphate tribasic (144 mg, 0.678 mmol) and 1,3,5,7-tetramethylphenyl-2,4,8-t1ioxa phosphaadamantane (8.85 mg, 0.030 mmol) in tetrahydrofuran (2.5 mL) and water (0.6 mL) was heated in a microwave reactor at 70 0C for 2 hours under nitrogen. The reaction mixture 107107 was cooled, ioned between ethyl acetate and water, and the aqueous phase was extracted twice with ethyl acetate. The combined organics were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to provide the crude. The crude product was puriﬁed by preparative HPLC (Column: Waters HSS C18, 21*50 mm, 1.8 pm, Mobile Phase A: water/10 mmol ammonium carbonate, Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, nt: 25 % B to 50 % B in 5 min, hold 0.5 min, 254 nm) to provide the title compound (68 mg, 0.118 mmol, 52.4 % yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) 5 8.03 (d, J: 2.5 Hz, 1H), 7.95 (d, J: 2.5 Hz, 1H), 7.34 (s, 1H), 6.97 (s, 1H), 6.71 (d, J: 8.9 Hz, 2H), 3.62 (s, 3H), 1.94 (s, 6H), 1.58 (s, 6H), 1.49 (s, 6H). MS (ESI+) m/z 575.2 (M+H)+.

Example 57 4-[2-(2-chlorofluoromethylphenoxy)(2-hydroxypropanyl)phenyl]methyl oxo-N-(1 1 -t1iﬂuoromethylpropanyl)-6,7-dihydro- rolo[2,3 -c]pyridine carboxamide Example 57 was prepared according to the ure used for the preparation of Example 56, substituting Example 49b for Example 43b, and heating in a microwave reactor at 60 0C for two hours. 1H NMR (400 MHz, Methanol-d4) 5 7.54 (d, J = 2.4 Hz, 1H), 7.29 (s, 1H), 7.26 (dd, J: 8.6, 2.4 Hz, 1H), 7.06 (dd, J: 8.1, 3.0 Hz, 1H), 7.02 (s, 1H), 6.96 — 6.89 (m, 1H), 6.32 (d, J: 8.6 Hz, 1H), 3.62 (s, 3H), 2.00 (s, 3H), 1.57 (s, 6H), 1.46 (s, 6H). MS (ESI+) m/z 594.2 (M+H)+. 2O Example 58 4-[2-(2-chlorofluoromethylphenoxy)(2-hydroxypropanyl)pyIidin-3 -yl]methyl- 7-oxo-N—(1,1,1-triﬂuoromethylpropanyl)-6,7-dihydro-1H—pyrrolo[2,3 -c]pyridine carboxamide The triﬂuoroacetic acid salt of e 58 was ed according to the procedure used for the preparation of Example 56, substituting Example 5 lb for Example 43b. The e was heated in a microwave reactor at 60 0C for two hours, and the crude product was puriﬁed by HPLC (C18 column, CH3CN/water (0.1 % triﬂuoroacetic acid)). 1H NMR (400 MHz, Methanol-d4) 5 8.03 (d, J: 2.4 Hz, 1H), 7.96 (d, J: 2.5 Hz, 1H), 7.37 (s, 1H), 6.99 — 7.04 (m, 2H), 6.90 (dd, J: 9.1, 3.1 Hz, 1H), 3.62 (s, 3H), 2.01 (s, 3H), 1.57 (s, 6H), 1.49 (s, 6H). MS (ESI+) m/z 595.2 (M+H)+.

Example 59 4-[2-(2-chlorofluoromethylphenoxy)(2-hydroxypropanyl)phenyl]-N-(2,2- diﬂuoro-l-methylcyclopropyl)methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]py1idine carboxamide 108108 A e of tris(dibenzylideneacetone)dipalladium(0) (9.19 mg, 10.04 umol), Example 49b (0.075 g, 0.201 mmol), Example 34c (0.090 g, 0.221 mmol), 1,3,5,7- tetramethylphenyl-2,4,8-trioxaphosphaadamantane (5.86 mg, 0.020 mmol), and potassium phosphate tribasic (0.128 g, 0.602 mmol) in tetrahydrofuran (4 mL) water (1 mL) was heated in a microwave reactor at 60 0C under nitrogen for 2 hours. After cooling to t temperature, the mixture was ﬁltered through a pad of diatomaceous earth and washed with ethyl acetate (30 mL). The ﬁltrate was washed with water (20 mL), and concentrated to dryness. The crude product was puriﬁed by Preparative HPLC (Column: Waters HSS C18, 2.1*50 mm, 1.8 pm, Mobile Phase A: water/10 mmol ammonium carbonate, Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, Gradient: 25 % B to 50 % B in 5 min, hold 0.5 min, 254 nm), and the collected fractions was lyophilized to provide the title compound (0.038 g, 0.066 mmol, 33.0 % yield). 1H NMR (400 MHz, Methanol-d4) 5 7.54 (d, J: 2.4 Hz, 1H), 7.30 (s, 1H), 7.25 (dd, J: 8.7, 2.4 Hz, 1H), 7.06 (dd, J: 8.1, 3.0 Hz, 1H), 6.95 — 6.88 (m, 2H), 6.31 (d, J: 8.6 Hz, 1H), 3.61 (s, 3H), 1.99 (s, 3H), 1.45—1.55 (m, 2H), 1.46 (s, 6H), 1.43 (s, 3H). MS (ESI+) m/z 594.2 .

Example 60 N—(2,2-diﬂuoromethylcyclopropyl)[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2- hydroxypropanyl)phenyl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridine carboxamide id="p-381" id="p-381" id="p-381" id="p-381" id="p-381" id="p-381" id="p-381" id="p-381" id="p-381" id="p-381" id="p-381" id="p-381" id="p-381"

[00381] Example 60 was prepared according to the procedure used for the ation of Example 59, substituting Example 35c for Example 49b, and heating in a microwave reactor at 70 °C for two hours. 1H NMR (400 MHz, Methanol-d4) 5 7.52 (s, 1H), 7.2 — 7.3 (m, 2H), 6.87 (s, 1H), 6.73 (d, J: 8.9 Hz, 2H), 6.30 (d, J: 8.6 Hz, 1H), 3.62 (s, 3H), 1.95 (s, 6H), 1.35 — 1.55 (m, 11H). MS (ESI+) m/z 554.2 .

Example 61 N—(2,2-diﬂuoromethylcyclopropyl)[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2- hydroxypropanyl)pyridin-3 -yl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridine carboxamide Example 61 was prepared according to the procedure used for the preparation of e 59, substituting e 43b for Example 49b, and heating in a microwave reactor at 70 0C for two hours. 1H NMR (400 MHz, ol-d4) 5 8.02 (d, J = 2.5 Hz, 1H), 7.95 (d, J: 2.5 Hz, 1H), 7.34 (s, 1H), 6.87 (s, 1H), 6.70 (d, J: 8.9 Hz, 2H), 3.62 (s, 3H), 1.93 (s, 6H), 1.45 — 1.55 (m, 8H), 1.43 (q, J: 2.7 Hz, 3H). ). MS (ESI+) m/z 555.2 (M+H)+.

Example 62 109109 4-[2-(2-chloroﬂuoromethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl]-N—(2,2- diﬂuoromethylcyclopropyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3 -c]pyridine carboxamide ] Example 62 was prepared according to the procedure used for the ation of Example 59, substituting Example 5 lb for Example 49b. 1H NMR (400 MHz, Methanol-d4) 8.03 (d, J: 2.4 Hz, 1H), 7.97 (d, J: 2.5 Hz, 1H), 7.40 (s, 1H), 7.03 (dd, J: 8.1, 3.0 Hz, 1H), 6.88 — 6.98 (m, 2H), 3.62 (s, 3H), 2.02 (s, 3H), 1.45 — 1.55 (m, 8H), 1.44 (s, 3H). MS (ESI+) m/z 575.2 (M+H)+.

Example 63 N-(bicyclo[ 1 . 1 . anyl)[2-(2-chloromethylphenoxy)(2-hydroxypropan yl)py1idinyl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 63a N—(bicyclo[l . l . l]pentan- l -yl)bromomethyloxo-6,7-dihydro- 1H-pyrrolo[2,3- dinecarboxamide id="p-384" id="p-384" id="p-384" id="p-384" id="p-384" id="p-384" id="p-384" id="p-384" id="p-384" id="p-384" id="p-384" id="p-384" id="p-384"

[00384] Example 63a was prepared according to the procedure used for the preparation of Example 32b, replacing 2-methylpropanamine with o[1.1.1]pentanamine.

Example 63b yclo[1.1.1]pentanyl)methyloxo(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide id="p-385" id="p-385" id="p-385" id="p-385" id="p-385" id="p-385" id="p-385" id="p-385" id="p-385" id="p-385" id="p-385" id="p-385" id="p-385"

[00385] Example 63b was prepared according to the procedure used for the preparation of Example 32c, replacing Example 32b with Example 63a.

Example 63c N-(bicyclo[ 1 . 1 . l]pentanyl)[2-(2-chloromethylphenoxy)(2-hydroxypropan yl)py1idinyl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide id="p-386" id="p-386" id="p-386" id="p-386" id="p-386" id="p-386" id="p-386" id="p-386" id="p-386" id="p-386" id="p-386" id="p-386" id="p-386"

[00386] A mixture of Example 29b (40 mg, 0.112 mmol), Example 63b (47.3 mg, 0.123 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.80 mg, 4.15 umol), potassium ate tribasic (71.4 mg, 0.336 mmol) and 7-tetramethylphenyl-2,4,8-trioxa phosphaadamantane (4.39 mg, 0.015 mmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was heated in a microwave reactor at 80 0C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate and water, the s phase was extracted twice with ethyl acetate, and the combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by preparative HPLC (Column:Waters HSS C18, 2.1*50 mm,1.8 um, Mobile Phase Azwater/10 mmol ammonium 110110 carbonate, Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, Gradient:25 % B to 50 % B in 5 min, hold 0.5 min, 254 nm) to provide the title compound (11 mg, 0.021 mmol, 18.40 % yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) 5 8.01 (s, 1H), 7.97 (s, 1H), 7.43 (s, 1H), 7.20 (d, J: 7.8 Hz, 1H), 7.11 (d, J: 7.4 Hz, 1H), 7.02 (t, J: 7.7 Hz, 1H), 6.93 (s, 1H), 3.62 (s, 2H), 2.38 (s, 1H), 2.08 (s, 6H), 2.02 (s, 3H), 1.50 (s, 6H). MS (ESI+) m/z 533.2 (M+H)+.

Example 64 4-[2-(2,6-dimethylphenoxy)ﬁuoro(2-hydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro- rolo[2,3-c]pyridinecarboxamide Example 64a methyl 5-bromo-2,4-diﬁuorobenzoate To a solution of 5-bromo-2,4-diﬁuorobenzoic acid (400 mg, 1.688 mmol) in methanol (8.44 mL) was added thionyl chloride (0.493 mL, 6.75 mmol) and the on mixture was stirred at 65 0C for 1 hour. The reaction mixture was poured into 50 mL ice-water and then partitioned with ethyl acetate (3 x 30 mL). The organic layer was washed with ted aqueous sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated under reduced pressure. The residue was puriﬁed by ﬂash chromatography (silica gel, hexanes) to provide the title nd (0.269 g, 1.05 mmol, 62.3 % .

Example 64b methyl 5-bromo(2,6-dimethylphenoxy)ﬁuorobenzoate A e of cesium ate 1.537 g, 4.72 mmol), 2,6-dimethylphenol (0.137 g, 1.120 mmol), and Example 64a (0.296 g, 1.179 mmol) in dimethyl sulfoxide (6 mL) was stirred at 80 0C for 1 hour. The reaction e was poured into ice-water (50 mL) and partitioned with ethyl acetate (3 x 30 mL). The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated under d pressure. The residue was puriﬁed by ﬂash chromatography (hexanes) to provide the title compound (0.362 g, 1.026 mmol, 87 % yield) as colorless oil.

Example 64c 2-(5-bromo(2,6-dimethylphenoxy)ﬁuorophenyl)propanol id="p-389" id="p-389" id="p-389" id="p-389" id="p-389" id="p-389" id="p-389" id="p-389" id="p-389" id="p-389" id="p-389" id="p-389" id="p-389"

[00389] Example 64c was prepared according to the procedure used for the preparation of Example 35c, replacing Example 35b with example 64b.

Example 64d 4-[2-(2,6-dimethylphenoxy)ﬁuoro(2-hydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide 111111 e 64d was prepared according to the procedure used for the preparation of e 1m, substituting Example 64c for Example 11. 1H NMR (400 MHz, Methanol-d4) 5 7.65 (d, J: 9.2 Hz, 1H), 7.27 (s, 1H), 7.05 — 6.93 (m, 3H), 6.86 (s, 1H), 5.98 (d, J: 13.2 Hz, 1H), 3.62 (s, 3H), 3.31 (q, J: 7.2 Hz, 2H), 1.98 (s, 6H), 1.50 (d, J: 1.0 Hz,6H),1.12(t,J= 7.2 Hz, 3H). MS (ESI+) m/z 492.2 (M+H)+.

Example 65 N-ethyl[4-ﬂuoro(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl] methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide Example 65a methyl 5-bromofluoro(4-ﬂuoro-2,6-dimethylphenoxy)benzoate Example 65a was prepared according to the procedure used for the preparation of Example 64b, ing 2,6-dimethylphenol with 4-ﬂuoro-2,6-dimethylphenol.

Example 65b 2-(5-bromoﬂuoro(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)propanol id="p-392" id="p-392" id="p-392" id="p-392" id="p-392" id="p-392" id="p-392" id="p-392" id="p-392" id="p-392" id="p-392" id="p-392" id="p-392"

[00392] Example 65b was prepared ing to the procedure used for the preparation of e 35c, replacing Example 35b with example 65a.

Example 65c N-ethyl[4-ﬂuoro(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl] methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide id="p-393" id="p-393" id="p-393" id="p-393" id="p-393" id="p-393" id="p-393" id="p-393" id="p-393" id="p-393" id="p-393" id="p-393" id="p-393"

[00393] Example 65c was prepared according to the procedure used for the preparation of Example 1m, substituting Example 65b for Example 11. 1H NMR (400 MHz, DMSO-d6) 5 12.21 (d, J: 2.3 Hz, 1H), 8.27 (t, J: 5.4 Hz, 1H), 7.59 (d, J: 9.3 Hz, 1H), 7.27 (s, 1H), 6.95 (d, J: 9.1 Hz, 2H), 6.75 (d, J: 2.1 Hz, 1H), 6.01 (d, J: 12.9 Hz, 1H), 5.22 (s, 1H), 3.26 (s, 2H), 3.20 (m, 2H), 1.96 (s, 6H), 1.42 (s, 6H), 1.05 (t, J: 7.2 Hz, 3H). MS (ESI+) m/z 510.2 (M+H)+.

Example 66 4-[5-(1,2-dihydroxypropanyl)(2,6-dimethylphenoxy)phenyl]-N-ethylmethyloxo- 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide Example 66a 2-(2-bromo(prop-l-enyl)phenoxy)-1,3-dimethylbenzene To a mixture of methyltriphenylphosponium bromide (3.68 g, 10.34 mmol) in anhydrous tetrahydrofuran (40 mL) was added n-butyllithium in hexane (6.46 mL, 10.34 mmol) at 0 0C, and the mixture was d at 0 0C for 1 hour. To the mixture was added dropwise a solution of Example 3c (3 g, 9.40 mmol) in ous tetrahydrofuran (10 mL) at 112112 0 oC, and the mixture was allowed to warm to room temperature slowly for 16 hours. The e was partitioned between water (50 mL) and ethyl acetate (30 mL), extracted with ethyl e (30 mL), dried over ous sodium sulfate, ﬁltered, and concentrated under reduced pressure. The residue was puriﬁed by ﬂash chromatography (silica gel, eluting with hexane) to provide the title compound (2 g, 6.30 mmol, 67.1 % yield) as colorless oil.

Example 66b 2-(3 -bromo(2,6-dimethylphenoxy)phenyl)propane-1,2-diol To a mixture of Example 66a (0.2 g, 0.630 mmol) in water (10 mL) and ZerZ-butanol (10 mL) was added potassium ate (0.261 g, 1.891 mmol), potassium osmate hydrate (4.67 mg, 0.013 mmol) and potassium hexacyanoferrate (111) (0.933 g, 2.84 mmol) at 0 CC, and the mixture was stirred at ambient temperature for 48 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate, dried over ous sodium sulfate, ﬁltered, and concentrated to provide the title compound (0.2 g, 0.199 mmol, 31.6 % yield), which was contaminated with Example 66a. This material was used in Example 66c without further puriﬁcation.

Example 66c 4- [5 -(1,2-dihydroxypropanyl)(2,6-dimethylphenoxy)phenyl]-N—ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide A mixture of tris(dibenzylideneacetone)dipalladium (7.82 mg, 8.54 umol), Example 66b (0.2 g, 0.171 mmol), Example 1h (0.071 g, 0.205 mmol), 1,3,5,7-tetramethylphenyl- 2,4,8-trioxaphosphaadamantane (4.99 mg, 0.017 mmol) and potassium ate (0.109 g, 0.512 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was heated in a microwave r at 60 0C under nitrogen for 2 hours. After cooling to room temperature, the e was ﬁltered through a pad of aceous earth, rinsing with ethyl acetate (30 mL). The ﬁltrate was washed with water (20 mL), dried over anhydrous sodium sulfate, ﬁltered, and concentrated to dryness. The crude product was puriﬁed by prep-HPLC (Column: Waters HSS C18, 21*50 mm, 1.8 pm, Mobile Phase A: water/10 mmol ammonium carbonate, Mobile Phase B: acetonitrile, Flow rate: 25 mL/min, Gradient: 25 % B to 50 % B in 5 min, hold 0.5 min, 254 nm), and the fractions collected were concentrated under reduced pressure.

The e was lyophilized to provide the title compound (0.03 g, 0.061 mmol, 35.9 % yield). 1HNMR (400 MHz, DMSO-dg) 5 12.24 (s, 1H), 8.34 (s, 1H), 7.51 (s, 1H), 7.35 — 7.25 (m, 2H), 7.15—7.00 (m, 3H), 6.86 (s, 1H), 6.26 (d, J = 8.2 Hz, 1H), 4.86 (s, 1H), 4.70 (s, 1H), 3.59 (s, 3H), .20 (m, 4H), 2.00 (s, 6H), 1.39 (s, 3H), 1.16 — 1.05 (m, 3H). MS (ESI+) m/z 490.5 (M+H)+. 113113 Example 67 4-[5-(2,4-dihydroxybutanyl)(2,6-dimethylphenoxy)phenyl]-N-ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 67a 2-(3 -bromo(2,6-dimethylphenoxy)phenyl)butenol To a solution of Example 3c (0.5 g, 1.566 mmol) in tetrahydrofuran (10 mL) was added vinylmagnesium bromide (1M in tetrahydrofuran, 1.6 mL) at 0 oC, and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between water and ethyl acetate, and extracted with ethyl acetate. The ed extracts were concentrated to dryness and the crude product was puriﬁed by ﬂash chromatography a gel, ethyl acetate/hexanes) to provide the title compound (0.2 g, 0.576 mmol, 36.8 % yield).

Example 67b 3 -(3 -bromo(2,6-dimethylphenoxy)phenyl)butane-1, 3 -diol ] To a solution of Example 67a (0.4 g, 1.152 mmol) in tetrahydrofuran (5 mL) was added borane-tetrahydrofuran complex (2.304 mL, 2.304 mmol) at 0 OC, and the mixture was d at 0 0C for 3 hours. To the e was added 5 M sodium hydroxide in water (0.276 g, 6.91 mmol) slowly, followed by 30 % en peroxide (1.883 mL, 18.43 mmol), and the mixture was stirred at ambient temperature for 16 hours. The e was partitioned between water and ethyl acetate, ted with ethyl acetate, dried over anhydrous sodium sulfate, ﬁltered, and concentrated to provide the title compound (0.4 g, 95 % yield).

Example 67c 4-[5-(2,4-dihydroxybutanyl)(2,6-dimethylphenoxy)phenyl]-N-ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide ] Example 67c was prepared according to the procedure used for the preparation of Example 1m, substituting Example 67b for Example 11. 1H NMR (400 MHz, Methanol-d4) 5 7.59 (d, J: 2.4 Hz, 1H), 7.38 (s, 1H), 7.28 (dd, J: 8.7, 2.4 Hz, 1H), 7.13 — 6.99 (m, 3H), 6.96 (s, 1H), 6.40 (d, J: 8.7 Hz, 1H), 3.72 (s, 3H), 3.67 — 3.49 (m, 2H), 3.40 (q, J: 7.2 Hz, 2H), 2.0 — 2.1 (m, 8H), 1.56 (s, 3H), 1.21 (t, J = 7.2 Hz, 4H). MS (ESI+) m/z 504.5 .

Example 68 4-{ 5 -[(2R)-1,2-dihydroxypropanyl](2,6-dimethylphenoxy)phenyl } -N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 68 was obtained as the ﬁrst eluting enantiomer from the separation of the two enantiomers of Example 66c by chiral SFC-HPLC (70% (C02):30% methanol (0.1% triﬂuoroacetic acid as additive, AD-H column (10 mmx250 mm, 5 pm). 1H NMR (400 MHz, 114114 6) 5 12.17 (bs, 1H), 8.28 (t, J: 5.3 Hz, 1H), 7.45 (d, J: 2.3 Hz, 1H), 7.27 (s, 1H), 7.22 (dd, J: 8.5, 2.3 Hz, 1H), 7.05 (d, J: 7.4 Hz, 2H), 6.98 (dd, J: 8.5, 6.3 Hz, 1H), 6.80 (s, 1H), 6.21 (d, J: 8.6 Hz, 1H), 4.79 (s, 1H), 4.63 (t, J: 5.8 Hz, 1H), 3.53 (s, 3H), 3.34 (m, 1H), 3.20 (dd, J: 7.3, 5.4 Hz, 1H), 2.01 (s, 1H), 1.95 (s, 6H), 1.33 (s, 3H), 1.05 (t, J: 7.2 Hz, 3H). MS (ESI+) m/z 490.5 (M+H)+. Stereochemistry was assigned arbitrarily.

Example 69 4- { 5 -[(25)—1,2-dihydroxypropanyl](2,6-dimethylphenoxy)phenyl } -N—ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 69 was ed as the second eluting enantiomer from the separation of the two enantiomers of Example 66c by chiral SFC-HPLC (70% (C02):30% methanol (0.1% triﬂuoroacetic acid as additive, AD-H column (10 mmx250 mm, 5 pm). 1H NMR (400 MHz, DMSO-d6) 5 12.17 (s, 1H), 8.28 (t, J: 5.4 Hz, 1H), 7.45 (d, J: 2.4 Hz, 1H), 7.27 (s, 1H), 7.22 (dd, J: 8.6, 2.3 Hz, 1H), 7.05 (d, J: 7.4 Hz, 2H), 6.99 (dd, J: 8.5, 6.3 Hz, 1H), 6.80 (s, 1H), 6.21 (d, J: 8.6 Hz, 1H), 4.80 (s, 1H), 4.63 (t, J: 5.8 Hz, 1H), 3.53 (s, 3H), 3.34 (m, 1H), 3.24 — 3.15 (m, 1H), 1.95 (s, 6H), 1.33 (s, 3H), 1.17 (s, 1H), 1.05 (t, J: 7.3 Hz, 3H).

MS (ESI+) m/z 490.5 (M+H)+. Stereochemistry was assigned arbitrarily.

Example 70 4- { 2-[2-(diﬂuoromethyl)methylphenoxy] -5 -(2-hydroxypropanyl)phenyl } -N-ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide Example 70a methyl 3-bromo(2-formylmethylphenoxy)benzoate Example 70a was prepared according to the procedure used for the preparation of e 35b, tuting 2-hydroxy-3 -methylbenzaldehyde for Example 35a.

Example 70b methyl 3-bromo(2-(diﬂuoromethyl)methylphenoxy)benzoate Example 70a (0.56 g, 1.604 mmol) in dichloromethane (20 mL) was treated with DAST (diethylaminosulfur triﬂuoride) (0.636 mL, 4.81 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature overnight, and treated with saturated aqueous sodium carbonate. The aqueous layer was ted with additional dichloromethane three times. The combined c layers were washed with brine, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated. The e was puriﬁed by ﬂash column chromatography on silica gel eluting with 10% ethyl acetate in heptanes to provide the title compound (0.52 g, 1.401 mmol, 87 % yield).

Example 70c 115115 2-(3 -bromo(2-(diﬂuoromethyl)methylphenoxy)phenyl)propanol Example 70c was prepared according to the procedure used for the preparation of Example 28d, substituting Example 70b for e 28c. e 70d 4- { 2-[2-(diﬂuoromethyl)methylphenoxy] -5 -(2-hydroxypropanyl)phenyl } -N-ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 70d was prepared according to the procedure used for the preparation of Example 1m, substituting Example 70c for Example 11. 1H NMR (501 MHz, DMSO-dg) 5 12.22 (d, J = 2.3 Hz, 1H), 8.33 (t, J = 5.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.39 (s, 1H), 7.35 — 7.30 (m, 2H), 6.94 (J = 57.4 Hz, 1H), 6.84 (t, J = 2.2 Hz, 1H), 6.31 (d, J = 8.6 Hz, 1H), 3.57 (s, 3H), 3.26 (qd, J = 7.2, 5.3 Hz, 2H), 1.90 (s, 3H), 1.43 (s, 6H), 1.11 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 510.1 (M+H)+.

Example 71 N-lerl—butyl { 2- [2-(diﬂuoromethyl)methylphenoxy] (2-hydroxypropanyl)phenyl } - 6-methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 71 was prepared according to the procedure used for the preparation of Example 1m, substituting Example 70c for Example 11, and tuting Example 32c for Example 1h, respectively. 1H NMR (400 MHz, DMSO-dg) 5 12.32 (d, J = 2.4 Hz, 1H), 7.82 (s, 1H), 7.69 — 7.23 (m, 5H), 6.95 (d, J = 54.8 Hz, 1H), 6.84 (t, J = 2.2 Hz, 1H), 6.30 (d, J = 2O 8.6 Hz, 1H), 3.58 (s, 3H), 1.89 (s, 3H), 1.42 (s, 6H), 1.36 (s, 9H). MS (ESI+) m/z 538.1 (M+H)+.

Example 72 4-[2-(4-bromo-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N—ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 72a 4-(5-acetylﬂuorophenyl)-N—ethylmethyloxo-6,7-dihydro- rolo[2,3-c]pyridine- 2-carboxamide 3'-bromo-4'-ﬂuoroacetophenone (0.126 g, 0.579 mmol), Example 1h (0.2 g, 0.579 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.016 g, 0.017 mmol), 1,3,5,7-tetramethyl- 6-phenyl-2,4,8-trioxaphosphaadamantane (0.017 g, 0.058 mmol) and sodium carbonate (0.246 g, 2.317 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 tetrahydrofuran/water (6.0 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the on vessel under argon. The mixture was stirred for 6 hours under argon at 60 0C, , and ioned between water and ethyl acetate. The 116116 organic layer was washed with ted aqueous sodium chloride, dried over anhydrous sodium sulfate, d with 3-mercaptopropyl functionalized silica gel, ﬁltered and concentrated. Puriﬁcation by trituration in 1:1 dichloromethane/heptanes (5 mL) provided the title compound as a white powder (0.180 g, 85%).

Example 72b 4-(5-acetyl(4-bromo-2,6-dimethylphenoxy)phenyl)-N-ethylmethyloxo-6,7-dihydro- 1H—pyrrolo[2,3-c]pyridinecarboxamide 4-bromo-2,6-dimethylphenol (0.204 g, 1.013 mmol), Example 72a (0.18 g, 0.507 mmol) and cesium carbonate (0.413 g, 1.266 mmol) were combined in dimethyl sulfoxide (1.688 mL) under argon in a sealed tube and heated at 90 0C for 18 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. ation by chromatography (silica, 30-60 % of 3 :1 ethyl acetate/ethanol in heptanes) provided the title compound (0.12 g, 43%).

Example 72c 4-[2-(4-bromo-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N—ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 72b (0.03 g, 0.056 mmol) in tetrahydrofuran (1.119 mL) under en at ambient temperature was d dropwise with 1.4 M methylmagnesium bromide in tetrahydrofuran (0.160 mL, 0.224 mmol). The mixture was stirred for 16 hours and partitioned n 5 % aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, d, and concentrated. Puriﬁcation by chromatography (silica, 1-10 % methanol in dichloromethane) provided the title compound (0.0018 g, 6 %). 1H NMR (500 MHz, DMSO- d6) 5 12.25 (s, 1H), 8.32 (t, J = 5.3 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.32 — 7.28 (m, 2H), 7.19 (d, J = 0.8 Hz, 2H), 6.81 (d, J = 2.1 Hz, 1H), 6.30 (d, J = 8.6 Hz, 1H), 4.97 (s, 1H), 3.58 (s, 3H), 3.24 (qd, J = 7.2, 5.3 Hz, 2H), 1.99 (s, 6H), 1.42 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 552 [M+H]+.‘ Example 73 4-[2-(4-cyano-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethylmethyl 7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide e 73a 4-(4-acetylbromophenoxy)-3,5-dimethylbenzonitrile 117117 4-hydroxy-3,5-dimethylbenzonitrile (0.356 g, 2.419 mmol), 3'-bromo-4'- ﬂuoroacetophenone (0.5 g, 2.304 mmol) and cesium carbonate (1.126 g, 3.46 mmol) were combined in dimethyl sulfoxide (7.68 mL) under argon in a sealed tube and heated at 90 0C for 18 hours. The e was cooled and partitioned between 5% aqueous sodium bicarbonate and ethyl e. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. Puriﬁcation by chromatography (silica, 0-40 % ethyl acetate in heptanes) provided the title nd (0.3 g, 51%).

Example 73b 4-(2-bromo(2-hydroxypropanyl)phenoxy)-3,5-dimethylbenzonitrile Example 73a (0.22 g, 0.639 mmol) in tetrahydrofuran (6.39 mL) under nitrogen at 0C was treated dropwise with 1.4 M methylmagnesium bromide in tetrahydrofuran (0.913 mL, 1.278 mmol). The mixture was stirred for 1 hour and partitioned between 5 % aqueous ammonium chloride and ethyl acetate. The c layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered and, concentrated. Puriﬁcation by chromatography (silica, 5-50 % ethyl acetate in heptanes) provided the title compound as a white solid (0.21 g, 88%).

Example 73c 4-cyano-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamid Example 73b (0.052 g, 0.145 mmol), Example 1h (0.05 g, 0.145 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.98 mg, 4.35 umol), 7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (4.23 mg, 0.014 mmol) and sodium carbonate (0.061 g, 0.579 mmol) were combined and sparged with argon for 15 s. Meanwhile a solution of 4:1 ydrofuran/water (1.5 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the on vessel under argon. The e was stirred for 16 hours under argon at 60 oC, cooled, and partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, ﬁltered, and concentrated. Puriﬁcation by chromatography (25-60 % of 3 :1 ethyl acetate/ethanol in heptanes) ed the title compound as a white solid (0.055 g, 73 %). 1H NMR (400 MHz, DMSO-dg) 5 12.19 (s, 1H), 8.30 (t, J = 5.4 Hz, 1H), 7.63 (s, 2H), 7.51 (d, J = 2.4 Hz, 1H), 7.30 (m, 2H), 6.80 (s, 1H), 6.29 (d, J = 8.6 Hz, 1H), 4.98 (s, 1H), 3.56 (s, 3H), 3.25 — 3.16 (m, 2H), 2.01 (s, 6H), 1.41 (s, 6H), 1.08 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 499 [M+H].‘ 118118 Example 74 4- { 2-[(2,4-dimethylpyridin-3 y] -5 droxypropanyl)phenyl } -N—ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 74a 1-(3 -bromo((2,4-dimethylpy1idin-3 -yl)oxy)phenyl)ethanone A suspension of 3'-bromo-4'-ﬁuoroacetophenone (1.0128 g, 4.67 mmol), 2,4- dimethylpyridinol (0.603 g, 4.90 mmol), and cesium carbonate (2.281 g, 7.00 mmol) in dimethyl sulfoxide (15.56 mL) was stirred at about 90 oC overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, d, and concentrated. The e was puriﬁed by ﬂash chromatography (10-70 % (3 :1 ethyl acetate:ethanol):heptanes) to provide the title compound as a ess oil (1.1753 g, 79%).

Example 74b 2-(3 -bromo((2,4-dimethylpyridin-3 y)phenyl)propanol To a solution of Example 74a (1 . 1753 g, 3.67 mmol) in tetrahydrofuran (25 mL) was added methylmagnesium bromide (4.46 mL, 6.24 mmol) dropwise. The reaction e was stirred at ambient temperature for 3 hours. The reaction mixture was quenched with saturated um chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous ium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (20-80% (3 :1 ethyl acetate:ethanol):heptanes) to provide the title compound as a colorless oil that solidiﬁed to a white solid upon standing overnight (0.7518 g, 61 %).

Example 74c 4- { 2-[(2,4-dimethylpyridin-3 -yl)oxy] -5 -(2-hydroxypropanyl)phenyl } -N—ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 74c (0.0858 g, 61 %) was prepared according to the procedure used for the ation of Example 1m, substituting Example 74b for Example 11. 1H NMR (400 MHz, DMSO-d6)512.21(s, 1H), 8.32 (t, J = 5.3 Hz, 1H), 8.17 (d, J = 4.9 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.34 (s, 1H), 7.32 (dd, J = 8.6, 2.4 Hz, 1H), 7.16 (d, J = 5.0 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.29 (d, J = 8.6 Hz, 1H), 4.99 (s, 1H), 3.58 (s, 3H), 3.31 — 3.19 (m, 2H), 2.18 (s, 3H), 2.04 (s, 3H), 1.43 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 524.2 (M+H)+.

Example 75 119119 N-(bicyclo[1.1.1]pentanyl)[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropan yl)phenyl]methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 75a ethyl 6-methyloxo(4,4, 5,5-tetramethyl-1,3 ,2-dioxaborolanyl)tosyl-6,7-dihydro- 1H—pyrrolo[2,3-c]pyridinecarboxylate Example 75a was prepared according to the ure used for the ation of Example 1h, substituting e 1f for Example 1 g.

Example 75b ethyl 4-(2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl)methyl oxotosyl-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxylate A ﬂask charged with Example 75a (3.506 g, 7.01 mmol), cesium carbonate (3.11 g, 9.55 mmol), tris(dibenzylideneacetone)dipalladium(0) (65 mg, 0.071 mmol) and 1,3,5,7- tetramethylphenyl-2,4,8-trioxaphosphaadamantane (84 mg, 0.287 mmol) was sealed and purged with nitrogen for 15 minutes, followed by addition of a degassed on of Example 35c (2.056 g, 5.82 mmol) in tetrahydrofuran (40.0 mL)/ water (10 mL). The e was heated at 60 0C for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The c phase was dried over anhydrous sodium sulfate. After ﬁltration and solvent removal, the residues were chromatographed on a 80 g silica cartridge eluting with 0-100 % ethyl acetate/heptanes to provide 3,21g (85%) of the title compound.

Example 75c 4-(2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl)methyloxo-6,7- dihydro- rolo[2,3-c]py1idinecarboxylic acid A mixture of Example 75b (3.21 g, 4.96 mmol) and lithium hydroxide monohydrate (2.13 g, 50.8 mmol) in a mixture of 1,4-dioxane (75 mL) and water (25 mL) was heated at 70 0C for 2 hours, then cooled to ambient temperature and adjusted to pH 2-3 with 1 M HCl.

The mixture was diluted with 400 mL of ice water, extracted with 2 x 200 mL of methyl tert- butyl ether. The ed organics were dried over anhydrous sodium sulfate. After filtration and solvent removal, the residues were chromatographed on a 40 g HP silica column eluting with 10-100 % 3 :1 ethyl acetate:ethanol/heptanes to e 1.95g (85%) of the title compound.

Example 75d N-(bicyclo[1.1.1]pentanyl)(2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropan yl)phenyl)methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide 120120 A mixture of Example 75c (59.4 mg, 0.128 mmol), N1-((ethylimino)methylene)- N3,I\73-dimethylpropane-1,3-diamine hydrochloride (36 mg, 0.188 mmol), 1H- benzo[d][1,2,3]triazolol hydrate (33 mg, 0.215 mmol), bicyclo[1.1.1]pentanamine, hydrochloride (24.7 mg, 0.207 mmol) and 4-methylmorpholine (65 ul, 0.591 mmol) in dichloromethane (4 mL) was stirred for 16 hours at ambient temperature. The mixture was partitioned between aqueous sodium bicarbonate and dichloromethane. The cs were dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residues were chromatographed (silica gel, 0-10 % ammonia saturated ol/dichloromethane) to provide the title compound (0.045 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) 5 12.14 (s, 1H), 8.85 (s, 1H), 7.49 (d, J = 2.4 Hz, 2H), 7.31-7.28 (m, 3H), 6.96 (d, J = 9.1 Hz, 1H), 6.83 (s, 1H), 6.29 (d, J = 8.6 Hz, 1H), 4.96 (s, 1H), 3.57 (s, 3H), 2.42 (s 1H), 2.02 (s, 6H), 1.93 (s, 6H), 1.42 (s, 6H). MS (ESI+) m/z 530.1 (M+H)+.

Example 76 N—lerl—butyl[3-(2,6-dimethylphenoxy)(2-hydroxypropanyl)py1idinyl]methyl 7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide Example 76a methyl o(2,6-dimethylphenoxy)picolinate Example 76a was prepared according to the procedure used for the preparation of Example 35b, substituting 2,6-dimethylphenol for Example 35a, and substituting methyl 6- bromoﬂuoropicolinate for methyl 3-bromoﬂuorobenzoate, respectively.

Example 76b romo(2,6-dimethylphenoxy)pyridinyl)propanol e 76b was prepared according to the procedure used for the preparation of Example 28d, tuting Example 76a for Example 28c.

Example 76c N—lerl—butyl[3-(2,6-dimethylphenoxy)(2-hydroxypropanyl)py1idinyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 76c was prepared according to the procedure used for the preparation of Example 37, tuting Example 76b for Example 29b. 1H NMR (501 MHz, DMSO-d6) 5 12.23 (d, J = 2.4 Hz, 1H), 8.32 (t, J = 5.3 Hz, 1H), 7.82 (s, 1H), 7.66 — 7.57 (m, 2H), 7.57 — 7.49 (m, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 7.10 (dd, J = 8.4, 6.4 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 3.61 (s, 3H), 2.03 (s, 3H), 1.48 (s, 6H), 1.37 (s, 9H). Ms (ESI+) m/z 503.2 (M+H)+.

Example 77 121121 4-[3-(2,6-dimethylphenoxy)(2-hydroxypropanyl)py1idinyl]-N-ethylmethyloxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 77 was prepared according to the procedure used for the preparation of Example lm, tuting Example 76b for Example 11. 1H NMR (501 MHz, DMSO-d6) 5 12.23 (d, J = 2.4 Hz, 1H), 8.32 (t, J = 5.3 Hz, 1H), 7.82 (s, 1H), 7.66 = 8.6 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.16 — 7.57 (m, 2H), 7.57 — 7.49 (m, 2H), 7.45 (d, J (d, J = 7.4 Hz, 1H), 7.10 (dd, J = 8.4, 6.4 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 3.61 (s, 3H), 3.27 (qd, J = 7.2, 5.2 Hz, 2H), 2.02 (s, 3H), 1.48 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 475.1 (M+H)+.

Example 78 N-ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)-5 -( l -ﬂuorohydroxypropanyl)pyridin-3 - methyloxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide Example 78a romo(4-ﬂuoro-2,6-dimethylphenoxy)pyridinyl)-l-ﬂuoropropanol id="p-424" id="p-424" id="p-424" id="p-424" id="p-424" id="p-424" id="p-424" id="p-424" id="p-424" id="p-424" id="p-424" id="p-424" id="p-424"

[00424] A solution of Example 43b (0.200 g, 0.565 mmol) and oromethyl)ﬂuoro-l,4- diazabicyclo[2.2.2]octane-l,4-diium tetraﬂuoroborate (0.231 g, 0.652 mmol) in anhydrous acetonitrile (6 mL), was heated at 82 0C in a sealed Vial for 68 hours. The mixture was cooled to t temperature and partitioned between 50 mL each of saturated aqueous sodium bicarbonate and dichloromethane. The organics were washed twice with water, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by chromatographed (silica, 0-50 % ethyl acetate/heptanes) to provide the title compound (0.052 g, 25%). e 78b N-ethyl(2-(4-ﬂuoro-2,6-dimethylphenoxy)-5 -( l -ﬂuorohydroxypropanyl)pyridin-3 - yl)methyloxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide Example 78b was prepared according to the procedure used for the preparation of Example lm, substituting Example 78a for Example 11. 1H NMR (400 MHz, DMSO-d6) 5 12.06 (s, 1H), 8.33 (t, J = 5.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.43 (s, 1H), 6.91 (d, J = 9.1 Hz, 2H), 6.84 (s, 1H), 5.63 (s, 1H), 4.46 (s, 1H), 4.34 (s, 1H), 3.59 (s, 3H), 3.25 (m, 2H), 1.97 (s, 6H), 1.48 (d, J = 2.0 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z = 511.2 (M+H)+.

Example 79 N—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(l , l , l-triﬂuorohydroxypropan yl)pyridinyl]methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide 122122 e 79a -bromo(4-ﬂuoro-2,6-dimethylphenoxy)nicotinic acid Example 79a was prepared according to the procedure used for the preparation of e 3a, substituting methyl 5-bromochloronicotinate for methyl 3-bromo ﬂuorobenzoate and substituting e 35a for 2,6-dimethylphenol.

Example 79b -bromo(4-ﬂuoro-2,6-dimethylphenoxy)-N—methoxy-N-methylnicotinamide Example 79b was prepared according to the procedure used for the ation of Example 1j, substituting Example 79a for Example 1i.

Example 79c 1-(5 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)pyridin-3 -yl)ethanone Example 79c was prepared according to the procedure used for the ation of Example 1k, substituting Example 79b for Example 1j. e 79d 2-(5-bromo(4-ﬂuoro-2,6-dimethylphenoxy)py1idin-3 -yl)-1,1,1-triﬂuoropropanol A solution of Example 79c (0.585 g, 1.730 mmol) and cesium ﬂuoride (0.284 g, 1.870 mmol) in tetrahydrofuran (12.00 mL) was treated with a solution of trimethyl(triﬂuoromethyl)silane (2.0 M in tetrahydrofuran, 1.2 mL, 2.400 mmol). The mixture was stirred at t temperature for 3 hours and partitioned between ethyl acetate and water. The organics were dried over anhydrous magnesium sulfate, ﬁltered, and trated, and the residue d by chromatography (silica gel, 0-50 % ethyl acetate/heptanes) to provide the title compound (0.132 g, 19 %).

Example 79e N—ethyl(2-(4-ﬂuoro-2,6-dimethylphenoxy)(1 , 1, 1-triﬂuorohydroxypropan yl)py1idinyl)methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 79e was prepared according to the procedure used for the preparation of Example 1m, substituting Example 79d for Example 11. 1H NMR (400 MHz, DMSO-d6) 5 12.33 (s, 1H), 8.33 (t, J = 5.4 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.45 (s, 1H), 6.92 (d, J = 9.1 Hz, 2H), 6.82 (s, 1H), 6.81 (s, 1H), 3.59 (s, 3H), 3.25 (m, 2H), 1.97 (s, 6H), 1.73 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 547.1 (M+H)+.

Example 80 N—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(1, 1,1,3 ,3 ,3 -hexaﬂuorohydroxypropan yl)py1idinyl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 80a 123123 (5-bromo(4-ﬂuoro-2,6-dimethylphenoxy)py1idinyl)(1H—imidazolyl)methanone A solution of Example 79a (0.488 g, 1.435 mmol) and imidazol yl)methanone (0.282 g, 1.739 mmol) in dichloromethane (10 mL) was stirred overnight at ambient ature. The mixture was partitioned n pH7 buffer on and dichloromethane. The organics were dried over anhydrous magnesium sulfate, ﬁltered, and trated to provide 0.551g (98 %) of the title compound.

Example 80b 2-(5-bromo(4-ﬂuoro-2,6-dimethylphenoxy)py1idin-3 -yl)-1,1, 1,3 ,3 ,3 -hexaﬂuoropropan id="p-432" id="p-432" id="p-432" id="p-432" id="p-432" id="p-432" id="p-432" id="p-432" id="p-432" id="p-432" id="p-432" id="p-432" id="p-432"

[00432] A solution of Example 80a (0.551 g, 1.412 mmol) and cesium e (.436 g, 2.87 mmol) in tetrahydrofuran (12.00 mL) was treated with a solution of t1imethyl(triﬂuoromethyl)silane, 2.0 M in tetrahydrofuran (2.118 mL, 4.24 mmol). The mixture was d at ambient temperature for 90 minutes and partitioned between ethyl e and water. The organics were dried over anhydrous magnesium sulfate, ﬁltered, and concentrated. The residue was chromatographed on a 40 g silica cartridge eluting with 0- 50 % ethyl acetate/heptanes to provide 0.618 g (95 %) of the title compound.

Example 80c N—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(1, 1,1,3 ,3 ,3 -hexaﬂuorohydroxypropan yl)py1idinyl]methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide id="p-433" id="p-433" id="p-433" id="p-433" id="p-433" id="p-433" id="p-433" id="p-433" id="p-433" id="p-433" id="p-433" id="p-433" id="p-433"

[00433] Example 80c was prepared according to the procedure used for the preparation of Example 1m, substituting Example 80b for Example 11. 1H NMR (400 MHz, DMSO-dg) 5 12.38 (s, 1H), 9.06 (s, 1H), 8.34 (t, J = 5.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H), 6.94 (d, J = 9.1 Hz, 2H), 6.80 (s, 1H), 3.59 (s, 3H), 3.26 (m, 2H), 1.97 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 601.1 (M+H)+.

Example 81 N-ethyl[2-(2-ﬂuoromethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]py1idinecarboxamide Example 81a methyl 3-bromo(2-ﬂuoromethylphenoxy)benzoate id="p-434" id="p-434" id="p-434" id="p-434" id="p-434" id="p-434" id="p-434" id="p-434" id="p-434" id="p-434" id="p-434" id="p-434" id="p-434"

[00434] Example 81a was prepared according to the procedure used for the preparation of Example 35b, substituting 2-methylﬂuorophenol for Example 35a.

Example 81b Example 81b was prepared according to the procedure used for the preparation of Example 28d, tuting Example 81a for Example 28c. 124124 Example 81c N-ethyl[2-(2-fluoromethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide e 81c was prepared according to the ure used for the preparation of Example 1m, substituting Example 81b for Example 11. 1H NMR (400 MHz, DMSO-dg) 5 12.18 (d, J = 2.3 Hz, 1H), 8.29 (t, J = 5.3 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.39 — 7.24 (m, 2H), 7.19 — 7.03 (m, 2H), 6.82 (d, J = 2.3 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 3.56 (s, 3H), 3.23 (qd, J = 7.2, 5.2 Hz, 4H), 2.09 (s, 3H), 1.41 (s, 6H), 1.08 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 478.1 (M+H)+.

Example 82 N—(d5)ethyl[2-(4-fluoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide A ﬂask was charged with Example 75c (103 mg, 0.222 mmol), N1- ((ethylimino)methylene)-N3,Ng-dimethylpropane-1,3-diamine hydrochloride (51 mg, 0.266 mmol), 1H—benzo[d][1,2,3]triazolol hydrate (41 mg, 0.268 mmol) and 4- methylmorpholine (100 uL, 0.910 mmol) in tetrahydrofuran (4 mL). The ﬂask was ﬁtted with a dry ice condenser and chilled in an ice/water bath. Ethylamine-d5 (1.3 g, 25.9 mmol) from a gas cylinder was streamed into the reaction vessel. The mixture was allowed to warm to ambient temperature while stirring overnight. The mixture was partitioned n ethyl 2O acetate and aqueous sodium bicarbonate, and the organics were dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was chromatographed on a 4 g silica cartridge eluting with 10-100 % 3 :1 ethyl acetate:ethanol/heptanes to provide 12 mg (11 %) of the title compound. 1HNMR (400 MHz, DMSO-dg) 8 12.21 (s, 1H), 8.32 (t, J = 5.4 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.37 = 9.0 Hz, 2H), 6.83 - 7.21 (m, 2H), 6.96 (d, J (s, 1H), 6.29 (d, J = 8.6 Hz, 1H), 4.96 (s, 1H), 3.58 (s, 3H), 2.00 (s, 6H), 1.42 (s, 6H). MS (ESI+), m/z = 497.2 (M+H)+.

Example 83 N-ethyl [2-(4-fluoro-2,6-dimethylphenoxy)(1-fluorohydroxypropanyl)phenyl] oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 83a 2-(3 -bromo(4-fluoro-2,6-dimethylphenoxy)phenyl)fluoropropanol ] Example 83a was ed according to the procedure used for the preparation of Example 78a, substituting Example 35c for Example 43b.

Example 83b 125125 N-ethyl(2-(4-ﬂuoro-2,6-dimethylphenoxy)(1-ﬂuorohydroxypropanyl)phenyl) methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 83b was prepared ing to the procedure used for the ation of Example 1m, substituting Example 83a for Example 11. 1H NMR (501 MHz, DMSO-dg) 5 12.21 (s, 1H), 8.32 (t, J = 5.4 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.34 (m, 1H), 7.33 (s, 1H), 6.97 (d, J = 9.1 Hz, 2H), 6.82 (s, 1H), 6.33 (d, J = 8.6 Hz, 1H), 5.43 (s, 1H), 4.38 (m, 1H), 4.30 (m, 1H), 3.58 (s, 3H), 3.25 (m, 2H), 2.00 (s, 6H), 1.45 (d, J = 2.0 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H). Ms (ESI+) m/z 510.1 (M+H)+.

Example 84 4-[2-(4-chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 84a methyl 3-bromo(4-chloro-2,6-dimethylphenoxy)benzoate 4-chloro-2,6-dimethylphenol (0.672 g, 4.29 mmol), methyl 3-bromoﬂuorobenzoate (1.0 g, 4.29 mmol) and cesium ate (2.097 g, 6.44 mmol) were combined in dimethyl sulfoxide (4.29 mL) under argon in a sealed tube and heated at 80 0C for 3 hours. The mixture was partitioned n water and ethyl acetate. The organic layer was washed with saturated s sodium chloride, dried over anhydrous sodium sulfate, ﬁltered and concentrated. Puriﬁcation by chromatography a, 0-30 % ethyl acetate in heptanes) provided the title compound (1.57 g, 93 %).

Example 84b 2-(3 -bromo(4-chloro-2,6-dimethylphenoxy)phenyl)propanol To a solution of Example 84a (0.4 g, 1.082 mmol) in tetrahydrofuran (5.41 mL) under nitrogen at 23 0C was added dropwise magnesium chloride (1.082 mL, 3.25 mmol, 3.0M in diethyl ether). The mixture was stirred for 2 hours at ambient temperature, poured into 5 % aqueous ammonium de, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. Puriﬁcation of the resulting residue by chromatography (silica gel, 0-60 % ethyl acetate in heptanes) provided the title compound (0.376 g, 81 %).

Example 84c 4-[2-(4-chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide 126126 Example 1h (0.05 g, 0.145 mmol), e 84b (0.054 g, 0.145 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.98 mg, 4.35 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (4.23 mg, 0.014 mmol) and sodium carbonate (0.061 g, 0.579 mmol) were combined and d with argon for 15 minutes. Meanwhile a solution of 4:1 tetrahydrofuran/water (2.0 mL) was sparged with nitrogen for 15 minutes and transferred by e into the reaction vessel under argon. The mixture was stirred for 16 hours under argon at 60 oC, cooled, and ioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over ous sodium sulfate, treated with aptopropyl functionalized silica gel, ﬁltered, and concentrated. Puriﬁcation of the resulting residue by chromatography (silica, 25-60 % of 3 :1 ethyl acetate/ethanol in heptanes) provided the title compound (0.020 g, 25 %). 1H NMR (500 MHz, DMSO-dg) 5 12.25 (s, 1H), 8.32 (t, J = 5.3 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.32 — 7.28 (m, 2H), 7.19 (d, J = 0.8 Hz, 2H), 6.81 (d, J = 2.1 Hz, 1H), 6.30 (d, J = 8.6 Hz, 1H), 4.97 (s, 1H), 3.58 (s, 3H), 3.24 (qd, J = 7.2, 5.3 Hz, 2H), 1.99 (s, 6H), 1.42 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 508 [M+H]+.‘ Example 85 N-ethyl{ 5 droxypropanyl) [4-(methanesulfonyl)-2,6-dimethylphenoxy]phenyl } - 6-methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 85a methyl 3-bromo(2,6-dimethyl(methylsulfonyl)phenoxy)benzoate 2,6-dimethyl(methylsulfonyl)phenol (0.307 g, 1.533 mmol), methyl 3-bromo ﬂuorobenzoate (0.375 g, 1.609 mmol) and cesium carbonate (0.749 g, 2.299 mmol) were combined in dimethyl sulfoxide (1.533 mL) under argon in a sealed tube and heated at 100 0C for 24 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. Puriﬁcation of the resulting residue by chromatography (silica, 20-40 % of 3 :1 ethyl acetate/ethanol in heptanes) provided material that was 80-90 % pure. This al was triturated in 1:1 ethyl acetate/heptane to provide the title compound (0.29 g, 44 %).

Example 85b 2-(3 -bromo(2,6-dimethyl(methylsulfonyl)phenoxy)phenyl)propanol To a solution of Example 85a (0.289 g, 0.699 mmol) in tetrahydrofuran (3.50 mL) under nitrogen at ambient temperature was added se methylmagnesium chloride (0.699 mL, 2.098 mmol, 3.0 M in tetrahydrofuran). The mixture was stirred for 2 hours at 127127 ambient temperature, poured into 5 % s ammonium chloride and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium de, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. Puriﬁcation of the resulting residue by chromatography (silica gel, 0-50 % ethyl acetate in heptanes) ed the title compound as a tacky white solid (0.162 g, 47 %).

Example 85c N-ethyl{ 5 -(2-hydroxypropanyl) [4-(methanesulfonyl)-2,6-dimethylphenoxy]phenyl } - yloxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide Example 1h (0.05 g, 0.145 mmol), Example 85b (0.060 g, 0.145 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.98 mg, 4.35 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (4.23 mg, 0.014 mmol) and sodium carbonate (0.061 g, 0.579 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 tetrahydrofuran/water (2.0 mL) was sparged with nitrogen for 15 minutes and erred by syringe into the reaction vessel under argon. The mixture was stirred for 16 hours under argon at 60 oC, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, d with 3-mercaptopropyl functionalized silica gel, ﬁltered and concentrated. Puriﬁcation by chromatography (silica, 25-60 % of 3 :1 ethyl acetate/ethanol in heptanes) provided the title compound as a white solid (0.070 g, 82 %). 1H NMR (400 MHz, DMSO-dg) 5 12.20 (s, 1H), 8.31 (t, J = 5.3 Hz, 1H), 7.66 (s, 2H), 7.52 (d, J = 2.4 Hz, 1H), 7.33 (s, 1H), 7.30 (dd, J = 8.6, 2.4 Hz, 1H), 6.82 (d, J = 1.8 Hz, 1H), 6.31 (d, J = 8.6 Hz, 1H), 4.98 (s, 1H), 3.56 (s, 3H), 3.25 — 3.18 (m, 2H), 3.15 (s, 3H), 2.07 (s, 6H), 1.41 (s, 6H), 1.08 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 552 [M+H]+.‘ Example 86 l[2-(4-ﬁuoro-2,6-dimethylphenoxy)(l,1,l-triﬁuorohydroxypropan nyl]methyloxo-6,7-dihydro- rolo[2,3-c]pyridinecarboxamide Example 86a 3-bromo(4-ﬁuoro-2,6-dimethylphenoxy)benzoic acid A solution of Example 35b (2.0 g, 5.66 mmol) and lithium hydroxide hydrate (0.951 g, 22.65 mmol) in a mixture of ol (3.79 mL), tetrahydrofuran (3.79 mL), and water (1.897 mL) was stirred for 90 minutes. The mixture was concentrated, then diluted with 15mL of water and acidiﬁed to pH 2 with 2M HCl. The precipitate was dried in vacuum oven to provide 1.77 g (92 %) of the title compound.

Example 86b 128128 3-bromo(4-ﬂuoro-2,6-dimethylphenoxy)-N—methoxy-N—methylbenzamide Example 86b was prepared according to the procedure used for the preparation of Example lj, substituting Example 86a for Example li.

Example 86c l-(3 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)ethanone Example 86c was prepared according to the procedure used for the preparation of Example lk, substituting e 86b for Example lj.

Example 86d 2-(3 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)- l , l, l -triﬂuoropropanol id="p-449" id="p-449" id="p-449" id="p-449" id="p-449" id="p-449" id="p-449" id="p-449" id="p-449" id="p-449" id="p-449" id="p-449" id="p-449"

[00449] Example 86d was ed according to the ure used for the ation of Example 79d, substituting Example 86c for Example 79c.

Example 86e N—ethyl(2-(4-ﬂuoro-2,6-dimethylphenoxy)(l , l , l-triﬂuorohydroxypropan yl)phenyl)methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide id="p-450" id="p-450" id="p-450" id="p-450" id="p-450" id="p-450" id="p-450" id="p-450" id="p-450" id="p-450" id="p-450" id="p-450" id="p-450"

[00450] Example 86e was ed according to the procedure used for the preparation of Example lm, substituting e 86d for Example 11. 1H NMR (501 MHz, DMSO-dg) 5 12.12 (s, 1H), 8.34 (t, J = 5.4 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.7, 2.4 Hz, 1H), 7.34 (s, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.80 (s, 1H), 6.58 (s, 1H), 6.40 (d, J = 8.7 Hz, 1H), 3.58 (s, 3H), 3.25 (qd, J = 7.2, 5.3 Hz, 2H), 2.00 (s, 6H), 1.68 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI) M/Z 544.1 (M+H)+.

Example 87 N—lerl-butyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(l-ﬂuorohydroxypropan yl)phenyl]methyloxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide Example 32c (0.05 g, 0.134 mmol), Example 83a (0.050 g, 0.134 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.68 mg, 4.02 umol), l,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (3.92 mg, 0.013 mmol) and sodium carbonate (0.057 g, 0.536 mmol) were combined and sparged with argon for 15 s. Meanwhile a solution of 4:1 tetrahydrofuran/water (2.0 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 3 hours under argon at 60 oC, cooled, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl onalized silica gel, ﬁltered, and concentrated. Puriﬁcation of the resulting residue by chromatography (silica, 25-60 % of 3 :l ethyl acetate/ethanol in es) provided the title compound as a white solid (0.0491 g, 129129 62 %). 1H NMR (400 MHz, DMSO-dg) 5 12.32 (s, 1H), 7.82 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.36 — 7.27 (m, 2H), 6.95 (d, J = 9.1 Hz, 2H), 6.80 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 8.6 Hz, 1H), 5.42 (s, 1H), 4.42 — 4.34 (m, 1H), 4.29 — 4.23 (m, 1H), 3.57 (s, 3H), 1.98 (s, 6H), 1.43 (d, J = 2.0 Hz, 3H), 1.33 (s, 9H). MS (ESI+) m/z 538 [M+H].‘ Example 88 4-[2-(4-chloro-2,6-dimethylphenoxy)(1-ﬁuorohydroxypropanyl)phenyl]-N—ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide e 88a 2-(3 -bromo(4-chloro-2,6-dimethylphenoxy)phenyl)ﬁuoropropanol id="p-452" id="p-452" id="p-452" id="p-452" id="p-452" id="p-452" id="p-452" id="p-452" id="p-452" id="p-452" id="p-452" id="p-452" id="p-452"

[00452] A solution of Example 84b (0.3 g, 0.812 mmol) and 1-(chloromethyl)ﬁuoro-1,4- diazabicyclo[2.2.2]octane-1,4-diium tetraﬁuoroborate (0.316 g, 0.893 mmol) in acetonitrile (8.12 mL) under argon in a sealed tube was heated at 80 0C for 30 minutes. The on mixture was cooled and partitioned between ethyl acetate and 5 % aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium de, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. Puriﬁcation by chromatography a, 5-35 % ethyl e in heptanes) provided the title compound as a viscous oil that solidiﬁed upon standing (0.2 g, 64 %).

Example 88b 4-[2-(4-chloro-2,6-dimethylphenoxy)(1-ﬁuorohydroxypropanyl)phenyl]-N—ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 1h (0.05 g, 0.145 mmol), Example 88a (0.056 g, 0.145 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.98 mg, 4.35 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (4.23 mg, 0.014 mmol) and sodium carbonate (0.061 g, 0.579 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 tetrahydrofuran/water (2.0 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 18 hours under argon at 60 oC, cooled, and ioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, ﬁltered and concentrated. Puriﬁcation of the resulting residue by tography (silica, 25-60 % of 3 :1 ethyl acetate/ethanol in heptanes) provided the title compound as a white solid (0.06 g, 79 %). 1H NMR (500 MHz, DMSO-dg) 5 12.25 (s, 1H), 8.38 = 2.4 Hz, 1H), — 8.30 (m, 1H), 7.55 (d, J 7.36 (d, J = 9.0 Hz, 2H), 7.23 (t, J = 0.8 Hz, 2H), 6.84 (d, J = 1.8 Hz, 1H), 6.37 (d, J = 8.6 Hz, 1H), 5.47 (s, 1H), 4.44 = 7.2, 5.3 — 4.38 (m, 1H), 4.35 — 4.28 (m, 1H), 3.60 (s, 3H), 3.27 (qd, J 130130 Hz, 2H), 2.01 (s, 6H), 1.47 (d, J = 2.0 Hz, 3H), 1.12 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 526 [M+H]+.~ 4-[2-(2,4-diﬂuorophenyl)(2-hydroxypropanyl)pyridin-3 -ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 89a Methyl 5-chloro(2,4-diﬂuorophenyl)nicotinate 2-(2,4-Diﬂuorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 5 g, 4.21 mmol), methyl 5,6-dichloronicotinate (0.953 g, 4.63 mmol), sodium carbonate (1.560 g, 14.72 mmol), tris(dibenylidene acetone)dipalladium (0) (0.193 g, 0.210 mmol), and 1,3,5,7- tetramethylphenyl-2,4,8-trioxaphosphaadamantane (0.209 g, 0.715 mmol) were ﬂow purged with en for 1 hour. Degassed tetrahydrofuran (11.21 mL) and water (2.80 mL) were added. The on mixture was heated at 60 0C for 6 hours. The reaction mixture was cooled to ambient ature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, d, and concentrated. The residue was puriﬁed by ﬂash chromatography (10 % ethyl acetate:heptanes to 50 % ethyl acetate:heptanes over 20 minutes). The collected fractions were concentrated.

The residue was puriﬁed by ﬂash chromatography (100 % CHzClz over 15 minutes) to provide the title compound as a white solid (0.8605 g, 72 % yield).

Example 89b 2-(5-chloro(2,4-diﬂuorophenyl)pyridin-3 opanol To a solution of Example 89a 1 g, 0.727 mmol) in tetrahydrofuran (4.38 mL) was added methylmagnesium bromide (1.557 mL, 2.180 mmol) dropwise. The reaction mixture was stirred at ambient temperature for about 3 hours. The reaction mixture was quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (20-60 % ethyl acetate/heptanes) to provide the title compound as a colorless oil that solidiﬁed to a white solid upon standing overnight (0.1817 g, 88 % yield). e 89c 4-[2-(2,4-diﬂuorophenyl)(2-hydroxypropanyl)pyridin-3 -yl]-N-ethylmethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 89c (0.0319 g, 22 %) was prepared according to the procedure used for the preparation of Example 1m, substituting Example 89b for Example 11. 1H NMR (500 MHz, 131131 DMSO-d6)612.29 — 12.15 (m, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.30 — 8.23 (m, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.54 = 1.7 Hz, 1H), — 7.45 (m, 1H), 7.13 — 7.01 (m, 2H), 7.02 (s, 1H), 6.52 (d, J .38 (s, 1H), 3.42 (s, 3H), 3.24 (qd, J = 7.2, 5.3 Hz, 2H), 1.56 (s, 6H), 1.11 (t, J = 7.2 Hz, 3H).

MS (ESI+) m/z 467.2 (M+H)+.

N—Zerl-butyl{5-(2-hydroxypropanyl)[4-(methanesulfonyl)-2,6- dimethylphenoxy]phenyl }methyloxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine carboxamide Example 32c (0.04 g, 0.107 mmol), Example 85b (0.044 g, 0.107 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.94 mg, 3.21 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (3.13 mg, 10.72 umol) and sodium carbonate (0.045 g, 0.429 mmol) were combined and sparged with argon for 15 minutes. ile a solution of 4:1 tetrahydrofuran/water (1.4 mL) was sparged with nitrogen for 15 s and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 4 hours under argon at 60 oC, cooled, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, ﬁltered, and concentrated. Puriﬁcation of the residue by chromatography (silica, 25-60 % of 3 :1 ethyl e/ethanol in heptanes) provided the title compound (0.056 g, 88 %). 1H NMR (400 MHz, DMSO-dg) 5 12.34 (s, 1H), 7.84 (s, 1H), 7.69 (s, 2H), 7.54 (d, J = 2.4 Hz, 1H), 7.35 (s, 1H), 7.31 (dd, J = 8.5, 2.4 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 6.32 (d, J = 8.5 Hz, 1H), 5.01 (s, 1H), 3.59 (s, 3H), 3.17 (s, 3H), 2.09 (s, 6H), 1.43 (s, 6H), 1.35 (s, 9H). MS (ESI+) m/z 580 [M+H]+.~ Example 91 N-ethyl[2-(3 -ﬁuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl]—6- methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 91a methyl mino-2,6-dimethylphenoxy)bromonicotinate The mixture of methyl 5-bromoﬁuoronicotinate (900 mg, 3.85 mmol), Example 99d (528 mg, 3.85 mmol) and cesium carbonate (2506 mg, 7.69 mmol) in dimethyl sulfoxide (12 mL) was d at 65 0C for 2 hours. The reaction mixture was partitioned between water (80 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate once more and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The e was d by column chromatography 132132 (silica gel, 20 % to 50 % ethyl acetate in petroleum ether) to provide the title compound (365 mg, 0.831 mmol, 21.62 % yield).

Example 91b methyl 5-bromo(3-ﬂuoro-2,6-dimethylphenoxy)nicotinate Example 91b was ed according to the procedure used for the preparation of Example 104a, substituting Example 91a for Example 99e.

Example 91c 2-(5-bromo(3 -ﬂuoro-2,6-dimethylphenoxy)pyridinyl)propanol Example 91c was prepared ing to the procedure used for the preparation of Example 28d, substituting Example 91b for Example 28c.

Example 91d l[2-(3 -ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide e 91d was prepared according to the ure used for the preparation of Example 1m, substituting Example 91c for Example 11. 1H NMR (400 MHz, ol-d4) 5 8.14 (s, 1H), 8.08 (s, 1H), 7.47 (s, 1H), 7.06 (d, J = 7.0 Hz, 1H), 6.97 (s, 1H), 6.87 (t, J = 8.8 Hz, 1H), 3.74 (s, 3H), 3.43 (d, J = 6.9 Hz, 2H), 2.02 (s, 3H), 1.99 (s, 3H), 1.61 (s, 6H), 1.24 (t7 J = 6.9 Hz, 3H). MS (ESI+) m/z 493 (M+H)+.

Example 92 N—Zerl-butyl{5-(2-hydroxypropanyl)[4-(methanesulfonyl)-2,6- dimethylphenoxy]pyridinyl}methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridine carboxamide Example 92a methyl 5-bromo(2,6-dimethyl(methylsulfonyl)phenoxy)nicotinate id="p-462" id="p-462" id="p-462" id="p-462" id="p-462" id="p-462" id="p-462" id="p-462" id="p-462" id="p-462" id="p-462" id="p-462" id="p-462"

[00462] 2,6-dimethyl(methylsulfonyl)phenol (0.420 g, 2.096 mmol), methyl 5-bromo chloronicotinate (0.5 g, 1.996 mmol) and cesium carbonate (0.976 g, 2.99 mmol) were combined in dimethyl sulfoxide (4.0 mL) under argon in a sealed tube and stirred at 80 0C for 4 hours. The mixture was cooled, diluted with 100 mL of water and d for 15 minutes.

The solid was collected by ﬁltration, and dried to constant mass to provide the title compound as a tan solid (0.62 g, 75 %).

Example 92b 2-(5-bromo(2,6-dimethyl(methylsulfonyl)phenoxy)py1idinyl)propanol ] To a solution of Example 92a (0.62 g, 1.497 mmol) in tetrahydrofuran (7.48 mL) under nitrogen at ambient temperature was added dropwise methylmagnesium chloride 133133 (1.497 mL, 4.49 mmol, 3.0M in tetrahydrofuran). The mixture was stirred for 2 hours at ambient temperature, poured into 5 % aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium e, ﬁltered, and concentrated. Puriﬁcation of the residue by tography (silica gel, 0-50 % ethyl acetate in heptanes) provided the title compound 1 (0.17 g, 27 %). e 92c N—Zerl-butyl{5-(2-hydroxypropanyl)[4-(methanesulfonyl)-2,6- dimethylphenoxy]pyridinyl}methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridine carboxamide Example 32c (0.045 g, 0.121 mmol), e 92b (0.05 g, 0.121 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.32 mg, 3.62 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (3.53 mg, 0.012 mmol) and sodium carbonate (0.051 g, 0.483 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 tetrahydrofuran/water (1.8 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 4 hours under argon at 60 oC, cooled, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, ﬁltered, and concentrated. Puriﬁcation by chromatography (silica, 25-60 % of 3 :1 ethyl acetate/ethanol in heptanes) provided the title compound (0.065 g, 90 %). 1H NMR (400 MHz, g) 5 12.42 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.64 (s, 2H), 7.44 (s, 1H), 6.85 (d, J = 1.9 Hz, 1H), 5.19 (s, 1H), 3.58 (s, 3H), 3.16 (s, 3H), 2.05 (s, 6H), 1.44 (s, 6H), 1.34 (s, 9H). MS (ESI+) m/z 581 [M+H]+.‘ Example 93 N—ethyl{5-(2-hydroxypropanyl)[4-(methanesulfonyl)-2,6-dimethylphenoxy]pyridin- 3-yl}methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 1h (0.042 g, 0.121 mmol), Example 92b (0.05 g, 0.121 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.32 mg, 3.62 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (3.53 mg, 0.012 mmol) and sodium carbonate (0.051 g, 0.483 mmol) were combined and sparged with argon for 15 s. Meanwhile a solution of 4:1 tetrahydrofuran/water (2.0 mL) was sparged with en for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 4 hours under argon at 60 oC, , and partitioned between ethyl acetate and water. The 134134 organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, d, and concentrated. Puriﬁcation of the residue by chromatography (silica, 25-60 % of 3:1 ethyl e/ethanol in heptanes) provided the title compound as a white solid (0.060, 87 %). 1H N1V1R (400 MHz, DMSO-dg) 5 12.35 - 12.26 (m, 1H), 8.31 (t, J = 5.3 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.63 (s, 2H), 7.44 (s, 1H), 6.84 (d, J =18 Hz, 1H), 5.18 (s, 1H), 3.57 (s, 3H), 3.27 — 3.19 (m, 2H), 3.16 (s, 3H), 2.05 (s, 6H), 1.45 (s, 6H), 1.09 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 553 [M+H]+.

Example 94 4-[2-(4-chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl]—N—ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide Example 94a methyl 5-bromo(4-chloro-2,6-dimethylphenoxy)nicotinate Methyl 5-bromochloronicotinate (1.50 g, 6.00 mmol), 4-chloro-2,6-dimethylphenol (0.940 g, 6.00 mmol), and cesium carbonate (2.93 g, 9.00 mmol) were ed in dimethyl ide (6 mL). The reaction mixture was heated at 60 0C for 2 hours, cooled to t temperature and d with water. The resulting precipitate was collected by ﬁltration, washed with water, and dried to provide the title compound (2.01 g, 90 %).

Example 94b 2-(5-bromo(4-chloro-2,6-dimethylphenoxy)py1idinyl)propanol To a solution of Example 94a (2.00 g, 5.40 mmol) in tetrahydrofuran (15 mL) was added 3M methylmagnesium chloride in tetrahydrofuran (5.40 mL, 16.2 mmol) at 0 oC. The reaction mixture was stirred at ambient temperature for 2 hours, treated with 5 % aqueous um chloride carefully, and partitioned with ethyl acetate and water. The organic layer was washed with saturated s sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 20- 40 % ethyl acetate in heptanes) to provide the title compound (1.01 g, 51 %).

Example 94c 4-[2-(4-chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl]—N—ethyl methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide e 94c (38 mg, 75 %) was prepared according to the procedure used for the preparation of Example lm, substituting Example 94b for e 11. 1H NMR (500 MHz, DMSO-d6)512.30(s, 1H), 8.33 (t, J: 5.4 Hz, 1H), 8.09 (d, J: 2.4 Hz, 1H), 7.94 (d, J: 2.5 135135 Hz, 1H), 7.42 (s, 1H), 7.14 (s, 2H), 6.84 (s, 1H), 5.18 (s, 1H), 3.59 (s, 3H), 3.30 — 3.20 (m, 2H), 1.96 (s, 6H), 1.46 (s, 6H), 1.10 (t, J: 7.2 Hz, 3H). MS (ESI+) m/z 509 .

Example 95 N-lerl-butyl[2-(4-chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 95 (47 mg, 88%) was prepared according to the procedure used for the preparation of Example 37, substituting Example 94b for Example 29b. 1H NMR (500 MHz, 6) 5 12.41 (s, 1H), 8.08 (d, J: 2.4 Hz, 1H), 7.94 (d, J: 2.4 Hz, 1H), 7.85 (s, 1H), 7.43 (s, 1H), 7.14 (s, 2H), 6.84 (d, J: 1.5 Hz, 1H), 5.18 (s, 1H), 3.59 (s, 3H), 1.97 (s, 6H), 1.46 (s, 6H), 1.35 (s, 9H). MS (ESI+) m/z 537 (M+H)+.

Example 96 N-ethyl[3-(4-fluoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 96a methyl 6-bromo(4-ﬂuoro-2,6-dimethylphenoxy)picolinate Example 96a was prepared according to the procedure used for the preparation of e 35b, substituting methyl 6-bromoﬂuoropicolinate for methyl 3-bromo ﬂuorobenzoate. e 96b 2-(6-bromo(4-fluoro-2,6-dimethylphenoxy)pyridinyl)propanol e 96b was prepared according to the procedure used for the preparation of Example 28d, substituting Example 96a for Example 28c.

Example 96c l[3-(4-fluoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide The triﬂuoroacetic acid salt of Example 96c was prepared according to the procedure used for the preparation of Example 1m, substituting Example 96b for Example 11. 1H NMR (400 MHz, DMSO-dg) 5 12.23 (d, J = 2.4 Hz, 1H), 8.31 (t, J = 5.3 Hz, 1H), 7.79 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 9.1 Hz, 2H), 6.78 (d, J = 8.6 Hz, 1H), 3.61 (s, 3H), 3.27 (qd, J = 7.2, 5.1 Hz, 2H), 2.02 (s, 6H), 1.47 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H).

MS (ESI+) m/z 493.1 (M+H)+.

Example 97 N—ZerZ-butyl[3-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridinyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide 136136 The triﬂuoroacetic acid salt of Example 97 was prepared according to the procedure used for the preparation of Example 37, substituting Example 96b for Example 29b. The crude t was puriﬁed by HPLC (C18 column, CH3CN/water (0.1 % triﬁuoroacetic acid)). 1H NMR (400 MHz, DMSO-dg) 5 12.39 (s, 1H), 7.84 (dd, J = 16.6, 2.7 Hz, 1H), 7.53 = 2.5 Hz, 1H), 7.03 (dd, J = 9.2, 2.7 Hz, 1H), 6.87 — 7.36 (m, 1H), 7.22 (t, J — 6.71 (m, 1H), 3.61 (s, 3H), 2.02 (s, 6H), 1.48 (s, 6H), 1.36 (s, 9H). MS (ESI+) m/z 521.1 .

Example 98 4- { 2-[2-(diﬁuoromethyl)ﬁuoromethylphenoxy] (2-hydroxypropanyl)phenyl } -N— ethylmethyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide e 98a 2-(dimethoxymethyl)ﬁuoromethylphenol A on of 5-ﬁuorohydroxymethylbenzaldehyde (0.38 g, 2.47 mmol) in methanol (12.4 mL) at 0 0C under a nitrogen atmosphere was treated with titanium (IV) chloride (60 11L, 0.06 mmol) and stirred at 0 CC for 20 minutes. Triethylamine (100 11L, 0.72 mmol) was added and the on e was stirred at 0 0C for 1 hour. The temperature was allowed to gradually increase to 10 0C while stirring for another 4.5 hours. The reaction mixture was then partitioned between ethyl acetate and water. The aqueous layer was ted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, ﬁltered, and trated to provide the title compound (0.339 g, 62 % yield, 90 % purity).

Example 98b methyl o(2-(dimethoxymethyl)ﬂuoromethylphenoxy)benzoate Example 98b was prepared according to the procedure used for the preparation of Example 35b, substituting Example 98a for e 35a. The mixture was heated for 5 hours instead of 2 hours. e 98c methyl 3-bromo(4-ﬁuoroformylmethylphenoxy)benzoate A solution of Example 98b (0.29 g, 0.7 mmol) in tetrahydrofuran (6 mL) was treated with hydrogen chloride solution (2 M aqueous, 0.35 mL, 0.7 mmol) and stirred at 50 0C for 1.25 hours. The reaction mixture was then cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution, partitioned between ethyl acetate and water, washed with brine, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated to provide the title compound (0.251 g, 98 %).

Example 98d 137137 methyl 3-bromo(2-(diﬂuoromethyl)ﬂuoromethylphenoxy)benzoate A solution of Example 98c (0.25 g, 0.68 mmol) in dichloromethane (5 mL) was added dropwise to a solution of diethylaminosulfur triﬂuoride (0.25 mL, 1.9 mmol) in dichloromethane (5 mL) at 0 oC. The resulting solution was stirred at 0 0C for 1 hour and then at ambient temperature for 3.5 hours. The reaction mixture was lly quenched with saturated sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine. The aqueous layers were combined and extracted with dichloromethane (2 x 40 mL). The organic layers were combined, dried over anhydrous ium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel 50 g Biotage KP-Sil Snap column, 0 to 12 % ethyl acetate in heptanes) to provide the title compound (0.26 g, 97 %).

Example 98e 2-(3 -bromo(2-(diﬂuoromethyl)ﬂuoromethylphenoxy)phenyl)propanol Example 98e was prepared according to the ure used for the preparation of e 35c, substituting Example 98d for Example 35b. The reaction mixture was d overnight d of 30 minutes. e 98f 4- { 2-[2-(diﬂuoromethyl)ﬂuoromethylphenoxy] (2-hydroxypropanyl)phenyl } -N— ethylmethyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide 2O [00479] Example 98f was prepared according to the procedure used for the preparation of Example lm, substituting Example 98e for Example 11. The on mixture was heated at 60 0C overnight instead of3 hours. 1HNMR (501 MHz, DMSO-dg) 5 12.23 (s, 1H), 8.34 (t, J = 5.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.36 (m, 3H), 6.95 (t, J = 54.1 Hz, 1H), 6.84 (s, 1H), 6.37 (d, J = 8.6 Hz, 1H), 5.03 (s, 1H), 3.59 (s, 3H), 3.27 (qd, J = 7.2, 5.7 Hz, 2H), 1.92 (s, 3H) 1.45 (s, 6H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 528.2 (M+H)+.

Example 99 4-[2-(3-chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 99a 2,6-dimethylphenyl acetate To a solution of 2,6-dimethylphenol (10 g, 82 mmol) in acetic anhydride (30 mL) was added 4 drops of concentrated H2S04 at 0 oC and the on e was stirred at 20 0C for 1 hour. Then ice water was added and the product was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated sodium bicarbonate 138138 solution(3 x 30 mL) and brine, dried over anhydrous sodium sulfate, ﬁltered, and concentrated to provide the title compound (17.6 g, 77 mmol, 94 % yield).

Example 99b methylnitrophenyl acetate To a solution of Example 99a (17.6 g, 77 mmol) in acetic anhydride (10 mL) was added dropwise the suspension of cupric nitrate rate (51.9 g, 215 mmol) in acetic anhydride (10 mL) at the rate that the internal temperature was maintained below 10 0C.

After the on was ﬁnished, the mixture was stirred at this temperature for 20 minutes, then warmed to 40 oC and stirred for 1 hour. The reaction mixture was poured onto ice water and the product was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with sodium carbonate solution (3 x 30 mL) and brine, dried over anhydrous sodium sulfate, ﬁltered, and concentrated to e the title compound, (17.8 g, 55.7 mmol, 72.6 % yield), as colorless oil.

Example 99c 2,6-dimethyl-3 -nitrophenol To a solution of sodium hydroxide (1.682 g, 42.1 mmol) in water (20 mL) was added Example 99b (1.1 g, 5.26 mmol) and the mixture was stirred at 20 0C for 18 hours. The pH was adjusted to 2-3 with 15 % HCl solution. The product was extracted with ethyl acetate (4 x 20 mL), The organic layer was washed with brine, dried over anhydrous sodium sulfate, 2O ﬁltered, and concentrated to e the title compound (810 mg, 4.85 mmol, 92 % yield), as yellow solid.

Example 99d 3-amino-2,6-dimethylphenol To a on of Example 99c (5 g, 29.9 mmol) in acetic acid (20 mL) was added zinc (1.956 g, 29.9 mmol) and the on mixture was stirred at 90 CC for 90 min. After cooling, the reaction e was ﬁltered and adjusted the pH to about 8 with solid sodium carbonate.

Then the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 5 % methanol in dichloromethane) to e the title compound (3.6 g, 23.09 mmol, 77 % yield).

Example 99e methyl mino-2,6-dimethylphenoxy)bromobenzoate Example 99e was prepared according to the procedure used for the ation of Example 35b, substituting Example 99d for Example 35a. 139139 e 99f methyl o(3-chloro-2,6-dimethylphenoxy)benzoate A solution of copper (II) sulfate (54.7 mg, 0.343 mmol) and sodium de (53.4 mg, 0.914 mmol) in water (6 mL) was heated to 95 OC, and then a solution of sodium hydroxide (13.71 mg, 0.343 mmol) and sodium metabisulf1te (19.54 mg, 0.103 mmol) in water (5 mL) was added to the hot solution. The reaction mixture was stirred at this temperature for 20 minutes, then cooled to 75 oC. Example 99e (80 mg, 0.228 mmol) was dissolved in dioxane (1 mL), concentrated HCl (2 mL), and water (1 mL), and the mixture was cooled to -5~0 °C.

To this solution was added sodium nitrite (17.34 mg, 0.251 mmol) in 1 mL of water. The reaction mixture was stirred at this temperature for 30 min. This reaction mixture was then added to the freshly ed CuCl solution at 75 0C. The reaction mixture was stirred for 1 hour, and then cooled to ambient temperature. The mixture was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by silica gel column chromatography (eluted with 5 % ethyl acetate in petroleum ether) to provide the title nd, (38 mg, 0.074 mmol, 32.4 % yield).

Example 99g 2-(3 -bromo(3-chloro-2,6-dimethylphenoxy)phenyl)propanol ] Example 99g was prepared according to the procedure used for the preparation of Example 28d, substituting Example 99f for Example 28c.

Example 99h 4-[2-(3-chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro- rolo[2,3-c]pyridinecarboxamide Example 99h was prepared according to the procedure used for the preparation of e 1m, substituting Example 99g for Example 11. 1H NMR (400 MHz, Methanol-d4) 5 7.65 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.36 (dd, J = 8.7, 2.5 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.96 (s, 1H), 6.38 (d, J = 8.6 Hz, 1H), 3.73 (s, 3H), 3.42 (q, J = 7.3 Hz, 2H), 2.12 (s, 3H), 2.06 (s, 3H), 1.58 (s, 6H), 1.23 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 508.1 (M+H)+.

Example 100 N—lerl—butyl[2-(2, 6-dichloroﬂuorophenoxy)(2-hydroxypropanyl)pyridin-3 -yl]—6- methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 100a methyl 5-bromo(2,6-dichloroﬂuorophenoxy)nicotinate 140140 Methyl 5-bromochloronicotinate (1.384 g, 5.53 mmol), 2,6-dichloro ﬂuorophenol (1.0 g, 5.53 mmol) and cesium carbonate (2.70 g, 8.29 mmol) were combined in dimethyl sulfoxide (11.05 mL) under argon in a sealed tube and stirred at 50 0C for 18 hours.

The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, d, and concentrated. ation of the residue by ation in 9:1 heptanes/ethyl acetate provided the title nd (1.386 g, 69 %).

Example 100b 2-(5-bromo(2,6-dichloroﬁuorophenoxy)py1idin-3 -yl)propanol id="p-489" id="p-489" id="p-489" id="p-489" id="p-489" id="p-489" id="p-489" id="p-489" id="p-489" id="p-489" id="p-489" id="p-489" id="p-489"

[00489] To a slurry of cerium(III) chloride (1.135 g, 4.61 mmol) in tetrahydrofuran (16 mL) under nitrogen at 5 0C was added dropwise a solution of Example 100a (1.516 g, 3.84 mmol) in tetrahydrofuran (16 mL). The mixture was d for 1.5 hours, cooled to -78 oC and treated dropwise with methylmagnesium chloride (3.84 mL, 11.51 mmol, 3 .0 M in tetrahydrofuran). The mixture was stirred for 2 hours and allowed to warm to ambient temperature, poured into 5 % aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered, and concentrated. Puriﬁcation of the residue by chromatography (silica gel, 0-50 % ethyl acetate in es) provided the title compound as a viscous oil that ﬁed upon standing (1.19 g, 78 %).

Example 100c N—lerl—butyl[2-(2,6-dichloroﬂuorophenoxy)(2-hydroxypropanyl)py1idinyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 32c (0.05 g, 0.134 mmol), Example 100b (0.053 g, 0.134 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.68 mg, 4.02 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (3.92 mg, 0.013 mmol) and sodium ate (0.057 g, 0.536 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 tetrahydrofuran/water (1.8 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 18 hours under argon at 50 oC, cooled, and ioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, ﬁltered, and concentrated. ation of the residue by chromatography (silica, 25-60 % of 3 :1 ethyl acetate/ethanol in heptanes) provided the title compound as a white solid (0.05 g, 63%). 1H NMR (400 MHz, DMSO-dg) 5 12.42 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 141141 1H), 7.84 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.46 (s, 1H), 6.98 (s, 1H), 5.22 (s, 1H), 3.59 (s, 3H), 1.46 (s, 6H), 1.35 (s, 9H). MS (ESI+) m/z 561 [M+H]+.

Example 101 4-[2-(2,6-dichloroﬁuorophenoxy)(2-hydroxypropanyl)pyridin-3 -yl]—N—ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 1h (0.05 g, 0.145 mmol), Example 100b (0.057 g, 0.145 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.98 mg, 4.35 umol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (4.23 mg, 0.014 mmol) and sodium carbonate (0.061 g, 0.579 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 tetrahydrofuran/water (2.0 mL) was d with en for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was d for 4 hours under argon at 60 oC, cooled, and ioned n ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, d with 3-mercaptopropyl onalized silica gel, ﬁltered, and concentrated. Puriﬁcation of the residue by chromatography (silica, 25-60 % of 3 :1 ethyl acetate/ethanol in heptanes) provided the title compound as a white solid (0.-55 g, 68 %). 1H NMR (400 MHz, DMSO-dg) 5 12.31 (s, 1H), 8.32 (t, J = 5.4 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.46 (s, 1H), 6.98 (s, 1H), 5.22 (s, 1H), 3.58 (s, 3H), 3.28 — 3.16 (m, 2H), 1.46 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 533 [M+H]+.

Example 102 4-[2-(4-chloro-2,6-dimethylphenoxy)(1-ﬁuorohydroxypropanyl)py1idin-3 -yl]—N— ethylmethyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 102a 2-(5-bromo(4-chloro-2,6-dimethylphenoxy)py1idinyl)ﬂuoropropanol Example 94b (556 mg, 1.50 mmol) and Selectﬁuor (1-chloromethylﬁuoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetraﬁuoroborate), 585 mg, 1.65 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated at 80 ° C for 44 hours, cooled to ambient temperature, and ioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated s sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 10-20 % ethyl acetate in heptanes) to provide the title compound (250 mg, 43 %).

Example 102b 142142 4-[2-(4-chloro-2,6-dimethylphenoxy)-5 -( l -ﬂuorohydroxypropanyl)py1idin-3 -yl]—N— ethylmethyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide Example 102b was prepared according to the procedure used for the ation of Example 1m, substituting Example 102a for Example 11. The crude product was puriﬁed by ﬂash chromatography a gel, 20-40 % 3 :1 ethyl acetate/ethanol in heptanes) and then by reverse phase HPLC (C18, 20-80 % acetonitrile/0.1 % triﬂuoroacetic acid in water) provided the title compound (27 mg, 42 %) as a triﬂuoroacetic acid salt. 1H NMR (400 MHz, DMSO- d6)812.31 (s, 1H), 8.32 (t, J: 5.4 Hz, 1H), 8.11 (d, J: 2.4 Hz, 1H), 7.97 (d, J: 2.4 Hz, 1H), 7.43 (s, 1H), 7.14 (s, 2H), 6.84 (d, J: 2.2 Hz, 1H), 5.56 (s, br, 1H), 4.46 (s, 1H), 4.34 (s, 1H), 3.59 (s, 3H), 3.30 — 3.20 (m, 2H), 1.96 (s, 6H), 1.48 (d, J: 2.0 Hz, 3H), 1.10 (t, J: 7.2 Hz, 3H). MS (ESI+) m/z 527 (M+H)+.

Example 103 N-lerl-butyl[2-(4-chloro-2,6-dimethylphenoxy)-5 -(l -ﬂuorohydroxypropan yl)py1idinyl]methyloxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide id="p-494" id="p-494" id="p-494" id="p-494" id="p-494" id="p-494" id="p-494" id="p-494" id="p-494" id="p-494" id="p-494" id="p-494" id="p-494"

[00494] Example 103 was prepared according to the procedure used for the preparation of Example 37, substituting Example 102a for Example 29b. Puriﬁcation by ﬂash chromatography (silica gel, 20-40 % 3 :1 ethyl acetate/ethanol in heptanes) and then by e phase HPLC (C18, 20-80% acetonitrile/0.1 % triﬂuoroacetic acid in water) provided the title compound (28 mg, 42 %) as a roacetic acid salt. 1H NMR (400 MHz, DMSO- 2O d6) 5 12.43 (s, 1H), 8.10 (d, J: 2.5 Hz, 1H), 7.97 (d, J: 2.4 Hz, 1H), 7.85 (s, 1H), 7.43 (s, 1H), 7.15 (s, 2H), 6.84 (d, J: 2.2 Hz, 1H), 5.55 (s, br, 1H), 4.46 (s, 1H), 4.34 (s, 1H), 3.59 (s, 3H), 1.97 (s, 6H), 1.48 (d, J = 2.0 Hz, 3H), 1.35 (s, 9H). MS (ESI+) m/z 555 (M+H)+.

Example 104 N-ethyl[2-(3 -ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 104a methyl 3-bromo(3 -ﬂuoro-2,6-dimethylphenoxy)benzoate ] A solution of sodium nitrite (21.67 mg, 0.314 mmol) in water(1 mL) was added dropwise to a solution of Example 99e (100 mg, 0.286 mmol) in pyridine-HF solution (4 mL) at an internal temperature of 5 oC, and the mixture was sealed and stirred at this temperature for 30 minutes. This suspension was then heated to 85 0C for 3 hours. The reaction mixture was cooled to t temperature and the mixture extracted with ethyl acetate (3 x 30 mL).

The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, d, and trated. The e was puriﬁed by column chromatography (silica gel, 143143 % ethyl acetate in petroleum ether) to provide the title compound, (59 mg, 0.120 mmol, 42.0 % yield), as white solid.

Example 104b 2-(3 -bromo(3 -ﬂuoro-2,6-dimethylphenoxy)phenyl)propanol Example 104b was prepared according to the procedure used for the preparation of Example 28d, substituting Example 104a for Example 28c.

Example 104c N—ethyl[2-(3 -2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide id="p-497" id="p-497" id="p-497" id="p-497" id="p-497" id="p-497" id="p-497" id="p-497" id="p-497" id="p-497" id="p-497" id="p-497" id="p-497"

[00497] Example 104c was prepared ing to the procedure used for the preparation of Example lm, substituting Example 104b for e 11. 1H NMR (400 MHz, Methanol-d4) 5 7.65 (d, J = 2.4 Hz, 1H), 7.38 (s, 1H), 7.36 (dd, J = 8.7, 2.4 Hz, 1H), 7.14 — 7.06 (m, 1H), 6.97 (s, 1H), 6.89 (t, J = 8.8 Hz, 1H), 6.41 (d, J = 8.6 Hz, 1H), 3.74 (s, 3H), 3.42 (q, J = 7.2 Hz, 2H), 2.05 (s, 3H), 2.00 (d, J = 1.7 Hz, 3H), 1.58 (s, 6H), 1.23 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 492 (M+H)+.

Example 105 4-[2-(2,6-dimethylphenoxy)(2-hydroxymethylpentanyl)phenyl]-N—ethylmethyl 7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 105a 2-(3 -bromo(2,6-dimethylphenoxy)phenyl)methylpentanol Example 105a was prepared according to the procedure used for the preparation of Example 3d (Method A), substituting isobutylmagnesium chloride for methylmagnesium chloride. e 105b 4-[2-(2,6-dimethylphenoxy)(2-hydroxymethylpentanyl)phenyl]-N—ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 105b was prepared according to the ure used for the preparation of Example lm, tuting Example 105a for Example 11. 1H NMR (400 MHz, DMSO-dg) 5 12.20 (d, J = 2.3 Hz, 1H), 8.29 (t, J = 5.3 Hz, 2H), 7.45 (d, J = 2.3 Hz, 1H), 7.28 (s, 1H), 7.22 (dd, J = 8.6, 2.4 Hz, 1H), 7.07 (d, J = 7.3 Hz, 2H), 7.01 (dd, J = 8.5, 6.3 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.25 (d, J = 8.6 Hz, 1H), 3.57 (s, 3H), 3.24 (qd, J = 7.2, 5.1 Hz, 2H), 1.97 (s, 6H), 1.64 — 1.50 (m, 3H), 1.40 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H), 0.81 (dd, J = 8.9, 6.2 Hz, 3H), 0.63 (d, J = 5.9 Hz, 3H). MS (ESI+) m/z 516.2 (M+H)+.

Example 106 144144 N—lerl-butyl[2-(2,6-dimethylphenoxy)(2-hydroxymethylpentanyl)phenyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide e 106 was prepared according to the procedure used for the preparation of Example 37, tuting Example 105a for Example 29b. 1H NMR (400 MHz, DMSO-dg) 5 12.34 (d, J = 2.3 Hz, 1H), 7.83 (s, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.31 — 7.14 (m, 2H), 7.15 — 6.92 (m, 2H), 6.79 (d, J = 2.2 Hz, 1H), 6.25 (d, J = 8.6 Hz, 1H), 3.58 (s, 5H), 1.97 (s, 6H), 1.68 — 1.51 (m, 2H), 1.40 (s, 2H), 1.34 (s, 9H), 0.79 (d, J = 6.2 Hz, 2 3H), 0.63 (d, J = 6.2 Hz, 3H). MS (ESI+) m/z 516.2 .

Example 107 l{ 5 -(2-hydroxypropanyl)[4-(2-hydroxypropanyl)-2, 6- dimethylphenoxy]phenyl }methyloxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine carboxamide Example 107a methyl 4-(4-acetyl-2,6-dimethylphenoxy)—3-bromobenzoate ]Methyl oﬂuorobenzoate (699 mg, 3.00 mmol), 1-(4-hydroxy-3,5- dimethylphenyl)ethanone (493 mg, 3.00 mmol), and cesium carbonate (1.47 g, 4.50 mmol) were combined in dimethyl sulfoxide (3 mL). The reaction mixture was heated at 100 0C for 16 hours, cooled to ambient temperature, and partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 10-20 % ethyl acetate in heptanes) to provide the title nd (540 mg, 48 %).

Example 107b 2-(4-(2-bromo(2-hydroxypropanyl)phenoxy)-3,5-dimethylphenyl)propanol ] To a on of Example 107a (528 mg, 1.40 mmol) in tetrahydrofuran (10 mL) was added 3M methylmagnesium chloride in tetrahydrofuran (2.80 mL, 8.40 mmol) dropwise at - 78 oC. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was cooled to -78 oC and additional 3M methylmagnesium chloride in tetrahydrofuran (2.80 mL, 8.40 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for another 3 hours, treated with 5% aqueous ammonium chloride carefully, and partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and trated. The residue was puriﬁed by ﬂash chromatography (silica gel, 20-40 % ethyl acetate in heptanes) to provide the title compound (375 mg, 68 %).

Example 107c 145145 N-ethyl{ 5 -(2-hydroxypropanyl)[4-(2-hydroxypropanyl)-2, 6- dimethylphenoxy]phenyl }methyloxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine carboxamide Example 107c (50 mg, 94 %) was ed according to the procedure used for the preparation of Example 1m, substituting Example 107b for Example 11. 1H NMR (400 MHz, DMSO-d6) 5 12.18 (s, 1H), 8.30 (t, J: 5.3 Hz, 1H), 7.49 (d, J: 2.4 Hz, 1H), 7.31 (s, 1H), 7.27 (dd, J: 8.6, 2.4 Hz, 1H), 7.15 (s, 2H), 6.83 (s, 1H), 6.25 (d, J: 8.6 Hz, 1H), 4.93 (s, 1H), 4.90 (s, 1H), 3.57 (s, 3H), 3.28 — 3.20 (m, 2H), 1.98 (s, 6H), 1.41 (s, 6H), 1.37 (s, 6H), 1.08 (t, J: 7.2 Hz, 3H). MS (ESI-) m/z 530 (M-H)+. e 108 N-lerl—butyl { 5 -(2-hydroxypropanyl)[4-(2-hydroxypropanyl)-2, 6- ylphenoxy]phenyl }methyloxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine carboxamide Example 108 (54 mg, 96 %) was prepared according to the ure used for the preparation of Example 37, substituting Example 107b for 29b. 1H NMR (400 MHz, DMSO- d6) 5 12.31 (s, 1H), 7.83 (s, 1H), 7.50 (d, J: 2.4 Hz, 1H), 7.31 (s, 1H), 7.27 (dd, J: 8.6, 2.4 Hz, 1H), 7.16 (s, 2H), 6.83 (s, 1H), 6.25 (d, J: 8.5 Hz, 1H), 4.94 (s, 1H), 4.90 (s, 1H), 3.57 (s, 3H), 1.98 (s, 6H), 1.41 (s, 6H), 1.37 (s, 6H), 1.34 (s, 9H). MS (ESI—) m/z 558 (M-H)+.

Example 109 4-[2-(3 -chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl]-N—ethyl methyloxo-6,7-dihydro- lH—pyrrolo[2,3-c]pyridinecarboxamide e 109a methyl 5-bromo(3-chloro-2,6-dimethylphenoxy)nicotinate Example 109a was prepared according to the procedure used for the preparation of Example 99f, substituting Example 91a for Example 99e.

Example 109b 2-(5-bromo(3-chloro-2,6-dimethylphenoxy)pyridinyl)propanol Example 109b was prepared according to the procedure used for the preparation of e 28d, substituting Example 109a for Example 28c.

Example 109c 4-[2-(3 -chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -yl]-N—ethyl methyloxo-6,7-dihydro- rolo[2,3-c]pyridinecarboxamide Example 109c was prepared according to the procedure used for the preparation of Example 1m, substituting e 109b for Example 11. 1H NMR (400 MHz, Methanol-d4) 5 146146 8.14 (d, J = 2.5 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H), 7.47 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 3.74 (s, 3H), 3.43 (q, J = 7.2 Hz, 2H), 2.11 (s, 3H), 2.04 (s, 3H), 1.61 (s, 6H), 1.24 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 509.2 (M+H)+.

Example 110 N—ethyl[4-(2-hydroxypropanyl)-4'-(triﬂuoromethoxy)[1,1'-biphenyl]yl]—6-methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide e 110a 2-(3 -bromochlorophenyl)propanol Example 110a was prepared ing to the procedure used for the preparation of Example 35c, substituting methyl 3-bromochlorobenzoate for Example 35b. The reaction mixture was stirred overnight instead of 30 minutes. e 110b 4-(2-chloro-5 -(2-hydroxypropanyl)phenyl)-N-ethylmethyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide id="p-509" id="p-509" id="p-509" id="p-509" id="p-509" id="p-509" id="p-509" id="p-509" id="p-509" id="p-509" id="p-509" id="p-509" id="p-509"

[00509] Example 110b was prepared according to the procedure used for the preparation of e 1m, substituting Example 110a for Example 11. The reaction e was heated for 6 hours instead of 3 hours.

Example 110c N—ethyl[4-(2-hydroxypropanyl)-4'-(triﬂuoromethoxy)[1,1'-biphenyl]yl]—6-methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 110b (0.035 g, 0.09 mmol), (4-(triﬂuoromethoxy)phenyl)boronic acid (0.028 g, 0.135 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0083 g, 0.009 mmol), dicyclohexyl(2',6'—dimethoxy-[1,1'-biphenyl]yl)phosphine (0.011 g, 0.027 mmol) and potassium ﬂuoride (0.026 g, 0.45 mmol) were combined and sparged with nitrogen for 30 minutes. To this mixture were added nitrogen-sparged e (0.9 mL) and water (0.1 mL) via syringe. The on mixture was stirred at 90 oC overnight and then partitioned between ethyl acetate and water. The organic layer was washed with brine, treated with 3- mercaptopropyl-functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, ﬁltered through a plug of diatomaceous earth, and concentrated. The residue was puriﬁed by ﬂash chromatography a gel 12 g Grace Reveleris column, 12 to 50 % of a 3 :1 mixture of ethyl acetate/ethanol in heptanes) to provide the title compound and some fractions. The mixed fractions were puriﬁed by a second ﬂash chromatography a gel 12 g Grace Reveleris column, 2 to 35 % of a 3 :1 mixture of ethyl e/ethanol in heptanes). A combined yield of 0.024 g (52 %) of the title compound was obtained. 1H NMR (501 MHz, 147147 DMSO-dg) 8 12.09 (s, 1H), 8.20 (t, J = 5.3 Hz, 1H), 7.58 (dd, J = 8.0, 1.9 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.31 (m, 2H), 7.19 (d, J = 8.1 Hz, 2H), 6.97 (s, 1H), 6.41 (d, J = 1.3 Hz, 1H), 5.13 (s, 1H), 3.42 (s, 3H), 3.22 (qd, J = 7.2, 5.4 Hz, 2H), 1.50 (s, 6H), 1.08 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 514.0 (M+H)+.

Example 1 1 1 4-[4',4'-diﬂuoro(2-hydroxypropanyl)[2',3 ',4', 5'-tetrahydro[1,1'-biphenyl]]yl]-N—ethyl- 6-methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 111 was prepared according to the procedure used for the ation of Example 110c, substituting 2-(4,4-difluorocyclohexenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane for (4-(triﬂuoromethoxy)phenyl)boronic acid. 1H NMR (400 MHz, DMSO-dg) 8 12.21 (s, 1H), 8.32 (t, J = 5.3 Hz, 1H), 7.47 (s, 1H), 7.44 (dd, J = 8.0, 1.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.68 (s, 1H), 5.51 (s, 1H), 5.05 (s, 1H), 3.53 (s, 3H), 3.25 (m, 2H), 2.49 (m, 2H), 2.18 (t, J = 5.7 Hz, 2H), 1.81 (dt, J = 14.6, 7.4 Hz, 2H), 1.46 (s, 6H), 1.11 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 470.1 (M+H)+.

Example 112 4-[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo-6,7- dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide 1-Hydroxybenzotriazole hydrate (9.0 mg, 0.059 mmol), Example 75c (17 mg, 0.037 mmol) were dissolved in dichloromethane (2.5 mL). Ammonia (0.5 M in e, 1.0 mL, 0.500 mmol) was added and the mixture was d at ambient temperature as 1-(3- dimethylaminopropyl)ethylcarbodiimide hydrochloride (13.1 mg, 0.068 mmol) was added.

The mixture was stirred for 23 hours, and the resulting white suspension was concentrated under vacuum. The residue was puriﬁed by HPLC (30 x 100 mm XBridge column, eluted with 10 mM aqueous C03 - CH3CN, 80:20 - 0:100 over 15 minutes) to provide the title compound (13 mg). 1H NMR (400 MHz, DMSO-dg) d 12.23 (s, 1H), 7.81 (s, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.44 (s, 1H), 7.36 7.26 (m, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.84 (s, 1H), 6.31 (d, J = 8.6 Hz, 1H), 4.98 (s, 1H), 3.60 (s, 3H), 2.01 (s, 6H), 1.44 (s, 6H). MS (ESI+) m/z 464 (M+H)+.

Example 113 N-ethyl[4-(2-hydroxypropanyl)-4'-methyl[2',3',4',5'—tetrahydro[1,1'-biphenyl]]yl] oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 113 was prepared according to the procedure used for the preparation of Example 110c, substituting (4-methylcyclohexenyl)boronic acid for (4- uoromethoxy)phenyl)boronic acid. 1H NMR (500 MHz, DMSO-dg) 5 12.17 (s, 1H), 148148 8.32 (t, J = 5.5 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.0, 2.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 6.66 (s, 1H), 5.58 (m, 1H), 5.03 (s, 1H), 3.53 (s, 3H), 3.26 (m, 2H), 2.07 (dt, J = 16.6, 4.5 Hz, 1H), 1.93 (m, 2H), 1.53 (m, 3H), 1.45 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H), 0.96 (m, 1H), 0.81 (d, J = 6.4 Hz, 3H). MS (ESI+) m/z 448.2 (M+H)+. e 114 4-[2-(cyclopentenyl)(2-hydroxypropanyl)phenyl]-N—ethylmethyloxo-6,7- dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 114 was prepared ing to the procedure used for the preparation of Example 110c, substituting 2-(cyclopentenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for (4-(triﬂuoromethoxy)phenyl)boronic acid. Additional puriﬁcation by reverse phase HPLC (C18, acetonitrile/water (0.1 %t1iﬂuroacetic acid), 10-80 %) provided the title compound. 1HNMR (501 MHz, DMSO-dg) 5 12.16 (s, 1H), 8.30 (t, J = 5.3 Hz, 1H), 7.43 (dd, J = 8.1, 2.0 Hz, 1H), 7.39 (d, J :19 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.11 (s, 1H), 6.54 (d, J = 2.2 Hz, 1H), 5.62 (p, J = 2.2 Hz, 1H), 5.03 (s, 1H), 3.55 (s, 3H), 3.24 (qd, J = 7.2, 5.3 Hz, 2H), 2.28 (m, 2H), 2.18 (m, J = 9.2, 7.6, 2.2 Hz, 2H), 1.66 (p, J = 7.5 Hz, 2H), 1.45 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H). LCMS ) m/z 420.5 (M+H)+.

Example 1 15 4-[2-(2-chloromethylphenoxy)(1,2-dihydroxypropanyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide 2O Example 1 15a 1-(3 -bromo(2-chloromethylphenoxy)phenyl)ethanone Example 115a was prepared according to the procedure used for the preparation of Example 35b, substituting 2-methychlorolphenol for Example 35a, and substituting 1-(3- bromoﬂuorophenyl)ethanone for methyl 3-bromoﬂuorobenzoate, respectively.

Example 1 15b 2-(2-bromo(propenyl)phenoxy)chloro-3 -methylbenzene To a solution of methyltriphenylphosphonium bromide (1.893 g, 5.30 mmol) in tetrahydrofuran (12 mL) was added 2.5 M llithium (2.120 mL, 5.30 mmol) at 0 °C. The reaction e was stirred at this temperature for 1 hour, and then Example 115a (900 mg, 2.65 mmol) in 2 mL of tetrahydrofuran was added to the reaction solution. The reaction mixture was allowed to warm to ambient temperature gradually and stirred for 16 hours. The reaction mixture was then quenched with water. The mixture was ioned between water (15 mL) and ethyl acetate (15 mL), extracted with ethyl acetate (10 mL), dried over anhydrous sodium e, ﬁltered, and trated. The crude product was puriﬁed by ﬂash 149149 tography on silica gel eluting with 100:5 hexane: acetate to provide the title compound, (810 mg, 2.267 mmol, 86 % yield), as a colorless oil.

Example 1 15c 2-(3 -bromo(2-chloromethylphenoxy)phenyl)propane-1,2-diol To a solution of Example 115b (810 mg, 2.399 mmol) and potassium carbonate (995 mg, 7.20 mmol) in water (15 mL) and tert-butanol (15.000 mL) was added potassium hexacyanoferrate (111) (3.949 g, 12.00 mmol) and potassium osmate dihydrate (35.4 mg, 0.096 mmol) at ambient temperature. The on mixture was stirred at ambient temperature for 48 hours. The mixture was partitioned between water (15 mL) and ethyl e (25 mL), extracted with ethyl acetate (3 x 20 mL), dried over ous sodium sulfate, ﬁltered, and concentrated. The crude product was puriﬁed by ﬂash chromatography (silica gel, ethyl acetate/petroleum 1:2) to provide the title nd (620 mg, 1.668 mmol, 69.5 % yield).

Example 1 15d 4-[2-(2-chloromethylphenoxy)(1,2-dihydroxypropanyl)phenyl]-N-ethylmethyl 7-dihydro- rolo[2,3-c]pyridinecarboxamide Example 115d was prepared according to the procedure used for the preparation of Example 1m, substituting Example 115c for Example 11. 1H NMR (400 MHz, g) 5 12.21 (s, 1H), 8.34 (t, J = 5.3 Hz, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.35 — 7.28 (m, 2H), 7.19 (t, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.30 (d, J = 8.6 Hz, 1H), 4.89 (s, 1H), 4.71 (t, J = 5.8 Hz, 1H), 3.60 (s, 3H), 3.43 (dd, J = 5.6, 2.7 Hz, 2H), 3.32 — 3.22 (m, 2H), 2.08 (s, 3H), 1.41 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 510.1 (M+H)+.

Example 116 N-lerZ-butyl[2-(2-chloromethylphenoxy)(1,2-dihydroxypropanyl)phenyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide id="p-519" id="p-519" id="p-519" id="p-519" id="p-519" id="p-519" id="p-519" id="p-519" id="p-519" id="p-519" id="p-519" id="p-519" id="p-519"

[00519] Example 116 was prepared according to the procedure used for the preparation of Example 37, substituting Example 115c for Example 29b. 1H NMR (400 MHz, DMSO-dg) 5 12.35 (s, 1H), 7.86 (s, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.34 — 7.27 (m, 2H), 7.20 (t, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.30 (d, J = 8.6 Hz, 1H), 4.90 (s, 1H), 4.71 (t, J = 5.8 Hz, 1H), 3.60 (s, 3H), 3.46 — 3.39 (m, 2H), 2.09 (s, 3H), 1.41 (s, 3H), 1.37 (s, 9H). Ms (ESI+) m/z 538.1 (M+H)+.

Example 117 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo-6,7-dihydro- 1H—pyrrolo[2,3-c]pyridinecarboxamide Example 117a 150150 ethyl 4-(2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl)methyloxotosyl- 6,7-dihydro- 1H—pyrrolo[2,3-c]pyridinecarboxylate Example 117a (615 mg, 98 %) was prepared according to the procedure used for the preparation of Example 75b, substituting Example 3d for Example 35c.

Example 117b 2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl)methyloxo-6,7-dihydro- 1H—pyrrolo[2,3-c]pyridinecarboxylic acid Example 117a (610 mg, 0.970 mmol) and lithium hydroxide (232 mg, 9.70 mmol) were combined in the mixture of dioxane (15 mL) and water (5 mL). The reaction mixture was heated at 70 0C for 2 hours, cooled, diluted with water, adjusted pH to 4 by addition of 1M HCl, ﬁltered, washed with water and dried to provide the title compound (322 mg, 74 %).

Example 117c 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]methyloxo-6,7-dihydro- 1H—pyrrolo[2,3-c]pyridinecarboxamide id="p-522" id="p-522" id="p-522" id="p-522" id="p-522" id="p-522" id="p-522" id="p-522" id="p-522" id="p-522" id="p-522" id="p-522" id="p-522"

[00522] Example 117b (89 mg, 0.20 mmol), 1-hydroxybenzotriazole hydra (49 mg, 0.32 mmol), 1-ethyl[3-(dimethylamino)propyl]-carbodiimide hydrochloride (61 mg, 0.32 mmol) and 0.5 M ammonia in dioxane (6.0 mL, 3.0 mmol) were combined in dichloromethane (1 mL). The reaction e was stirred at ambient temperature for 48 hours. To this reaction mixture was added 0.5 M ammonia in e (6.0 mL, 3.0 mmol) again. The reaction mixture stirred at t ature for another 48 hours. To this reaction mixture was added 0.5 M ammonia in dioxane (6.0 mL, 3.0 mmol) again. The reaction mixture stirred at ambient temperature for r 48 hours and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 20-40 % 3 :1 ethyl acetate/ethanol in heptanes) to provide the title compound (25 mg, 28 %). 1H NMR (400 MHz, DMSO-d6) 5 12.21 (s, 1H), 7.80 (s, 1H), 7.51 (d, J: 2.4 Hz, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 7.28 (dd, J: 8.6, 2.4 Hz, 1H), 7.13 — 7.00 (m, 3H), 6.84 (s, 1H), 6.26 (d, J = 8.6 Hz, 1H), 4.96 (s, 1H), 3.59 (s, 3H), 2.00 (s, 6H), 1.42 (s, 6H). MS (ESI+) m/z 446 (M+H)+. e 1 18 N-ZerZ-butyl[2-(2-chloroﬂuoromethylphenoxy)(1,2-dihydroxypropan yl)phenyl]methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide e 1 18a 1-(3 -bromo(2-chloroﬂuoromethylphenoxy)phenyl)ethanone Example 118a was prepared according to the procedure used for the ation of Example 35b, substituting 2-methyﬂuorochlorolphenol for Example 35a, and 151151 substituting 1-(3 -bromoﬂuorophenyl)ethanone for methyl 3-bromoﬂuorobenzoate respectively.

Example 1 18b 2-(2-bromo(propenyl)phenoxy)chloroﬂuoro-3 -methylbenzene ] Example 118b was prepared according to the procedure used for the preparation of Example 115b, substituting Example 118a for Example 115a.

Example 1 18c 2-(5-bromo(3 -ﬂuoro-2,6-dimethylphenoxy)pyridinyl)propanol ] Example 118c was prepared according to the procedure used for the preparation of Example 1 15c, substituting Example 1 18b for Example 1 15b.

Example 1 18d -butyl[2-(2-chloroﬂuoromethylphenoxy)(1,2-dihydroxypropan yl)phenyl]methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 118d was prepared ing to the procedure used for the ation of Example 37, substituting Example 118c for e 29b. 1H NMR (400 MHz, Methanol-d4) 7.67 (d, J = 2.3 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J = 8.7, 2.3 Hz, 1H), 7.18 (dd, J = 8.0, 3.0 Hz, 1H), 7.09 — 7.00 (m, 2H), 6.44 (d, J = 8.6 Hz, 1H), 3.73 (s, 3H), 3.70 — 3.60 (m, J = 5.9 Hz, 2H), 2.10 (s, 3H), 1.55 (s, 3H), 1.46 (s, 9H). MS (ESI+) m/z 556.2 (M+H)+.

Example 119 2O 4-[2-(2-chloroﬂuoromethylphenoxy)(1,2-dihydroxypropanyl)phenyl]-N—ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 119 was prepared according to the procedure used for the preparation of e 1m, substituting Example 118c for Example 11. 1H NMR (400 MHz, Methanol-d4) 7.69 (d, J = 2.3 Hz, 1H), 7.43 (s, 1H), 7.38 (dd, J = 8.7, 2.3 Hz, 1H), 7.17 (dd, J = 8.1, 3.0 Hz, 1H), 7.06 — 6.99 (m, 2H), 6.45 (d, J = 8.7 Hz, 1H), 3.72 (s, 3H), 3.66 (q, J = 5.6 Hz, 2H), 3.42 (q, J = 7.3 Hz, 2H), 2.11 (s, 3H), 1.56 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 528.2 (M+H)+.

Example 120 4-[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N,6-dimethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 120a 4-bromo-N,6-dimethyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 32a (1.084 g, 4 mmol) in dichloromethane (25 mL) was treated with oxalyl dichloride (0.700 mL, 8.00 mmol) and N,N—dimethylfonnamide (0.062 mL, 0.800 mmol). 152152 Gas was generated, and the reaction mixture turned from a white suspension to a yellow ﬁne suspension. The reaction mixture was d at ambient temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was treated with tetrahydrofuran (20 mL) and N,N—dimethylformamide (10 mL). To this reaction mixture was added 2.0 N amine in tetrahydrofuran (20.00 mL, 40.0 mmol). The white suspension was stirred at t temperature for 2 hours. Excess tetrahydrofuran was removed under reduced pressure. The remaining mixture was poured into water (300 mL). The resulting solid was collected by ﬁltration to provide the title compound (0.95 g, 84 % yield) after drying in a vacuum oven overnight.

Example 120b 2-(4-(4-ﬂuoro-2,6-dimethylphenoxy)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl)propanol A solution of e 35c (21 g, 59.5 mmol) in tetrahydrofuran (396 ml) was cooled to -78 OC and n-butyl lithium (71.3 mL, 178 mmol) was added. The reaction mixture was d for 30 minutes. Neat 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37.6 mL, 184 mmol) was added. The cold bath was d after 10 minutes and the on mixture was allowed to warm to ambient temperature for one hour. The reaction mixture was quenched by addition of saturated aqueous sodium carbonate and ted with ethyl acetate.

The c phase was separated, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated under reduced pressure. The crude material was d via ﬂash chromatography using a Grace silica gel column eluting with 10-25 % ethyl acetate/heptanes to give the title compound (15 g, 63 %) as a white solid.

Example 120c 4-[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl]-N,6-dimethyloxo- 6,7-dihydro-1H—pyrrolo[2,3-c]py1idinecarboxamide A mixture of Example 120a (0.057 g, 0.2 mmol), Example 120b (0.096 g, 0.240 mmol), tetrakis(triphenylphosphine)palladium(0) (0.012 g, 10.00 umol), and cesium ﬂuoride (0.091 g, 0.600 mmol) in dimethoxyethane (1 mL) and methanol (0.5 mL) was heated at 120 0C for 40 minutes under microwave heating conditions. The reaction mixture was loaded onto a 15 g silica gel cartridge, and dried. It was then loaded onto a 12 g silica gel column, eluted with 15:85 methanol: ethyl acetate to give crude product, which was then puriﬁed by reverse phase Preparative HPLC (C18 column, acetonitrile/water (0.1 % triﬂuoroacetic acid)) to give the title nd (0.062 g, 0.130 mmol, 64.9 % yield). 1H NMR (400 MHz, DMSO- d6)512.26 — 12.09 (m, 1H), 8.31 (q, I = 4.5 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.34 — 7.26 (m, 153153 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 2.2 Hz, 1H), 6.29 (d, J = 8.6 Hz, 1H), 3.58 (s, 3H), 2.74 (d, J = 4.5 Hz, 3H), 1.99 (s, 6H), 1.42 (s, 6H). MS (ESI+) m/z 478.1 (M+H)+.

Example 121 N—cyclopropyl[2-(4-ﬁuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl] methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 121a 4-bromo-N—cyclopropylmethyloxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine carboxamide A solution of Example 32a (1 g, 3.69 mmol) in dimethyl sulfoxide (18.5 mL) was treated with [1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexaﬂuorophosphate(V) (HATU, 1.543 g, 4.06 mmol) and N—ethyl-N-isopropylpropan amine (2 mL, 11.45 mmol). The resulting mixture was stirred at ambient temperature for 5 minutes and was then treated with cyclopropanamine (0.3 mL, 4.33 mmol). The resulting mixture was stirred at ambient temperature overnight. Water (80 mL) was added to the reaction mixture, inducing itation of a light yellow solid. The solid was collected by ﬁltration, rinsed with 300 mL of water and 50 mL of heptanes, and dried in a vacuum oven at 65 0C to provide 0.966 g (84%) of the title compound.

Example 121b N—cyclopropyl(2-(4-ﬁuoro-2,6-dimethylphenoxy)(2-hydroxypropanyl)phenyl) oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 121a (0.12 g, 0.387 mmol), Example 120b (0.155 g, 0.387 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.018 g, 0.019 mmol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamantane (0.017 g, 0.058 mmol) and sodium carbonate (0.176 g, 1.664 mmol) were combined and sparged with nitrogen for 30 minutes. To this e were added nitrogen-sparged tetrahydrofuran (2 mL) and water (0.5 mL) via syringe.

The reaction mixture was stirred at 60 0C for 4.5 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with saturated s sodium chloride, treated with 3-mercaptopropyl-functionalized silica gel overnight, dried over anhydrous magnesium e, d through a plug of diatomaceous earth, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel 24 g Grace Reveleris column, eluting with a gradient of 0 to 60 % of a 3 :1 mixture of ethyl acetate/ethanol in heptanes) to provide the title compound as a mixture. The material was puriﬁed by a second ﬂash tography (silica gel 24 g Grace Reveleris column, 15 to % of a 3 :1 mixture of ethyl acetate/ethanol in heptanes) to provide 0.147 g (75%) of the 154154 title compound. 1H NMR (501 MHz, DMSO-dg) 5 12.17 (s, 1H), 8.35 (d, J = 4.2 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.33 (s, 1H), 7.32 (dd, J = 9.0, 2.5 Hz, 1H), 6.98 (d, J = 9.1 Hz, 2H), 6.83 (s, 1H), 6.31 (d, J = 8.6 Hz, 1H), 4.98 (s, 1H), 3.59 (s, 3H), 2.82 (tq, J = 7.7, 4.0 Hz, 1H) 2.01 (s, 6H), 1.44 (s, 6H), 0.70 (td, J = 7.0, 4.9 Hz, 2H), 0.52 (m, 2H). MS (ESI+) m/z 504.1 (M+H)+.

Example 122 N-ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(1-hydroxycyclobutyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 122a 2-(2-bromoiodophenoxy)ﬂuoro- 1 , 3 -dimethylbenzene A mixture of oﬂuoroiodobenzene (3.01 g, 10 mmol), Example 35a (1.472 g, 10.50 mmol), and cesium carbonate (3.42 g, 10.50 mmol) in dimethylsulfoxide (20 mL) was heated at 110 oC overnight. After cooling to ambient temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by column tography on silica gel eluting with heptanes to give the title compound (3.21 g, 76% yield) as a white solid.

Example 122b 2O 1-(3 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)cyclobutanol Example 122a (0.421 g, 1.0 mmol) in hexane (10 mL) was cooled to -78 0C. To this solution was added 1.7 M utyllithium (0.647 mL, 1.1 mmol) at -78 oC. The reaction was stirred at -78 0C for 1 hour. Then toluene (3 mL) was added, and the solution became clear.

To this solution was added cyclobutanone (0.105 g, 1.5 mmol) in toluene (1 mL). The reaction was allowed to warm up to ambient ature slowly overnight. The reaction mixture was ed with saturated NH4C1. It was then partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, ﬁltered, and concentrated. The residue was puriﬁed by column chromatography on silica gel eluting with 10 % ethyl acetate in haptanes to give the title compound (0.086 g, 0.235 mmol, 24 % yield).

Example 122c l[2-(4-ﬂuoro-2,6-dimethylphenoxy)(1-hydroxycyclobutyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide 155155 Example 122c was prepared according to the procedure for the preparation of Example 28e, substituting e 122b for Example 28d. 1H NMR (400 MHz, DMSO-dg) 5 12.21 (s, 1H), 8.32 (t, J = 5.4 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.37 — 7.30 (m, 2H), 6.97 (d, J = 9.1 Hz, 2H), 6.83 (s, 1H), 6.33 (d, J = 8.6 Hz, 1H), 5.44 (s, 1H), 3.58 (s, 3H), 3.31 — 3.19 (m, 2H), 2.49 — 2.38 (m, 2H), 2.24 (ddd, J = 11.6, 9.2, 7.2 Hz, 2H), 2.00 (s, 6H), 1.98 — 1.81 (m, 1H), 1.68 — 1.55 (m, 1H), 1.16 — 1.05 (m, 3H). MS (ESI+) m/z 504.1 (M+H)+.

Example 123 N-ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)-5 -(3 -hydroxyoxetan-3 -yl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 123a 3-(3 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)oxetanol ] e 123a was prepared according to the procedure for the preparation of Example 122b, substituting oxetanone for cyclobutanone.

Example 123b N-ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)-5 -(3 -hydroxyoxetan-3 enyl]methyl oxo-6,7-dihydro- rolo[2,3-c]pyridinecarboxamide Example 123b was prepared according to the procedure for the preparation of Example 28e, substituting Example 123a for Example 28d. 1H NMR (400 MHz, DMSO-dg) 12.23 (s, 1H), 8.31 (t, J = 5.3 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 8.6, 2.4 Hz, 2O 1H), 7.36 (s, 1H), 6.98 (d, J = 9.1 Hz, 2H), 6.84 (s, 1H), 6.40 (d, J = 8.6 Hz, 1H), 6.33 (s, 1H), 4.78 — 4.67 (m, 4H), 3.58 (s, 3H), 3.25 (qd, J = 7.2, 5.3 Hz, 2H), 2.01 (s, 6H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 506.1 (M+H)+.

Example 124 N-ethyl{ 5 droxypropanyl)[4-(2-hydroxypropanyl)-2, 6- ylphenoxy]pyridinyl}methyloxo-6,7-dihydro- lH—pyrrolo[2,3-c]pyridine carboxamide Example 124a methyl 6-(4-acetyl-2,6-dimethylphenoxy)bromonicotinate Methyl 5-bromochloronicotinate (751 mg, 3.00 mmol), l-(4-hydroxy-3,5- dimethylphenyl)ethanone (493 mg, 3.00 mmol), and cesium carbonate (1.47 g, 4.50 mmol) were combined in dimethyl sulfoxide (3 mL). The reaction mixture was heated at 100 0C for 2 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated s sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated to provide the title compound (980 mg, 86 %). 156156 Example 124b 2-(4-((3 -bromo(2-hydroxypropanyl)pyridinyl)oxy)-3,5-dimethylphenyl)propanol To a solution of Example 124a (970 mg, 2.56 mmol) in tetrahydrofuran (15 mL) was added 3M methylmagnesium chloride in tetrahydrofuran (5.13 mL, 15.4 mmol) dropwise at - 78 oC. The reaction mixture was stirred at ambient temperature for 2 hours, treated carefully with 5 % s um chloride, and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, ﬁltered, and concentrated. The residue was d by ﬂash tography (silica gel, 20-40 % ethyl acetate in heptanes) to provide the title compound (854 mg, 84 %).

Example 124c N-ethyl{ 5 -(2-hydroxypropanyl)[4-(2-hydroxypropanyl)-2, 6- dimethylphenoxy]pyridinyl}methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridine carboxamide Example 1h (34.5 mg, 0.100 mmol), Example 124b (39.4 mg, 0.100 mmol), sodium carbonate (37.1 mg, 0.350 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.75 mg, 3.00 umol) and 1,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamantane (2.63 mg, 9.00 umol) ) were combined in a microwave tube and purged with nitrogen for 15 minutes. A e of tetrahydrofuran (2 mL) and water (0.5 mL) was purged with nitrogen for 15 minutes and transferred to the reaction vessel. The reaction mixture was heated at 60 0C for 3 hours, cooled to ambient temperature, and partitioned between ethyl acetate and water. The organic layer was washed with saturated s sodium chloride, dried with anhydrous sodium sulfate, treated with aptopropyl functionalized silica gel, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 20-60 % 3 :1 ethyl acetate/ethanol in heptanes) to provide the title compound (50 mg, 94 %). 1H NMR (500 MHz, DMSO-d6) 5 ppm 12.33 (d, J: 1.8 Hz, 1H), 8.36 (t, J: 5.4 Hz, 1H), 8.10 (d, J: 2.4 Hz, 1H), 7.95 (d, J: 2.4 Hz, 1H), 7.45 (s, 1H), 7.14 (s, 2H), 6.89 (d, J: 2.2 Hz, 1H), .19 (s, 1H), 4.93 (s, 1H), 3.61 (s, 3H), 3.31 — 3.25 (m, 2H), 1.99 (s, 6H), 1.48 (s, 6H), 1.41 (s, 6H), 1.13 (t, J = 7.2 Hz, 3H). (ESI+) m/z 533 (M+H)+.

Example 125 N-lerl—butyl { 5 -(2-hydroxypropanyl)[4-(2-hydroxypropanyl)-2, 6- dimethylphenoxy]pyridinyl}methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridine amide Example 125 was ed according to the procedure used for the preparation of Example 124c, substituting Example 32c for Example 1h. Puriﬁcation by ﬂash 157157 chromatography (silica gel, 20-40 % 3 :1 ethyl e/ethanol in heptanes) provided the title compound (49 mg, 87 %). 1H NMR (500 MHz, DMSO-d6) 5 ppm 12.45 (s, 1H), 8.10 (d, J: 2.4 Hz, 1H), 7.96 (d, J: 2.4 Hz, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.15 (s, 2H), 6.90 (d, J: 1.7 Hz, 1H), 5.20 (s, 1H), 4.93 (s, 1H), 3.62 (s, 3H), 1.99 (s, 6H), 1.48 (s, 6H), 1.41 (s, 6H), 1.38 (s, 9H). (ESI+) m/z 561 (M+H)+.

Example 126 4- { 5 -(1,2-dihydroxypropanyl)[2-methyl(triﬁuoromethyl)phenoxy]phenyl}-N-ethyl- 6-methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 126a 1-(3 -bromo(2-methyl(triﬁuoromethyl)phenoxy)phenyl)ethanone A mixture of 2-methyl(triﬁuoromethyl)phenol (213 mg, 1.21 mmol), cesium carbonate (751 mg, 2.30 mmol), and 1-(3-bromoﬁuorophenyl)ethanone (250 mg, 1.15 mmol) in dimethyl ide (3 mL) was stirred at 60 0C in sealed tube for 2 days and then at 80 0C for another day. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (50 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, ﬁltered, and concentrated.

The e was puriﬁed by ﬂash column chromatography (silica gel, 5 % to 20 % ethyl acetate in petroleum ether) to give the title compound (180 mg, 39 % yield). MS (ESI+) m/z 2O 373.0, 375.0 (M, M+2)+.

Example 126b 2-(2-bromo(propenyl)phenoxy)methyl-3 -(triﬁuoromethyl)benzene To a solution of methyltriphenylphosphonium bromide (402 mg, 1.13 mmol) in anhydrous tetrahydrofuran (10 mL) was added n-butyl m (0.703 mL, 1.6 M in tetrahydrofuran, 1.13 mmol) at 0 OC and the reaction mixture was stirred at this temperature for 1 hour. Then Example 126a (280 mg, 0.750 mmol) in 2 mL of tetrahydrofuran was added to the reaction solution and the reaction mixture was d to warm to 15 0C for 16 hours.

The e was partitioned between water (10 mL) and ethyl acetate (30 mL). The organic layer was separated and the s layer was extracted with ethyl acetate (20 mL) once more. The combined organic layers were dried over anhydrous sodium e, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 5 % to 10 % ethyl acetate in petroleum ether) to give the title compound (230 mg, 83 % yield). 1H NMR (400 MHz, CDC13) 5 7.73 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.29 (d, 158158 J = 7.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.29 (d, J = 8.6 Hz, 1H), 5.30 (s, 1H), 5.05 (s, 1H), 2.09 (s, 6H).

Example 126c 2-(3 -bromo(2-methyl(triﬂuoromethyl)phenoxy)phenyl)propane-1,2-diol To a solution of Example 126b (230 mg, 0.620 mmol) and ium carbonate (257 mg, 1.86 mmol) in water (15 mL) and lerl—butanol (15 mL) was added potassium anoferrate(III) (1020 mg, 3.10 mmol) and potassium osmate dehydrate (9.13 mg, 0.025 mmol) at 15 oC. The reaction mixture was stirred at 15 0C for 18 hours. Water was added and the product was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, d, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel, 50 % to 100 % ethyl acetate in petroleum ether) to give the title compound (230 mg, 92 % yield). Ms (ESI+) m/z 387.0, 389.1 (M-18, M—16)+. e 126d 4- { 5 -(1,2-dihydroxypropanyl)[2-methyl(triﬂuoromethyl)phenoxy]phenyl}-N-ethyl- 6-methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide e 126d was prepared according to the procedure used for the preparation of Example 1m, substituting e 126c for Example 11. 1H NMR (400 MHz, DMSO-d6) 5 12.25 (s, 1H), 8.34 (s, 1H), 7.69 — 7.59 (m, 2H), 7.56 (s, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.34 — 2O 7.25 (m, 2H), 6.83 (s, 1H), 6.33 (d, J = 8.6 Hz, 1H), 4.91 (s, 1H), 4.73 (t, J = 5.8 Hz, 1H), 3.57 (s, 3H), 3.45 — 3.38 (m, 2H), 3.29 — 3.23 (m, 2H), 1.93 (s, 3H), 1.41 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H). Ms (ESI+) m/z 544.1 (M+H)+.

Example 127 N—lerl-butyl{5-(1,2-dihydroxypropanyl)[2-methyl (triﬂuoromethyl)phenoxy]phenyl}methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]py1idine carboxamide Example 127 was prepared according to the procedure used for the preparation of Example 32d, substituting Example 126d for Example 3d. 1H NMR (400 MHz, DMSO- d6) 5 12.35 (s, 1H), 7.86 (s, 1H), 7.67 — 7.59 (m, 2H), 7.57 (d, J: 2.1 Hz, 1H), 7.37 (t, J: 7.7 Hz, 1H), 7.33 — 7.27 (m, 2H), 6.82 (s, 1H), 6.33 (d, J: 8.6 Hz, 1H), 4.93 (s, 1H), 4.73 (t, J: 5.7 Hz, 1H), 3.58 (s, 3H), 3.41 (d, J: 5.8 Hz, 2H), 1.93 (s, 3H), 1.41(s,3H), 1.38 (s, 9H). MS (ESI+) m/z 572.1 (M+H)+.

Example 128 159159 4-[5-(2,5-dihydroxypentanyl)(4-ﬂuoro-2,6-dimethylphenoxy)phenyl]-N-ethyl methyloxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 128a 2-(2-bromoiodophenoxy)ﬂuoro-1,3-dimethylbenzene id="p-547" id="p-547" id="p-547" id="p-547" id="p-547" id="p-547" id="p-547" id="p-547" id="p-547" id="p-547" id="p-547" id="p-547" id="p-547"

[00547] A mixture of 2-bromoﬂuoroiodobenzene (3.01 g, 10 mmol), 4-ﬂuoro-2,6- dimethylphenol (1.47 g, 10.5 mmol), and cesium carbonate (3.42 g, 10.5 mmol) in dimethyl sulfoxide (20 mL) was heated at 110 0C for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, ﬁltered, and trated. The residue was puriﬁed by ﬂash chromatography (silica gel, 2 % ethyl acetate in heptanes) to give the title compound (3.21 g, 76 % yield). 1H NMR (400 MHz, DMSO- d6) 5 7.98 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.6, 2.1 Hz, 1H), 7.03 (dt, J = 9.1, 0.7 Hz, 2H), 6.15 (d, J = 8.6 Hz, 1H), 2.00 (t, J = 0.6 Hz, 6H).

Example 128b 1-(3 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)hydroxybutanone ] A mixture of Example 128a (0.421 g, 1.0 mmol), tributyl(4,5-dihydrofuran yl)stannane (0.395 g, 1.100 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.050 mmol) in toluene (5 mL) was heated at 90 0C for 2 hours. The solvent was evaporated under reduced re, and the residue was puriﬁed by ﬂash chromatography (silica gel, % ethyl acetate in heptanes) to give the title compound (0.29 g, 76 % yield).

Example 128c 4-(3 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)pentane-1,4-diol Example 128b (0.1 g, 0.262 mmol) in tetrahydrofuran (5 mL) was treated with methylmagnesium bromide (0.350 mL, 3 M in ydrofuran, 1.049 mmol) at ambient temperature overnight. The reaction mixture was ed carefully with methanol and then partitioned between water and ethyl e. The s layer was ted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash chromatography (silica gel eluting, 30 % ethyl acetate in heptanes) to give the title nd (0.079 g, 76 % yield). 1H NMR (501 MHz, DMSO-d6) 5 7.70 (d, J = 2.2 Hz, 2H), 7.22 (dd, J = 8.6, 2.2 Hz, 2H), 7.09 — 7.02 (m, 4H), 6.30 (d, J = 8.6 Hz, 2H), 4.97 (s, 2H), 4.33 (t, J = 5.2 Hz, 2H), 3.29 (tdd, J = 6.7, 5.2, 1.5 Hz, 4H), 2.05 (d, J = 160160 0.6 Hz, 11H), 1.70 — 1.56 (m, 4H), 1.38 (s, 6H), 1.23 — 1.10 (m, 3H). MS (DCI+) m/z 398.1 (M+H)+.

Example 128d 4-[5-(2,5-dihydroxypentanyl)(4-ﬂuoro-2,6-dimethylphenoxy)phenyl]-N-ethyl oxo-6,7-dihydro-1H—pyrrolo[2,3-c]pyridinecarboxamide Example 128d was prepared according to the ure used for the preparation of Example 1m, tuting Example 128c for Example 11. 1H NMR (501 MHz, DMSO-d6) 5 12.21 (d, J = 2.4 Hz, 1H), 8.31 (t, J = 5.4 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.31 (s, 1H), 7.25 (dd, J = 8.6, 2.4 Hz, 1H), 6.96 (d, J = 9.1 Hz, 2H), 6.81 (d, J = 2.2 Hz, 1H), 6.30 (d, J = 8.6 Hz, 1H), 3.58 (s, 3H), 3.34 — 3.20 (m, 4H), 2.00 (s, 6H), 1.72 — 1.59 (m, 2H), 1.41 (s, 3H), 1.45 — 1.35 (m, 1H), 1.24 (ddd, J = 12.3, 8.8, 5.8 Hz, 1H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 536.2 (M+H)+. e 129 N—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(4-hydroxyoxanyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 129a 4-(3 -bromo(4-ﬂuoro-2,6-dimethylphenoxy)phenyl)tetrahydro-2H-pyranol ]Example 128a (0.842 g, 2 mmol) in hexanes (20 mL) was cooled to -78 0C. To this solution was added lerZ-butyllithium (1.35 mL, 2.30 mmol) at -78 oC. The reaction e was stirred at -78 0C for 1 hour. Then the reaction mixture was allowed to worm to ambient temperature, and stirred at ambient temperature for 1 hour. The reaction mixture was cooled back to -78 oC again. To this solution was added dihydro-2H-pyran-4(3H)—one (0.200 g, 2 mmol) in toluene (1 mL). The reaction mixture was allowed to warm up to ambient temperature ght. The reaction mixture was quenched with saturated aqueous ammonium chloride. The reaction mixture was partitioned between water and ethyl acetate.

The aqueous was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium e, ﬁltered, and concentrated. The residue was puriﬁed by column chromatography (silica gel, 10 % ethyl acetate in heptanes) to give the title compound (0.14 g, 18 % yield). 1H N1\/IR(501MHZ, DMSO-d6) 5 7.76 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.6, 2.3 Hz, 1H), 7.08 — 7.02 (m, 2H), 6.31 (d, J = 8.6 Hz, 1H), 5.08 (d, J =10 Hz, 1H), 3.77 — 3.54 (m, 4H), 2.6 (s, 6H), 1.89 (td, J = 12.7, 5.2 Hz, 2H), 1.58 (td, J = 12.6, 5.9 Hz, 2H). MS (ESL) m/z 394.9 (MH Example 129b 161161 N—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(4-hydroxyoxanyl)phenyl]methyl oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 12% was prepared according to the procedure used for the preparation of e 1m, substituting Example 129a for Example 11. 1H NMR (400 MHz, DMSO-d6) 5 12.21 = 5.3 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.37 — 12.22 (m, 1H), 8.32 (t, J — 7.29 (m, 2H), 6.97 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 2.2 Hz, 1H), 6.33 (d, J = 8.6 Hz, 1H), 3.81 — 3.64 (m, 4H), 3.59 (s, 3H), 3.24 (td, J = 7.3, 5.2 Hz, 2H), 2.00 (s, 6H), 1.94 (dt, J = 12.5, 6.7 Hz, 2H), 1.55 (d, J = 13.0 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 534.1 (M+H)+. g. ical Examp_les Bromodomain domain binding assay A time-resolved ﬂuorescence resonance energy transfer (TR-FRET) assay was used to determine the affinities of compounds of the Examples listed in Table l for each omain of BRD4. His-tagged ﬁrst (BDI: amino acids K57-E168) and second (BDII: amino acids E3 52- M457) bromodomains of BRD4 were expressed and purified. An 47-labeled BET-inhibitor was used as the ﬂuorescent probe in the assay.

Synthesis of Alexa647-labeled bromodomain inhibitor compound 2-((6S,Z)—4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno [3,2-f] [1,2,4]triazolo [4,3- a] [1,4]diazepinyl)acetic acid.

Methyl 2-((6S,Z)(4-chlorophenyl)-2,3,9-trimethyl-6H—thieno[3,2- 2O j][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetate (see e.g., WO 2006129623)(100.95 mg, 0.243 mmol was suspended in 1 mL methanol to which was added a freshly ed solution of m ide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken at ambient temperature for 3 hours. The methanol was evaporated and the pH adjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) and extracted four times with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and evaporated to afford 2- ((6S,Z)—4-(4-chlorophenyl)-2,3,9-trimethyl-6H—thieno[3,2-j][1,2,4]t1iazolo[4,3- ]diazepinyl)acetic acid (85.3 mg, 87.0%), ESI—MS m/z = 401.1 [(M+H)+] which was used directly in the next reaction.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)((6S,Z)—4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f] [1,2,4]triazolo[4,3-a] iazepinyl)acetamide bis(2,2,2-trifluoroacetate). 2-((6S,Z)(4-chlorophenyl)-2,3,9-t1imethyl-6H—thieno[3,2-j][1,2,4]t1iazolo[4,3- a][1,4]diazepinyl)acetic acid )(853 mg, 0.213 mmol) was combined with 2,2'—(ethane-1,2- diylbis(oxy))diethanamine (Sigma-Aldrich, 0.315 mg, 2.13 mmol) were combined in 5 mL 162162 anhydrous dimethylfonnamide. (1H-benzo[d] [ 1 ,2,3 ]triazolyloxy)tripyrrolidin ylphosphonium hexaﬁuorophosphate(V) (PyBOB, CSBio, Menlo Park CA, 332 mg, 0.638 mmol) was added and the reaction shaken at ambient temperature for 16 hours. The reaction was diluted to 6 mL with dimethylsulfoxide:water (9:1, vzv) and puriﬁed in two injections with time collection Waters Deltapak C18 200 X 25 mm column eluted with a gradient of 0.1% triﬂuoroacetic acid (V/V) in water and acetonitrile. The ons containing the two puriﬁed ts were lyophilized to afford N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)((6S,Z)- 4-(4-chlorophenyl)-2,3,9-trimethyl-6H—thieno[3,2-j][1,2,4]triazolo[4,3-a][1,4]diazepin yl)acetamide bis(2,2,2-triﬂuoroacetate) (134.4 mg, 82.3%), ESI—MS m/z = 531.1 [(M+H)+], 529.1 [(M-H)'] and MN'—(2,2'—(ethane-1,2-diylbis(oxy))bis(ethane-2,l-diyl))bis(2- ((6S,Z)—4-(4-chlorophenyl)-2,3,9-t1imethyl-6H—thieno[3,2-j][l,2,4]triazolo[4,3- a][1,4]diazepinyl)acetamide) bis(2,2,2-triﬁuoroacetate) (3.0 mg, 1.5%), ESI—MS m/z = 913.2 [(M+H)+], 911.0 '].

N—(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)((6S,Z)—4-(4-chlor0phenyl)-2,3,9- trimethyl-6H-thien0 [3,2-f] [1,2,4]triaz010 [4,3-a] [1,4]diazepinyl)acetamide(2,2,2- trifluoroacetate).

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)((6S,Z)(4-chlorophenyl)-2, 3 ,9-trimethyl- 6H-thieno[3,2-j][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetamide bis(2,2,2-triﬂuoroacetate) (5.4 mg, 0.0071 mmol) was ed with Alexa Fluor® 647 carboxylic Acid, succinimidyl ester (Life Technologies, Grand Island, NY, 3 mg, 0.0024 mmol) were ed in 1 mL anhydrous dimethylsulfoxide containing diisopropylethylamine (1% V/V) and shaken at ambient temperature for 16 hours. The reaction was diluted to 3 mL with dimethylsulfoxide:water (9:1, vzv) and puriﬁed in one injection with time collection Waters ak C18 200 X 25 mm column eluted with a gradient of 0.1% triﬂuoroacetic acid (V/V) in water and acetonitrile. The fractions containing the puriﬁed product were lyophilized to afford N-(2-(2-(2-amido-(Alexa647)—ethoxy)ethoxy)ethyl)((6S,Z)(4-chlorophenyl)- 2,3,9-trimethyl-6H—thieno[3,2-j][1,2,4]triazolo[4,3-a][l,4]diazepinyl)acetamide(2,2,2- triﬁuoroacetate) (1.8 mg), MALDI—MS m/z = , 1373.1 [(M+H)+] as a dark blue powder.

Compound dilution series were prepared in DMSO Via an approximately 3-fold serial dilution. Compound dilutions were added directly into white, low-volume assay plates (Perkin Elmer Proxiplate 384 Plus# 6008280) using a e Echo in conjunction with 163163 Labcyte Access and Thermo Multidrop CombinL robotics. Compounds were then suspended in eight microliters (uL) of assay buffer (20 mM Sodium ate, pH 6.0, 50 mM NaCl, 1 mM Ethylenediaminetetraacetic acid disodium salt dihydrate, 0.01% Triton X-100, 1 mM hiothreitol) containing His-tagged bromodomain, Europium-conjugated anti-His antibody (Invitrogen PV5596) and Alexaconjugated probe.

The ﬁnal concentration of IX assay mixture contained 2% DMSO, 12 nM His tagged BRD4 (BDI_K57-El68) and 100 nM probe or 4 nM His tagged BRD4 (BDII_E352-M457) and 30 nM probe, and 1 nM Europium-conjugated anti-His-tag antibody, and compound concentrations in the range of: 49.02 uM-0.61 nM or 0.98 uM — 0.15 nM. id="p-559" id="p-559" id="p-559" id="p-559" id="p-559" id="p-559" id="p-559" id="p-559" id="p-559" id="p-559" id="p-559" id="p-559" id="p-559"

[00559] After a one-hour equilibration at room temperature, TR—FRET ratios were determined using an on multilabel plate reader (EX 340, Em 495/520).

TR-FRET data were ized to the means of 24 no-compound controls ") and 8 controls containing 1 uM un-labeled probe ("low"). Percent inhibition was plotted as a function of compound concentration and the data were ﬁt with the 4 parameter logistic equation to obtain ICsos. Inhibition constants (K) were ated from the ICsos, probe K1 and probe concentration.

The mean K values are reported in Table 1.

Table 1 TR-FRET Binding Ki: TR-FRET Binding Ki: Example # BRD4 57-E168) BRD4 (BDII_E352-M457) (11M) (11M) 1 0.462 0.0023 2 0.220 0.0030 3 0.404 0.0011 4 0.215 0.0031 0.187 0.0016 6 0.273 0.0023 7 0.632 0.0041 8 0.359 0.0023 9 0.601 0.0038 0.715 0.0054 11 0.170 0.0026 12 0.097 0.0019 13 0.114 0.0020 14 0.965 0.0023 1.84 0.0265 16 0.333 0.0023 17 0.467 0.0030 18 0.449 0.0038 19 0.196 0.0040 164164 TR-FRET g Ki: TR-FRET Binding Ki: Example # BRD4 (BDI_K57-E168) BRD4 (BDII_E352-M457) (HM) (MM) 0.363 0.0031 21 0.521 0.0015 22 2.50 0.0105 23 0.701 0.0032 24 0.079 0.0017 0.171 0.0030 26 0.015 0.0015 27 0.044 0.0018 28 1.18 0.0054 29 0.594 0.0013 0.279 0.0019 31 0.260 0.0033 32 0.599 0.0028 33 0.921 0.0064 34 0.729 0.0051 0.426 0.0014 36 0.579 0.0034 37 0.195 0.0037 38 0.241 0.0057 39 0.640 0.0113 40 0.773 0.0021 41 0.759 0.0048 42 0.704 0.0057 43 0.525 0.0050 44 0.323 0.0073 45 1.08 0.0125 46 2.52 0.0195 47 2.06 0.0244 48 1.60 0.0060 49 0.284 0.0010 50 0.318 0.0013 51 0.263 0.0049 52 0.325 0.0009 53 0.432 0.0046 54 4.52 0.0060 55 4.69 0.0069 56 0.917 0.0047 57 2.89 0.0175 58 0.723 0.0081 59 1.77 0.0074 60 3.51 0.0075 61 1.58 0.0120 62 1.11 0.0102 63 0.406 0.0015 64 0.181 0.0004 165165 TR-FRET Binding Ki: TR-FRET Binding Ki: Example # BRD4 57-E168) BRD4 (BDII_E352-M457) (HM) (HM) 65 0.222 0.0013 66 0.289 0.0014 67 0.259 0.0011 68 0.341 0.0022 69 0.499 0.0023 70 1.34 0.0037 71 2.31 0.0075 72 0.794 0.0013 73 0.417 0.0015 74 0.551 0.0030 75 0.743 0.0029 76 0.927 0.0087 77 0.606 0.0022 78 0.253 0.0022 79 0.225 0.0025 80 0.486 0.0052 81 0.043 0.0011 82 1.03 0.0014 83 0.350 0.0011 84 0.610 0.0019 85 0.433 0.0018 86 0.416 0.0014 87 0.501 0.0028 88 0.389 0.0011 89 0.281 0.0017 90 0.158 0.0020 91 0.271 0.0016 92 0.410 0.0121 93 0.502 0.0109 94 0.236 0.0037 95 0.333 0.0048 96 0.801 0.0091 97 0.657 0.0247 98 0.682 0.0096 99 0.431 0.0018 100 0.115 0.0056 101 0.11 0.0025 102 0.309 0.0025 103 0.450 0.0033 104 0.375 0.0012 105 1.34 0.0025 106 6.69 0.0066 107 0.231 0.0008 108 0.175 0.0016 109 0.169 0.0011 166166 TR-FRET Binding Ki: TR-FRET Binding Ki: Example # BRD4 (BDI_K57-E168) BRD4 (BDII_E352-M457) (HM) (MM) 110 0.224 0.0020 111 0.150 0.0014 112 0.332 0.0023 113 0.098 0.0015 114 0.096 0.0013 115 0.323 0.0014 116 0.756 0.0029 117 0.215 0.0015 118 1.39 0.0104 119 0.346 0.0022 120 0.161 0.0008 121 0.356 0.0006 122 0.308 0.0020 123 0.168 0.0010 124 0.269 0.0017 125 0.140 0.0035 126 1.51 0.0063 127 6.58 0.0205 128 0.469 0.0013 129 0.649 0.0023 Compound X 0.00209 52 nd Y 0.0216 0.00132 Compound Z 0.0699 0.0155 Compound X is 2,4-diﬂuorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide, Compound Y is 4-[2-(2,4-diﬂuorophenoxy)(methylsulfonyl)phenyl]-N-ethylmethyl oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide, and Compound Z is 4-[5-(hydroxymethyl)phenoxyphenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone.

All tested compounds were found to have selectivity for BRD4 BDII over BRD4 BDI in the TR-FRET assay described above, and are at least 10 fold selective for BRD4 BDII over BRD4 BDI. In one ment, the present compounds are about 50 to about 100 fold selective for BRD4 BDII over BRD4 BDI. In one embodiment, the present compounds are about 100 to about 200 fold selective for BRD4 BDII over BRD4 BDI. In one embodiment, the present compounds are at least about 200 fold selective for BRD4 BDII over BRD4 BDI.

Xenograft tumor growth inhibition assay 167167 The effect of compound of Example 32, 35 and Compound X to inhibit the growth of SKM-1_FP1 and LNCaP-FGC xenograft tumors was evaluated. Female SCID Beige mice es River) were utilized for the SKM-1_FP1 ﬂank xenograft model. Male NSG mice (JAX Labs) were used for the LNCaP-FGC study. Cells were suspended in PBS, mixed with Matrigel (phenol red free, Becton Dickinson Biosciences Discovery e) in a ratio of 1:4 (V/V) and inoculated subcutaneously into the ﬂank (ﬁve n cells per site) of the mice. Inoculated mice were randomized into groups and ent was initiated when mean tumor volume was 0.2-0.25 cm3. The compounds were administered orally in (volume %): 1.5% DMSO, 30% PEG 400, and 68.5% Phosol 53 MCT. Tumor growth in the ﬂank was assessed by measuring tumor size with calipers and calculating volume using the formula (L X W2/2). Study groups were ated prior to tumor volume reaching 3 cm3. Inhibition of tumor growth was assessed at the time the vehicle-treated group was terminated by calculating the ratio of the mean volume of the test drug group to the mean volume of the untreated ol) group (T/C) and calculating percent tumor growth inhibition (%TGI).

%TGI = ((l-T/C) X 100). Results are reported in Table 2. cy and Exposure Margins of BDII Selective BET Inhibitors Efﬁcacy in AML (acute myeloid ia) and prostate cancer was studied with two BDII selective BET inhibitor compounds (Example 35 and e 32), and a pan BET 2O tor (Compound X), in mouse SKM-l (AML) and LNCaP (prostate) xenograft (Table 2).

Fourteen day rat toxicology studies were conducted with Example 35, Example 32, and nd X, and maximum tolerated exposures were determined based on in-life observations including clinical signs, body weight, and food consumption. Compounds were dosed orally once daily, in Sprague-Dawley rats. Exposure margins calculated from the tolerated exposures in rat relative to the efﬁcacious exposures in mouse xenograft models are reported in Table 2.

Table 2 AUC ratio Rat (rat maximum maximum tolerated Mouse efﬁcacy results from xenograft studies tolerated exposure/mouse exposure efﬁcacious exposure) 168168 %TGI (ug*hr EX. 35 25X EX. 32 5.5x It is understood that the foregoing detailed description and accompanying es are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is deﬁned solely by the appended claims and their equivalents. Various changes and modiﬁcations to the disclosed embodiments will be apparent to those d in the art. Such changes and modiﬁcations, ing without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. 169169

Claims

CLAIMS :

1.A compound of formula (I) or a pharmaceutically able salt thereof, wherein R1 is hydrogen, CD2CD3, C1-C6 alkyl, C1-C6 haloalkyl, a C3-C6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl, wherein the C3-C6 cycloalkyl, the phenyl, and the 5-6 membered monocyclic heteroaryl are each optionally 10 substituted with l, 2, 3, or 4 independently selected RX groups, R2 is Gza, C1-C6 haloalkyl, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of G2b and —OH, G2a is a phenyl or a C3-C6 monocyclic cycloalkyl, wherein each G2a is optionally 15 substituted with l, 2, 3, or 4 independently selected RX groups, G2b is phenyl ally substituted with l, 2, 3, or 4 independently selected RX groups, R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a C3-C6 monocyclic cycloalkyl wherein the C3- C6 clic cycloalkyl is optionally substituted with l, 2, 3, or 4 2O independently selected RX groups, or R2 and R3, together with the carbon atom to which they are attached, form a C3-C6 clic cycloalkyl, a C4-C6 monocyclic cycloalkenyl, or a 4-6 membered clic cycle, wherein the C3-C6 monocyclic cycloalkyl, the C4-C6 monocyclic cycloalkenyl, and the 4-6 membered monocyclic cycle are 25 each ally substituted with l, 2, 3, or 4 independently selected RX groups, R4 is phenyl, pyridinyl, a C3-C6 monocyclic cycloalkyl, or a C4-C6 clic cycloalkenyl, wherein each R4 is optionally substituted with l, 2, 3, or 4 independently selected Ry groups, or 170170 R4 is formula (a) R4d Oi R4C Y/ R4b R4a and R4b are each independently halogen, C1-C6 alkyl, or C1-C6 kyl, R4C and R4d are each independently hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -S(C1-C6 alkyl), -S(O)2(C1-C6 , or 6 alkylenyl)-OH, Y is C(R4e) or N, wherein R46 is hydrogen, n, -CN, C1-C6 alkyl, or C1-C6 haloalkyl, Rx, at each occurrence, is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl, 10 Ry, at each occurrence, is independently n, C1-C6 alkyl, C1-C6 haloalkyl, -O(C1- C6 alkyl), -O(C1-C6 haloalkyl), or —(C1-C6 alkylenyl)-OH, X1 and X2 are C(RS), or one of X1 and X2 is N and the other is C(RS), R5, at each occurrence, is independently hydrogen or halogen, and 15 R6 is hydrogen, halogen, -CN, C1-C6 haloalkyl, or C1-C6 alkyl.

2.The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is CD2CD3, C1-C6 alkyl, C1-C6 haloalkyl, or a C3-C6 cycloalkyl, wherein the C3-C6 lkyl is optionally substituted with l, 2, 3, or 4 ndently selected 2O RX groups.

3.The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is phenyl, cyclopropyl, cyclopentyl, C1-C6 haloalkyl, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the 25 group consisting of G2b and —OH, and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with l, 2, 3, or 4 ndently selected RX groups, and R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with l, 2, 3, or 4 independently selected RX groups.

4.The compound of claim 1 or a pharmaceutically acceptable salt f, wherein 171171 R2 and R3, together with the carbon atom to which they are attached, form a C3-C6 monocyclic cycloalkyl, a C4-C6 monocyclic lkenyl, or a 4-6 membered monocyclic heterocycle, wherein the C3-C6 monocyclic lkyl, the C4-C6 clic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each ally substituted with l, 2, 3, or 4 independently selected RX groups.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl, nyl, a C3-C6 monocyclic cycloalkyl, or a C4-C6 clic 10 cycloalkenyl, wherein each R4 is optionally substituted with l, 2, 3, or 4 independently selected Ry groups.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is formula (a) R4d \ Cg 15 R40 Y/ R4b

7.The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R4a is halogen, C1-C6 alkyl, or crc6 haloalkyl, 2O R4b is halogen or C1-C6 alkyl, R4d is hydrogen or halogen, and Y is C(R4e) or N, wherein R46 is hydrogen.

8.The compound of claim 1 or a pharmaceutically acceptable salt thereof, n 25 X1 is N or C(RS), X2 is C(RS), and R5 is hydrogen.

9.The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein 3O R2 and R3, together with the carbon atom to which they are attached, form a C3-C6 monocyclic cycloalkyl, a C4-C6 monocyclic cycloalkenyl, or a 4-6 membered 172172 monocyclic heterocycle, wherein the C3-C6 monocyclic cycloalkyl, the C4-C6 monocyclic cycloalkenyl, and the 4-6 membered monocyclic heterocycle are each optionally substituted with l, 2, 3, or 4 independently selected RX groups.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R4 is formula (a), wherein R4a is halogen, C1-C6 alkyl, or crc6 kyl, R4b is halogen or C1-C6 alkyl, 10 R4d is hydrogen or n, and Y is C(R4e) or N, wherein R46 is hydrogen, and R6 is en or halogen.

11.ll. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein 15 R2 is phenyl, cyclopropyl, cyclopentyl, C1-C6 haloalkyl, or C1-C6 alkyl wherein the C1-C6 alkyl is ally substituted with one substituent selected from the group ting of G2b and —OH, and wherein the phenyl, the cyclopropyl, and the cyclopentyl are each optionally substituted with l, 2, 3, or 4 independently selected RX groups, and 2O R3 is C1-C6 haloalkyl, C1-C6 alkyl, or a cyclopropyl wherein the cyclopropyl is optionally substituted with l, 2, 3, or 4 ndently selected RX groups.

12. The compound of claim 11 or a pharmaceutically able salt thereof, wherein R4 is phenyl, pyridinyl, a C3-C6 monocyclic cycloalkyl, or a C4-C6 monocyclic 25 cycloalkenyl, wherein each R4 is optionally substituted with l, 2, 3, or 4 independently selected Ry groups, and R6 is hydrogen.

13. The nd of claim 12 or a pharmaceutically acceptable salt thereof, wherein 3O X1 is C(RS), X2 is C(RS), R5 is hydrogen, and R1, R2, and R3 are C1-C6 alkyl. 173173

14. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R4 is a (a), and R6 is hydrogen or halogen.

15. The compound of claim 14 or a ceutically acceptable salt thereof, n R4a is halogen, C1-C6 alkyl, or crc6 kyl, R4b is halogen or C1-C6 alkyl, R4d is hydrogen or halogen; and Y is C(R4e) or N, wherein R46 is hydrogen.

16.l6. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R4a is 01—03 alkyl, R4b is C1-C3 alkyl, R4C is hydrogen or halogen, 15 R4d is hydrogen, and Y is C(R4e) or N wherein R46 is hydrogen.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C6 haloalkyl or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted 20 with one —OH, and R3 is 01—06 haloalkyl or 01—06 alkyl.

18. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3 are C1-C6 alkyl, and 25 Y is C(R4e) wherein R46 is hydrogen.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein X1 is C(RS), X2 is C(RS), and 3O R5 is hydrogen.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the nd is selected from the group consisting of 174174 4-[2-(2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridin-3 -y1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -I]pyridine-Z-carboxamide; 4-[2-(2,6-dimethy1phenoxy)(3 -hydroxypentan-3 -y1)pyn' din-3 -y1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)pheny1]-N—ethy1methyl oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(2,6-dimethy1phenoxy)(1-hydroxycyclopent-3 -en-1 -y1)pyridin-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[2-(2,6-dimethy1phenoxy)(1-hydroxycyclopent-3 y1)pheny1]—N—ethyl 10 methyloxo—6,7-dihydro- Tolo[2,3 -c]pyridinecarboxamide; 4-[2-(2,6-dimethylphenoxy)(1-hydroxycyclopenty1)pyﬁdin-3 -y1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 4- [2-(2, 6-dimethy1phenoxy)(1-hydroxypheny1propy1)pyridin-3 -y1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 15 4-[2-(2,6-dimethy1phenoxy)(2-hydroxybutanyl)pyridin-3 -y1]-N-ethy1methy1- 7-0X0-6,7-dihydro-1H—pyrrolo[2,3 'dinecarboxamide; 4-{2-(2,6-dimethy1phenoxy)[1-(4-ﬂuorophenyl)—1-hydroxypropy1]pyridin-3 -y1}-N— ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dimethy1phenoxy)(3 -hydroxymethy1hexan-3 -y1)pyn'din-3 -ethy1- 20 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 idinecarboxamide; 4-[5-(1-cyclopenty1-1 -hydroxypropy1)—2-(2,6-dimethylphenoxy)pyridin-3 -ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[5-(1 -cyclopropy1-1 -hydroxypropyl)(2,6-dimethy1phenoxy)pyﬁdin-3 -y1]-N- ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 25 4-[2-(2,6-dimethy1phenoxy)(3 -hydroxymethy1hexan-3 -y1)pyn'din-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4- [2-(2, 6-dimethy1phenoxy)-5 -(3 -hydroxypheny1pentan-3 -y1)pyridin-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-{2-(2,6-dimethy1phenoxy)[1-(4-ﬂuorophenyl)hydroxybutanyl]pyridin-3 - 30 yl }-N-ethy1methy1oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(2,6-dimethylphenoxy)(1 -hydroxyphenylethy1)pyn'din-3 -y1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 idinecarboxamide; 4-{2-(2,6-dimethylphenoxy)[1-(4-ﬂuoropheny1)—1-hydroxyethyl]pyﬁdin-3 -y1}-N— 6-methy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 175175 4-[2-(2,6-dimethylphenoxy)(2-hydroxymethylpentan-Z-y1)pyn'din-3 -y1]-N- 6-methy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dimethylphenoxy)(2-hydroxy-3 -methy1butanyl)pyﬁdin-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[2-(2,6-dimethylphenoxy)(2-hydroxy-3 -methy1pentan-Z-yl)pyﬁdin-3 -y1]-N- ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dimethy1phenoxy)(2-hydroxyphenylbutany1)pyridin-3 -y1]-N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-{2-(2,6-dimethy1phenoxy)[1-(4-ﬂuorophenyl)hydroxypropany1]pyn'din-3 - 10 yl hy1methy1oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; cyclopropyl(4-ﬂuoropheny1)hydroxymethyl](2,6-dimethy1phenoxy)pyﬁdiny1}-N—ethy1methy1oxo—6,7-dihydro—1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; 4- { 5 -[cyclopenty1(cyclopropyl)hydroxymethyl](2,6-dimethy1phenoxy)pyridin-3 - yl }-N-ethy1methy1oxo—6,7-dihydro—1H-py1Tolo[2,3 dine-Z-carboxamide; 15 4- { 5 -[dicyclopropy1(hydroxy)methyl](2,6-dimethy1phenoxy)pyridin-3 -y1 } -N-ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[5-(1 -cyclopropy1-1 -hydroxymethy1propy1)(2,6-dimethy1phenoxy)pyridin-3 - yl]-N—ethy1methy1oxo—6,7-dihydro- rolo[2,3 -c]pyridinecarboxamide; 4-[5-(1 -cyclopropy1-1 -hydroxymethylbutyl)(2,6-dimethy1phenoxy)pyridin-3 - 20 yl]-N—ethy1methy1oxo—6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide; N-ethy1 { 5-(2-hydroxypropany1)[2-methy1 (triﬂuoromethyl)phenoxy]pheny1}methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(2-hydroxypropan-Z-yl)pyridin-3 -y1]-N-ethy1 25 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 4-[2-(2-ch1oromethy1phenoxy)—5-(2-hydroxypropany1)pheny1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; -butyl[2-(2-ch1oro—6-methylphenoxy)(2-hydroxypropany1)pheny1] methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 30 N-lerl-butyl[2-(2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl]methy1- 6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; N—lerl-butyl[2',4'—diﬂuoro(2-hydroxypropany1)[1,1'—bipheny1]—2-y1]—6- methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 176176 N—(2,2-diﬂuoro—1-methy1cyclopropyl)[2-(2,6-dimethylphenoxy)(2- hydroxypropan-Z-y1)pyﬁdin-3 -methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyn'dine carboxamide; N-ethy1[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropany1)pheny1] oxo—6,7-dihydro- Tolo[2,3 -c]pyridinecarboxamide; N-lerZ-butyl[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)pheny1]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-Zerl-butyl[2-(2-ch1oromethylphenoxy)(2-hydroxypropany1)pyridin-3 - y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 10 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(2-hydroxypropany1)pyridin-3 -y1]methy1 oxo—N—(l, 1, 1-tn'ﬂuoro—2-methy1propany1)-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(2-hydroxypropan-Z-yl)pyridin-3 -y1]-N-(2,2- diﬂuoro-l -methy1cyclopropy1)methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine 15 carboxamide; 4-{2-[2,6-dimethy1(methy1sulfanyl)phenoxy]—5-(2-hydroxypropany1)phenyl } -N— 6-methy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(2-hydroxypropan-Z-yl)pheny1]methy1oxo— N—(l, 1, 1-tn'ﬂuoro—2-methy1propany1)-6,7-dihydro—1H—pyrrolo[2,3 -c]pyn' dine 20 carboxamide; 4-[2-(2-ch1oromethy1phenoxy)—5-(2-hydroxypropany1)pheny1]-N-(2,2-diﬂuoro- 1-methy1cyclopropy1)methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyﬁdine-Z-carboxamide; N-ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropanyl)pyridin-3 -y1]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 25 N-lerl-buty1[2-(4-ﬂuoro—2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridiny1]methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; N-lerl-buty1{ 5 -(2-hydroxypropany1)[2-methy1 (triﬂuoromethyl)phenoxy]pyridin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 - dinecarboxamide; 30 4- { 5-(2-hydroxypropanyl)[2-methy1(tﬁﬂuoromethy1)phenoxy]pyridin-3 -y1}- 6-methy1oxo—N—(1,1,1-triﬂuoromethy1propanyl)-6,7-dihydro—1H—pyrrolo[2,3 - c]pyridinecarboxamide; 177177 N—(2,2-diﬂuoromethy1cyclopropy1){ 5-(2-hydroxypropany1)[2-methyl (triﬂuoromethyl)phenoxy]pyridin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 - c]pyridinecarboxamide; N-ethy1 { 5-(2-hydroxypropany1)[2-methy1 (triﬂuoromethyl)phenoxy]pyridin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 - c]]pyn'dinecarboxamide; 4-[2-(2-ch1oroﬂuoro—6-methy1phenoxy)(2-hydroxypropany1)pheny1]-N—ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 idinecarboxamide; -buty1[2-(2,6-dimethylphenoxy)(2-hydroxypropany1)pyridin-3 -y1] 10 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropan 'din-3 -y1]methy1oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropany1)pyn'din-3 -y1]-N- ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 15 N-lerl-buty1[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropan y1)pheny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; N-lerl-buty1{ 5 droxypropany1)[2-methy1 (triﬂuoromethyl)phenoxy]pheny1}methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 'dine carboxamide; 20 4-[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl]methy1 oxo—N—(l, 1,1-tn'ﬂuoro—2-methy1propanyl)-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridin-3 -y1] methyloxo—N—(1,1,1-triﬂuoro-Z-methylpropanyl)-6,7-dihydro—1H—pyrrolo[2,3 - 25 c]pyridinecarboxamide; 4-[2-(2-ch1oroﬂuoro—6-methy1phenoxy)(2-hydroxypropany1)pheny1] methyloxo—N—(1,1,1-triﬂuoro-Z-methylpropanyl)-6,7-dihydro—1H—pyrrolo[2,3 - c]pyridinecarboxamide; 4-[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropany1)pyn'din-3 -y1] 30 methyloxo—N—(1,1,1-triﬂuoro-Z-methylpropanyl)-6,7-dihydro—1H—pyrrolo[2,3 - c]pyridinecarboxamide; 4-[2-(2-chloroﬂuoromethy1phenoxy)(2-hydroxypropany1)pheny1]-N—(2,2- diﬂuoro-l -methy1cyclopropy1)methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 178178 N—(2,2-diﬂuoro—1-methy1cyclopropy1)[2-(4-ﬂuoro—2,6-dimethy1phenoxy)(2- ypropan-Z-y1)pheny1]methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N—(2,2-diﬂuoro—1-methy1cyclopropy1)[2-(4-ﬂuoro—2,6-dimethy1phenoxy)(2- hydroxypropan-Z-y1)pyﬁdin-3 -y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyn'dine carboxamide; 4-[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(2-hydroxypropany1)pyn'din-3 -y1]-N- (2,2-diﬂuoro— 1 -methyl cyclopropyl)methy1oxo-6,7-dihydro— 1H-py1Tolo[2, 3 -c]pyridine- 2-carboxamide; 10 N-(bicyclo[ 1 . 1.1]pentany1)[2-(2-ch1oromethy1phenoxy)(2-hydroxypropan- 2-y1)pyridin-3 -y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyn'dine-Z-carboxamide; 4-[2-(2,6-dimethylphenoxy)ﬂuoro(2-hydroxypropany1)phenyl]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N-ethy1[4-ﬂuoro—2-(4-ﬂuoro—2,6-dimethylphenoxy)(2-hydroxypropan 15 y1)pheny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[5-(1 ,2-dihydroxypropany1)—2-(2,6-dimethy1phenoxy)phenyl]-N—ethy1methy1- 6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; 4-[5-(2,4-dihydroxybutany1)(2,6-dimethy1phenoxy)pheny1]-N—ethy1methyl oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 20 4-{5-[(2R)-1,2-dihydroxypropanyl](2,6-dimethy1phenoxy)phenyl}-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 4-{5-[(25)—1,2-dihydroxypropanyl](2,6-dimethy1phenoxy)pheny1}-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 2-(diﬂuoromethy1)methy1phenoxy](2-hydroxypropany1)phenyl } -N— 25 ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; -butyl{2-[2-(diﬂuoromethyl)methy1phenoxy](2-hydroxypropan y1)pheny1 } methy1oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(4-bromo—2,6-dimethylphenoxy)(2-hydroxypropanyl)pheny1]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 30 4-[2-(4-cyano—2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl]-N—ethy1 methyloxo—6,7-dihydro- Tolo[2,3 -c]pyridinecarboxamide; 4-{2-[(2,4-dimethylpyn'din-3 y](2-hydroxypropany1)phenyl}-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 179179 N—(bicyclo[1.1.1]pentany1)[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2- hydroxypropan-Z-y1)pheny1]methy1oxo—6,7-dihydro— 1H-pyrrolo[2,3 -c]pyﬁdine carboxamide, N-lerl-buty1[3 -(2,6-dimethylphenoxy)(2-hydroxypropan-Z-yl)pyridin-Z-yl] oxo—6,7-dihydro- Tolo[2,3 -c]pyridinecarboxamide, 4-[3 -(2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridiny1]-N-ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, N—ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)( 1 -ﬂuorohydroxypropan yl)pyﬁdin-3 -y1]methy1oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide, 10 N—ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(1,1,1-tﬁﬂuoro—Z-hydroxypropan-Z- yl)pyﬁdin-3 -y1]methy1oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide, N—ethyl[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(1, 1,1,3 ,3 ,3 -hexaﬂuoro—2- hydroxypropan-Z-y1)pyﬁdin-3 -y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine carboxamide, 15 N-ethy1[2-(2-ﬂuoromethylphenoxy)(2-hydroxypropany1)pheny1] methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, ethyl[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)pheny1]- 6-methy1oxo-6,7-dihydro-1H-pyrrolo[2,3 -c]pyridinecarboxamide, N—ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)( 1 -ﬂuorohydroxypropan 20 y1)pheny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide, 4-[2-(4-ch1ore-2,6-dimethy1phenoxy)(2-hydroxypropanyl)pheny1]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide, N-ethy1 { 5-(2-hydroxypropany1)[4-(methanesulfony1)-2,6- dimethylphenoxy]pheny1 } methy1oxo—6,7-dihydro-1H-pyrrolo[2,3 dine 25 carboxamide, N—ethy1[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(1,1,1-tﬁﬂuoro—Z-hydroxypropan-Z- y1)pheny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide, -butyl[2-(4-ﬂuoro-2,6-dimethy1phenoxy)( 1 -ﬂuorohydroxypropan y1)pheny1]methy1oxo—6,7-dihydro—1H-pyrrolo[2,3 -c]pyn'dine-Z-carboxamide, 30 4-ch1ore-2,6-dimethy1phenoxy)(1-ﬂuoro—2-hydroxypropany1)phenyl]-N— ethylmethy1oxo—6,7-dihydro—1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide, 4-[2-(2,4-diﬂuoropheny1)(2-hydroxypropanyl)pyﬁdin-3 -y1]-N-ethy1methy1 oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide, 180180 N-lerl-buty1{ 5 -(2-hydroxypropany1)[4-(methanesulfony1)-2,6- dimethylphenoxy]pheny1 thy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N-ethy1[2-(3 -ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropany1)pyridin-3 -y1]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1{ 5 -(2-hydroxypropany1)[4-(methanesulfony1)-2,6- dimethylphenoxy]pyﬁdin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; N-ethy1 { ydroxypropany1)[4-(methanesulfony1)-2,6- 10 dimethylphenoxy]pyﬁdin-3 -y1}methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine carboxamide; 4-[2-(4-ch1ore-2,6-dimethy1phenoxy)(2-hydroxypropanyl)pyridin-3 -y1]—N—ethy1- y1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1[2-(4-chloro-2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridin- 15 3 -y1]methy1oxo—6,7-dihydro-1H-pyrrolo[2,3 -c]pyn'dine-Z-carboxamide; N-ethy1[3 -(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropanyl)pyridiny1]- y1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-lerl-buty1[3 -(4-ﬂuoro—2,6-dimethy1phenoxy)(2-hydroxypropany1)pyridin- 2-yl]methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; 20 4-{2-[2-(diﬂuoromethy1)ﬂuoromethy1phenoxy](2-hydroxypropan y1)pheny1}-N—ethy1methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(3 -ch1ore-2,6-dimethy1phenoxy)(2-hydroxypropanyl)phenyl]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N—lerl-buty1[2-(2,6-dichloroﬂuorophenoxy)(2-hydroxypropanyl)pyridin-3 - 25 y1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(2,6-dichloroﬂuor0phenoxy)(2-hydroxypropanyl)pyridin-3 -y1]—N—ethy1- y1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[2-(4-ch1ore-2,6-dimethy1phenoxy)(1 -ﬂuorohydroxypropany1)pyridin-3 - yl]-N—ethy1methy1oxo—6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide; 30 N-lerl-buty1[2-(4-ch1ore-2,6-dimethy1phenoxy)(1 -ﬂuorohydroxypropan yl)pyn'din-3 -y1]methy1oxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridine-Z-carboxamide; N-ethy1[2-(3 -ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl] methyloxo—6,7-dihydro- Tolo[2,3 -c]pyridinecarboxamide; 181181 4-[2-(2,6-dimethy1phenoxy)(2-hydroxymethylpentan-Z-y1)phenyl]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; N—lerl-buty1[2-(2,6-dimethylphenoxy)(2-hydroxymethy1pentan-Z-y1)phenyl]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N—ethy1{5-(2-hydroxypropany1)[4-(2-hydroxypropanyl)-2,6- ylphenoxy]pheny1 }methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine amide; -buty1{ 5 droxypropany1)[4-(2-hydroxypropanyl)-2,6- dimethylphenoxy]pheny1 }methy1oxo—6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dine 10 carboxamide; 4-[2-(3 -chloro-2,6-dimethylphenoxy)(2-hydroxypropanyl)pyridin-3 -y1]—N—ethy1- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; N-ethy1[4-(2-hydroxypropany1)-4'-(triﬂuoromethoxy)[ 1 1 '-bipheny1]—2-y1]—6- methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 15 4-[4',4'-diﬂuoro—4-(2-hydroxypropanyl)[2',3 ',4', 5'—tetrahydro[1,1'—bipheny1]]—2-y1]— N-ethy1methy1oxo—6,7-dihydro— 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl]methy1 oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; N—ethy1[4-(2-hydroxypropany1)-4'-methy1 [2'3 ',4', 5'-tetrahydro[1,1'—bipheny1]]— 20 2-yl]methy1oxo-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; cyclopenteny1)—5-(2-hydroxypropany1)pheny1]-N-ethy1methyl oxo—6,7-dihydro—1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(2-ch1oro—6-methy1phenoxy)—5-(1,2-dihydroxypropanyl)pheny1]-N—ethy1 methyloxo—6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridinecarboxamide; 25 N—lerl-butyl[2-(2-ch1oro—6-methylphenoxy)(1,2-dihydroxypropany1)pheny1]- 6-methy1oxo-6,7-dihydro—1H—pyrrolo[2,3 -c]pyridinecarboxamide; 4-[2-(2,6-dimethylphenoxy)(2-hydroxypropanyl)pheny1]methy1oxo-6,7- o-1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; N—lerl-buty1[2-(2-ch1oro—4-ﬂuoromethy1phenoxy)(1,2-dihydroxypropan 30 y1)pheny1]methy1oxo-6,7-dihydro-1H-py1Tolo[2,3 -c]pyﬁdine-Z-carboxamide; 4-[2-(2-ch1oro—4-ﬂuoro—6-methy1phenoxy)(1,2-dihydroxypropany1)phenyl]-N— ethylmethy1oxo-6,7-dihydro- 1H-py1Tolo[2,3 -c]pyridine-Z-carboxamide; 4-[2-(4-ﬂuoro-2,6-dimethy1phenoxy)(2-hydroxypropany1)phenyl]-N,6-dimethyl- 7-0X0-6,7-dihydro-1H—pyrrolo[2,3 -c]pyn'dinecarboxamide; 182182 N—cyclopropyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(2-hydroxypropan yl)phenyl]methyloxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridinecarboxamide, N-ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)-5 -( l -hydroxycyclobutyl)phenyl] methyloxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridinecarboxamide, and N—ethyl[2-(4-ﬂuoro-2,6-dimethylphenoxy)(3 -hydroxyoxetan-3 -yl)phenyl] methyloxo-6,7-dihydro- rolo[2,3-c]pyridinecarboxamide.

21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1) according to claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

22. A method for treating cancer in a subject comprising stering a therapeutically effective amount of a compound of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 15

23. The method of claim 22 wherein the cancer is selected from the group consisting of: acoustic a, acute leukemia, acute cytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, 2O chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, c lymphocytic leukemia, chronic ytic locytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and asias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, 25 geal cancer, en-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, f1brosarcoma, follicular lymphoma, germ cell testicular , glioma, glioblastoma, gliosarcoma, heavy chain e, hemangioblastoma, hepatoma, cellular cancer, hormone insensitive te cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, 30 lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, , colon, lung, ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, enous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), 183183 non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate , rectal cancer, renal cell oma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin , small cell lung carcinoma, solid tumors (carcinomas and as), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine , and Wilms’ tumor.

24. A method for treating a disease or condition in a subject sing administering a 10 therapeutically effective amount of a compound of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, s skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's e, itis, eczema, giant cell 15 arteritis, glomerulonephritis, hepatitis, hypophysitis, inﬂammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, rthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing gitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, 2O thyroiditis, type I diabetes, tive colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

25. A method for treating an acquired immunodeﬁciency syndrome (AIDS) in a subject comprising administering a therapeutically effective amount of a compound of formula (1) 25 ing to claim 1 or a pharmaceutically acceptable salt f, to a subject in need thereof.

26. A method for treating a disease or condition in a subject comprising stering a therapeutically effective amount of a compound of formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or 30 condition is selected from the group consisting of: obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, c steatosis, type II diabetes, n resistance, diabetic pathy, and diabetic neuropathy. 184184

27. A method of contraception in a male subject comprising administering a therapeutically effective amount of a compound of formula (1) according to claim 1 or a pharmaceutically acceptable acceptable salt thereof, to a t in need thereof.

28. A method for treating an acute kidney disease or condition in a t sing administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said acute kidney disease or condition is selected from the group consisting of: ischemia-reperfusion induced kidney disease, cardiac and major surgery induced kidney e, percutaneous 10 coronary intervention d kidney disease, radio-contrast agent induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney disease, and drug toxicity induced kidney disease.

29. A method of ng a chronic kidney disease or condition in a subject comprising 15 administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said c kidney disease or condition is selected from the group ting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, nous glomerulonephritis, 2O minimal change disease, polycystic kidney disease and tubular interstitial nephritis.

30. A process for preparing compounds of formula (A), wherein the process comprises bromination of compounds of formula (B) 25 wherein PG1 is a nitrogen ting group, and R105 lS C1-C6 211le.

31. The process of claim 30 n PG1 is selected from the group consisting of p- 30 toluenesulfonyl, benzyl, and 2-(trimethylsilyl)ethoxymethyl. 185185

32. The process of claim 30 wherein R105 is ethyl.

33. The process of claim 30 wherein compound (B) is brominated using a brominating agent in the presence of an acid and with or without a solvent.

34. The process of claim 33 wherein the brominating agent is selected from the group consisting of bromine and N—bromosuccinimide.

35. The process of claim 33 wherein the acid is selected from the group consisting of p- 10 toluenesulfonic acid and acetic acid.

36. The process of claim 33 n the t is selected from tetrahydrofuran and acetonitrile. 15

37. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is ed from the group consisting of N-ethyl { ydroxypropanyl)[4-(2-hydroxypropanyl)-2,6- dimethylphenoxy]py1idin-3 -yl } methyloxo-6,7-dihydro-1H-pyrrolo[2,3 -c]pyridine carboxamide; 20 N-lerl-butyl{ 5 -(2-hydroxypropanyl)[4-(2-hydroxypropanyl)-2,6- ylphenoxy]py1idin-3 -yl } methyloxo-6,7-dihydro-1H-pyrrolo[2,3 -c]pyridine carboxamide; 4-{5-(1,2-dihydroxypropanyl)[2-methyl(t1iﬂuoromethyl)phenoxy]phenyl}-N— ethylmethyloxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide; 25 N-lerl-butyl{ 5 -( l ,2-dihydroxypropanyl)[2-methyl (triﬂuoromethyl)phenoxy]phenyl } methyloxo-6,7-dihydro-1H-pyrrolo[2,3 -c]pyridine carboxamide; 4-[5-(2, 5-dihydroxypentanyl)(4-ﬂuoro-2,6-dimethylphenoxy)phenyl]-N—ethyl methyloxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide; and 30 l[2-(4-ﬂuoro-2,6-dimethylphenoxy)(4-hydroxyoxanyl)phenyl] methyloxo-6,7-dihydro- 1H-pyrrolo[2,3 -c]pyridinecarboxamide. Abeie Inc. By the eys for the Applicant SPRUSON & FERGUSON