HK1203511B

HK1203511B - Bromodomain inhibitors

Info

Publication number: HK1203511B
Application number: HK15104248.5A
Authority: HK
Inventors: Le Wang; John K. Pratt; Keith F. Mcdaniel; Yujia Dai; Steven D. FIDANZE; Lisa Hasvold; James H. Holms; Warren M. Kati; Dachun Liu; Robert A. Mantei; William J Mcclellan; George S. Sheppard; Carol K. Wada
Original assignee: Abbvie Inc.
Priority date: 2011-12-30
Filing date: 2012-12-11
Publication date: 2018-05-11

Description

Bromodomain inhibitors

Background

Bromodomains (bromodomain) refer to conserved protein structural folds linked to N-acetylated lysine residues found in certain proteins. The BET family of bromodomain-containing proteins includes four members (BRD2, BRD3, BRD4, and BRDt). Each member of the BET family uses two bromodomains to recognize N-acetylated lysine residues found primarily, but not exclusively, at the amino-terminal tail (amino-terminal tail) of histone proteins. These interactions regulate gene expression by recruiting transcription factors to specific genomic locations within chromatin. For example, histone-linked BRD4 recruits the transcription factor P-TEFb to the promoter, resulting in the expression of a set of genes involved in cell cycle progression (Yangtt al, mol. cell. biol. 28: 967-976 (2008)). BRD2 and BRD3 also function as transcriptional regulators of growth promoting genes (LeRoy et al, mol. Cell 30: 51-60 (2008)). BET family members are currently identified as playing an important role in the maintenance of several cancer types (Zuber et al, Nature 478:524-528 (2011); Mertzet al; Proc. Nat' l. Acad. Sci. 108:16669-16674 (2011); Delmore et al, Cell146:1-14 (2011); Dawson et al, Nature 478:529-533 (2011)). BET family members have also been implicated in mediating acute inflammatory responses through the classical NF-KB pathway (Huang et al, mol. cell. biol. 29:1375-1387 (2009)) which results in upregulation of genes involved in cytokine production (nicoderm et al, Nature468: 1119-1123, (2010)). In addition, bromodomain function has been implicated in renal disease (Zhang, et al., J. biol. chem. 287:28840-28851 (2012)). BRD2 function has also been implicated in predisposition to dyslipidemic or adipogenic dysregulation, elevated inflammatory properties and increased susceptibility to autoimmune disease (Denis, Discovery Medicine 10:489-499 (2010)). Human immunodeficiency virus uses BRD4 to initiate transcription of viral RNA from stably intact viral DNA (Jang et al, mol. Cell, 19:523-534 (2005)). BET bromodomain inhibitors have also been shown to restore activity to HIV transcription in potential T cell infection and potential monocyte infection models (Banerjee, et al, J.Leukocyte biol. doi: 10.1189/jlb.0312165). BRDt plays an important role in spermatogenesis (Matzuk, et al, Cell 150: 673-. Therefore, there is a current medical need to develop new drugs to treat diseases and indications involving bromodomain function, including BET bromodomain function.

SUMMARY

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein

R^xIs hydrogen or C₁-C₃An alkyl group;

R^yis C₁-C₃Alkyl, - (C)₂-C₃Alkylene) -OH, or C₁-C₃A haloalkyl group;

X¹is N or CR^x1Wherein

R^x1Is hydrogen, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -C (O) OR^ax1、-C(O)NR^bx1R^cx1、-C(O)R^dx1、S(O)₂R^dx1、-S(O)₂NR^bx1R^cx1、G^x1、C₁-C₆Haloalkyl, or C₁-C₆An alkyl group; wherein, C₁-C₆The alkyl group is optionally substituted with one substituent selected from OR^ax1、SR^ax1、S(O)R^dx1、S(O)₂R^dx1、NR^bx1R^cx1、-C(O)R^ax1、-C(O)OR^ax1、-C(O)NR^bx1R^cx1、-S(O)₂NR^bx1R^cx1And G^x1；

R^ax1、R^bx1And R^cx1Each occurrence independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, G^aOr is- (C)₁-C₆Alkylene) -G^a；

R^dx1Each occurrence independently is C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, G^aOr is- (C)₁-C₆Alkylene) -G^a；

X²Is N or CR^x2(ii) a Wherein

R^x2Is hydrogen, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -C (O) OR^ax2、-C(O)NR^bx2R^cx2、-C(O)R^dx2、-C(O)H、S(O)₂R^dx2、-S(O)₂NR^bx2R^cx2、G^x2、C₁-C₆Alkyl halidesRadical, or C₁-C₆An alkyl group; wherein C is₁-C₆The alkyl group is optionally substituted with one substituent selected from OR^ax2、SR^ax2、S(O)R^dx2、S(O)₂R^dx2、NR^bx2R^cx2、-C(O)R^ax2、-C(O)OR^ax2、-C(O)NR^bx2R^cx2、-S(O)₂NR^bx2R^cx2And G^x2；

R^ax2、R^bx2And R^cx2Each occurrence independently is hydrogen, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, G^bOr is- (C)₁-C₆Alkylene) -G^b；

R^dx2Independently at each occurrence is C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, G^bOr is- (C)₁-C₆Alkylene) -G^b；

Y¹Is N or CR^u(ii) a Wherein R is^uIs hydrogen, C₁-C₆Alkyl, halogen, or C₁-C₆A haloalkyl group;

A¹is N or CR¹、A²Is N or CR²、A³Is N or CR³(ii) a And A is⁴Is N or CR⁴(ii) a With the proviso that A¹、A²、A³And A⁴0, 1,2 or 3 of (a) is N;

R¹、R³and R⁴Each independently is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, CN, or NO₂；

R²Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN、NO₂、G^2a、-OR^2a、-OC(O)R^2d、-OC(O)NR^2bR^2c、-SR^2a、-S(O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)OR^2a、-C(O)NR^2bR^2c、-NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)C(O)O(R^2d)、-N(R^2e)C(O)NR^2bR^2c、-N(R^2e)S(O)₂NR^2bR^2c、–(C₁-C₆Alkylene) -G^2a、–(C₁-C₆Alkylene) -OR^2a、-(C₁-C₆Alkylene) -OC (O) R^2d、–(C₁-C₆Alkylene) -OC (O) NR^2bR^2c、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、–(C₁-C₆Alkylene) -C (O) OR^2a、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2d、–(C₁-C₆Alkylene) -N (R)^2e)C(O)O(R^2a)、–(C₁-C₆Alkylene) -N (R)^2e)C(O)NR^2bR^2c、–(C₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2cAnd- (C)₁-C₆Alkylene) -CN;

R^2a、R^2b、R^2cand R^2eEach occurrence independently is hydrogen, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, G^2bOr C₁-C₆Alkyl radical, wherein C₁-C₆The alkyl group is optionally substituted with one substituent selected from-OR^z1、NR^z1R^z2、-C(O)OR^z1、-C(O)NR^z1R^z2、-S(O)₂R^z1、-S(O)₂NR^z1R^z2And G^2b；

R^2dIndependently at each occurrence is C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, G^2bOr C₁-C₆Alkyl radical, wherein C₁-C₆The alkyl group is optionally substituted with one substituent selected from-OR^z1、NR^z1R^z2、-C(O)OR^z1、-C(O)NR^z1R^z2、-S(O)₂R^z1、-S(O)₂NR^z1R^z2And G^2b；

R^z1And R^z2Each occurrence independently is hydrogen, C₁-C₆Alkyl, or C₁-C₆A haloalkyl group;

G^x1、G^x2、G^a、G^b、G^2aand G^2bEach occurrence is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each is independently unsubstituted or substituted with 1,2,3, 4, or 5R^vSubstitution;

L¹is absent, CH₂、C(O)、C(H)(OH)、(CH₂)_mO、(CH₂)_mS(O)_nWherein n is 0, 1, or 2; or (CH)₂)_mN(R^z) Wherein R is^zIs hydrogen, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, (C)₂-C₃Alkylene) -OH, or unsubstituted cyclopropyl;

m is 0 or 1;

G¹is C₁-C₆Alkyl, alkoxyalkyl, G^1aOr- (C)₁-C₆Alkylene) -G^1a(ii) a Wherein each G^1aIndependently is aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G^1aIndependently unsubstituted or substituted by 1,2,3, 4, or 5R^wSubstitution;

R^vand R^wEach occurrence independently is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, oxo, -OR^h、-OC(O)Rⁱ、-OC(O)NR^jR^k、-SR^h、-S(O)₂R^h、-S(O)₂NR^jR^k、-C(O)R^h-C (O) -monocyclic heterocycle, -C (O) -monocyclic heteroaryl, -C (O) OR^h、-C(O)NR^jR^k、-NR^jR^k、-N(R^h)C(O)Rⁱ、-N(R^h)S(O)₂Rⁱ、-N(R^h)C(O)O(Rⁱ)、-N(R^h)C(O)NR^jR^k、–(C₁-C₆Alkylene) -OR^h、–(C₁-C₆Alkylene) -OC (O) Rⁱ、-(C₁-C₆Alkylene) -OC (O) NR^jR^k、–(C₁-C₆Alkylene) -S (O)₂R^h、–(C₁-C₆Alkylene) -S (O)₂NR^jR^k、-(C₁-C₆Alkylene) -C (O) R^h、–(C₁-C₆Alkylene) -C (O) OR^h、-(C₁-C₆Alkylene) -C (O) NR^jR^k、–(C₁-C₆Alkylene) -NR^jR^k、–(C₁-C₆Alkylene) -N (R)^h)C(O)Rⁱ、-(C₁-C₆Alkylene) -N (R)^h)S(O)₂Rⁱ、–(C₁-C₆Alkylene) -N (R)^h)C(O)O(Rⁱ)、–(C₁-C₆Alkylene) -N (R)^h)C(O)NR^jR^kOr is- (C)₁-C₆Alkylene) -CN;

R^h、R^j、R^keach occurrence independently is hydrogen, C₁-C₆Alkyl, or C₁-C₆A haloalkyl group; and

Rⁱindependently at each occurrence is C₁-C₆Alkyl or C₁-C₆A haloalkyl group.

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein

R^xIs hydrogen or C₁-C₃An alkyl group;

X¹is N or CR^x1Wherein

R^x1Is hydrogen, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -C (O) OR^ax1、-C(O)NR^bx1R^cx1、-C(O)R^dx1、S(O)₂R^dx1、-S(O)₂NR^bx1R^cx1、G^x1、C₁-C₆Haloalkyl, or C₁-C₆An alkyl group; wherein C is₁-C₆The alkyl group is optionally substituted with one substituent selected from OR^ax1、SR^ax1、S(O)R^dx1、S(O)₂R^dx1、NR^bx1R^cx1、-C(O)R^ax1、-C(O)OR^ax1、-C(O)NR^bx1R^cx1、-S(O)₂NR^bx1R^cx1And G^x1；

X²Is N or CR^x2(ii) a Wherein

R^x2Is hydrogen, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -C (O) OR^ax2、-C(O)NR^bx2R^cx2、-C(O)R^dx2、S(O)₂R^dx2、-S(O)₂NR^bx2R^cx2、G^x2、C₁-C₆Haloalkyl, or C₁-C₆An alkyl group; wherein C is₁-C₆The alkyl group is optionally substituted with one substituent selected from OR^ax2、SR^ax2、S(O)R^dx2、S(O)₂R^dx2、NR^bx2R^cx2、-C(O)R^ax2、-C(O)OR^ax2、-C(O)NR^bx2R^cx2、-S(O)₂NR^bx2R^cx2And G^x2；

R^dx2Independently at each occurrence is C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, G^bOr-(C₁-C₆Alkylene) -G^b；

R²Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, NO₂、G^2a、-OR^2a、-OC(O)R^2d、-OC(O)NR^2bR^2c、-SR^2a、-S(O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)OR^2a、-C(O)NR^2bR^2c、-NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)C(O)O(R^2d)、-N(R^2e)C(O)NR^2bR^2c、-N(R^2e)S(O)₂NR^2bR^2c、–(C₁-C₆Alkylene) -G^2a、–(C₁-C₆Alkylene) -OR^2a、-(C₁-C₆Alkylene) -OC (O) R^2d、–(C₁-C₆Alkylene) -OC (O) NR^2bR^2c、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、–(C₁-C₆Alkylene) -C (O) OR^2a、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2d、–(C₁-C₆Alkylene) -N (R)^2e)C(O)O(R^2a)、–(C₁-C₆Alkylene) -N (R)^2e)C(O)NR^2bR^2c、–(C₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2cAnd- (C)₁-C₆Alkylene) -CN;

L¹is absent, CH₂、C(O)、(CH₂)_mO、(CH₂)_mS(O)_nWherein n is 0, 1, or 2; or (CH)₂)_mN(R^z) Wherein R is^zIs hydrogen, C₁-C₃Alkyl radical, C₁-C₃Haloalkyl, (C)₂-C₃Alkylene) -OH, or unsubstituted cyclopropyl;

m is 0 or 1;

G¹is G^1aOr- (C)₁-C₆Alkylene) -G^1a(ii) a Wherein each G^1aIndependently is aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G^1aIndependently unsubstituted or substituted by 1,2,3, 4, or 5R^wSubstitution;

R^vand R^wEach occurrence independently is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, oxo, -OR^h、-OC(O)Rⁱ、-OC(O)NR^jR^k、-SR^h、-S(O)₂R^h、-S(O)₂NR^jR^k、-C(O)R^h、-C(O)OR^h、-C(O)NR^jR^k、-NR^jR^k、-N(R^h)C(O)Rⁱ、-N(R^h)S(O)₂Rⁱ、-N(R^h)C(O)O(Rⁱ)、-N(R^h)C(O)NR^jR^k、–(C₁-C₆Alkylene) -OR^h、–(C₁-C₆Alkylene) -OC (O) Rⁱ、-(C₁-C₆Alkylene) -OC (O) NR^jR^k、–(C₁-C₆Alkylene) -S (O)₂R^h、–(C₁-C₆Alkylene) -S (O)₂NR^jR^k、-(C₁-C₆Alkylene) -C (O) R^h、–(C₁-C₆Alkylene) -C (O) OR^h、-(C₁-C₆Alkylene) -C (O) NR^jR^k、–(C₁-C₆Alkylene) -NR^jR^k、–(C₁-C₆Alkylene) -N (R)^h)C(O)Rⁱ、-(C₁-C₆Alkylene) -N (R)^h)S(O)₂Rⁱ、–(C₁-C₆Alkylene) -N (R)^h)C(O)O(Rⁱ)、–(C₁-C₆Alkylene) -N (R)^h)C(O)NR^jR^kOr is- (C)₁-C₆Alkylene) -CN;

In another aspect, the invention provides methods of treating or preventing a condition ameliorated by the inhibition of BET. Such methods comprise administering to the individual a therapeutically effective amount of a compound of formula (I), either alone or in combination with a pharmaceutically acceptable carrier.

Certain methods relate to the treatment or prevention of inflammatory diseases or cancer or AIDS.

In another aspect, the present invention relates to a method of treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the cancer is selected from: auditory neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (myelogenous) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, poorly proliferative changes (dysplasia and metaplasia), embryonic carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, neuroblastoma, colorectal carcinoma, chondrosarcoma, neuroblastoma, melanoma, neuroblastoma, and myelogenous leukemia, Estrogen receptor positive breast cancer, essential thrombocythemia, ewing's sarcoma, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma (lymphoblastiiosarcoma), lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus malignancies and hyperproliferative disorders, T-cell or B-cell derived lymphoid malignancies, leukemia, lymphoma, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, neuroblastoma, lymphoma, neuroblastoma, melanoma, neuroblastoma, lymphoma, melanoma, neuroblastoma, lymphoma, melanoma, neuroblastoma, melanoma, Myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid carcinoma, primary macroglobulinemia, testicular tumor, uterine cancer, and wilms tumor. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is an anti-cancer agent. In a particular embodiment, the additional therapeutic agent is selected from cytarabine, bortezomib, and 5-azacitidine.

In another aspect, the invention relates to a method of treating a disease or condition in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcet's disease, bullous skin disease, Chronic Obstructive Pulmonary Disease (COPD), crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, pituitary inflammation, inflammatory bowel disease, kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, localized pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, Chronic Obstructive Pulmonary Disease (COPD), crohn's disease, chronic inflammatory bowel disease, chronic obstructive pulmonary disease, chronic obstructive, Sclerosing cholangitis, sepsis, systemic lupus erythematosus, takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention relates to a method of treating chronic kidney disease or a disease state in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the disease or disease state is selected from: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal disease, polycystic kidney disease and tubulointerstitial nephritis. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the present invention relates to a method of treating an acute kidney injury or disease or condition in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the acute kidney injury or disease or condition is selected from the group consisting of: ischemia-reperfusion-induced, cardiotonic and major surgery-induced, percutaneous coronary intervention-induced, radiocontrast-induced, sepsis-induced, pneumonia-induced, and drug intoxication-induced acute kidney injury or disease or condition. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

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

In another aspect, the present invention relates to a method of treating obesity, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

In another aspect, the invention relates to a method of preventing pregnancy by inhibiting spermatogenesis in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further comprises administering a therapeutically effective amount of at least one additional therapeutic agent.

Another aspect of the invention provides the use of a compound of formula (I), alone or in combination with a second active agent, with or without a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment or prevention of the disease states and conditions disclosed herein.

Also provided are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with a second active agent.

Detailed description of the invention

Disclosed herein are compounds of formula (I)

Wherein A is¹、A²、A³、A⁴、X¹、X²、Y¹、L¹、G¹、R^xAnd R^yAs defined in the summary of the invention above and in the detailed description below. In addition, compositions comprising such compounds and methods of treating disease states and conditions using such compounds and compositions are also disclosed.

The compounds disclosed herein may comprise one or more variants that occur more than once in any substituent or formula herein. The definition of a variant at each occurrence is independent of its definition at another occurrence. Furthermore, combinations of substituents are permissible only if such combinations result in stable compounds. A stabilizing compound is a compound that can be isolated from the reaction mixture.

a) Definition of

It should be noted that, as used in this specification and the appended claims, the singular forms "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, and reference to "an optional pharmaceutically acceptable carrier" refers to a single optional pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and the like.

Unless specified to the contrary, as used in this specification and the appended claims, the following terms have the indicated meanings:

the term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon containing 2 to 10 carbons and containing at least one carbon-carbon double bond, optionally substituted with 1,2 or 3 halogen atoms. The term "C₂-C₆Alkenyl "means an alkenyl group containing 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include but-1, 3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term "alkenylene" refers to a divalent group derived from a straight or branched chain hydrocarbon of 2 to 4 carbon atoms and containing at least one carbon-carbon double bond. Typical examples of alkenylene include, but are not limited to, -CH = CH-and-CH₂CH=CH-。

The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon group. In some cases, the number of carbon atoms in an alkyl group is preceded by the prefix "C_x-C_y"means where x is the minimum and y is the maximum of carbon atoms in the substituent. Thus, for example, "C₁-C₆Alkyl "means an alkyl substituent containing 1 to 6 carbon atoms, and" C₁-C₃Alkyl "refers to an alkyl substituent containing 1 to 3 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-,Sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1-methylpropyl, 1-ethylpropyl, 1,2, 2-trimethylpropyl, 3-methylhexyl, 2, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term "alkylene" refers to a polymer derived from, for example, 1 to 10 carbon atoms or 1 to 6 carbon atoms (C)₁-C₆Alkylene) or 1 to 4 carbon atoms or 2 to 3 carbon atoms (C)₂-C₃Alkylene) or a divalent radical of a straight or branched chain saturated hydrocarbon. Examples of alkylene include, but are not limited to, -CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂-, and-CH₂CH(CH₃)CH₂-。

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon group containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond, optionally substituted with 1,2 or 3 halogen atoms. The term "C₂-C₆Alkynyl "refers to alkynyl groups of 2-6 carbon atoms. Typical examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term "aryl" as used herein refers to phenyl or bicyclic aryl. Bicyclic aryl is naphthyl, or phenyl fused to a monocyclic cycloalkyl, or phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples of aryl groups include indanyl, indenyl, naphthyl, dihydronaphthyl, and tetrahydronaphthyl. The bicyclic aryl is connected to the parent molecular moiety through any carbon atom contained within the bicyclic ring system and may be unsubstituted or substituted.

The term "cycloalkyl" as used herein refers to a group that is a monocyclic cycloalkyl, bicyclic cycloalkyl or spirocycloalkyl. Monocyclic cycloalkyl is a carbocyclic ring system containing 3 to 8 carbon atoms, 0 heteroatoms and 0 double bonds. Monocyclic ringExamples of systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl is monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring. Monocyclic and bicyclic cycloalkyl groups can contain one or two alkylene bridges, each consisting of 1,2,3, or 4 carbon atoms in length, and each bridge connecting two non-adjacent carbon atoms of the ring system. Non-limiting examples of bicyclic ring systems include bicyclo [3.1.1]Heptane, bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane, bicyclo [3.2.2]Nonane, bicyclo [3.3.1]Nonanes and bicyclo [4.2.1]Nonane, tricyclo [3.3.1.0^3,7]Nonane (octahydro-2,5-methanopentalene (octahydro-2, 5-methanolene) or noradamantane) and tricyclo [3.3.1.1^3,7]Decane (adamantane). Spirocycloalkyl is monocyclic cycloalkyl in which two substituents on the same carbon atom of the monocyclic cycloalkyl ring and said carbon atom form a second monocyclic cycloalkyl ring. Monocyclic, bicyclic, and spirocycloalkyl groups can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.

The term "cycloalkenyl" as used herein refers to a monocyclic or bicyclic hydrocarbon ring group. Monocyclic cycloalkenyls have four-, five-, six-, seven-, or eight-carbon atoms and zero heteroatoms. The four-membered ring system has one double bond, the five-or six-membered ring system has one or two double bonds, and the seven-or eight-membered ring system has one, two or three double bonds. Typical examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The bicyclic cycloalkenyl is monocyclic cycloalkenyl fused to a monocyclic cycloalkyl, or monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl. The monocyclic or bicyclic cycloalkenyl ring may comprise one or two alkylene bridges, each of said alkylene bridges consisting of one, two, or three carbon atoms, each of which connects two non-adjacent carbon atoms of the ring system. Typical examples of bicyclic cycloalkenyls include, but are not limited to, 4,5,6, 7-tetrahydro-3 aH-indene, octahydronaphthyl and 1, 6-dihydro-pentalene. Monocyclic and bicyclic cycloalkenyl groups can be attached to the parent molecular moiety through any substitutable atom contained within the ring system, and can be unsubstituted or substituted.

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

The term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term "C₁-C₆Haloalkyl "refers to C as defined herein₁-C₆Alkyl in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term "C₁-C₃Haloalkyl "refers to C as defined herein₁-C₃Alkyl, wherein one, two, or three hydrogen atoms are replaced by halogen. Typical examples of haloalkyl groups include, but are not limited to, chloromethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl.

The term "heterocycle" or "heterocyclic" as used herein refers to monocyclic heterocycles, bicyclic heterocycles, and spiroheterocyclic groups. Monocyclic heterocycles are three-, four-, five-, six-, seven-, or eight-membered carbocyclic rings further containing at least one heteroatom independently selected from O, N and S. The three-or four-membered ring contains zero or one double bond, and one heteroatom selected from O, N and S. When two O atoms or one O atom and one S atom are present in the heterocyclic ring, then the two O atoms or one O atom and one S atom are not directly attached to each other. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from O, N and S. Examples of five-membered heterocycles include those containing in the ring: 1O; 1S; 1N; 2N; 3N; 1S and 1N; 1S and 2N; 1O and 1N; or those of 1O and 2N. Examples of five-membered heterocyclic groups include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, and 3-pyrrolinyl. The six-membered ring contains zero, one or two double bonds, and one, two or three heteroatoms selected from O, N and S. Six-membered heterocyclic ringExamples of (b) include those containing in the ring: 1O; 2O; 1S; 2S; 1N; 2N; 3N; 1S, 1O and 1N; 1S and 1N; 1S and 2N; 1S and 1O; 1S and 2O; 1Q and 1N; and those of 1O and 2N. Examples of six-membered heterocyclic groups include tetrahydropyranyl, dihydropyranyl, dioxanyl, 1, 3-dioxolanyl, 1, 4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, 1,2,3, 6-tetrahydropyridinyl, tetrahydrothiopyranyl, 1-dioxo-hexahydro-1-thiopyranyl, 1-dioxo-1. lambda⁶Thiomorpholinyl, oxathianyl, and trithianyl. The seven-and eight-membered rings contain zero, one, two or three double bonds, and one, two or three heteroatoms selected from O, N and S. Typical examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1, 3-dioxanyl, 1, 3-dioxolanyl, 1, 3-dithiolane, 1, 3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl group, or a monocyclic heterocycle fused to a monocyclic heterocycle. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, 2, 3-dihydrobenzofuranyl, 2, 3-dihydrobenzothienyl, 2, 3-dihydro-1H-indolyl, 3, 4-dihydroisoquinolin-2 (1H) -yl, 2,3,4, 6-tetrahydro-1H-pyrido [1,2-a ] group]Pyrazin-2-yl, hexahydropyrano [3,4-b ]][1,4]Oxazin-1 (5H) -yl. The monocyclic heterocyclic ring and the bicyclic heterocyclic ring may comprise one or two alkylene bridges or alkenylene bridges, or a mixture thereofCombinations each consisting of no more than four carbon atoms and each connecting two non-adjacent atoms of the ring system. Examples of such bridged heterocycles include, but are not limited to, azabicyclo [2.2.1]Heptyl (including 2-azabicyclo [2.2.1]]Hept-2-yl), 8-azabicyclo [3.2.1]Oct-8-yl, octahydro-2, 5-epoxypentalene, hexahydro-2H2, 5-methanocyclopenta [ alpha ], [ beta ], [ alpha ]b]Furan, hexahydro-1H-1, 4-methanocyclopenta [2 ]c]Furan, aza-adamantane (1-azatricyclo [ 3.3.1.1)^3,7]Decane) and oxa-adamantane (2-oxatricyclo [ 3.3.1.1)^3,7]-decane). Spiroheterocycles are monocyclic heterocycles in which two substituents on the same carbon atom of the monocyclic heterocycle and the carbon atom together form a second ring system selected from monocyclic cycloalkyl, bicyclic cycloalkyl, monocyclic heterocycle, or bicyclic heterocycle. Examples of spiroheterocycles include, but are not limited to, 6-azaspiro [2.5 ]]Oct-6-yl, 1 'H, 4H-spiro [1, 3-benzodioxine-2, 4' -piperidine]-1 ' -yl, 1' H, 3H-spiro [ 2-benzofuran-1, 4' -piperidine]-1' -yl and 1, 4-dioxa-8-azaspiro [4.5]]Decan-8-yl. Monocyclic, bicyclic, and spiroheterocycles can be unsubstituted or substituted. The monocyclic, bicyclic and spiroheterocyclic rings are attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring system. The nitrogen and sulfur heteroatoms in the heterocycle may be optionally oxidized (e.g., tetrahydrothienyl 1, 1-dioxide, 1, 1-dioxide-1, 2-thiazolidinyl, 1, 1-sulfur dioxide-morpholino)), and the nitrogen atom may be optionally quaternized.

The term "heteroaryl" as used herein refers to monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryl is a five-or six-membered ring. The five-membered ring includes two double bonds. The five-membered ring may include one heteroatom selected from O or S, or one, two, three or four nitrogen atoms, and optionally one oxygen atom or one sulfur atom. The six-membered ring includes three double bonds and one, two, three or four nitrogen atoms. Typical examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1, 3-oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1, 3-thiazolyl, thienyl, triazolylAnd triazinyl groups. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle. Typical examples of bicyclic heteroaryls include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzooxadiazolyl, phenoxazinyl, 2, 6-dihydropyrrolo [3,4-c]Pyrazol-5 (4H) -yl, 6, 7-dihydro-pyrazolo [1,5-a]Pyrazin-5 (4H) -yl, 6, 7-dihydro-1, 3-benzothiazolyl, imidazo [1,2-a]Pyridyl, indazolyl, indolyl, isoindolyl, isoquinolyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 2,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c]Pyridin-5-yl, thiazolo [5,4-b ]]Pyridin-2-yl, thiazolo [5,4-d ]]Pyrimidin-2-yl and 5,6,7, 8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroaryl groups can be substituted or unsubstituted, and are attached to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the ring system. The nitrogen atoms in the heteroaryl ring may optionally be oxidized and may optionally be quaternized.

The term "heteroatom" as used herein refers to nitrogen, oxygen and sulfur.

The term "oxo" as used herein refers to an = O group.

If a group is described as "substituted," then a non-hydrogen radical replaces a hydrogen radical of any substitutable atom of the group. Thus, for example, a substituted heterocyclic group is one in which at least one non-hydrogen group replaces a hydrogen group on the heterocyclic ring. It will be appreciated that if there is more than one substitution on a group, each non-hydrogen group may be the same or different (unless otherwise indicated).

If a group is described as "optionally substituted," that group may be (1) unsubstituted or (2) substituted. If a group is described as being optionally substituted with up to a specified number of non-hydrogen groups, that group may be (1) unsubstituted or (2) substituted with up to the specified number of non-hydrogen groups or up to the maximum number of substitutable positions on that group, whichever is less. Thus, for example, if the group is described as a heteroaryl group optionally substituted with up to 3 non-hydrogen groups, any heteroaryl group having less than 3 substitutable positions may be optionally substituted with up to only as many non-hydrogen groups as the heteroaryl group has substitutable positions. For illustration, tetrazolyl (which has only one substitutable position) can be optionally substituted with up to one non-hydrogen group. For further illustration, if the amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen groups, the primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen groups, while the secondary amino nitrogen will be optionally substituted with only up to 1 non-hydrogen group.

The terms "treatment", "treating" and "treating" refer to a method of reducing or eliminating a disease and/or its attendant symptoms.

The terms "preventing", "preventing" and "prevention" refer to a method of preventing the attack of a disease and/or its attendant symptoms, or preventing an individual from suffering from a disease. "preventing", "preventing" and "prevention" as used herein also include delaying the attack of a disease and/or its attendant symptoms and reducing the risk of an individual suffering from a disease.

The phrase "therapeutically effective amount" refers to an amount of a compound or pharmaceutically acceptable salt thereof that, when administered alone or in combination with other agents or treated in a particular individual or group of individuals, is sufficient to prevent the development of, or alleviate to some extent, the symptoms of one or more disease states or conditions being treated. For example, in humans or other mammals, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting for the particular disease and individual being treated, or may be that amount required by the guidelines of the U.S. food and drug administration or equivalent foreign administration.

The term "subject" is defined herein to mean an animal, such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In a preferred embodiment, the individual is a human.

b. Compound (I)

The compounds of the present invention have the general formula (I) described above.

Specific values for the variable groups in the compounds of formula (I) are as follows. Values may be used that are compatible with any other value, definition, claim or embodiment defined above or below.

In the compounds of formula (I), R^xAs defined in the summary. For example, in certain embodiments, R^xIs hydrogen or methyl. In certain embodiments, R^xIs hydrogen.

In the compounds of formula (I), R^yAs disclosed in the summary. For example, in certain embodiments, R^yIs C₁-C₃Alkyl (e.g., methyl, ethyl). In certain embodiments, R^yIs methyl.

X¹As disclosed in the summary. For example, in certain embodiments, X¹Is N. In certain embodiments, X¹Is CR^x1。R^x1As defined in the summary or embodiments herein. In certain embodiments, R^x1Is hydrogen, C₂-C₆Alkenyl, -C (O) OR^ax1、-C(O)NR^bx1R^cx1、-C(O)R^dx1、G^x1Or C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl is optionally selected from OR^ax1、NR^bx1R^cx1And G^x1Is substituted with one substituent. In certain embodiments, R^x1Is hydrogen, -C (O) OR^ax1、-C(O)NR^bx1R^cx1、G^x1Or C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl is optionally substituted by OR^ax1And (4) substitution. In certain embodiments, R^x1Is hydrogen, -C (O) OR^ax1、-C(O)NR^bx1R^cx1Optionally substituted phenyl, or C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl is optionally substituted by OR^ax1And (4) substitution. In certain embodiments, R^x1Is hydrogen, -C (O) OR^ax1or-C (O) NR^bx1R^cx1. In certain embodiments, R^x1Is hydrogen or unsubstituted C₁-C₆An alkyl group. In certain embodiments, R^x1is-C (O) OR^ax1、-C(O)NR^bx1R^cx1OR by OR^ax1Substituted C₁-C₆An alkyl group. In certain embodiments, R^x1Is hydrogen or-C (O) NR^bx1R^cx1. In certain embodiments, R^x1Is hydrogen. R^ax1、R^bx1、R^cx1、R^dx1And G^x1As disclosed in the summary. For example, R^ax1And R^bx1Each independently is hydrogen, C₁-C₆Alkyl (e.g., methyl, ethyl, isopropyl), or C₁-C₆Haloalkyl (e.g., trifluoromethyl). In certain embodiments, R^ax1And R^bx1Each independently is hydrogen or C₁-C₆Alkyl (e.g., methyl, ethyl, isopropyl). In certain embodiments, R^ax1And R^bx1Each independently hydrogen, methyl, or ethyl. For example, R^cx1Is hydrogen, C₁-C₆Alkyl (e.g., methyl, ethyl, isopropyl), or C₁-C₆Haloalkyl (e.g., trifluoromethyl, 2,2,2 trifluoroethyl), wherein C₁-C₆Alkyl is optionally substituted by G^x1And (4) substitution. In certain embodiments, R^cx1For example hydrogen or C₁-C₆Alkyl (e.g., methyl, ethyl, isopropyl). In certain embodiments, R^cx1For example, is G^x1Or by G^x1Substituted C₁-C₆An alkyl group; wherein G is^x1Is thiazolyl, morpholinyl, piperazinyl, tetrahydrofuranyl, or phenyl, each of which is optionally substituted with 1,2, or 3 substituents selected from C₁-C₃Alkyl and C₁-C₃Halogenated alkyl radicals.

X²As disclosed in the summary. For example,in certain embodiments, X²Is N. In certain embodiments, X²Is CR^x2。R^x2As defined in the summary or embodiments herein. In certain embodiments, X²Is C (O) H or by a G^x2Substituted C₁-C₆An alkyl group. In certain embodiments, X²Is C (O) H or by a G^x2Substituted C₁-C₃Alkyl radical, wherein G^x2Is piperidinyl, piperazinyl, or morpholinyl, each of which is optionally substituted with 1,2, or 3C₁-C₃Alkyl substitution. In certain embodiments, R^x2Is hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl). In certain embodiments, R^x2Is hydrogen.

Y¹Is N or CR^u. For example, in certain embodiments, Y¹Is N. In certain embodiments, Y¹Is CR^u。R^uAs defined in the summary or embodiments herein. For example, in certain embodiments, R^uIs hydrogen or C₁-C₆Alkyl (e.g., methyl). In certain embodiments, R^uIs hydrogen or C₁-C₃Alkyl (e.g., methyl). In certain embodiments, R^uIs hydrogen or methyl. In certain embodiments, R^uIs hydrogen.

A¹、A²、A³And A⁴As defined by the summary. In certain embodiments, a¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Is CR⁴(ii) a Or A¹、A²、A³And A⁴One of which is N. In certain embodiments, a¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Is CR⁴. In certain embodiments, a¹、A²、A³And A⁴One of which is N. In A¹、A²、A³And A⁴Embodiment in which one is NExamples of a group of compounds include, but are not limited to, those wherein A¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Those that are N. In certain embodiments, a¹、A²、A³And A⁴Two of (A) are N, e.g. A¹Is N, A²Is CR²、A³Is N and A⁴Is CR⁴(ii) a Or, for example, A¹Is N, A²Is CR²、A³Is CR³And A⁴Is N. In certain embodiments, a¹、A²、A³And A⁴Three of (A) are N, e.g. A¹Is N, A²Is CR²、A³Is N and A⁴Is N.

R¹、R³And R⁴As defined by the summary. For example, in certain embodiments, R¹、R³And R⁴Each independently is hydrogen, C₁-C₆Alkyl (e.g., methyl, ethyl), halogen (e.g., Br, F, or Cl), or CN. For example, in certain embodiments, R¹、R³And R⁴Each independently is hydrogen, C₁-C₆Alkyl (e.g., methyl, ethyl), or C₁-C₆Haloalkyl (e.g., trifluoromethyl). In certain embodiments, R¹、R³And R⁴Each independently hydrogen or methyl. In certain embodiments, R¹、R³And R⁴Is hydrogen.

R²As disclosed in the summary. For example, in certain embodiments, R²Is halogen, haloalkyl (e.g. CF)₃) Or is- (C)₁-C₃Alkylene) -CN. In certain embodiments, R²For example, hydrogen, C₁-C₆Alkyl radical, NO₂、G^2a、-S(O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)OR^2a、-C(O)NR^2bR^2c、-NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)S(O)₂NR^2bR^2c、–(C₁-C₆Alkylene) -G^2a、–(C₁-C₆Alkylene) -OR^2a、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、–(C₁-C₆Alkylene) -C (O) OR^2a、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2c. In certain embodiments, R²For example, hydrogen, or NO₂. In certain embodiments, R²For example, is G^2a、-S(O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)OR^2a、-C(O)NR^2bR^2c、-NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)S(O)₂NR^2bR^2c、–(C₁-C₆Alkylene) -G^2a、–(C₁-C₆Alkylene) -OR^2a、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、–(C₁-C₆Alkylene) -C (O) OR^2a、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2c. In certain embodiments, R²For example, is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)S(O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2c. In certain embodiments, R²For example, is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dor-N (R)^2e)S(O)₂NR^2bR^2c. In certain embodiments, R²For example, is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -S (O)₂R^2d. In certain embodiments, R²For example is- (C)₁-C₃Alkylene) -S (O)₂R^2dWherein R is^2dIs C₁-C₃An alkyl group. In certain embodiments, R²For example is- (CH)₂)-S(O)₂R^2dWherein R is^2dIs methyl or ethyl.

G^2a、R^2a、R^2b、R^2c、R^2dAnd R^2eAs disclosed in the summary and embodiments herein below.

In embodiments, where R is²Is G^2a，G^2aAs disclosed in the summary and embodiments herein. For example, in certain embodiments, G^2aIs an optionally substituted heterocycle. In certain embodiments, G^2aIs an optionally substituted monocyclic heterocycle. In certain embodiments, G^2aIs 1, 2-dioxo-1, 2-thiazolidin-2-yl or tetrahydropyridinyl, each of which is optionally substituted. In certain embodiments, G^2aIs an optionally substituted 1, 2-dioxo-1, 2-thiazolidin-2-yl group. In certain embodiments, G^2aIs aryl or heteroaryl, each of which is optionally substituted. In certain embodiments, G^2aIs optionally substituted phenyl. In certain embodiments, G^2aIs pyridyl or pyrazolyl, each of which is optionally substituted. In certain embodiments, G^2aIs unsubstituted.

In embodiments, where R is²Is- (C)₁-C₆Alkylene) -G^2a，G^2aAs disclosed in the summary and embodiments herein. For example, in certain embodiments, G^2aIs a heterocycle or heteroaryl, each of which is optionally substituted. In certain embodiments, G^2aIs a monocyclic heterocycle or a monocyclic heteroaryl, each of which is optionally substituted. In certain embodiments, G^2aIs 1, 1-dioxido-1, 2-thiazolidin-2-yl, pyrrolidinyl, morpholinyl, or pyrazolyl, each of which is optionally substituted. In certain embodiments, G^2aIs unsubstituted. In certain embodiments, G^2aIs optionally substituted phenyl.

Wherein G is^2aThe radical being optionally substituted, e.g. by 1,2,3, 4, or 5R^vOptionally substituted. R^vAs summarized and described herein, e.g., R^vIs C₁-C₆Alkyl (e.g., methyl), halogen (e.g., F, Cl), C₁-C₆Haloalkyl, -CN, -NR^jR^kOR-C (O) OR^h(ii) a Or for example, R^vIs C₁-C₆Alkyl (e.g., methyl), halogen (e.g., F, Cl), or C₁-C₆A haloalkyl group.

In embodiments, where R is²is-S (O)₂R^2d，R^2dAs disclosed in the summary and embodiments herein. In certain embodiments, R^2dIs C₁-C₆Haloalkyl (e.g. CF)₃)、G^2bUnsubstituted C₁-C₆Alkyl (e.g. methyl, ethyl, isopropyl), or by a G^2bRadical substituted C₁-C₆An alkyl group; wherein G is^2bIs phenyl, monocyclic cycloalkyl, or monocyclic heterocycle, each of which is optionally substituted. In certain such embodiments, G^2bThe radical being substituted by 1,2, or 3R^vThe radicals being optionally substituted, wherein R^vAs summarized and described herein, for example, each R^vIndependently is C₁-C₆Alkyl (e.g., methyl), halogen (e.g., F, Cl), C₁-C₆Haloalkyl, -OR^h-CN, or-NR^jR^kIn certain embodiments, R^2dIs C₁-C₆Haloalkyl or unsubstituted C₁-C₆An alkyl group. In certain embodiments, R^2dIs methyl or ethyl.

In embodiments, where R is²is-S (O)₂NR^2bR^2c，R^2bAnd R^2cAs disclosed in the summary and embodiments. For example, in certain embodiments, R^2bIs hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl), and R^2cIs hydrogen, unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl), or C₁-C₆Haloalkyl (e.g. 2,2, 2-trifluoroethyl, 2-fluoroethyl)). In certain embodiments, R^2bIs hydrogen, and R^2cIs optionally substituted phenyl, or R^2cTo be a G^2bradical-substituted-C₁-C₃Alkyl radical, wherein G^2bIs an optionally substituted pyridyl group.

In embodiments, where R is²is-C (O) R^2d，R^2dAs disclosed in the summary and embodiments. For example, in certain embodiments, R^2dIs G^2bWherein G is^2bAs disclosed in the summary and embodiments herein. For example, in certain embodiments, G^2bIs an optionally substituted heterocycle. In certain embodiments, G^2bIs an optionally substituted monocyclic heterocycle. In certain embodiments, G^2bIs 1, 1-thiomorpholin-4-yl, piperazinyl, piperidinyl, pyrrolidin-1-yl, or morpholin-4-yl, each of which is optionally substituted. Each G^2bIs optionally substituted as described in the summary and embodiments herein. For example, each G^2bIndependently unsubstituted or substituted by 1,2, or 3R^vAnd (4) substitution. R^vAs described in the summary and embodiments herein. For example, each R^vIndependently is C₁-C₆Alkyl (e.g., methyl), oxo, N (H) C (O) O (C)₁-C₆Alkyl), -CH₂-C(O)NR^jR^k-C (O) -monocyclic heterocycle, or-C (O) -monocyclic heteroaryl. In certain embodiments, each R is^vIndependently is C₁-C₆Alkyl (e.g., methyl), oxo, or N (H) C (O) O (C)₁-C₆Alkyl groups).

In embodiments, where R is²is-C (O) OR^2a，R^2aAs disclosed in the summary and embodiments herein. For example, in certain embodiments, R^2aIs hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl).

In embodiments, where R is²is-C (O) NR^2bR^2c，R^2bAnd R^2cAs disclosed in the summary and embodiments hereinIn (1). For example, in certain embodiments, R^2bIs hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl), and R^2cIs hydrogen, G^2b、C₁-C₆Haloalkyl (e.g. 2, 2-difluoroethyl), C₁-C₆Alkyl (e.g., methyl, ethyl), wherein C₁-C₆Alkyl is selected from-OR^z1、NR^z1R^z2And G^2bOne substituent of (a) is optionally substituted. R^z1、R^z2And G^2bAs defined in the summary and embodiments herein. For example, in certain embodiments, G^2bIs optionally substituted phenyl. In certain embodiments, G^2bIs cycloalkyl, heteroaryl, or heterocycle, each of which is optionally substituted. In certain embodiments, G^2bIs a monocyclic cycloalkyl, monocyclic heteroaryl, or monocyclic heterocycle, each of which is optionally substituted. In certain embodiments, G^2bIs pyridyl, pyrimidinyl, indazolyl, indolyl, cyclopentyl, thiazolyl, tetrahydrothienyl 1, 1-dioxide, tetrahydrofuranyl, piperazinyl, piperidinyl, or pyrrolidinyl, each of which is optionally substituted. Each G^2bIs optionally substituted as described in the summary and embodiments herein. For example, each G^2bIndependently unsubstituted or substituted by 1,2, or 3R^vAnd (4) substitution. R^vAs described in the summary and embodiments herein. For example, each R^vIndependently is C₁-C₆Alkyl (e.g. methyl), C₁-C₆Haloalkyl, -OR^h、-C(O)OR^h、-S(O)₂R^hHalogen, or oxo. In certain embodiments, each R is^vIndependently is C₁-C₆Alkyl (e.g., methyl) or oxo.

In embodiments, where R is²is-NR^2bR^2c，R^2bAnd R^2cAs disclosed in the summary and embodiments herein. For example, in certain embodiments, R^2bAnd R^2cEach independently hydrogen or unsubstituted C₁-C₆The alkyl group (for example,methyl, ethyl).

In embodiments, where R is²is-N (R)^2e)C(O)R^2d，R^2dAnd R^2eAs disclosed in the summary and embodiments herein. For example, in certain embodiments, R^2eIs hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl), and R^2dIs unsubstituted C₁-C₆Alkyl (e.g. methyl, ethyl, tert-butyl) or C₁-C₆Haloalkyl (e.g., 2,2, 2-trifluoroethyl).

In embodiments, where R is²is-N (R)^2e)S(O)₂R^2d，R^2dAnd R^2eAs disclosed in the summary and embodiments herein. For example, in certain embodiments, R^2eIs hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl), and R^2dIs unsubstituted C₁-C₆Alkyl (e.g. methyl, ethyl) or C₁-C₆Haloalkyl (e.g., 2,2, 2-trifluoroethyl, 2-fluoroethyl, 2, 2-difluoroethyl). In certain embodiments, R^2eIs hydrogen and R^2dIs unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl). In certain embodiments, R^2eIs C₁-C₆Haloalkyl, OR by a radical selected from-OR^z1、-NR^z1R^z2And G^2bC substituted by one substituent of₁-C₆Alkyl, and R^2dIs unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl). In certain embodiments, R^2eIs C₁-C₆Haloalkyl (e.g. 3,3, 3-trifluoropropyl), OR substituted by-OR^z1、-NR^z1R^z2And G^2bC substituted by one substituent of₁-C₃Alkyl, and R^2dIs unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl), wherein G^2bIs a monocyclic cycloalkyl (e.g., cyclopropyl), monocyclic heterocycle (e.g., pyrrolidinyl or tetrahydro)Furyl), or monocyclic heteroaryl (e.g., pyridyl), each of which is optionally substituted.

In embodiments, where R is²is-N (R)^2e)S(O)₂NR^2bR^2c，R^2b、R^2cAnd R^2eAs disclosed in the summary and embodiments herein. For example, in certain embodiments, R^2b、R^2cAnd R^2eEach independently hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl).

In embodiments, where R is²Is- (C)₁-C₆Alkylene) -OR^2a，R^2aAs described in the summary and embodiments herein. In certain embodiments, R^2aIs hydrogen. In certain embodiments, R²is-CH₂-OH or-CH₂CH₂-OH。

In embodiments, where R is²Is- (C)₁-C₆Alkylene) -C (O) OR^2a，R^2aAs described in the summary and embodiments herein. For example, R^2aIs hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl).

In embodiments, where R is²Is- (C)₁-C₆Alkylene) -C (O) NR^2bR^2c，R^2bAnd R^2cAs disclosed in the summary and embodiments herein. For example, in certain embodiments, R^2bAnd R^2cEach independently hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl).

In embodiments, where R is²Is- (C)₁-C₆Alkylene) -N (R)^2e)C(O)R^2d，R^2dAnd R^2eAs disclosed in the summary and embodiments herein. For example, in certain embodiments, R^2eIs hydrogen or unsubstituted C₁-C₆Alkyl (e.g., methyl, ethyl), and R^2dIs represented by C (O) OR^z1Optionally substituted C₁-C₆Alkyl (e.g., methyl).

In embodiments, where R is²Is- (C)₁-C₆Alkylene) -S (O)₂R^2d，R^2dAs disclosed in the summary and embodiments herein. For example, in certain embodiments, R^2dIs optionally substituted phenyl or unsubstituted C₁-C₆An alkyl group. In certain embodiments, R^2dIs unsubstituted C₁-C₃An alkyl group. In certain embodiments, R^2dIs methyl or ethyl. In certain embodiments, R^2dIs optionally substituted phenyl.

L¹As described in the summary and embodiments herein. For example, in certain embodiments, L¹Is absent, CH₂、C(H)(OH)、C(O)、(CH₂)_mO or (CH)₂)_mN(R^z). For example, in certain embodiments, L¹Is CH₂、C(O)、(CH₂)_mO or (CH)₂)_mN(R^z). In certain embodiments, L¹Is (CH)₂)_mO or (CH)₂)_mN(R^z). In certain embodiments, L¹Is (CH)₂)_mAnd O. In certain embodiments, L¹Is (CH)₂)_mN(R^z)。

The variant m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.

R^zAs described in the summary and embodiments herein. For example, R^zIs hydrogen or C₁-C₃An alkyl group. In certain embodiments, R^zIs hydrogen.

G¹As described in the summary and embodiments herein. For example, G¹Is G^1a. In certain embodiments, G¹Is- (C)₁-C₆Alkylene) -G^1a. In certain embodiments, G¹Is C₁-C₆Alkyl or alkoxyalkyl. In certain embodiments, G¹Is C₁-C₆Alkyl (e.g., methyl, ethyl, isobutyl, or 2, 2-dimethylpropyl). In certain embodiments, G¹Is an alkoxyalkyl group.

G^1aAs defined in the summary and embodiments herein. For example, in certain embodiments, G^1aIs aryl, heterocycle, or cycloalkyl, each of which is optionally substituted. In certain embodiments G^1aIs aryl, heterocycle, heteroaryl, or cycloalkyl, each of which is optionally substituted. In certain embodiments G^1aIs an optionally substituted aryl group. In certain embodiments G^1aIs an optionally substituted heterocycle. In certain embodiments G^1aIs an optionally substituted heteroaryl group. In certain embodiments G^1aIs an optionally substituted cycloalkyl group.

In embodiments, wherein G^1aIs optionally substituted aryl, G^1aFor example, phenyl, naphthyl, or indanyl, each of which is optionally substituted. In certain embodiments, G^1aFor example, an optionally substituted phenyl group. In certain embodiments, G^1aFor example, phenyl optionally substituted with one or two halogens (e.g., F). In certain embodiments, G^1aIs composed of

。

In certain embodiments, G^1aIs unsubstituted phenyl or

。

In embodiments, wherein G^1aAre optionally substituted heterocyclic rings, examples of which include, but are not limited to, oxetanyl, tetrahydrofuranyl (e.g., tetrahydro)Furan-2-yl, tetrahydrofuran-3-yl), pyrrolidinyl, morpholinyl, piperidinyl, tetrahydrothiopyranyl, and tetrahydropyranyl (e.g., tetrahydropyran-4-yl, tetrahydropyran-3-yl), each of which (including the exemplary ring) is optionally substituted.

In embodiments, wherein G^1aIs optionally substituted heteroaryl, G^1aFor example pyrazolyl, pyridyl, pyrimidinyl, 2,1, 3-benzothiadiazolyl, quinolinyl, or isoquinolinyl, each of which is optionally substituted.

In embodiments, wherein G^1aIs optionally substituted cycloalkyl (e.g., optionally substituted monocyclic cycloalkyl), examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1]Heptyl and adamantyl, each of which is optionally substituted. In certain embodiments, G^1aIs an optionally substituted cycloalkyl group. In certain embodiments, G^1aIs an unsubstituted cycloalkyl group. In certain embodiments, G^1aIs a substituted cycloalkyl group. In certain embodiments, G^1aIs selected from one or two of C₁-C₃Alkyl (e.g. methyl), O (C)₁-C₃Alkyl), and optionally substituted cyclohexyl with halogen substituents. In certain embodiments, G^1aIs substituted by one or two groups selected from methyl and O (CH)₃) And (b) optionally substituted cyclohexyl. In certain embodiments, G^1aIs 4, 4-difluorocyclohexyl. In certain embodiments, G^1aIs an optionally substituted cyclopropyl group. In certain embodiments, G^1aIs unsubstituted cyclopropyl.

G^1aAre as described in the summary and embodiments herein. For example, each G^1aIndependently unsubstituted or substituted by 1,2,3, 4, or 5R^wAnd (4) substitution. In certain embodiments, R^wFor example as C₁-C₆Alkyl, -CN, halogen (e.g., F, Cl), oxo, C₁-C₆Haloalkyl (e.g., trifluoromethyl), -OR^h、NR^jR^k、-S(O)₂R^h、-C(O)R^h、-C(O)OR^h、-C(O)NR^jR^k、-(C₁-C₃Alkylene) -OR^hOr is- (C)₁-C₃Alkylene group) C (O) NR^jR^k. In certain embodiments, R^wFor example as C₁-C₆Alkyl, -CN, halogen (e.g., F, Cl), or C₁-C₆Haloalkyl (e.g., trifluoromethyl). In certain embodiments, R^wIs halogen, -OR^hOr C₁-C₆An alkyl group. In certain embodiments, R^wIs halogen. In certain embodiments, R^wIs F.

It is contemplated that the compounds of formula (I) may be combined with the above embodiments, including specific, more specific and preferred embodiments. All embodiments of the compounds of formula (I) formed by combining the above substituent embodiments are within the scope of applicants' invention, and some exemplary embodiments of the compounds of formula (I) are provided below.

Accordingly, one aspect of the present invention relates to a group of compounds of formula (I), wherein L¹Is (CH)₂)_mO, and G¹Is G^1aAnd G is^1aAs disclosed in the summary above and in the embodiments herein.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1(ii) a And X²Is CR^x2Those of (a).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2And R is^yThose which are methyl.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2，R^yIs methyl, and L¹Is CH₂、C(O)、(CH₂)_mO or (CH)₂)_mN(R^z) ThatAnd (3) a plurality of. In certain embodiments, L¹Is (CH)₂)_mAnd O. In other embodiments, L¹Is (CH)₂)_mO, and m is 0. In other embodiments, L¹Is (CH)₂)_mO and m is 1. In certain embodiments, L¹Is (CH)₂)_mN(R^z). In certain embodiments, L¹Is (CH)₂)_mN(R^z) And m is 0. In certain embodiments, L¹Is (CH)₂)_mN(R^z) And m is 1. R^zHaving the values outlined above and described in the embodiments herein.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is- (C)₁-C₆Alkylene) -G^1aWherein G is^1aThose which are optionally substituted phenyl groups.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is- (C)₁-C₆Alkylene) -G^1aWherein G is^1aThose which are optionally substituted cycloalkyl. In certain embodiments, G^1aIs unsubstituted cyclopropyl.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is G^1aThose of (a).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose which are optionally substituted aryl groups.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose which are optionally substituted phenyl groups.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose that are optionally substituted cycloalkyl (e.g., optionally substituted monocyclic cycloalkyl).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is N; x¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose that are optionally substituted heterocycles (e.g., optionally substituted monocyclic heterocycles).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1(ii) a And X²Is CR^x2Those of (a).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2And R is^yThose which are methyl.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, and L¹Is CH₂、C(O)、(CH₂)_mO or (CH)₂)_mN(R^z) Those of (a). In certain embodiments, L¹Is (CH)₂)_mAnd O. In other embodiments, L¹Is (CH)₂)_mO and m is 0. In other embodiments, L¹Is (CH)₂)_mO and m is 1. In certain embodiments, L¹Is (CH)₂)_mN(R^z). In certain embodiments, L¹Is (CH)₂)_mN(R^z) And m is 0. In other embodiments, L¹Is (CH)₂)_mN(R^z) And m is 1. R^zHaving the values outlined above and described in the embodiments herein.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mN(R^z) And G is¹Is G^1aOr- (C)₁-C₆Alkylene) -G^1aWherein G is^1aIs phenyl, a monocyclic heterocycle (e.g., tetrahydrofuranyl), or a monocyclic cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), each of which (including the exemplary ring) is optionally substituted.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mN(R^z) M is 0, R^zIs hydrogen, and G¹Is G^1aWherein G is^1aIs phenyl, a monocyclic heterocycle (e.g., tetrahydrofuranyl), or a monocyclic cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), each of which (including the exemplary ring) is optionally substituted.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mN(R^z) M is 0, R^zIs hydrogen, and G¹Is- (C)₁-C₆Alkylene) -G^1aWherein G is^1aAre monocyclic heterocycles (e.g., tetrahydrofuranyl), or monocyclic cycloalkyls (e.g., cyclopropyl, cyclopentyl, cyclohexyl), each of which (including the exemplary ring) is optionally substituted. In certain embodiments, G¹Is- (C)₁-C₃Alkylene) -G^1aWherein G is^1aIs an optionally substituted monocyclic cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl, each of which is optionally substituted). In certain embodiments, G¹Is- (CH)₂)-G^1aWherein G is^1aIs an optionally substituted monocyclic cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl, each of which is optionally substituted). In certain embodiments, G^1aIs an optionally substituted monocyclic heterocycle (e.g., an optionally substituted tetrahydrofuranyl). In certain embodiments, G^1aIs an optionally substituted cyclopropyl group. In certain embodiments, G^1aIs unsubstituted cyclopropyl.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is C₁-C₆Alkyl or alkoxyalkyl groups. In certain embodiments, G¹Is C₁-C₆Alkyl (e.g., methyl, ethyl, isobutyl, or 2, 2-dimethylpropyl). In certain embodiments, G¹Is an alkoxyalkyl group.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is- (C)₁-C₆Alkylene) -G^1aWherein G is^1aThose which are optionally substituted phenyl groups.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is- (C)₁-C₆Alkylene) -G^1aWherein G is^1aThose which are optionally substituted cycloalkyl. In certain embodiments, G^1aIs an optionally substituted cyclopropyl group. In certain embodiments, G^1aIs unsubstituted cyclopropyl.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is G^1aThose of (a).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose which are optionally substituted aryl groups.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose which are optionally substituted phenyl groups.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose that are optionally substituted cycloalkyl (e.g., optionally substituted monocyclic cycloalkyl).

A group of (A)I) Further examples of compounds relate to those in which Y¹Is CR^u；X¹Is CR^x1；X²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose that are optionally substituted heterocycles (e.g., optionally substituted monocyclic heterocycles).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is N; x²Is CR^x2And R is^yThose which are methyl.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is N; x²Is CR^x2，R^yIs methyl, and L¹Is CH₂、C(O)、(CH₂)_mO or (CH)₂)_mN(R^z) Those of (a). In certain embodiments, L¹Is (CH)₂)_mAnd O. In other embodiments, L¹Is (CH)₂)_mO and m is 0. In other embodiments, L¹Is (CH)₂)_mO and m is 1. In certain embodiments, L¹Is (CH)₂)_mN(R^z). In certain embodiments, L¹Is (CH)₂)_mN(R^z) And m is 0. In certain embodiments, L¹Is (CH)₂)_mN(R^z) And m is 1. R^zHaving the values outlined above and described in the embodiments herein.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is N; x²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is G^1aThose of (a).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is N; x²Is CR^x2，R^yIs a firstBase, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose which are optionally substituted aryl groups.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is N; x²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose which are optionally substituted phenyl groups.

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is N; x²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose that are optionally substituted cycloalkyl (e.g., optionally substituted monocyclic cycloalkyl).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is N; x²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO，G¹Is G^1aAnd G is^1aThose that are optionally substituted heterocycles (e.g., optionally substituted monocyclic heterocycles).

A further example of a group of compounds of formula (I) relates to the compounds of formula (I) wherein Y is¹Is CR^u；X¹Is N; x²Is CR^x2，R^yIs methyl, L¹Is (CH)₂)_mO, and G¹Is- (C)₁-C₆Alkylene) -G^1aWherein G is^1aThose which are optionally substituted cycloalkyl. In certain embodiments, G^1aIs an optionally substituted cyclopropyl group. In certain embodiments, G^1aIs unsubstituted cyclopropyl.

In each of the groups of compounds of formula (I) described herein above, A¹、A²、A³And A⁴Having the meanings disclosed in the summary above and in the embodiments herein.

For example, in each of the groups of compounds of formula (I) described herein above, examples of subgroups include those wherein A is¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Is CR⁴(ii) a Or A¹、A²、A³And A⁴One of which is N.

Other examples of subgroups include, but are not limited to, those wherein A¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Is CR⁴Those of (a).

Other examples of subgroups include, but are not limited to, those wherein A¹、A²、A³And A⁴One of which is N.

Other examples of subgroups include, but are not limited to, those wherein A¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Those that are N.

Other examples of subgroups include, but are not limited to, those wherein A¹、A²、A³And A⁴Are those of N.

Other examples of subgroups include, but are not limited to, those wherein A¹Is N, A²Is CR²、A³Is N, and A⁴Is CR⁴Those of (a).

Other examples of subgroups include, but are not limited to, those wherein A¹Is N, A²Is CR²、A³Is CR³And A⁴Those that are N.

Other examples of subgroups include, but are not limited to, those wherein A¹、A²、A³And A⁴Are those where three of N.

Other examples of subgroups include, but are not limited to, those wherein A¹Is N, A²Is CR²、A³Is N, and A⁴Those that are N.

In all groups and subgroups of the compounds of formula (I) as disclosed in the preceding paragraphs, R¹、R²、R³、R⁴、R^x、R^u；R^x1、R^x2M, and G¹The optional substituents of (a) are as outlined above and in the embodiments herein.

For example, in all groups and subgroups of the compounds of formula (I) disclosed in the preceding paragraphs, R²Is hydrogen, C₁-C₆Alkyl radical, NO₂、G^2a、-S(O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)OR^2a、-C(O)NR^2bR^2c、-NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)S(O)₂NR^2bR^2c、–(C₁-C₆Alkylene) -G^2a、–(C₁-C₆Alkylene) -OR^2a、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、-(C₁-C₆Alkylene) -C (O) OR^2a、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2c. In certain embodiments, R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dor-N (R)^2e)S(O)₂NR^2bR^2c. In certain embodiments, R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -S (O)₂R^2d。

For example, in all groups and subgroups of the compounds of formula (I) disclosed in the preceding paragraphs, R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dor-N (R)^2e)S(O)₂NR^2bR^2cAnd R is^xIs hydrogen or methyl. In certain embodiments, R^xIs hydrogen.

For example, in all groups and subgroups of the compounds of formula (I) disclosed in the preceding paragraphs, R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dor-N (R)^2e)S(O)₂NR^2bR^2c，R^xIs hydrogen, and R^x1Is hydrogen, -C (O) OR^ax1、-C(O)NR^bx1R^cx1、G^x1Or C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl is OR^ax1Optionally substituted. In certain embodiments, R^x1Is hydrogen, -C (O) OR^ax1or-C (O) NR^bx1R^cx1。

For example, in all groups and subgroups of the compounds of formula (I) disclosed in the preceding paragraphs, R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dor-N (R)^2e)S(O)₂NR^2bR^2c，R^xIs hydrogen, R^x1Is hydrogen, -C (O) OR^ax1or-C (O) NR^bx1R^cx1And R is^x2Is hydrogen.

For example, in all groups and subgroups of the compounds of formula (I) disclosed in the preceding paragraphs, R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) S (O)₂R^2d，R^xIs hydrogen, R^x1Is hydrogen or-C (O) NR^bx1R^cx1And R is^x2Is hydrogen.

One aspect of the present invention is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

R^xIs hydrogen;

R^yis methyl;

Y¹is CR^uWherein R is^uIs hydrogen;

X¹is CR^x1Wherein R is^x1Is hydrogen or-C (O) NR^bx1R^cx1；

X²Is CR^x2Wherein R is^x2Is hydrogen;

L¹is (CH)₂)_mO, wherein m is 0;

G¹is G^1aOr- (C)₁-C₆Alkylene) -G^1aWherein G is^1aIs optionally substituted phenyl or optionally substituted cycloalkyl; and

R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -S (O)₂R^2d。

In certain such embodiments, a¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Is CR⁴. In certain other embodiments, a¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Is N.

Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

R^xIs hydrogen;

R^yis methyl;

Y¹is CR^uWherein R is^uIs hydrogen;

X¹is CR^x1Wherein R is^x1Is hydrogen;

X²is CR^x2Wherein R is^x2Is hydrogen;

L¹is (CH)₂)_mN(R^z) Or wherein m is 0 and R^zIs hydrogen;

G¹is- (C)₁-C₆Alkylene) -G^1aWherein G is^1aIs optionally substituted cycloalkyl; and

wherein

R^xIs hydrogen or C₁-C₃An alkyl group;

X¹is N or CR^x1Wherein

X²Is N or CR^x2(ii) a Wherein

A¹is N or CR¹、A²Is N or CR²、A³Is N or CR³(ii) a And A⁴Is N or CR⁴(ii) a With the proviso that A¹、A²、A³And A⁴0, 1,2, or 3 of (a) is N;

R^2a、R^2b、R^2cand R^2eAt each occurrence independently isHydrogen, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, G^2bOr C₁-C₆Alkyl radical, wherein C₁-C₆The alkyl group is optionally substituted with one substituent selected from-OR^z1、NR^z1R^z2、-C(O)OR^z1、-C(O)NR^z1R^z2、-S(O)₂R^z1、-S(O)₂NR^z1R^z2And G^2b；

m is 0 or 1;

The compounds of formula (I) may contain one or more asymmetrically substituted atoms. The compounds of formula I may also exist as individual stereoisomers (including enantiomers and diastereomers) and mixtures thereof. The individual stereoisomers of the compounds of formula I can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparing racemic mixtures and then resolving the individual stereoisomers using methods known to those skilled in the art. Examples of resolution are, for example, (i) linking a mixture of enantiomers with a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and then liberating the optically pure product; or (ii) separating a mixture of enantiomers or diastereomers on a chiral chromatography column.

The compounds of formula I may also include various geometric isomers and mixtures thereof resulting from the placement of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups, or heterocyclic groups. Substituents around a carbon-carbon double bond or a carbon-nitrogen double bond are referred to as Z or E configuration, and substituents around a cycloalkyl or heterocycle are referred to as cis or trans configuration.

Within the present invention, it is understood that the compounds disclosed herein may exhibit tautomerism and that all tautomers are included within the scope of the present invention.

Thus, a general scheme within the specification may represent only one possible tautomeric, geometric or stereoisomeric form. It is to be understood that the present invention includes any tautomeric, geometric or stereoisomeric form and mixtures thereof, and is not to be limited solely to any tautomeric, geometric or stereoisomeric form used within the general formulae drawings.

Exemplary compounds of formula (I) include, but are not limited to:

6-methyl-4- (2-phenoxyphenyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- (5-nitro-2-phenoxyphenyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (5-amino-2-phenoxyphenyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] methanesulfonamide;

2,2, 2-trifluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] ethanesulfonamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] acetamide;

N-methyl-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] methanesulfonamide;

ethyl 3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzoate;

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzoic acid;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (pyridin-3-yloxy) phenyl ] methanesulfonamide;

6-methyl-4- [2- (morpholin-4-ylmethyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n-ethyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide;

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxy-N- (tetrahydrofuran-2-ylmethyl) benzamide;

n-cyclopentyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide;

n- (2, 2-difluoroethyl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide;

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxy-N- (1, 3-thiazol-2-yl) benzamide;

n- (1, 1-tetrahydrothiophen-3-yl-dioxide) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide;

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide;

4- [5- (hydroxymethyl) -2-phenoxyphenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] ethanesulfonamide;

n, N-dimethyl-N' - [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] sulfamide;

n- [5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6-phenoxypyridin-3-yl ] methanesulfonamide;

n- [ 3-fluoro-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] methanesulfonamide;

n- [4- (2-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

n- [4- (4-fluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

n- [ 3-chloro-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] methanesulfonamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] methanesulfonamide;

6-methyl-4- [ 2-phenoxy-5- (1H-pyrazol-1-ylmethyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydrofuran-3-yloxy) phenyl ] methanesulfonamide;

n- {3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- [2- (trifluoromethyl) phenoxy ] phenyl } methanesulfonamide;

n- [4- (4-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

n- [4- (2-chloro-4-fluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

[4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] acetic acid;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] acetamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -3,3, 3-trifluoropropionamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2, 2-dimethylpropionamide;

4- (cyclopentylamino) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoic acid ethyl ester;

4- {5- [ (1, 1-dioxido-1, 2-thiazolidin-2-yl) methyl ] -2-phenoxyphenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- { [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzyl ] amino } -4-oxobutanoic acid;

4- [2- (2, 4-difluorophenoxy) -5- (1, 1-dioxido-1, 2-thiazolidin-2-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (benzyloxy) -5- (2-hydroxyethyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

methyl [4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] acetate;

2- [4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N-ethylacetamide;

2- [4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N, N-dimethylacetamide;

n- [4- (3, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] methanesulfonamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (tetrahydrofuran-3-yl) benzamide;

4- {2- (2, 4-difluorophenoxy) -5- [ (1, 1-thiomorpholin-4-yl) carbonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (1-methyl-2-oxopyrrolidin-3-yl) benzamide;

{1- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoyl ] pyrrolidin-3-yl } carbamic acid tert-butyl ester;

4- [2- (2, 4-difluorophenoxy) -5- (pyrrolidin-1-ylcarbonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (morpholin-4-ylcarbonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (cyclohexyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

n- [4- (cyclopentyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

n- {4- [ (4, 4-difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } methanesulfonamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] methanesulfonamide;

6-methyl-4- [2- (morpholin-4-ylcarbonyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] ethanesulfonamide;

n- [4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

2-fluoroethylenesulfonamide, N- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2-fluoroethylenesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N' -methylsulfamoamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydrofuran-3-yloxy) phenyl ] ethanesulfonamide;

6-methyl-7-oxo-4- (2-phenoxyphenyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid methyl ester;

1, 6-dimethyl-7-oxo-4- (2-phenoxyphenyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid methyl ester;

4- (5-amino-2-phenoxyphenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester;

6-methyl-4- (5- (methylsulfonamido) -2-phenoxyphenyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid;

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester;

n-ethyl-6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide;

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide;

4- (5-amino-2-phenoxyphenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxylic acid ethyl ester;

4- [5- (ethylamino) -2-phenoxyphenyl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxylic acid ethyl ester;

4- {5- [ ethyl (methylsulfonyl) amino ] -2-phenoxyphenyl } -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxylic acid ethyl ester;

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxylic acid;

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxamide;

6-methyl-N- [2- (4-methylpiperazin-1-yl) ethyl ] -4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-4-yl) -4-phenoxyphenyl ] methanesulfonamide;

n-ethyl-6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxamide;

6-methyl-4- (2-phenoxyphenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one;

N-ethyl-N, 6-dimethyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxamide;

4- {4- [ (ethylsulfonyl) amino ] -2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy } benzamide;

6-methyl-4- [5- (methylsulfonyl) -2-phenoxyphenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (tetrahydrofuran-3-yloxy) pyridine-3-sulfonamide;

n-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (tetrahydrofuran-3-yloxy) pyridine-3-sulfonamide;

6-methyl-4- (2-phenoxyphenyl) -2-phenyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

N- {3- [2- (hydroxymethyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c]Pyridin-4-yl]-4-phenoxyphenyl } methanesulfonamide;

n- [4- (4-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

2-fluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydrofuran-3-yloxy) phenyl ] ethanesulfonamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydrofuran-3-yloxy) phenyl ] propane-1-sulfonamide;

n- [4- (4-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] propane-1-sulfonamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] propane-1-sulfonamide;

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzenesulfonamide;

6- (cyclohexylamino) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

6- (cyclohexylamino) -N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

N-methyl-N' - [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] sulfamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] propane-1-sulfonamide;

2,2, 2-trifluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] ethanesulfonamide;

n- {4- [ (4, 4-difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } ethanesulfonamide;

n- {4- [ (4, 4-difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } propane-1-sulfonamide;

n- {4- [ (4, 4-difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } -2,2, 2-trifluoroethanesulfonamide;

n- {4- [ (4, 4-difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } -N' -methylsulfamoamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] ethanesulfonamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] propane-1-sulfonamide;

2,2, 2-trifluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] ethanesulfonamide;

N-methyl-N' - [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] sulfamide;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] ethanesulfonamide;

n, N-dimethyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (tetrahydrofuran-3-yloxy) pyridine-3-sulfonamide;

5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (phenylamino) pyridine-3-sulfonamide;

n-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (phenylamino) pyridine-3-sulfonamide;

n- [4- (4-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2-fluoroethylsulfonamide;

2-fluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] propane-1-sulfonamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyrimidin-2-yl) benzamide;

4- (2, 4-difluorophenoxy) -N- (2, 6-dimethoxypyridin-3-yl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

4- (2, 4-difluorophenoxy) -N- (1H-indazol-6-yl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

4- [2- (2, 4-difluorophenoxy) -5- { [4- (pyrrolidin-1-ylcarbonyl) piperazin-1-yl ] carbonyl } phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (2, 4-difluorophenoxy) -N- [4- (dimethylamino) phenyl ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-4-ylmethyl) benzamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- [2- (2-oxopyrrolidin-1-yl) ethyl ] benzamide;

4- (2, 4-difluorophenoxy) -N- (2-hydroxy-2-methylpropyl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

4- (2, 4-difluorophenoxy) -N- [2- (5-methoxy-1H-indol-3-yl) ethyl ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

n- (3, 4-difluorobenzyl) -4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- [4- (trifluoromethoxy) benzyl ] benzamide;

2- {4- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoyl ] piperazin-1-yl } -N, N-dimethylacetamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-3-ylmethyl) benzamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-2-ylmethyl) benzamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (3,4, 5-trimethoxybenzyl) benzamide;

4- (2, 4-difluorophenoxy) -N- [2- (dimethylamino) ethyl ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

n- [2- (1, 3-benzodioxol-5-yl) ethyl ] -4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

4- (2, 4-difluorophenoxy) -N- [2- (1H-indol-3-yl) ethyl ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide;

4- [2- (2, 4-difluorophenoxy) -5- { [4- (furan-2-ylcarbonyl) piperazin-1-yl ] carbonyl } phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

{1- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoyl ] piperidin-4-yl } carbamic acid tert-butyl ester;

4- { [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoyl ] amino } piperidine-1-carboxylic acid tert-butyl ester;

4- [2- (2, 4-difluorophenoxy) -5- { [4- (ethylsulfonyl) piperazin-1-yl ] carbonyl } phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (4-chlorobenzoyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (4-chlorophenyl) (hydroxy) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (pyrimidin-5-yloxy) phenyl ] ethanesulfonamide;

n- {3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- [ (1-methyl-1H-pyrazol-5-yl) methoxy ] phenyl } ethanesulfonamide;

n- {4- [ (1, 3-dimethyl-1H-pyrazol-5-yl) methoxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } ethanesulfonamide;

n- [4- (2, 2-dimethylpropoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

n- [4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide;

4- [2- (cyclohexylamino) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [ 5-amino-2- (2, 4-difluorophenoxy) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one;

4- [2- (2-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (3-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (4-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2-chlorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (3-chlorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (4-chlorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

3- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] benzonitrile;

4- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] benzonitrile;

6-methyl-4- {5- (methylsulfonyl) -2- [3- (trifluoromethyl) phenoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-4-yl) phenyl ] methanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-4-yl) phenyl ] ethanesulfonamide;

4- [2- (isoquinolin-5-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- (quinolin-6-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ 2-chloro-5- (trifluoromethyl) phenoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ 2-fluoro-5- (trifluoromethyl) phenoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

2- {4- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] phenyl } acetamide;

4- [2- (3-aminophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- (tetrahydrofuran-3-ylamino) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (4, 4-difluorocyclohexyl) oxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {5- (ethylsulfonyl) -2- [ (1-methylpiperidin-4-yl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2,1, 3-benzothiadiazol-4-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (isoquinolin-7-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 5-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (3, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {5- (methylsulfonyl) -2- [ (1-oxo-2, 3-dihydro-1H-inden-4-yl) oxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (3, 5-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [2- (4-methylphenoxy) -5- (methylsulfonyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2-methoxyphenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {2- [ (2-methylpyridin-3-yl) oxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [3- (dimethylamino) phenoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {5- (methylsulfonyl) -2- [ (1-oxo-2, 3-dihydro-1H-inden-5-yl) oxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {5- (methylsulfonyl) -2- [ (3-oxo-2, 3-dihydro-1H-inden-5-yl) oxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

2- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] benzonitrile;

4- [2- (3-chloro-2-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- (naphthalen-1-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2-fluoro-5-methylphenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (5-fluoro-2-methylphenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- (quinolin-7-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (4-chloro-3-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- (pyridin-3-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 3-dihydro-1H-inden-5-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {5- (methylsulfonyl) -2- [4- (propan-2-yl) phenoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (isoquinolin-8-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- (3,4, 5-trifluorophenoxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (2-benzylphenyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (biphenyl-2-yl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (1, 4-dioxaspiro [4.5] decan-8-yloxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {5- (ethylsulfonyl) -2- [ (4-oxocyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (cyclopropylmethyl) amino ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {5- (methylsulfonyl) -2- [ (tetrahydrofuran-3-ylmethyl) amino ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {5- (ethylsulfonyl) -2- [ (cis-4-hydroxycyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {5- (ethylsulfonyl) -2- [ (trans-4-hydroxycyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- (tetrahydrofuran-3-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (3-fluorooxetan-3-yl) methoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6- (cyclopropylmethoxy) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

6- (cyclopropylmethoxy) -N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

6- [ (cyclopropylmethyl) amino ] -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

6- [ (cyclopropylmethyl) amino ] -N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

4- {5- (ethylsulfonyl) -2- [ (cis-4-hydroxy-4-methylcyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {5- (ethylsulfonyl) -2- [ (trans-4-hydroxy-4-methylcyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclobutyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopentylmethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclohexyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopentyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- (tetrahydrofuran-3-ylmethoxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {5- (methylsulfonyl) -2- [2- (2-oxoimidazolidin-1-yl) ethoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2-cyclopropylethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cycloheptyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [2- (2-methylpropoxy) -5- (methylsulfonyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } -5- (methylsulfonyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {2- [ (2-methylcyclopropyl) methoxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclohexylmethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {2- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- { [ (2R) -5-oxopyrrolidin-2-yl ] methoxy } phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {5- (methylsulfonyl) -2- [2- (morpholin-4-yl) ethoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- [5- (methylsulfonyl) -2- { [ (2S) -5-oxopyrrolidin-2-yl ] methoxy } phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (1-tert-butoxyprop-2-yl) oxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (1S,4R) -bicyclo [2.2.1] hept-2-ylmethoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {2- [ (1-methylcyclopropyl) methoxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {5- (methylsulfonyl) -2- [2- (2-oxopyrrolidin-1-yl) ethoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6-methyl-4- {2- [ (4-methylcyclohexyl) oxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclobutylmethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] cyclopropanesulfonamide;

2-methoxy-N- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -ethanesulfonamide;

6-methyl-4- {5- (methylsulfonyl) -2- [ tricyclo [3.3.1.1^3,7]Decyl-2-yloxy]Phenyl } -1, 6-dihydro-7H-pyrrolo [2, 3-c)]Pyridin-7-one;

4- [ (cyclopropylmethyl) amino ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide;

4- [ (cyclopropylmethyl) amino ] -N-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide;

4- {2- [ (2, 2-difluorocyclopropyl) methoxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (4-bromo-2-methoxyphenyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6- (2, 4-difluorophenoxy) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

4- {2- (cyclopropylmethoxy) -5- [ (trifluoromethyl) sulfonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (cyclopropylmethyl) amino ] -5- [ (trifluoromethyl) sulfonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6- [ (cyclopropylmethyl) amino ] -N, N-dimethyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

6- (2, 4-difluorophenoxy) -N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

4- [2- (cyclopropylmethoxy) -6-methylphenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {5- (ethylsulfonyl) -2- [ (cis-4-methoxycyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide;

4- (cyclopropylmethoxy) -N-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide;

n- [4- (cyclopropylmethoxy) -2-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-7-oxo-N- (2,2, 2-trifluoroethyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- (morpholin-4-ylcarbonyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (4-methylpiperazin-1-yl) carbonyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-7-oxo-N- (1, 3-thiazol-2-yl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide;

4- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] piperidine-1-carboxylic acid ethyl ester;

4- [ 2-ethoxy-5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {5- (ethylsulfonyl) -2- [ (trans-4-methoxycyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (cyclopropylmethyl) amino ] -5- (prop-2-ylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (cyclopropylmethoxy) -2-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

n- [4- (cyclopropylmethoxy) -2-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide;

4- [5- (ethylsulfonyl) -2- (tetrahydro-2H-thiopyran-4-yloxy) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (1, 1-tetrahydro-2H-thiopyran-4-yl) oxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6- (2, 4-difluorophenoxy) -N, N-dimethyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

4- [2- (cyclopropylamino) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (5- (ethylsulfonyl) -2- (cis-4-methoxy-4-methylcyclohexyloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -N, 6-trimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide;

6-methyl-4- {5- (methylsulfonyl) -2- [4- (methylsulfonyl) phenoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (prop-2-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

6- (cyclopropylmethoxy) -N, N-diethyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide;

4- (cyclopropylmethoxy) -N, N-dimethyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide;

4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -2- (hydroxymethyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 3-dihydro-1H-inden-2-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -2- (1-hydroxyethyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -2- [ (dimethylamino) methyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- (morpholin-4-ylmethyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (4-methylpiperazin-1-yl) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (phenylamino) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (1, 3-thiazol-2-ylamino) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (tetrahydrofuran-3-ylamino) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (phenylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (morpholin-4-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- (2, 4-difluorophenoxy) -5- [ (methylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) pyridin-3-yl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (pyridin-3-yloxy) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [5- (cyclopropylsulfonyl) -2- (2, 4-difluorophenoxy) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- (prop-1-en-2-yl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- (phenoxymethyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (morpholin-4-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (ethylsulfonyl) pyridin-3-yl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2- (morpholin-4-yl) ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- [2- (dimethylamino) ethyl ] ethanesulfonamide;

4- {2- (2, 4-difluorophenoxy) -5- [ (ethylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- (2, 4-difluorophenoxy) -5- [2- (ethylsulfonyl) propan-2-yl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (pyrrolidin-1-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2- (dimethylamino) ethanesulfonamide;

4- [4- (ethylsulfonyl) -2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy ] piperidine-1-carboxylic acid ethyl ester;

4- [2- (cyclopropylmethoxy) -5- (pyrrolidin-1-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (1-acetylpiperidin-4-yl) oxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [4- (ethylsulfonyl) -2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy ] benzonitrile;

4- [2- (cyclopropylmethoxy) -5- (2, 3-dihydro-1H-indol-1-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- (2, 4-difluorophenoxy) -5- [ (phenylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (2, 2-difluorocyclopropyl) methoxy ] -5- (pyrrolidin-1-ylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- (cyclopropylmethoxy) -5- [ (3, 3-difluoroazetidin-1-yl) sulfonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [2- (2-hydroxyethyl) phenoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- { [3- (dimethylamino) pyrrolidin-1-yl ] sulfonyl } phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- (2, 4-difluorophenoxy) -5- [ (methylsulfonyl) methyl ] pyridin-3-yl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [4- (ethylsulfonyl) -2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy ] piperidine-1-carboxylic acid tert-butyl ester;

4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N-phenylbenzenesulfonamide;

4- [2- (cyclopropylmethoxy) -5- (pyrrolidin-1-ylmethyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (pyridin-3-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (morpholin-4-ylmethyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {5- (ethylsulfonyl) -2- [3- (hydroxymethyl) phenoxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (1-methyl-1H-pyrazol-4-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (2, 3-dihydro-1H-indol-1-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrazolo [3,4-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

4- {2- (2, 4-difluorophenoxy) -5- [ (methylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrazolo [3,4-c ] pyridin-7-one;

4- [2- (2, 4-difluorophenoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrazolo [3,4-c ] pyridin-7-one;

4- [2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrazolo [3,4-c ] pyridin-7-one;

n- [ 2-cyano-4- (2, 4-difluorophenoxy) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

4- [4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester;

4- [5- (6-aminopyridin-3-yl) -2- (cyclopropylmethoxy) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (2, 2-difluorocyclopropyl) methoxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-7-oxo-N- (2,2, 2-trifluoroethyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide;

4- {2- [ (cyclopropylmethyl) amino ] -5- [ (methylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (cyclopropylmethyl) amino ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [5- (ethylsulfonyl) -2- (pyrrolidin-1-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- [5- (ethylsulfonyl) -2- (4-methylpiperazin-1-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (4-fluorophenyl) amino ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-3-ylmethyl) benzenesulfonamide;

4- [4- (cyclopropylmethoxy) -3' -fluorobiphenyl-3-yl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- {2- [ (4-fluorophenyl) amino ] -5- [ (methylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

[4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] acetonitrile;

n- {4- (2, 4-difluorophenoxy) -3- [2- (hydroxymethyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl ] phenyl } ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- { 6-methyl-2- [ (4-methylpiperazin-1-yl) carbonyl ] -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl } phenyl ] ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- { 6-methyl-2- [ (4-methylpiperazin-1-yl) methyl ] -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl } phenyl ] ethanesulfonamide;

4- [2- (cyclopropylmethoxy) -5- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- (2-methoxyethyl) ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- (pyridin-2-ylmethyl) ethanesulfonamide;

n- (cyclopropylmethyl) -N- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- [2- (2-oxopyrrolidin-1-yl) ethyl ] ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- (tetrahydrofuran-2-ylmethyl) ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- (3,3, 3-trifluoropropyl) ethanesulfonamide;

4- (cyclopropylmethoxy) -N- (4-fluorophenyl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide;

4- [2- (cyclopropylmethoxy) -5- (6-fluoropyridin-3-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

n- [4- (2, 4-difluorophenoxy) -3- (3-formyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide;

n- {4- (2, 4-difluorophenoxy) -3- [ 6-methyl-3- (morpholin-4-ylmethyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl ] phenyl } ethanesulfonamide;

n- [4- (2, 4-difluorophenoxy) -3- { 6-methyl-3- [ (4-methylpiperazin-1-yl) methyl ] -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl } phenyl ] ethanesulfonamide;

4- {2- [ (cyclopropylmethyl) amino ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4'- (cyclopropylmethoxy) -3' - (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) biphenyl-3-carbonitrile; and

4- {2- (cyclopropylmethoxy) -5- [ (4-hydroxypiperidin-1-yl) sulfonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one.

In certain embodiments, the compound of formula I is selected from:

n- {4- [ (4, 4-difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } methanesulfonamide; and

n- [4- (4-fluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide; or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I is selected from:

4- [2- (cyclohexyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one; and

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compounds of the invention are N- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

The compounds of formula I can be used in the form of pharmaceutically acceptable salts. The phrase "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, 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: 1-19.

The compounds of formula (I) may contain basic or acidic functional groups, or both, and can be converted into pharmaceutically acceptable salts by using an appropriate acid or base, if desired. Salts are 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, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate (camphorate), camphorsulfonate, digluconate (digluconate), glycerophosphoric acid, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate (palmitate), pectinate (pectate), persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromide and the like. Water-or oil-soluble or dispersible products are thereby obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.

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

The term "pharmaceutically acceptable prodrug" or "prodrug" as used herein denotes those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, 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.

The invention includes compounds of formula (I) formed by synthetic methods or by in vivo biotransformation of prodrugs.

The compounds described herein may exist in unsolvated as well as solvated forms, including hydrated forms, such as hemihydrate. In general, the solvated forms with pharmaceutically acceptable solvents such as water and ethanol and the like are equivalent to the unsolvated forms for purposes of the present invention.

General Synthesis

The compounds described herein, including the compounds of general formula (I) and specific examples, may be prepared, for example, by the reaction schemes described in schemes 1-5. Variants A used in the following schemes unless otherwise stated¹、A²、A³、A⁴、X¹、X²、Y¹、L¹、G¹、R^xAnd R^yHaving the meanings set forth in the summary and detailed description.

The abbreviations used to describe the schemes and specific examples have the following meanings: n-BuLi or BuLi as n-butyllithium and DBU as 1, 8-diazabicyclo [5.4.0]Undec-7-ene, DIAD is diisopropyl azodicarboxylate; DME is 1, 2-dimethoxyethane, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, and EtOAc is ethyl acetate; mCPBA as 3-chloroperoxybenzoic acid and MeOH as methanol; pd (PPh)₃)₄Tetrakis (triphenylphosphine) palladium (0), preparative HPLC for preparative HPLC; THF was tetrahydrofuran, TFA was trifluoroacetic acid, and HPLC was high performance liquid chromatography.

The compounds of formula (I) may be prepared by the following process: (a) treating an aryl halide, aryl mesylate or aryl triflate (N. Miyamaand A. Suzuki, chem. Rev. 1995, 95:2457-2483, J. Organomet. chem. 1999, 576:147-148) with an aryl boronic acid or derivative thereof (e.g., a boronate) under Suzuki coupling conditions, and (b) removing the Protecting Group (PG), as shown in scheme 1. Thus, compounds of formula (1) wherein R¹⁰¹Is Br, Cl, mesylate or triflate, with a compound of formula (2) wherein R is¹⁰²Is the coupling of boronic acids or derivatives thereof (e.g., boronic esters), or (1) wherein R¹⁰¹Is boric acid or a derivative thereof (e.g., a borate ester) with a compound (2) wherein R¹⁰²Provides intermediates of formula (3) for the coupling of Br, Cl, mesylate or triflate. Typically, the coupling reaction is effected in the presence of a palladium catalyst and a base, and optionally in the presence of a ligand, and in a suitable solvent at elevated temperature (e.g., at about 80 to about 150 ℃). The reaction may be carried out by microwave irradiationAnd (4) promoting. Examples of palladium catalysts include, but are not limited to, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and palladium (II) acetate. Examples of suitable bases that may be used include, but are not limited to, carbonates or phosphates of sodium, potassium, and cesium; and cesium fluoride. Examples of suitable ligands include, but are not limited to, 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane, 2-dicyclohexylphosp-2 ',4', 6 '-triisopropylbiphenyl (X-phos) and 1,1' -bis (diphenylphosphinyl) ferrocene. Non-limiting examples of suitable solvents include methanol, dimethoxyethane, N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydropyran, and water or mixtures thereof.

Or, treating formula (1) with a boronic acid of formula (4) wherein R¹⁰¹Is Br, Cl or trifluoromethanesulfonate, then with the formula G¹-L¹-H of a suitable alcohol or amine wherein L¹Replacement of the fluorine atom in (4) by O or NH provides a compound of formula (3) or formula (I) wherein R^xIs hydrogen.

Replacement of fluorine with an alcohol or amine can be accomplished in a solvent such as, but not limited to, dimethylsulfoxide, dimethylformamide, dioxane, or tetrahydrofuran, in the presence of a base such as, but not limited to, cesium carbonate, potassium carbonate, or sodium hydride, and at a temperature of about 40 to about 120 ℃.

The Protecting Group (PG) may be removed in situ during the above substitution reactions or coupling conditions.

Alternatively, removal of the Protecting Group (PG) to provide a compound of formula (I) wherein R^xThe hydrogenation can be carried out using reaction conditions or modifications thereof which are generally known to those skilled in the art. For example, the tosyl protecting group may be removed in the presence of a base such as, but not limited to, cesium carbonate, sodium hydroxide, or sodium hydride. The reaction is typically carried out in the presence of a suitable solvent such as, but not limited to, dimethyl sulfoxide, methanol or tetrahydrofuran, and at a temperature of about 40 to about 120 ℃. The benzyl protecting group can be removed by hydrogenation in the presence of a catalyst such as, but not limited to, palladium on carbon and under a hydrogen atmosphere. The reaction is typically carried out in the presence of a solvent such as, but not limited to, methanol or ethyl acetate and at about room temperature.

Removal of the (trimethylsilyl) ethoxy) methyl protecting group can be achieved by treatment with a base such as, but not limited to, cesium carbonate or sodium hydride or with a fluoride reactant such as, but not limited to, TBAF (tetrabutylammonium fluoride). The reaction is typically carried out in the presence of a suitable solvent such as, but not limited to, dimethylsulfoxide, ethanol, or tetrahydrofuran, and at a temperature of about 40 to about 120 ℃. Removal of the (trimethylsilyl) ethoxy) methyl protecting group can also be achieved by treatment with mild acid such as, but not limited to, aqueous hydrochloric acid. The reaction is typically carried out in the presence of a suitable solvent such as, but not limited to, ethanol or methanol, and at a temperature of about 25 to about 80 ℃.

A compound of formula (I) wherein R^xFor conversion of hydrogen to (I) wherein R^xIs C₁-C₃The alkyl group may be of the formula R^xR¹⁰³In which R is¹⁰³Is halogen, triflate or mesylate. Typically, the reaction is carried out in the presence of a base such as, but not limited to, sodium hydride or potassium carbonate and in a solvent such as, but not limited to, tetrahydrofuran or dimethylformamide and at a temperature of about 40 to about 120 ℃.

Scheme 1

A compound of formula (1) wherein Y¹Is CR^u，X¹And X²Is CH, and R^uIs hydrogen, C₁-C₆Alkyl or C₁-C₆Haloalkyl groups can be prepared by the general synthetic methods shown in scheme 2.

Treating a compound of formula (6) with 1, 1-dimethoxy-N, N-dimethylmethylamine at elevated temperature (e.g., about 60 to about 100 ℃) in the absence or presence of a base in a solvent such as, but not limited to DMF, wherein the halogen is Br, Cl or I provides a compound of formula (7). Examples of suitable bases include, but are not limited to, lithium methoxide or sodium methoxide. (7) Catalytic hydrogenation in the presence of a catalyst such as, but not limited to, Raney-nickel and under a hydrogen atmosphere (about 30 psi) and in a solvent such as, but not limited to, ethyl acetate at about room temperature typically provides a compound of formula (8). Protection of the nitrogen atom with protecting groups such as, but not limited to, benzyl, tosyl and (trimethylsilyl) ethoxy) methyl 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 a compound of formula (9).

Treatment of (9) with an acid such as, but not limited to, hydrochloric or hydrobromic acid in a solvent such as, but not limited to, dioxane or water at about 40 to about 100 ℃ typically provides a compound of formula (10).

Alkylation of (10) with a halide or mesylate in the presence of a base such as, but not limited to, sodium hydride, cesium carbonate or potassium carbonate in a solvent such as, but not limited to, dimethylformamide or dimethylsulfoxide at a temperature of about 0 to about 50 ℃ generally provides a compound of formula (11).

Treatment of a compound of formula (11) with 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) generally affords a compound of formula (12). Typically, the conversion may be carried out over a palladium catalyst such as, but not limited to, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), or palladium (II) acetate, optionally a ligand such as, but not limited to, 2-dicyclohexylphosphonium-2 ',4', 6 '-triisopropylbiphenyl (X-phos) or 1,1' -bis (diphenylphosphinoalkyl) ferrocene, and a base such as, but not limited to, a carbonate, acetate or phosphate of sodium, potassium and cesium; and cesium fluoride. Non-limiting examples of suitable solvents include methanol, dimethoxyethane, N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydropyran, and water, or mixtures thereof.

Scheme 2

Preparation of a Compound of formula (1) wherein Y¹Is N, R¹⁰¹Is Cl, and X¹And X²The method for CH is described in scheme 3.

Treatment of (13) with ammonium hydroxide at about 100 to about 150 ℃ affords amines of formula (14).

Iodination of (14) with N-iodosuccinimide in a solvent such as, but not limited to, acetonitrile or acetone at a temperature of about 40 to about 85 ℃ typically yields a compound of formula (15). Coupling with (E) -2- (2-ethoxyvinyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane using the Suzuki coupling reaction conditions described in scheme 1 then affords compounds of formula (16). (16) Cyclization followed by protection of the nitrogen atom typically affords compounds of formula (17).

(16) The cyclization of (a) can be effected in the presence of an acid such as, but not limited to, acetic acid or hydrochloric acid and at elevated temperatures (e.g., about 50 to about 100 ℃).

Scheme 3

A compound of formula (1) wherein Y¹Is N, R¹⁰¹Is Cl, X¹is-COOR^ax1or-C (O) NR^bx1R^cx1，R^ax1、R^bx1And R^cx1Is hydrogen or C₁-C₆Alkyl radical, and X²For CH, it can be prepared using the synthetic route illustrated in scheme 4.

Treatment of (15) with pyruvic acid in the presence of a palladium catalyst such as, but not limited to, palladium (II) acetate and a base such as, but not limited to, DBU and in a solvent such as, but not limited to, DMF and at elevated temperature (e.g., about 80 to about 150 ℃) typically results in the production of an acid of formula (18). Esterification of (18) to (19) can be achieved by reaction conditions known to those skilled in the art, for example by treatment with an alcohol under acidic conditions. Then, protecting (19) using scheme 2 for the reaction conditions described for converting (8) to (9) can provide a compound of formula (20). The conversion of (20) to (21) can be achieved by stepwise reactions: (a) hydrolysis of the ester to the corresponding acid and (b) conversion of the acid to the corresponding amide.

The acid may be converted to the appropriate acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF at about room temperature and in a suitable solvent such as, but not limited to, tetrahydrofuran or dichloromethane.

The acid chloride obtained can be obtained by using a compound of formula HNR^bx1R^cx1Is converted to the amide of formula (21) in a solvent such as, but not limited to, tetrahydrofuran, dimethylformamide or dichloromethane at a temperature of about room temperature to about 50 ℃, optionally in the presence of a base such as, but not limited to, triethylamine, diisopropylethylamine or potassium carbonate, and optionally in the presence of a catalyst such as 4-dimethylaminopyridine. Alternatively, the acid may be reacted with a compound of formula HNR^bx1R^cx1The amine of (a) is reacted in a solvent such as, but not limited to, tetrahydrofuran or dimethylformamide in the presence or absence of a coupling aid such as, but not limited to, 1-hydroxy-7-azidobenzotriazole (HOAT) or 1-hydroxybenzotriazole Hydrate (HOBT) in the presence of a coupling reagent such as, for example, 1' -Carbonyldiimidazole (CDI), bis (2-oxo-3-oxazolidinyl) hypophosphorylchloride (BOPCl), 1, 3-Dicyclohexylcarbodiimide (DCC), polymer-supported 1, 3-dicyclohexylcarbodiimide (PS-DCC), O- (7-azidobenzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HATU), or O-benzotriazol-1-yl-N, n, N' -tetramethyluronium tetrafluoroborate (TBTU). The reaction can generally be carried out in the presence or absence of a base such as, but not limited to, N-methylmorpholine, triethylamine or diisopropylethylamine.

Scheme 4

Scheme 5 demonstrates the preparation of a compound of formula (1) wherein Y¹Is CR^u，R¹⁰¹Is halogen, X¹is-COOR^ax1or-C (O) NR^bx1R^cx1，R^ax1、R^bx1And R^cx1Is hydrogen or C₁-C₆Alkyl radical, and X²Is a general method of CH.

The ester of formula (23) may be prepared from (a) treatment with diethyl oxalate in the presence of a base such as, but not limited to, potassium ethoxide or sodium ethoxide in a solvent such as, but not limited to, ethanol, dioxane, or diethyl ether and at a temperature of about 40 to about 80 ℃; and (b) cyclizing the resulting (22) in the presence of iron and in ethanol and acetic acid at a temperature of about 80 to about 100 ℃. The conversion of (23) to (26) can be achieved by using the reaction conditions described above.

The ethyl ester of formula (26) may then be hydrolyzed to the corresponding acid. The resulting acid can be converted to the appropriate ester or amide as described in scheme 4.

Scheme 5

The optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants used and the substituents present in the reactants used. Solvents, temperatures and other reaction conditions can be readily selected by one skilled in the art unless otherwise specified. Specific steps are provided in the synthesis examples section. The reaction may be further processed in a conventional manner, for example by removing the solvent from the residue and further purified according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise indicated, starting materials and reactants are commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

Routine experimentation, including appropriate adjustment of reaction conditions, reagents and sequences of synthetic routes, protection of any chemical functional groups, which may not be compatible with the reaction conditions, and deprotection at an appropriate point in the reaction sequence of the process, are included within the scope of the present invention. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples of this are found in T.Greene and P.Wuts, Protecting group Chemical Synthesis (third edition), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the invention may be achieved by methods analogous to those described in the synthetic schemes described above and in the specific examples.

The starting material, if not commercially available, may be prepared by a procedure selected from the group consisting of: standard organic chemistry techniques, techniques analogous to the synthesis of compounds of known structure, or techniques analogous to the procedures described in the schemes above or in the synthetic examples section.

When an optically active form of a compound of the invention is desired, it may be obtained by performing one of the steps described herein using an optically active starting material (e.g. prepared by asymmetric induction of an appropriate reaction step), or by resolving a mixture of stereoisomers of the compound or intermediate using standard procedures (e.g. chromatographic separation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the invention is desired, it may be obtained by performing one of the above steps using the pure geometric isomer as a starting material, or by resolving a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

Pharmaceutical composition

Also provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The phrase "pharmaceutical composition" refers to compositions suitable for administration in medical or veterinary use.

Pharmaceutical compositions containing compound (I) of formula (la), alone or in combination with a second active agent, may be administered to an individual orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccally or as an oral or intranasal spray. The term "parenteral" as used herein refers to routes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

The term "pharmaceutically acceptable carrier" as used herein refers to a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation excipient of any type. Some examples of materials capable of serving as pharmaceutically 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; powdered 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 as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline water; ringer's solution; ethanol and phosphate buffer, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, and coloring agents, releasing agents, coating agents, sweetening, flavoring 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 include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), vegetable oils (e.g., olive oil), injectable organic esters (e.g., ethyl oleate), and suitable mixtures thereof. For example, proper fluidity can be maintained by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersants, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the addition of agents which prolong absorption, such as aluminum monostearate and gelatin.

In some cases, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection in order to prolong the drug effect. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends on its rate of dissolution, which may depend on crystal size and crystal form. Alternatively, prolonged absorption of a parenterally administered drug form is achieved by dissolving or dispersing the drug in an oil medium.

Injectable depot forms are prepared by forming a microcapsule lattice in a biodegradable polymer such as polylactide glycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

For example, the injectable formulations can be sterilized by filtration through a bacterial-retaining filter, or by the addition of a sterilizing agent in the form of a sterile solid composition 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, the solid dosage form may comprise 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 from 5-70% (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) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; 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 glyceryl 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. For capsules, tablets and pills, the dosage forms may also comprise buffering agents.

The pharmaceutical composition may be in unit dosage form. In such forms, 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 tablets, capsules, and powders in vials or ampoules. Moreover, the unit dosage form can be its own capsule, tablet, cachet, or lozenge, or it can be the appropriate number of these in any packaged form. The amount of active ingredient in a unit dose formulation may vary or be adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w/w) of the unit dose, depending on the particular application and potency of the active ingredient. The composition may also contain other suitable therapeutic agents, as desired.

The dosage to be administered to an individual can be determined by the potency of the particular compound used and the condition of the individual as well as the weight or surface area of the individual to be treated. The size of the dose will also be determined by the presence, nature and extent of any adverse side effects that accompany the administration of a particular compound in a particular individual. In determining the effective amount of a compound to be administered in the treatment or prevention of a condition to be treated, a physician can evaluate factors such as circulating plasma levels of the compound, compound toxicity, and/or disease progression, among others. Generally, the dose equivalent of the compound is about 1 μ g/kg to 100 mg/kg for a typical individual.

For administration, a compound of formula I may be administered at a rate determined by factors including, but not limited to, the LD of the compound₅₀The pharmacokinetic profile of the compound, contraindications for drugs and side effects of compounds at different concentrations, is compatible with the weight of the individual and the general health. Administration can be effected in single or divided doses.

The compounds used in the pharmaceutical methods of the present invention may be administered daily at a starting dose of from about 0.001 mg/kg to about 100 mg/kg. In certain embodiments, the daily dose ranges from about 0.1 mg/kg to about 10 mg/kg. However, the dosage may vary according to the individual requirements, the severity of the disease state being treated, and the compound being used. It is within the skill of the practitioner to determine the appropriate dosage for a particular condition. Treatment may be initiated at smaller doses than the optimal dose of the compound. The dose is then increased in small amounts until the optimum effect in this environment is achieved. For convenience, the total daily dose may be divided and given in portions during the day, if desired.

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

Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally comprise opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferably in certain parts of the intestinal tract, optionally in a time-delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

The active compounds can also be in the form of microcapsules, if desired 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 compounds, liquid dosage forms may include inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, 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.

In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may include suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide (aluminum metahydroxide), bentonite, agar-agar, tragacanth, and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention 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.

The compounds of formula I can also be administered in the form of liposomes. Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by single-or multi-layered aqueous liquid crystals dispersed in an aqueous medium. Any non-toxic physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compound of formula (I), the present composition in liposome form can contain stabilizers, preservatives, excipients and the like. Examples of lipids include, but are not limited to, natural and synthetic phospholipids and phosphatidylcholine (lecithin), used alone or together.

Methods of forming liposomes are described, for example, in Prestot, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (l976), p.33 et seq.

Dosage forms for topical administration of the compounds described herein include powders, sprays, ointments and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants which may be required. Ophthalmic formulations, ocular ointments, powders and solutions within the scope of the invention are also contemplated.

Application method

A compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof can be administered to a subject having a bromodomain-mediated disorder or condition. The term "administering" refers to a method of contacting a compound with a subject. Thus, the compounds of formula I may be administered by injection, i.e. intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, parenterally, or intraperitoneally. Furthermore, the compounds described herein may be administered by inhalation, e.g., intranasally. In addition, the compounds of formula I may be administered transdermally, topically, by infusion, transdermally, topically and by infusion. In certain embodiments, the compounds of formula I may be delivered orally. The compounds may also be delivered rectally, buccally, intravaginally, ocularly, andially, or by insufflation. Bromodomain-mediated disorders and disease states compounds of formula I can be used for prophylactic, acute, and chronic treatments depending on the nature of the disorder or disease state. Typically, the host or subject in each of these methods is a human, although other mammals may also benefit from administration of the compounds of formula I.

A "bromodomain-mediated disorder or disease state" is characterized by an initial involvement of one or more bromodomains (e.g., BRD4), indicative of one or more symptoms or disease markers, severity or progression of the disorder or disease state. Thus, compounds of formula I may be used to treat cancer, including but not limited to: auditory neuroma, acute leukemia, acute lymphocytic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelogenous (myelogenous) leukemia, chronic myelogenous leukemia, colon carcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, poorly proliferative changes (dysplasia and metaplasia), embryonic carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal carcinoma, neuroblastoma, colorectal carcinoma, chondrosarcoma, neuroblastoma, melanoma, neuroblastoma, and myelogenous leukemia, Estrogen receptor positive breast cancer, essential thrombocythemia, ewing's sarcoma, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma (lymphoblastiiosarcoma), lymphatic sarcoma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus malignancies and hyperproliferative disorders, T-cell or B-cell derived lymphoid malignancies, leukemia, lymphoma, myeloid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, neuroblastoma, lymphoma, neuroblastoma, melanoma, neuroblastoma, lymphoma, melanoma, neuroblastoma, lymphoma, melanoma, neuroblastoma, melanoma, Myeloma, myxosarcoma, neuroblastoma, NUT Midline Carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous adenocarcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid carcinoma, primary macroglobulinemia, testicular tumor, uterine cancer, and wilms tumor.

Further, the compounds of formula I may be used to treat pulmonary diseases, inflammatory disease states and autoimmune diseases, including but not limited to: addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcet's disease, bullous skin disease, Chronic Obstructive Pulmonary Disease (COPD), crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysis, inflammatory bowel disease, kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and wegener's granulomatosis.

The compounds of formula I or pharmaceutically acceptable salts thereof may be used for the treatment of AIDS.

Compounds of formula I, or pharmaceutically acceptable salts thereof, may be used to treat chronic kidney disease or conditions, including but not limited to: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal disease, polycystic kidney disease and tubulointerstitial nephritis.

Compounds of formula I, or pharmaceutically acceptable salts thereof, may be used to treat acute kidney injury or disease or condition, including but not limited to: ischemia-reperfusion-induced, cardiotonic and major surgery-induced, percutaneous coronary intervention-induced, radiocontrast-induced, sepsis-induced, pneumonia-induced, and drug intoxication-induced acute kidney injury or disease or condition.

A compound of formula I or a pharmaceutically acceptable salt thereof may be used to treat obesity, dyslipidemia, hypercholesterolemia, alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy.

The compound of formula I or a pharmaceutically acceptable salt thereof may be used to provide male contraception in a male subject, comprising administering to a male subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of formula I may be co-administered to a subject. The term "co-administration" refers to the administration of two or more different agents or treatments (e.g., radiation therapy) by combined administration to an individual in the same pharmaceutical composition or in separate pharmaceutical compositions. Thus, co-administration involves the simultaneous administration of a single pharmaceutical composition comprising two or more agents, or the administration of two or more different compositions to the same individual at the same or different times.

The compounds of the invention may be administered to treat cancer with a therapeutically effective amount of one or more agents, examples of which include, for example, radiation, alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis promoter (e.g., Bcl-xL, Bcl-w, and Bfl-1) inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell engage) antibodies, antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (Dual variable Domain antibodies), leukemia Virus oncogene homolog (ErbB 2) receptor inhibitors, growth factor inhibitors, Heat Shock Protein (HSP) -90 inhibitors, inhibitors of apoptosis, and the like, Histone Deacetylase (HDAC) inhibitors, hormonal therapy agents, immunological agents, apoptosis protein (IAPs) inhibitors, intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian targets of rapamycin inhibitors, microribonucleic acids, mitogen-activated fine signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate) -ribose polymerase (PARP) inhibitors, platinum chemotherapeutic drugs, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (bromodomain) inhibitors, proteosome inhibitors, purine analogues, pyrimidine analogues, receptor tyrosine kinase inhibitors, retinoid/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like, and combinations of one or more of these agents.

BiTE antibodies are bispecific antibodies that direct T-cells to attack cancer cells by binding two cells simultaneously. The T-cells then attack the target cancer cells. Examples of BiTE antibodies include adalimumab (adecatumumab, MicrometMT 201), blinatumumab (Micromet MT 103), and the like. Without being bound by theory, one of the mechanisms by which T-cells initiate apoptosis of target cancer cells is exocytosis through cytotoxic granule components (including perforin and granzyme B). In this regard, Bcl-2 has been shown to attenuate induction of apoptosis by perforin and granzyme B. These data indicate that inhibition of Bcl-2 enhances T-cell-induced cytotoxic effects when targeting cancer cells (v.r. Sutton, d.l. Vaux and j.a. Trapani, j. of immunology 1997, 158 (12), 5783).

SiRNAs are molecules with endogenous RNA bases or chemically modified nucleotides. This modification does not abolish cellular activity, but results in increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2 '-deoxynucleotides, 2' -OCH-containing groups₃The ribonucleotide of (1), 2 '-F-ribonucleotide, 2' -methoxyethyl ribonucleotide, a combination thereof and the like. sirnas can have different lengths (e.g., 10-200 bps) and structures (e.g., hairpin structures, single/double strands, bulge, gap/space, mismatch) and are processed in cells to provide active gene silencing. Double stranded sirna (dsrna) can have the same number of nucleotides on each strand (blunt end) or asymmetric end (overhang). Overhangs of 1-2 nucleotides may be present on the sense and/or antisense strand, as well as on the 5 '-and/or 3' -end of a given strand.

Multivalent binding proteins are binding proteins that comprise two or more antigen binding sites. Multivalent binding proteins are engineered to have three or more antigen binding sites and are not typically naturally occurring antibodies. The term "multispecific binding protein" refers to a binding protein that is capable of binding two or more related or unrelated targets. A Dual Variable Domain (DVD) binding protein is a tetravalent or multivalent binding protein comprising two or more antigen binding sites. Such DVDs can be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable 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 the DVD Ig contains 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, each antigen binding site involving a total of 6 CDRs in antigen binding. Multispecific DVDs include DVD binding proteins that bind DLL4 and VEGF or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brositallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, cloletazine^®(laromustine, VNP 40101M), cyclophosphamide, dacarbazine (decarbazine), estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), macsfamide, melphalan, dibromomannitol, dibromodulcitol, nimustine, nitrogen mustard N-oxide, ramustine, temozolomide, thiotepa, TRANDA^®(bendamustine), busulfan, rofessifamide, and the like.

Angiogenesis inhibitors include endothelial specific receptor tyrosine kinase (Tie-2) inhibitors, Epidermal Growth Factor Receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, Platelet Derived Growth Factor Receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors, and the like.

Antimetabolites include ALIMTA^®(Pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA^®(Capecitabine), carmofur, Leustat^®(cladribine), clofarabine, cytarabine octadecylphosphate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1- β -D-ribofuranosyl imidazole-4-carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR^®(Gemcitabine), hydroxyurea, ALKERAN^®(melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pirifox (pellitrexol), pentostatin, raltitrexed, ribavirin, 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (triapine), trimetrexate, S-1, thifluzaline, tegafur, TS-1, vidarabine, UFT, and the like.

Antiviral agents 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, pan-aurora kinase inhibitors, and the like.

Bcl-2 protein inhibitors include AT-101 ((-) gossypol), GENASENSE^®(G3139 or oblimersen (Bcl-2-targeted antisense oligonucleotide)), IPI-194, IPI-565, N- (4- (4- ((4 '-chloro (1,1' -biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4- (((1R) -3- (dimethylamino) -1- ((phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT-737), N- (4- (4- ((2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- (((1R) -3- (morpholin-4-yl) -1- ((phenylsulfanyl) methyl) propyl) amino) -3- ((trifluoromethyl) sulfonyl) benzenesulfonamide (ABT-263), GX-070 (obaticlax), ABT-199, and the like.

Bcr-Abl kinase inhibitors includeDASATINIB^®（BMS-354825）、GLEEVEC^®(imatinib), and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flazadol (flavopiridol), GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709, and the like.

COX-2 inhibitors include ABT-963, ARCOXIA^®(Etoricoxib), BEXTRA^®(valdecoxib), BMS347070, CELEBREX^®(celecoxib), COX-189 (lumiracoxib), CT-3, DERAMXX^®(deracoxib), JTE-522, 4-methyl-2- (3, 4-dimethylphenyl) -1- (4-sulfamoylphenyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX X, VIOXY, and combinations thereof^®(rofecoxib), and the like.

The EGFR inhibitor comprises EGFR antibody, ABX-EGF, anti-EGFR immunoliposome, EGF-vaccine, EMD-7200, ERBITUX^®(cetuximab), HR3, IgA antibodies, IRESSA^®(Gefitinib), TARCEVA^®(erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB^®(lapatinib), and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN^®(trastuzumab), TYKERB^®(lapatinib), OMNITARG^®(2C 4, pertuzumab), TAK-165, GW-572016 (ionofarnib), GW-282974, EKB-569, PI-166, dHER2 (HER 2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2 neu bispecific antibody, B7.HER2IgG3, AS HER2 trifunctional bispecific antibody, mAB AR-209, mAB 2B-1, etc.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, vorinostat (SAHA), TSA, valproic acid, and the like.

The HSP-90 inhibitor comprises 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB^®(human recombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009, etc.

The apoptosis protein inhibitor includes HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242, etc.

Antibody drug conjugates include anti-CD 22-MC-MMAF, anti-CD 22-MC-MMAE, anti-CD 22-MCC-DM1, CR-011-vcMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75, and the like.

Death receptor pathway activators include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR 5), such as Apomab, conatumumab, ETR2-ST01, GDC0145 (lexamumab), HGS-1029, LBY-135, PRO-1762, and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors, such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesauritinib), XL019, INCB018424 and the like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059, and the like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus (temsirolimus), ATP-competitive TORC1/TORC2 inhibitors including PI-103, PP242, PP30, Torin 1, and the like.

The non-steroidal anti-inflammatory drug comprises amigisc^®(disalicylate), DOLOBID^®(diflunisal), MOTRIN^®(ibuprofen), ORUDIS^®(ketoprofen), RELAFEN^®(Nabumetone), felden^®(piroxicam), ibuprofen cream, ALEVE^®(naproxen) and NAPROSYN^®(naproxen), VOLTAREN^®(diclofenac), INDOCIN^®(anti-inflammatory pain) CLINORIL^®(sulindac)、TOLECTIN^®(tolmetin), LODINE^®(Etodolac), Toradol^®(ketorolac), DAYPRO^®(oxaprozin), and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

The platinum chemotherapeutic agent comprises cisplatin and ELOXATIN^®(oxaliplatin), eptaplatin, lobaplatin, nedaplatin, parapelatin^®(carboplatin), satraplatin, picoplatin, and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI 3K) inhibitors include wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, 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, AEE-788, ANGIOZYME (angiostatic ribozymes (Boulder, CO.) and Chiron (Emeryville, CA)), axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamide), NEXAVAR^®(sorafenib, BAY 43-9006), pazopanib (GW-786034), vartanib (PTK-787, ZK-222584), SUTENT^®(sunitinib, SU-11248), VEGF trap, ZACTIMA ™ (Vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), an antibody specific to ErbB3, an antibody specific to BSG2, an antibody specific to DLL4, and an antibody specific to C-met.

The antibiotics include the intercalated antibiotics aclarubicin, actinomycin D, amrubicin, anthracycline (annamycin), adriamycin, BLENOXANE^®(bleomycin), daunorubicin, CAELYX^®Or MYOCET^®(Liposomal doxorubicin), elsamitrucin, epirubicin, glarbuiin, ZAVEDOS^®(idabi)Star), mitomycin C, nemorubicin, neocarzinostatin, pelomomycin, pirarubicin, butrycin, stimalamer, streptozotocin, VALSTAR^®(valrubicin), neat stastatin, and the like.

The topoisomerase inhibitor comprises aclarubicin, 9-aminocamptothecin, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR^®(irinotecan hydrochloride), camptothecin, and CARDIOXANE^®(dextro-propyleneimine), difluotecan, edotecarine, elence^®Or PHARMOUBICIN^®(epirubicin), etoposide, irinotecan, 10-hydroxycamptothecin, gemmacetan, lurtotecan, mitoxantrone, rubitecan (orathecin), pirarubicin (pirarbcin), pixantrone, rubitecan, sobuzosin, SN-38, afluposide, topotecan, and the like.

Antibodies include AVASTIN^®(bevacizumab), CD 40-specific antibody, chTNT-1/B, dinoteumab, ERBITIX^®(cetuximab), HUMAX-CD4^®(zanolimumab), IGF 1R-specific antibodies, linotuzumab, PANOREX^®(Eycolub), RENCAREX^®（WX G250）、RITUXAN^®(rituximab), tizimumab (ticilimumab), trastuzumab, type I and type II CD20 antibodies, and the like.

Hormone therapy includes ARIMIDEX^®(anastrozole), AROMASIN^®(exemestane), azoxifene, CASODEX^®(bicalutamide), cettrotide^®(cetrorelix), degarelix, deslorelin, DESOPAN^®(trilostane), dexamethasone, DROGENIL^®(Flutamide), EVISTA^®(raloxifene), AFEMA (fadrozole), FARESTON^®(toremifene), FASLODEX^®(fulvestrant), FEMARA^®(letrozole), fulvestrant, glucocorticoid, hectone^®(Doxercalciferol) RENAGEL^®(sevelamer carbonate), lasofoxifene,Leuprorelin acetate, MEGACE^®(megestrol), MIFEPREX^®(mifepristone), NILANDRON ™ and NOLVADEX^®(tamoxifen citrate), PLENAXIS ™ cells (abarelix), prednisone, PROPECIA^®(finasteride), rilostate, SUPREFACT^®(buserelin), TRELSTRAR^®(luteinizing hormone releasing hormone (LHRH)), VANTAS^®(Histamine implants), VETORYL^®(trilostane or modastane), ZOLADEX^®(fosrelin, goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB 1089, CB 1093), lexacalcitol (KH 1060), fenretinide, PANRETIN^®(Aliviroc acid), ATRAGEN^®(Liposomal retinoic acid), TARGRETIN^®(bexarotene), LGD-1550, and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib (olaparib), KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-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-0052, PR-171, and the like.

Interferons include interferon α, interferon α -2a, interferon α -2b, interferon β, interferon gamma-1 a, activimtone^®(interferon gamma-1 b) or interferon gamma-n 1, combinations thereof, and the like. Other agents include ALFAFERONE^®(IFN- α), BAM-002 (oxidized glutathione), BEROMIN^®(tasolining), BEXXAR^®(Tusimomamab), CAMPATH^®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), dacarbazine, dinil interleukin, epratuzumab, GRANOYTE^®(lengstin), lentinan, leucocytesα interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, morastine, MYLOTARG (gemtuzumab ozogamicin), NEUPOGEN^®(filgrastim), OncoVAC-CL, OVAREX^®(agovozumab), pemtumumab (Y-muHMFG 1), PROVENGE^®(sipuleucel-T), sargaramostim, cilosta, tixi interleukin, THERACYS^®(BCG), ubenimex, VIRULIZIN^®(immunotherapeutic agents, Lorus Pharmaceuticals), Z-100 (Specific substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN^®(aldesleukin), ZADAXIN^®(thymalfasin), ZENAPAX^®(daclizumab), ZEVALIN^®(90Y-ibritumomab) and the like.

The biological response modifier is an agent for changing a defense mechanism or biological response of a living organism, such as survival, growth or differentiation of histiocytes to make them have an antitumor activity, and includes coriolus versicolor polysaccharide, lentinan, sizose, streptolysin PF-3512676 (CpG-8954), ubenimex, and the like.

The pyrimidine analogs include cytarabine (ara C or arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA^®(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR^®(Gemcitabine), TOMUDEX^®(raltitrexed), a TROXATYL ™ region (triacetyl uridine troxacitabine), and the like.

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

The antimitotic agent comprises Barabulin (Batalbulin), epothilone D (KOS-862), N- (2- ((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, and Taxotere^®(docetaxel), PNU100940 (109881), paclitaxel, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic Ebo @)Mycin), and the like.

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

The compounds of the present invention are also useful as radiosensitizers that enhance the efficacy of radiotherapy. Examples of radiation therapy include external beam radiation therapy, teletherapy, brachytherapy and sealed, unsealed source radiation therapy, and the like.

In addition, compounds having formula (I) may be combined with other chemotherapeutic agents such as: ABRAXANE (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN^®(Ad 5CMV-p53 vaccine), ALTOCOR^®Or MEVACOR^®(lovastatin), AMPLIGEN^®(poly I: poly C12U, synthetic RNA), APTOSYN^®(Exishulin), AREDIA^®(pamidronic acid), arglabin, L-asparaginase, atamestan (1-methyl-3, 17-dione-androsta-1, 4-diene), AVAGE^®(tazarotene), AVE-8062 (combretastatin derivative), BEC2 (mitumumab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC^®(cancer vaccine), CELEUK^®(Simon interleukin), CEPLENE^®(Histamine dihydrochloride), Cervarix^®(human papilloma virus vaccine), CHOP^®（C: CYTOXAN^®(cyclophosphamide); h, ADRIAMYCIN^®(hydroxydoxorubicin); vincristine (ONCOVIN)^®) (ii) a P: prednisone), CYPAT ™ regions (cyproterone acetate), combrestatin A4P, DAB (389) EGF (catalytic and translocation domain of diphtheria toxin fused to human epidermal growth factor via His-Ala linker) or TransMID-107R ™ (diphtheria toxin), dacarbazine, actinomycin D, 5, 6-dimethylxanthone-4-acetic acid (DMXAA), eniluracil, EVIZON ™ (squalamine lactate), DIMERICINE^®(T4N 5 liposome emulsion), discodermolide (discodermolide), DX-8951f (irinotecan mesylate), enzastaurin, EPO906 (epothilone B (epithilone B)), GARDASIL^®(tetravalent human papilloma virus (type 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE^®、GENASENSE^®GMK (ganglioside conjugate vaccine), GVAX^®(prostate cancer vaccine), halofuginone, histrelin, hydroxyurea, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintrekin besutox), IL-13-Pseudomonas exotoxin, interferon- α, interferon- γ, JUNOVAN &orMEPACT & (mivampin), lonafarnib, 5, 10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT^®（AE-941）、NEUTREXIN^®(Trimethoxsupraise glucuronate), NIPENT^®(pentostatin), ONCONASE^®(ribonuclease), ONCOPHAGE^®(melanoma vaccine therapy), ONCOVAX^®(IL-2 vaccine), ORATHECIN (rubitecan), OSIDE^®(antibody-based cellular pharmaceuticals), OVAREX^®MAb (murine monoclonal antibody), paclitaxel, PANDIEX ™ (aglycone saponin from ginseng comprising 20(S) -protopanaxadiol (aPPD) and 20(S) -protopanaxatriol (aPPT)), panitumumab, panVAC^®VF (cancer vaccine under study), pemetrexed, PEG interferon A, phenoxadiol, procarbazine, remamastat, REMOVAB^®(Cartotuzumab), REVLIMID^®(lenalidomide), RSR13 (ethacrylonil), SOMATULINE^®LA (lanreotide), SORIATANE^®(acitretin), staurosporine (Streptomyces stellate spore), talabostat (PT 100), TARGRETIN^®(bexarotene), TAXOPREXIN^®(DHA-Taxol), TELCYTA^®(canfosfamide, TLK 286), temilize, TEMODAR^®(temozolomide), timiperfene, thalidomide, THERATOPE^®(STn-KLH), thymitaq (2-amino-3, 4-dihydro-6-methyl-4-oxo-5- (4-pyridylthio) quinazoline dihydrochloride), TNFARADE ™ cells (adenoviral vector: DNA vector containing the gene for tumor necrosis factor- α), TRACLEER ™^®Or ZAVESCA^®(bosentan), vitaminFormic acid (Retin-A), tetrandrine, TRISENOX^®(arsenic trioxide), Virulizin^®Ukrain (alkaloid derivative from celandine plant), vitaxin (anti- α v β 3 antibody), XCYTRIN^®(motoxafen gadolinium), XINLAY ™ polypeptide (atrasentan), XYOTAX ™ polypeptide (polyglutamic acid taxol), YONDELIS^®(Tribetidine), ZD-6126, ZINECARD^®(dexrazoxane), ZOMETA^®(zoledronic acid), zorubicin, and the like.

The compounds of the invention may be administered with a therapeutically effective amount of one or more agents to treat an inflammatory disease or condition, or an autoimmune disease, wherein examples of agents include, for example, methotrexate, tofacitinib, 6-mercaptopurine, azathioprine, mesalamine, olsalazine chloroquine/hydroxychloroquine, penicillamine, gold (intramuscular and oral) malate, azathioprine, colchicine, corticosteroids (oral, inhalation, and topical injection), beta 2 adrenoceptor agonists (albuterol, terbutaline, salmeterol), xanthines (theophylline, aminophylline), cromolyn salt, nedocromil, ketotifen, ipratropium and etodoline, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSs such as ibuprofen, steroids such as prednisolone, phosphodiesterase inhibitors, or the like, Adenosine agonists, anticoagulants, complement inhibitors, adrenergic agents, agents that interfere with signaling via proinflammatory cytokines such as TNF α or IL-1 (e.g., NIK, IKK, p38, or MAP kinase inhibitors), IL-1 converting enzyme inhibitors, T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurine, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75TNF receptor and derivatives p75TNFRIGG (etanercept) and p55TNFRIGG (Lenercept), sIL-1RI, sIL-1RII, sIL-6R), anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, and TGF), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, celecoxib, and, Etanercept, infliximab, adalimumab, certolizumab, tacitumomab, aberrapu, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, aureothiomalate, aspirin, triamcinolone acetonide, naproxen/paracetamol naphthalenesulfonate, folate, naproxone, nataline, piroxicam, etodolac, diclofenac, sodium dichlorophenolate, oxaprozin, oxycodone hydrochloride, dihydrocodeinone bitartrate/paracetamol, diclofenac/misoprostol, fentanyl, anakinra, tramadol hydrochloride, salicylate, sulindac, cyanocobalamin/fa/pyridoxine, paracetamol, sodium alendronate, prednisolone, cortisone, betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin hydrochloride, Glucosamine sulfate (glucosamine sulfate)/chondroitin, amitriptyline hydrochloride, sulfadiazine, oxycodone hydrochloride/paracetamol, olopatadine hydrochloride, misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-18, anti-IL 15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast (Roflumilast), IC-485, CDC-801, S1P1 agonists (e.g., FTY720), PKC family inhibitors (e.g., Ruboxistaurin or AEB-071), and mesupama (Mesopramim). In certain embodiments, the combination comprises methotrexate or leflunomide, and in the case of moderate or severe rheumatoid arthritis, the combination comprises cyclosporine and an anti-TNF antibody as described above.

Non-limiting examples of therapeutic agents for inflammatory bowel disease that may be administered with the compounds of formula (I) of the present invention include the following: budesonide (budenoside); an epidermal growth factor; a corticosteroid; cyclosporine, sulfasalazine; an aminosalicylate; 6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor; mesalazine; oxalazine; balsalazide; an antioxidant; thromboxane inhibitors; an IL-1 receptor antagonist; anti-IL-1 monoclonal antibodies; anti-IL-6 monoclonal antibody; a growth factor; an elastase inhibitor; a pyridyl-imidazole compound; antibodies or antagonists against other human cytokines or growth factors, e.g., TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-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 ligands thereof; methotrexate; cyclosporine; FK 506; rapamycin; mycophenolate mofetil; leflunom; NSAIDs such as ibuprofen; corticosteroids such as prednisolone; a phosphodiesterase inhibitor; an adenosine agonist; an anticoagulant; a complement inhibitor; (ii) an adrenergic agent; agents that interfere with signaling via pro-inflammatory cytokines such as TNF or IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors); inhibitors of IL-1 converting enzyme; (ii) a TNF convertase inhibitor; t cell signaling inhibitors such as kinase inhibitors; (ii) a metalloprotease inhibitor; sulfasalazine; azathioprine; 6-mercaptopurine; an angiotensin converting enzyme inhibitor; soluble cytokine receptors and their derivatives (e.g., soluble p55 or p75TNF receptor, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, and TGF). Preferred examples of therapeutic agents for crohn's disease that may be mixed with the compound of formula (I) include the following: TNF antagonists, for example, anti-TNF antibodies, D2E7 (adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig construct (p75TNFRIGG (etanercept) and p55TNFRIGG (Lenercept)^TM) Inhibitors and PDE4 inhibitors. The compounds of formula (I) may be mixed with corticosteroids, such as budesonide and dexamethasone; sulfasalazine, 5-aminosalicylic acid; oxalazine; and agents that interfere with the synthesis and action of pro-inflammatory cytokines such as IL-1, such as IL-1 convertase inhibitors and IL-1 ra; t cell signaling inhibitors such as tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate/atropine sulfate; loperamide hydrochloride; methotrexate; omeprazole; folic acid; ciprofloxacin/glucose-water; dihydrocodeinone bitartrate/paracetamol; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; henbane sulfate; dolantin hydrochloride; midazolam hydrochloride; oxycodone hydrochloride/paracetamol hydrochlorideStopping pain; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene naphthalenesulfonate; hydrocortisone; a vitamin complex; balsalazide disodium; codeine phosphate/paracetamol; colesevelam hydrochloride; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab, and interferon- γ.

Non-limiting examples of therapeutic agents for multiple sclerosis that may be administered with a compound of formula (I) include the following: a corticosteroid; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-1 a (Avonex)^®(ii) a Biogen); interferon-1 b (Betaseron)^®(ii) a Chiron/Berlex); interferon-n 3 (Interferon Sciences/Fujimoto), Interferon (Alfa Wassermann/J)&J) Interferon 1A-IF (seroo/inlet Therapeutics), pegylated interferon 2b (Enzon/Schering-plus), copolymer 1 (Cop-1; copaxone^®(ii) a Teva Pharmaceutical Industries, Inc.); high pressure oxygen; intravenous immunoglobulin; cladribine; antibodies or antagonists to other human cytokines or growth factors and their receptors such as TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. The compounds of formula (I) may be mixed with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or ligands thereof. The compounds of formula (I) may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunom, S1P1 agonists, NSAIDs such as ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, anticoagulants, complement inhibitors, adrenergic agents, agents that interfere with signaling via pro-inflammatory cytokines such as TNF or IL-1 (e.g., NIK, IKK, P38 or MAP kinase inhibitors), IL-1 convertase inhibitors, TACE inhibitors, T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurine; angiotensin converting enzyme inhibitionAn agent; soluble cytokine receptors and their derivatives (e.g., soluble p55 or p75TNF receptor, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-13, and TGF).

The compound of formula (I) may also be co-administered with a formulation such as alemtuzumab, dronabinol, dallizumab, mitoxantrone, zaritodrine hydrochloride, aminopyridine, glatiramer acetate, natalizumab, sinnabidol, -immunokine NNSO3, ABR-215062, Angrix. MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposomal encapsulated mitoxantrone), THC.CBD (cannabinoids agonists), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibodies, neuromax, pirfenidone allotrap1258 (RDP-1258), sTNF-R1, talampanel (talampanel), teriflunomide (teriflunomide), TGF-beta 2, temozide, VLA-4 antagonists (e.g., TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitis that may be administered with a compound of formula (I) include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocycline, prednisolone and anti-TNF antibodies, D2E7 (HUMIRA)^®) CA2 (infliximab), CDP 571, TNFR-Ig construction, (p75TNFRIGG (ENBREL)^®) And p55TNFRIGG (Lenercept)^®)。

Non-limiting examples of therapeutic agents for asthma that may be administered with the compounds of formula (I) include the following: salbutamol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisolone, salmeterol xinafoate, levosalbutamol hydrochloride, salbutamol sulfate/ipratropium, prednisolone sodium phosphate hydride, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrate, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromoglycten sodium, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanic acid, levofloxacin, inhalation aid, guaifenesin, dexamethasone sodium phosphate, moxifloxacin hydrochloride, doxycycline hyclate, guaifenesin/d-dextromethorphan, p-ephedrine/cod/chrorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe/hydrocodone/chrorphenir, cetirizine HCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenol sulfate.

Non-limiting examples of therapeutic agents for COPD that may be administered with a compound of formula (I) include the following: salbutamol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, salbutamol, salmeterol xinafoate, fluticasone propionate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levosalbutamol hydrochloride, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanic acid, flunisolide/menthol, chlorphenamine/hydrocodone, metaproterenol sulfate, mometasone furoate, p-ephedrine/cod/chrorph, pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate, Tiotropium bromide, (R, R) -formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for psoriasis that may be administered with a compound of formula (I) include the following: calcipotriol, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, amplified beclomethasone dipropionate, fluocinonide, acitretin, tar shampooo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone acetonide, hydrocortisone valerate, fluocinolone acetonide, urea, betamethasone, clobetasol/emoll propionate, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula (mourtizing fomula), folic acid, desonide, pimecrolimus, coal tar, diflorasone acetate, etanercept folate, lactic acid, methoxsalen, hc/bismuth subgallate/znox/resx/resor, methylprednisolone acetate, prednisone, sunscreen, sikaneder, salicylic acid, dithranol, clocortolone valerate, coal extract, coal tar/salicylic acid, Coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollients, fluocinonide/emollients, mineral oil/castor oil/na lactt, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromosalen, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alfacaept, efacapt, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and usteka.

Non-limiting examples of therapeutic agents for psoriatic arthritis that may be administered with a compound of formula (I) include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, amplified beclomethasone dipropionate, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethyl sulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, aureothiomalate, dihydrocodeinone bitartrate/paracetamol, ibuprofen, risedronate sodium phosphate, sulfadiazine, thioguanine, valdecoxib, alfacamide, D2E7 (adalimumab), and efacizumab.

Can be administered with a compound of formula (I)Preferred examples of therapeutic agents for sle (lupus) include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, such as celecoxib, rofecoxib, valdecoxib; antimalarial drugs such as hydroxychloroquine; steroids, such as prednisone, prednisolone, budesonide, dexamethasone; cytotoxins, such as azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; PDE4 inhibitors or purine synthesis inhibitors, such as Cellcept ®. The compound of formula (I) may also be admixed with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran @, and agents that interfere with the synthesis, production or action of pro-inflammatory cytokines such as IL-1, for example caspase inhibitors such as IL-1 convertase inhibitors and IL-1 ra. The compounds of formula (I) may also be used with T cell signalling inhibitors, such as tyrosine kinase inhibitors; or molecules targeting T cell activating molecules, such as CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family antibodies. The compounds of formula (I) may be mixed with IL-11 or anti-cytokine antibodies, such as aryltuzumab (anti-IFNg antibody), or anti-receptor antibodies, such as anti-IL-6 receptor antibody and B-cell surface molecule antibody. The compounds of formula (I) can also be used with LJP 394 (abelimus), preparations which deplete or inactivate B-cells such as rituximab (anti-CD 20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists such as anti-TNF antibody, D2E7 (adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig construct, (p75TNFRIGG (etanercept) and p55TNFRIGG (Lenercept)^TM) Are used together.

The compounds of the present invention may also be administered with a therapeutically effective amount of one or more agents useful in the prevention or treatment of AIDS, examples of which include HIV reverse transcriptase inhibitors, HIV protease inhibitors, immunomodulators, and other retroviral agents. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir, adefovir, didanosine, delavirdine ester (dipivoxil delavirdine), efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine, and zidovudine. Examples of protease inhibitors include, but are not limited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Examples of other antiviral agents include, but are not limited to, entecavir, enfuvirdine, maraviroc, and raltegravir.

The compounds of the present invention may also be administered with a therapeutically effective amount of one or more agents for the prevention or treatment of type II diabetes, fatty liver, insulin resistance, metabolic syndrome, and related conditions, examples of which include, but are not limited to, insulin and insulin that has been modified to improve in vivo duration of action; agents that stimulate insulin secretion, such as acetohexamide, chlorpropamide, glyburide, glimepiride, glipizide, gliclazide, glipiride, gliquidone, repaglinide, nateglinide (nateglinide), tolazamide, and tolbutamide; formulations which are glucagon-like peptide agonists, such as exenatide (exenatide), liraglutide (liraglutide) and taspoglutide (taspoglutide); agents that inhibit dipeptidyl-peptidase IV, such as vildagliptin, sitagliptin, saxagliptin, linagliptin, alolitin (allogliptin), and septiagliptin; agents linked to the peroxisome proliferator activated receptor gamma, such as rosiglitazone and pioglitazone; agents that reduce insulin resistance, such as metformin; agents that reduce glucose absorption in the small intestine, such as acarbose, miglitol and voglibose.

The compounds of the present invention may be administered with a therapeutically effective amount of one or more agents for preventing or treating acute and chronic kidney disease, wherein examples of agents include, but are not limited to, dopamine, diuretics such as furosemide, bumetanide, thiazine, and the like, mannitol, calcium gluconate, sodium bicarbonate, salbutamol, paricalcitol, doxercalciferol, cinacalcet (cinacalcet), and bardoxolone methyl.

The compounds of the present invention may be administered with a therapeutically effective amount of one or more agents useful for providing male contraception in a male subject.

The following embodiments may be used for illustrative purposes and should not be taken as narrowing the scope of the present invention.

Examples

Example 1

6-methyl-4- (2-phenoxyphenyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 1a

(E) -2- (5-bromo-2-methoxy-3-nitropyridin-4-yl) -N, N-dimethylethylamine

5-bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) was dissolved in dimethylformamide (300 mL) and lithium methoxide (6.07 mL, 6.07 mmol, 1M) was added. The reaction mixture was heated to 100 ℃. To the mixture was added 1, 1-dimethoxy-N, N-dimethylmethylamine (64.5 mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95 ℃ for 16 hours. The reaction mixture was cooled to room temperature and water (300 mL, exothermic) was carefully added. The resulting precipitate was collected by vacuum filtration, washed with water, and dried to provide the title compound (13.9 g, 45.9 mmol, 76% yield).

Example 1b

4-bromo-7-methoxy-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 at 30 psi at room temperature for 30 min. The reaction mixture was filtered and concentrated. The residue was triturated with dichloromethane and the solid filtered to give the title compound (5.82 g). The mother liquor was evaporated and the residue triturated again with dichloromethane and filtered to provide a further 1.63 g of the title product. Total yield = 7.45 g, 72% yield.

Example 1c

4-bromo-7-methoxy-1-tosyl-1H-pyrrolo [2,3-c ] pyridine

A solution of example 1b (7.42 g, 32.7 mmol) in dimethylformamide (235 mL) was stirred at room temperature. To this solution was added sodium hydride (1.18 g, 1.96 g of a 60% oil dispersion, 49.0 mmol) and the reaction mixture was stirred for 10 minutes. Then p-toluenesulfonyl chloride (9.35 g, 49.0 mmol) was added in portions, and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was carefully quenched with water and 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 ℃ to provide 12.4 g (100%) of the title compound.

Example 1d

4-bromo-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A solution of example 1c (12.4 g, 32.6 mmol) in dioxane (140 mL) was stirred at room temperature. To this solution was added 4M HCl/dioxane (140 mL). The reaction mixture was stirred at 40 ℃ for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with ether, filtered, washed with additional ether and dried to provide the title compound as a beige solid (11.23 g, 30.6 mmol, 94% yield).

Example 1e

4-bromo-6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Sodium hydride (0.875 g, 36.5mmol, 1.46 g of a 60% oil dispersion) was added to a stirred solution of example 1d (11.2 g, 30.4 mmol) in dimethylformamide (217 mL) under nitrogen. After 30 min, iodomethane (2.27 mL, 36.5mmol) was added and the solution was stirred at room temperature for 3 h. Upon addition of water (250 mL), a precipitate formed. The precipitate was collected by vacuum filtration, washed with water (50mL) and dried in a vacuum oven at 55 ℃ overnight to provide 11.2 g of the title compound (96%).

Example 1f

6-methyl-4- (2-phenoxyphenyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 1e (152 mg, 0.40 mmol), 2-phenoxyphenylboronic acid (0.111 g, 0.520 mmol, 1.3 equiv.), Pd (PPh) were heated under microwave conditions (120 ℃ C., 30 minutes)₃)₄(0.023 g, 5 mol%) and cesium fluoride (0.182 g, 1.2 mmol) in a mixture of DME (3 mL) and methanol (1.5 mL). To the mixture was added potassium carbonate (0.055g, 0.40 mmol) and water (1mL), and the reaction mixture was heated again in a microwave oven at 120 ℃ for another 2 hours. The organic layer was separated and purified by flash chromatography (silica gel, ethyl acetate). The resulting material was triturated with acetone and filtered to provide 0.075 g of the title compound (59%).

Example 2

6-methyl-4- (5-nitro-2-phenoxyphenyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 2a

4- (2-fluoro-5-nitrophenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Method A:

In DME (7 mL) and water (7 mL) at 20mL microExample 1e (0.687 g, 1.802mmol), 2-fluoro-5-nitrophenylboronic acid (0.500 g, 2.70 mmol), Pd (PPh) were mixed in a wave tube₃)₄(0.104 g, 0.090 mmol) and sodium carbonate (2.70 mL, 5.41 mmol), sealed, sparged with nitrogen and heated under microwave at 120 ℃ for 30 minutes. The mixture was partitioned between EtAOc and water. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 0-100% ethyl acetate/hexanes) to provide 0.41 g (52%) of the title compound.

Method B:

Example 1e (6.00 g, 15.7mmol), 2-fluoro-5-nitrophenylboronic acid (5.82 g, 31.5 mmol), Pd (PPh) were combined in toluene (60 mL), ethanol (15 mL) and water (15 mL)₃)₄(0.909 g, 0.787 mmol) and sodium carbonate (3.34 g, 31.5 mmol), and the mixture was degassed and placed under nitrogen. The reaction mixture was heated at 90 ℃ overnight and then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried (MgSO)₄) Filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 20-50% ethyl acetate/hexanes) to provide 6.95 g (61%) of the title compound.

Example 2b

Phenol (0.094 g, 0.997 mmol), example 2a (0.4 g,0.906 mmol) and cesium carbonate (0.325 g, 0.997 mmol) were mixed in DMSO (4.53 mL) and heated at 100 ℃ for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the pH was adjusted to pH 7. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated. Purification by flash chromatography (silica gel, 0-4% methanol/dichloromethane) gave 0.28 g (84%) of the title compound.

Example 3

4- (5-amino-2-phenoxyphenyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 2b (0.25 g, 0.692mmol), iron powder (0.193 g, 3.46 mmol) and ammonium chloride (0.056 g, 1.038 mmol) were mixed in tetrahydrofuran (6 mL), ethanol (6 mL) and water (2 mL). The mixture was heated at 95 ℃ for 1.5 hours with vigorous stirring. The reaction mixture was cooled to room temperature and filtered through a pad of celite to remove solids. The pad was repeatedly rinsed with methanol and tetrahydrofuran. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography (silica gel, 1-4% methanol/dichloromethane) to give 0.21 g (82%) of the title compound.

Example 4

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] methanesulfonamide

Method A:

To a solution of example 3 (0.125 g, 0.377 mmol) and triethylamine (0.131 mL, 0.943 mmol) in dichloromethane (3.0 mL) was added dropwise methanesulfonyl chloride (0.064 mL, 0.830 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated. The residue was dissolved in a mixture of dioxane (5 mL) and 1M sodium hydroxide (2mL) and heated at 90 ℃ for 1 hour. The reaction mixture was cooled and diluted with ethyl acetate, brought to pH 7 with 1M HCl and the layers separated. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-4% methanol/dichloromethane) to give 0.20 g (77%) of the title compound.

Method B:

The product of example 7d (1.127 g, 2mmol), potassium hydroxide (1.82 g, 52.5 mmol) and cetyltrimethylammonium bromide (0.036 g, 0.100 mmol) were mixed in tetrahydrofuran (15.00 mL) and water (5.00 mL) and the mixture was heated at 100 ℃ for 14 h. The reaction mixture was partitioned between equal volumes of EtOAc and water and the pH was adjusted to pH 7 by careful addition of concentrated HCl. The organic layer was separated, washed three times with saturated brine and dried (Na)₂SO₄) And concentrated. Purification by trituration in dichloromethane afforded the title compound (0.76 g, 93%).

Example 5

2,2, 2-trifluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] ethanesulfonamide

To a solution of example 3 (0.05 g, 0.151 mmol) and triethylamine (0.053 mL, 0.377 mmol) in dichloromethane (1.0mL) was added 2,2, 2-trifluoroethanesulfonyl chloride (0.036 g, 0.196 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour and then purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to give 0.050 g (68%) of the title compound.

Example 6

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] acetamide

Example 6a

6-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 1e (6.55 g, 17.2 mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2 '-bis (1,3, 2-dioxaborolane) (8.73 g, 34.4 mmol), potassium acetate (3.71 g, 37.8 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.393 g, 0.430 mmol) and 2-dicyclohexylphosphonium-2', 4', 6' -triisopropylbiphenyl (X-PHOS, 0.819 g, 1.72 mmol) were mixed and sparged with argon for 1 hour with stirring. Dioxane (86mL) was sparged with nitrogen for 1 hour, transferred through a conduit to the solid component under nitrogen, and the mixture was heated at 80 ℃ under argon for 5 hours. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water, and filtered through celite. The ethyl acetate layer was washed twice with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by chromatography (silica gel, 25-80% ethyl acetate/hexane). The resulting material from chromatography was triturated with a minimum amount of hexane (30mL) and the particulate solid collected by filtration, washed with a minimum amount of hexane and dried to constant weight to give the title compound (5.4 g, 73%).

Example 6b

N- (3-bromo-4-phenoxyphenyl) acetamide

Example 7b (0.2 g, 0.757 mmol) and acetic anhydride (1mL, 10.60mmol) were mixed in a 5 mL microwave tube, sealed, and heated under microwave at 100 ℃ for 30 minutes. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to give the title compound (0.22 g, 95%).

Example 6c

N- (3- (6-methyl-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl) acetamide

Example 6a (0.07 g,0.163 mmol), example 6b (0.075 g, 0.245 mmol), tetrakis (triphenylphosphine) palladium (0) (9.44 mg, 8.17 μmol) and sodium carbonate (2.0M, 0.245 mL, 0.490 mmol) were mixed in DME (0.817 mL) and water (0.817 mL) in a 5 mL microwave tube, sealed, sparged with nitrogen and heated at 120 ℃ for 30 minutes under microwave. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) gave the title compound (0.048 g, 56%).

Example 6d

Example 6c (0.048 g,0.091 mmol) and potassium carbonate (0.044 g, 0.318 mmol) were mixed in a 2mL microwave tube in methanol (2mL) and water (0.200 mL), sealed, and heated under microwave at 110 ℃ for 30 minutes. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water and the pH was adjusted to 6 with 1M HCl. The organic layer was separated and concentrated. Purification by flash chromatography (silica gel, 0-4% methanol/dichloromethane) gave 0.018 g (53%) of the title compound.

Example 7

N- (3- { 6-methyl-1- [ (4-methylphenyl) sulfonyl ] -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl } -4-phenoxyphenyl) methanesulfonamide

Example 7a

2-bromo-4-nitro-1-phenoxybenzene

2-bromo-1-fluoro-4-nitrobenzene (2.5 g, 11.4 mmol), phenol (1.28 g, 13.6 mmol) and cesium carbonate (4.44 g, 13.6 mmol) were mixed in dimethyl sulfoxide (140 mL) and heated to 110 ℃ for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The combined organics were washed with brine and dried (MgSO)₄) Filtered and concentrated to give the title compound.

Example 7b

3-bromo-4-phenoxyaniline

Example 7a (3.43 g,11.7 mmol), iron powder (3.26 g, 58.4 mmol) and ammonium chloride (1.25 g, 23.4 mmol) were combined in ethanol (50mL), tetrahydrofuran (50mL) and water (16.7 mL) and heated at 100 ℃ for 2 hours. The reaction mixture was cooled to just below reflux, filtered through celite in vacuo, the filter cake was washed with hot methanol (3 × 35 mL), and the filtrate was concentrated under reduced pressure. The residue was taken up in saturated NaHCO₃The layers were separated between aqueous solution and ethyl acetate (3 × 125 mL). The combined organics were washed with brine and dried (MgSO)₄) Gravity filtration, followed by concentration gave the title compound.

Example 7c

N- (3-bromo-4-phenoxyphenyl) methanesulfonamide

Example 7b (2.86 g, 10.8 mmol) and triethylamine (6.03 mL, 43.3 mmol) were stirred in dichloromethane (48.1 mL) at ambient temperature. Methanesulfonyl chloride (2.53 mL, 32.4 mmol) was added dropwise and the solution stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dioxane (24 mL) and sodium hydroxide (10% w/v, 12mL, 0.427 mmol) were added and the solution was heated to 70 ℃ for 1h. With saturated NH₄The solution was neutralized to pH 7 with aqueous Cl (200 mL). The aqueous phase was extracted with ethyl acetate (3 × 125 mL). The combined organics were washed with brine and dried (MgSO)₄) Filtered and then concentrated. The residue was purified by flash chromatography (silica gel, 0-25% ethyl acetate/hexanes, gradient) to give the title compound.

Example 7d

Example 6a (0.670 g, 1.564 mmol), example 7c (0.562 g, 1.643 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.036 g, 0.039 mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (0.023 g, 0.078 mmol) and tripotassium phosphate (1.03 g, 4.85 mmol) were combined and sparged with argon for 30 minutes. The 4:1 dioxane/water (10mL total volume) solution was sparged with nitrogen for 30 minutes and transferred via syringe to the reaction vessel under argon. The reaction mixture was stirred at 60 ℃ for 2 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried (Na)₂SO₄) Treated with 3-mercaptopropyl-functionalized silica gel (Aldrich, 538086-100G) for 45 minutes, filtered and concentrated. Purification by chromatography (silica gel, 20-100% ethyl acetate/hexanes) gave 0.68 g (74%) of the title compound.

Example 8

N-methyl-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] methanesulfonamide

Example 7d (0.113 g, 0.2 mmol) and potassium carbonate (b 2mmol) were heated at 100 ℃0.111 g, 0.800mmol) of methanol (0.9 mL) and water (0.1 mL) for 1 hour. The reaction was partitioned between ethyl acetate and water and the pH was adjusted to 7. The organic layer was separated and dried (Na)₂SO₄) Filtered and concentrated. By reverse phase HPLC (C18,10-100% CH)₃CN/water (0.1% TFA)) to purify the residue to give the title compound (0.012g, 14%).

Example 9

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzoic acid ethyl ester

Example 9a

4-fluoro-3- (6-methyl-7-oxo-1-toluenesulfonyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoic acid ethyl ester

Example 1e (1.33 g, 3.5 mmol), 5- (ethoxycarbonyl) -2-fluorophenylboronic acid (1.04 g,4.9 mmol), Pd (PPh)₃)₄A mixture of (0.20 g, 5 mol%) and sodium carbonate (0.742 g, 7.0 mmol) in toluene (12 mL), ethanol (3 mL) and water (3 mL) was degassed and stirred under nitrogen. The reaction mixture was heated at 90 ℃ for 24 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20-50% ethyl acetate/hexanes) to give 1.43 g (87%) of the title compound.

Example 9b

A mixture of example 9a (1.43 g, 3.05 mmol), phenol (.0344 g, 3.66 mmol) and cesium carbonate (0.995, 3.05 mmol) in DMSO (15 mL) was heated at 110 ℃ for 12 h. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 30-80% ethyl acetate/hexanes) to give 0.85 g (72%) of the title compound.

Example 10

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzoic acid

A mixture of example 9b (0.23 g, 0.59 mmol) and sodium hydroxide (0.89 mL of a 2.0M aqueous solution) in dioxane (10mL) was heated at 60 ℃ for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). After addition of concentrated HCl (5 mL), the mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated to give 0.21 g (98%) of the title compound.

Example 11

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (pyridin-3-yloxy) phenyl ] methanesulfonamide

Example 11a

6-methyl-4- (5-nitro-2- (pyridin-3-yloxy) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparation example 11a was prepared according to the procedure used for preparation example 2b, substituting pyridine-3-ol for phenol to provide the title compound.

Example 11b

4- (5-amino-2- (pyridin-3-yloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 11b was prepared according to the procedure used to prepare example 3, substituting example 11a for example 2b to provide the title compound.

Example 11c

Example 11C was prepared according to the procedure used for method a of example 4, example 11b was substituted for example 3, and purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound as a TFA salt.

Example 12

6-methyl-4- [2- (morpholin-4-ylmethyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparative example 12 was prepared according to the procedure used for preparative example 1f, substituting 2- (morpholinomethyl) phenylboronic acid for 2-phenoxyphenylboronic acid, followed by purification by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound as a TFA salt.

Example 13

N-ethyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide

Example 13a

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzoyl chloride

A solution of example 10(0.24 g, 0.67 mmol) in dichloromethane (10mL) was treated with oxalyl chloride (0.17g, 1.33 mmol) and dimethylformamide (5 mg, 10 mol%). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the title compound (0.25 g, quantitative).

Example 13b

A solution of example 13a (0.040 g,0.11 mmol) in tetrahydrofuran (1mL) was treated with ethylamine (0.21 mL of a 2M solution in tetrahydrofuran, 0.42 mmol) for 2 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (C18, 10-90% acetonitrile/0.1% TFA/water) to give the title compound (0.025 g, 61%).

Example 14

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxy-N- (tetrahydrofuran-2-ylmethyl) benzamide

Example 14 was prepared according to the procedure used for the preparation of example 13b, substituting (tetrahydrofuran-2-yl) methylamine for ethylamine and dichloromethane for tetrahydrofuran, respectively, to provide the title compound.

Example 15

N-cyclopentyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide

Example 15 was prepared according to the procedure used for the preparation of example 13b, substituting cyclopentylamine for ethylamine and dichloromethane for tetrahydrofuran, respectively, to provide the title compound.

Example 16

N- (2, 2-difluoroethyl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide

Example 16 was prepared according to the procedure used for the preparation of example 13b substituting 2, 2-difluoroethylamine for ethylamine and dichloromethane for tetrahydrofuran respectively to provide the title compound.

Example 17

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxy-N- (1, 3-thiazol-2-yl) benzamide

Example 17 was prepared according to the procedure used for the preparation of example 13b substituting ethylamine with thiazol-2-amine and tetrahydrofuran with dichloromethane to provide the title compound, respectively.

Example 18

N- (1, 1-Tetrahydrothiophene-3-yl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide

Preparation of example 18 following the procedure used for preparation of example 13b substituting 1, 1-tetrahydrothiophen-3-ylamine for ethylamine and dichloromethane for tetrahydrofuran, respectively, provided the title compound.

Example 19

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzamide

Example 19 was prepared according to the procedure used for the preparation of example 13b substituting aqueous ammonium hydroxide for ethylamine to provide the title compound.

Example 20

4- [5- (hydroxymethyl) -2-phenoxyphenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 20a

3- (6-methyl-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzoic acid ethyl ester

Example 20a was prepared according to the procedure used to prepare example 1c, substituting example 9b for example 1b to provide the title compound.

Example 20b

Example 20a (0.32 g, 0.59 mmol) in tetrahydrofuran (5 mL) was cooled to 0 ℃. To this solution was added 1.0N lithium aluminum hydride (0.59 mL, 0.59 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 2.0N HCl (5 mL) and then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50-100% ethyl acetate/hexanes to give 0.08 g (39%) of the title compound.

Example 21

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] ethanesulfonamide

Example 21 was prepared according to the procedure used for method a of example 4 substituting ethanesulfonyl chloride for methanesulfonyl chloride to provide the title compound.

Example 22

N, N-dimethyl-N' - [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] sulfamide

Example 22 was prepared according to the procedure used for method a of example 4 substituting dimethylsulfamoyl chloride for methanesulfonyl chloride to provide the title compound.

Example 23

N- [5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6-phenoxypyridin-3-yl ] methanesulfonamide

Example 23a

3-bromo-5-nitro-2-phenoxypyridine

Phenol (0.416 g, 4.42 mmol), 3-bromo-2-chloro-5-nitropyridine (Combi-Blocks, CAS [5470-17-7 ] were mixed in DMSO (8 mL)]1g, 4.21 mmol) and cesium carbonate (1.372 g, 4.21 mmol) and heated at 80 ℃ for 30 minutes. ColdThe reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to give the title compound (1.13 g, 91%).

Example 23b

6-methyl-4- (5-nitro-2-phenoxypyridin-3-yl) -1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 23b was prepared according to the procedure used to prepare example 7d, the product of example 7c was replaced with the product of example 23a and stirred at 60 ℃ for 24 hours to provide the title compound.

Example 23c

4- (5-amino-2-phenoxypyridin-3-yl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 23c was prepared according to the procedure used to prepare example 3, substituting the product of example 23b for the product of example 2 to provide the title compound.

Example 23d

Example 23d was prepared according to the procedure used in method a of example 4 substituting the product of example 23c for the product of example 3 to provide the title compound (0.035 g, 36%).

Example 24

N- [ 3-fluoro-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] methanesulfonamide

Example 24a

4- (2, 3-difluoro-5-nitrophenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 24a was prepared according to the procedure used to prepare example 7d, substituting 1-bromo-2, 3-difluoro-5-nitrobenzene (Oakwood Products) for the product of example 7c to provide the title compound.

Example 24b

4- (3-fluoro-5-nitro-2-phenoxyphenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Phenol (0.043 g, 0.457 mmol), example 24a (0.2 g,0.435 mmol) and cesium carbonate (0.142 g,0.435 mmol) were mixed in DMSO (2.177 mL) and heated at 80 ℃ for 30 min. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated to give the title compound.

Example 24c

4- (5-amino-3-fluoro-2-phenoxyphenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 24c was prepared according to the procedure used to prepare example 3, substituting the product of example 24b for the product of example 2 to provide the title compound.

Example 24d

Example 24d was prepared according to the procedure used in method a of example 4 substituting the product of example 24c for the product of example 3 to provide the title compound (0.13 g, 67%).

Example 25

N- [4- (2-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 25a

2- (2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-nitrophenoxy) benzonitrile

Preparation example 25a was prepared according to the procedure used for preparation example 2b, substituting 2-hydroxybenzonitrile for phenol to provide the title compound.

Example 25b

2- (4-amino-2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy) benzonitrile

Example 25b was prepared according to the procedure used to prepare example 3, substituting the product of example 25a for the product of example 2b to provide the title compound.

Example 25c

Example 25c was prepared according to the procedure used for method a of example 4 substituting the product of example 25b for the product of example 3 to provide the title compound.

Example 26

N- [4- (4-fluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 26a

4- (2- (4-fluorophenoxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparation example 26a was prepared according to the procedure used for preparation example 2b, substituting 4-fluorophenol for phenol to provide the title compound.

Example 26b

4- (5-amino-2- (4-fluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 26b was prepared according to the procedure used to prepare example 3, substituting the product of example 26a for the product of example 2b to provide the title compound.

Example 26c

Example 26c was prepared according to the procedure used for method a of example 4 substituting the product of example 26b for the product of example 3 to provide the title compound.

Example 27

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 27a

4- (2- (2, 4-Difluorophenoxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 27a was prepared according to the procedure used for the preparation of example 2b substituting 2, 4-difluorophenol for phenol to provide the title compound.

Example 27b

4- (5-amino-2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 27b was prepared according to the procedure used to prepare example 3, substituting the product of example 27a for the product of example 2b to provide the title compound.

Example 27c

In CH₂Cl₂Example 27b (50 mg, 0.136 mmol) and triethylamine (0.057 mL,0.408 mmol) were mixed (9 mL). Methanesulfonyl chloride (0.042 mL, 0.544 mmol) was added dropwise) And the solution was stirred at ambient temperature for 1 hour. The solution was concentrated under reduced pressure, dioxane (5 mL) and sodium hydroxide (10% w/v, 3mL, 0.136 mmol) were added and the solution was heated at 70 ℃ for 1 hour. The mixture was cooled to ambient temperature and then saturated NH₄Cl (100 mL) was neutralized to pH 8. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine and dried (MgSO)₄) Filtered and concentrated. Purification by reverse phase HPLC (C18,10-100% acetonitrile/water, 0.1% TFA) gave 27.5 mg (45.4%) of the title compound.

Example 28

N- [ 3-chloro-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxyphenyl ] methanesulfonamide

Example 28a

4- (3-chloro-2-fluoro-5-nitrophenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Prepare example 28a according to the procedure used to prepare example 6c, replace the product of example 6b with 1, 3-dichloro-2-fluoro-5-nitrobenzene (0.176 g, 0.841 mmol) to provide the title compound.

Example 28b

Example 28b was prepared according to the procedure used to prepare examples 24b-24d, substituting example 28a for the product of example 24a to provide the title compound.

Example 29

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] methanesulfonamide

Example 29a

6-methyl-4- (5-nitro-2- (tetrahydro-2H-pyran-4-yloxy) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A solution of tetrahydro-2H-pyran-4-ol (0.046 g, 0.453 mmol) in tetrahydrofuran (2mL) was treated with sodium hydride (0.022g, 0.906 mmol, 0.036 g of a 60% oil dispersion) at room temperature. The reaction mixture was stirred for 10 minutes. To this solution was added example 2a (0.1 g. 0.227 mmol). The reaction mixture was heated at 50 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give 0.055g of the title compound.

Example 29b

4- (5-amino-2- (tetrahydro-2H-pyran-4-yloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A mixture of example 29b (0.055g) and 10% palladium on carbon (0.050 g) in ethyl acetate (10mL) was treated with hydrogen balloon overnight. The solids were removed by filtration. The filtrate was concentrated under reduced pressure to give 0.042 g of the title compound.

Example 29c

Example 29c was prepared according to the procedure used for method a of example 4 substituting the product of example 29b for the product of example 3 to provide the title compound.

Example 30

6-methyl-4- [ 2-phenoxy-5- (1H-pyrazol-1-ylmethyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

A mixture of example 20b (0.04 g, 0.115 mmol), 1H-pyrazole (0.016 g, 0.231 mmol) and triphenylphosphine (0.061 g, 0.231 mmol) in tetrahydrofuran (1mL) was stirred for 2 min. To this solution was added di-tert-butyl azodicarboxylate (DTBAD, 0.053 g, 0.231 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (C18, 10-80% acetonitrile/water with 0.1% TFA) to give 0.006 g of the title compound.

Example 31

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydrofuran-3-yloxy) phenyl ] methanesulfonamide

Example 31a

6-methyl-4- (5-nitro-2- (tetrahydrofuran-3-yloxy) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparation example 31a was prepared according to the procedure used for preparation example 29a, replacing tetrahydro-2H-pyran-4-ol with tetrahydrofuran-3-ol to provide the title compound.

Example 31b

4- (5-amino-2- (tetrahydrofuran-3-yloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 31b was prepared according to the procedure used to prepare example 29b, substituting the product of example 31a for the product of example 29a to provide the title compound.

Example 31c

Example 31 was prepared according to the procedure used for method a of example 4 substituting the product of example 31b for the product of example 3 to provide the title compound.

Example 32

N- {3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- [2- (trifluoromethyl) phenoxy ] phenyl } methanesulfonamide

Example 32a

6-methyl-4- (5-nitro-2- (2- (trifluoromethyl) phenoxy) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparative example 32a was prepared according to the procedure used for preparative example 2b substituting 2- (trifluoromethyl) phenol for phenol to provide the title compound.

Example 32b

4- (5-amino-2- (2- (trifluoromethyl) phenoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 32b was prepared according to the procedure used to prepare example 3, substituting the product of example 32a for the product of example 2b to provide the title compound.

Example 32c

Example 32c was prepared according to the procedure used for method a of example 4 substituting the product of example 32b for the product of example 3 to provide the title compound.

Example 33

N- [4- (4-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 33a

4- (2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-nitrophenoxy) benzonitrile

Preparation example 33a was prepared according to the procedure used for preparation example 2b, substituting 4-hydroxybenzonitrile for phenol to provide the title compound.

Example 33b

4- (4-amino-2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy) benzonitrile

Example 33b was prepared according to the procedure used to prepare example 3, substituting the product of example 33a for the product of example 2b to provide the title compound.

Example 33c

Example 33c was prepared according to the procedure used for method a of example 4 substituting the product of example 33b for the product of example 3 to provide the title compound.

Example 34

N- [4- (2-chloro-4-fluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 34a

4- (2- (2-chloro-4-fluorophenoxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparation example 34a was prepared according to the procedure used for preparation example 2b, substituting 2-chloro-4-fluorophenol for phenol to provide the title compound.

Example 34b

4- (5-amino-2- (2-chloro-4-fluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 34b was prepared according to the procedure used to prepare example 3, substituting the product of example 34a for the product of example 2b to provide the title compound.

Example 34c

Example 34c was prepared according to the procedure used for method a of example 4 substituting the product of example 34b for the product of example 3 to provide the title compound.

Example 35

[4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] acetic acid

Example 35a

2- (3-bromo-4-hydroxyphenyl) acetic acid ethyl ester

To a solution of ethyl 2- (4-hydroxyphenyl) acetate (Alfa, 2.70 g, 15 mmol) in acetic acid (20mL) was added dropwise a solution of bromine (0.773 mL, 15.00 mmol) in acetic acid (15 mL) over 15 minutes. The mixture was stirred at ambient temperature for 30 minutes and evaporated. Purification by chromatography (silica gel, 10-20% ethyl acetate/hexanes) gave the title compound (3.66 g, 94%).

Example 35b

2- (4- (benzyloxy) -3-bromophenyl) acetic acid ethyl ester

A solution of example 35a (2.011 mL, 16.90 mmol) and potassium carbonate (5.84 g, 42.3 mmol) in ethanol (100 mL) was refluxed for 2 hours, cooled, concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried (Na)₂SO₄) Filtered and concentrated. The residue was purified by chromatography (silica gel, 0-20% ethyl acetate/hexanes) to give the title compound (4.84 g, 98%).

Example 35c

2- (4- (benzyloxy) -3- (6-methyl-7-oxo-1-toluenesulfonyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) acetic acid ethyl ester

Example 35c was prepared according to the procedure used to prepare example 7d, substituting the product of example 35b for the product of example 7c to provide the title compound.

Example 35d

Example 35c (0.4 g, 0.701 mmol), potassium hydroxide (0.787 g, 14.02 mmol) and cetyltrimethylammonium bromide (0.013 g, 0.035 mmol) were mixed in dioxane (10mL) and water (5 mL) and heated at 100 ℃ for 3 hours, cooled and partitioned between equal volumes of ethyl acetate and water (20mL, portions). The pH was adjusted to pH 2 by careful addition of concentrated HCl. The organic layer was separated and washed with saturated brine and dried (Na)₂SO₄) Filtered and concentrated. Trituration of the residue in hexanes afforded the title compoundSubstance (0.27 g, 98%).

Example 36

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Example 36a

2-bromo-1- (2, 4-difluorophenoxy) -4-nitrobenzene

A mixture of 2-bromo-1-fluoro-4-nitrobenzene (15 g, 68 mmol), 2, 4-difluorophenol (7.82 mL, 82mmol) and cesium carbonate (26.7 g, 82mmol) in dimethyl sulfoxide (75 mL) was heated to 110 ℃ for 1 hour. The reaction mixture was cooled to ambient temperature and water (1000 mL) and saturated aqueous sodium chloride (1000 mL) were added. The mixture was extracted with ethyl acetate (3 × 200 mL). The combined organics were washed with saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate), filtered and concentrated under reduced pressure to provide the title compound (22.5 g, quantitative).

Example 36b

3-bromo-4- (2, 4-difluorophenoxy) aniline

A mixture of example 36a (22.5 g, 68.2 mmol), iron powder (19.04 g, 341mmol) and ammonium chloride (7.30 g, 136 mmol) in tetrahydrofuran (117 mL), ethanol (117 mL) and water (39.0mL) was heated at 100 deg.C under reflux for 2 h. The reaction mixture was cooled to just below reflux temperature, filtered through celite, and the filter cake was washed with hot methanol (3 × 50 mL). The resulting solution was concentrated under reduced pressure and then neutralized to pH 8 with saturated sodium bicarbonate (150 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexanes, gradient 0-15%) to provide the title compound (16.8 g, 82% yield).

Example 36c

4- (5-amino-2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A mixture of example 6a (5.0 g, 11.67 mmol), example 36b (3.85 g, 12.84 mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoadamantane (0.399 g, 1.366 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.321 g, 0.350 mmol) and potassium phosphate (6.19 g, 29.2 mmol) in dioxane (50mL) and water (12.5 mL) was degassed and backfilled with nitrogen several times. The reaction mixture was heated at 60 ℃ for 16 hours and then cooled to ambient temperature. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three more times with additional ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 60% ethyl acetate/hexanes) to provide the title compound (4.40 g, 72.3% yield).

Example 36d

N- (4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) -N- (ethylsulfonyl) ethanesulfonamide

A solution of example 36c (4.35 g, 8.34 mmol) in dichloromethane (50mL) was cooled to 0 ℃. To this solution was added ethanesulfonyl chloride (2.37 mL, 25.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 80% ethyl acetate/hexanes) to provide the title compound (5.34 g, 91% yield).

Example 36e

A mixture of example 36d (5.3 g, 7.5 mmol), potassium hydroxide (8.43 g, 150 mmol) and N, N, N-trimethylhexadecane-1-ammonium bromide (0.137 g, 0.375 mmol) in tetrahydrofuran (60 mL) and water (30mL) was heated at 90 deg.C for 16 h. The tetrahydrofuran was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was neutralized with 10% HCl to pH = 7. Then, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate). The desired fractions were mixed and dried. The residue was triturated with 20mL acetonitrile to provide the title compound (2.82 g, 82% yield).

Example 37

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] acetamide

In CH₂Cl₂Example 27b (50 mg, 0.136 mmol) and triethylamine (56.9 μ L,0.408 mmol) were mixed (10 mL). Acetyl chloride (11.6 μ L, 0.163 mmol) was added dropwise and the solution was stirred at ambient temperature for 1 hour. Water (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were added, and CH was used₂Cl₂The mixture was extracted (3 × 25 mL). The combined organics were washed with brine and dried (MgSO)₄) Filtering and concentrating. Purification of the residue by reverse phase HPLC (C18,10-100% acetonitrile/water, 0.1% TFA) gave 15 mg (28%) of the title compound.

Example 38

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -3,3, 3-trifluoropropionamide

Example 38 was prepared according to the procedure used to prepare example 37, substituting 3,3, 3-trifluoropropionyl chloride for acetyl chloride to provide the title compound.

Example 39

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2, 2-dimethylpropionamide

Example 39 was prepared according to the procedure used to prepare example 37, substituting t-valeryl chloride for acetyl chloride to provide the title compound.

Example 40

4- (Cyclopentylamino) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoic acid ethyl ester

A mixture of example 9a (0.094 g, 0.2 mmol), cyclopentylamine (0.034 g,0.4 mmol) and triethylamine (0.081 g,0.8 mmol) in DMSO (2mL) was heated at 120 deg.C overnight. The reaction mixture was purified by preparative HPLC (C18, 10-80% acetonitrile/0.1% TFA/water to give 0.019 g of the title product.

EXAMPLE 41

4- {5- [ (1, 1-dioxo-1, 2-thiazolidin-2-yl) methyl ] -2-phenoxyphenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 41a

4- (5- (hydroxymethyl) -2-phenoxyphenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 41a was isolated as a by-product from the preparation of example 20 b.

Example 41b

Methanesulfonic acid 3- (6-methyl-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzyl ester

A mixture of example 41a (0.15 g, 0.3 mmol), methanesulfonyl chloride (0.069 g, 0.6mmol) and triethylamine (0.121 g, 1.2 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by flash chromatography on silica gel eluting with 20-40% ethyl acetate/hexanes to give 0.105 g of the title product.

Example 41c

1, 2-Thiazolidine 1, 1-dioxide (0.031 g, 0.259 mmol) in dimethylformamide (1mL) was treated with 60% sodium hydride (0.012g, 0.518 mmol, 0.021 g of a 60% oil dispersion). The reaction mixture was stirred for 5 min. To this solution was added example 41b (0.05 g, 0.086 mmol). The reaction mixture was stirred at room temperature for 2 hours. 2N NaOH (1mL) was added and the reaction mixture was heated at 65 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile/0.1% TFA water) to give 0.025 g (64%) of the title compound.

Example 42

4- { [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzyl ] amino } -4-oxobutanoic acid

Example 42 was prepared according to the procedure used to prepare example 41c, substituting pyrrolidine-2, 5-dione for 1, 2-thiazolidine 1, 1-dioxide to provide the title compound.

Example 43

4- [2- (2, 4-Difluorophenoxy) -5- (1, 1-dioxo-1, 2-thiazolidin-2-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 43a

3-chloro-N- (3-chloropropylsulfonyl) -N- (4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) propane-1-sulfonamide

A mixture of example 27b (0.1g, 0.272 mmol), 3-chloropropane-1-sulfonyl chloride (0.145 g, 0.817mmol) and triethylamine (0.165 g, 1.633 mmol) in dichloromethane (3 mL) was stirred for 2 h. The solvent was removed and the residue was used directly for the next reaction.

Example 43b

Sodium (0.064 g, 2.78 mmol) was dissolved in ethanol (15 mL). To this solution was added example 43a (0.18 g, 0.278 mmol) in ethanol (5 mL). The reaction mixture was heated at 75 ℃ for 2 hours. After cooling, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (C18, 10-80% acetonitrile/0.1% TFA/water) to give 0.055g of the title compound.

Example 44

4- [2- (benzyloxy) -5- (2-hydroxyethyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 35d (0.039 g,0.1 mmol)/tetrahydrofuran (2mL) was treated dropwise with borane-tetrahydrofuran complex (1M, 0.200 mL, 0.200 mmol) and the mixture was stirred at 40 ℃ for 1h, diluted with 5 mL of methanol, heated at 50 ℃ for 30 min and concentrated. Purification by chromatography (silica gel, 0.5-4% methanol in dichloromethane) gave the title compound (0.03 g, 79%).

Example 45

[4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] acetic acid methyl ester

Example 45a

2- (4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) acetyl chloride

Example 35d (0.18 g, 0.463 mmol)/tetrahydrofuran (4.63mL) was treated with one drop of dimethylformamide, then oxalyl chloride (0.122 mL, 1.390 mmol) was added dropwise, stirred for twenty minutes and concentrated.

Example 45b

Example 45a (0.058 g, 0.143 mmol)/tetrahydrofuran (4 mL) was treated with methanol (5 mL, 124 mmol), stirred at room temperature for 1 hour and concentrated. Purification by chromatography (silica gel, 0.5-3% methanol in dichloromethane) gave the title compound (0.048 g, 79%).

Example 46

2- [4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N-ethylacetamide

Example 46 was prepared according to the procedure used for the preparation of example 45b, substituting ethylamine for methanol to provide the title compound (0.039 g, 64%).

Example 47

2- [4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N, N-dimethylacetamide

Example 47 was prepared according to the procedure used for the preparation of example 45b, substituting dimethylamine for methanol to provide the title compound (0.058 g, 98%).

Example 48

N- [4- (3, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 48a

4- (2- (3, 4-Difluorophenoxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 48a was prepared according to the procedure used for the preparation of example 2b, substituting 3, 4-difluorophenol for phenol to provide the title compound.

Example 48b

4- (5-amino-2- (3, 4-difluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 48b was prepared according to the procedure used to prepare example 3, substituting the product of example 48a for the product of example 2b to provide the title compound.

Example 48c

Example 48c was prepared according to the procedure used for method a of example 4 substituting the product of example 48b for the product of example 3 to provide the title compound.

Example 49

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] methanesulfonamide

Example 49a

6-methyl-4- (5-nitro-2- (2,4, 6-trifluorophenoxy) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 49a was prepared according to the procedure used for the preparation of example 2b, substituting 2,4, 6-trifluorophenol for phenol to provide the title compound.

Example 49b

4- (5-amino-2- (2,4, 6-Trifluorophenoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 49b was prepared according to the procedure used to prepare example 3, substituting the product of example 49a for the product of example 2b to provide the title compound.

Example 49c

Example 49c was prepared according to the procedure used in method a of example 4 substituting the product of example 49b for the product of example 3 to provide the title compound.

Example 50

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Example 50a

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoic acid ethyl ester

Preparation example 50a was prepared according to the procedure used for preparation example 9b, substituting 2, 4-difluorophenol for phenol to provide the title compound.

Example 50b

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoic acid

Example 50b was prepared according to the procedure used to prepare example 10, substituting example 50a for example 9b to provide the title compound.

Example 50c

Example 50c was prepared according to the procedure used to prepare example 13a, substituting example 50b for example 10 to provide the title compound.

Example 50d

Example 50d was prepared according to the procedure used for the preparation of example 13b, substituting example 50c for example 13a and aqueous ammonium hydroxide for ethylamine to provide the title compound, respectively.

Example 51

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (tetrahydrofuran-3-yl) benzamide

Example 51 was prepared according to the procedure used for the preparation of example 13b, substituting example 50c for example 13a and tetrahydrofuran-3-amine for ethylamine to provide the title compound, respectively.

Example 52

4- {2- (2, 4-Difluorophenoxy) -5- [ (1, 1-thiomorpholin-4-yl) carbonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation of example 52 following the procedure used for the preparation of example 13b substituting 1, 1-dioxo-1-thiomorpholine for ethylamine and example 50c for example 13a, respectively, afforded the title compound.

Example 53

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (1-methyl-2-oxopyrrolidin-3-yl) benzamide

Example 53 was prepared according to the procedure used for the preparation of example 13b, substituting example 50c for example 13a and 3-amino-1-methylpyrrolidin-2-one for ethylamine to provide the title compound, respectively.

Example 54

{1- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoyl ] pyrrolidin-3-yl } carbamic acid tert-butyl ester

Prepare example 54 according to the procedure used for the preparation of example 13b, replace example 13a with example 50c and ethylamine with tert-butyl pyrrolidin-3-ylcarbamate, respectively, to provide the title compound.

Example 55

4- [2- (2, 4-Difluorophenoxy) -5- (pyrrolidin-1-ylcarbonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 55 was prepared according to the procedure used for the preparation of example 13b, substituting example 50c for example 13a and pyrrolidine for ethylamine respectively to provide the title compound.

Example 56

4- [2- (2, 4-Difluorophenoxy) -5- (morpholin-4-ylcarbonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 56 according to the procedure used to prepare example 13b, substituting example 50c for example 13a and morpholine for ethylamine to provide the title compound, respectively.

Example 57

N- [4- (cyclohexyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 57a

4- (2- (cyclohexyloxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 57a was prepared according to the procedure used for the preparation of example 29a, substituting cyclohexanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 57b

4- (5-amino-2- (cyclohexyloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 57b was prepared according to the procedure used to prepare example 3, substituting the product of example 57a for the product of example 2b to provide the title compound.

Example 57c

Example 57c was prepared according to the procedure used in method a of example 4 substituting the product of example 57b for the product of example 3 to provide the title compound.

Example 58

N- [4- (cyclopentyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 58a

4- (2- (cyclopentyloxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparation example 58a was prepared according to the procedure used for preparation example 29a, substituting cyclopentanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 58b

4- (5-amino-2- (cyclopentyloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 58b was prepared according to the procedure used to prepare example 3, substituting the product of example 58a for the product of example 2b to provide the title compound.

Example 58c

Example 58c was prepared according to the procedure used in method a of example 4 substituting the product of example 58b for the product of example 3 to provide the title compound.

Example 59

N- {4- [ (4, 4-Difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } methanesulfonamide

Example 59a

4- (2- (4, 4-Difluorocyclohexyloxy) -5-Nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 59a was prepared according to the procedure used for the preparation of example 29a, substituting 4, 4-difluorocyclohexanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 59b

4- (5-amino-2- (4, 4-difluorocyclohexyloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 59b was prepared according to the procedure used to prepare example 3, substituting the product of example 59a for the product of example 2b to provide the title compound.

Example 59c

Example 59c was prepared according to the procedure used in method a of example 4, substituting the product of example 59b for the product of example 3 to provide the title compound.

Example 60

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] methanesulfonamide

Example 60a

6-methyl-4- (5-nitro-2- (tetrahydro-2H-pyran-3-yloxy) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparation example 60a was prepared according to the procedure used for the preparation of example 29a, substituting tetrahydro-2H-pyran-3-ol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 60b

4- (5-amino-2- (tetrahydro-2H-pyran-3-yloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 60b was prepared according to the procedure used to prepare example 29b, substituting the product of example 60a for the product of example 29a to provide the title compound.

Example 60c

Example 60c was prepared according to the procedure used in method a of example 4, substituting the product of example 60b for the product of example 3 to provide the title compound.

Example 61

6-methyl-4- [2- (morpholin-4-ylcarbonyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 61 was prepared according to the procedure used for preparation example 1f, substituting morpholino (2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanone for 2-phenoxyphenylboronic acid, then purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound.

Example 62

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] ethanesulfonamide

Example 62 was prepared according to the procedure used in method a of example 4 substituting example 33b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride to provide the title compound, respectively.

Example 63

N- [4- (benzyloxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 63a

4- (2- (benzyloxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 63a was prepared according to the procedure used for the preparation of example 29a, substituting phenylmethanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 63b

4- (5-amino-2- (benzyloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 63b was prepared according to the procedure used to prepare example 3, substituting the product of example 63a for the product of example 2b to provide the title compound.

Example 63c

Example 63c was prepared according to the procedure used for method a of example 4 substituting the product of example 63b for the product of example 3 to provide the title compound.

Example 64

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2-fluoroethanesulfonamide

Preparation example 64 was prepared according to the procedure used for preparation example 27c, substituting methanesulfonyl chloride with 2-fluoroethylsulfonyl chloride and bypassing the sodium hydroxide hydrolysis step to provide the title compound.

Example 65

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N' -methylsulfamoamide

Prepare example 65 according to the procedure used for prepare example 27c, substituting methylsulfamoyl chloride for methanesulfonyl chloride to provide the title compound.¹H NMR (300 MHz, DMSO-d ₆) 2.50 (M, 3H solvent fuzzy), 3.52 (s, 3H),6.28-6.22 (M, 1H), 7.08-6.86 (M, 3H), 7.15 (dd, J = 8.8, 2.7 Hz, 1H), 7.39-7.21 (M, 5H), 9.65 (s, 1H), 12.02 (bs, 1H), MS (ESI +) M/z 461.1 (M + H)⁺。

Example 66

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydrofuran-3-yloxy) phenyl ] ethanesulfonamide

Example 66 was prepared according to the procedure used in method a of example 4, substituting the product of example 31b for the product of example 3 and ethanesulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound.

Example 67

6-methyl-7-oxo-4- (2-phenoxyphenyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid methyl ester

Example 67a

4-bromo-6-methyl-7-oxo-1-toluenesulfonyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Diisopropylamine (0.111 g,1.102 mmol) in tetrahydrofuran (3 mL) was treated with BuLi (2.5M, 0.44 mL, 1.102 mmol) at-78 ℃. The solution was stirred at-78 ℃ for 20 minutes and warmed to room temperature for 5 minutes and cooled again to-78 ℃. Adding N to the solution¹,N¹,N²,N²Tetramethylethylene-1, 2-diamine (0.128 g,1.102 mmol). Example 1e (0.30 g, 0.787 mmol)/tetrahydrofuran (3 mL) was then added to the reaction mixture through a catheter under nitrogen. At-7The reaction mixture was stirred at 8 ℃ for 1 hour, briefly raised to 0 ℃ and cooled to-78 ℃. To the suspension was added ethyl chloroformate (0.205 g, 1.889 mmol) by syringe. The reaction mixture was gradually warmed to room temperature overnight. The mixture was then partitioned between water and ethyl acetate. The aqueous layer was extracted three more times with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 30-50% ethyl acetate/hexanes to give 0.074 g of the title compound.

Example 67b

Example 67b was prepared according to the procedure used for preparation example 1f, substituting example 67a for example 1e and avoiding the use of potassium carbonate, and then purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound.

Example 68

1, 6-dimethyl-7-oxo-4- (2-phenoxyphenyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid methyl ester

The title compound was obtained as a by-product from the preparation of example 67 b.

Example 69

4- (5-amino-2-phenoxyphenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 69a

1-benzyl-4-bromo-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 69a was prepared according to the procedure used to prepare example 2a (method B) substituting example 67a for example 1e to provide the title compound.

Example 69b

6-methyl-4- (5-nitro-2-phenoxyphenyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 69b was prepared according to the procedure used to prepare example 2b substituting example 69a for example 2a to provide the title compound.

Example 69c

Example 69C was prepared according to the procedure used for the preparation of example 29b, substituting example 69b for example 29a and purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound as a TFA salt.

Example 70

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid

Example 70a

(Z) -3- (5-bromo-2-methoxy-3-nitropyridin-4-yl) -2-hydroxyacrylic acid ethyl ester

To a solution of ethanol (15 mL) and diethyl ether (150 mL) were added 5-bromo-2-methoxy-4-methyl-3-nitropyridine (14.82 g, 60mmol), diethyl oxalate (13.15 g, 90 mmol) and potassium ethoxide (6.06 g, 72 mmol). The reaction mixture was heated at 45 ℃ for 24 hours. During the reaction, the flask was shaken by hand several times. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three more times with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10-20% ethyl acetate/hexanes to give 9.5 g of the title compound (46% yield).

Example 70b

4-bromo-7-methoxy-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

A mixture of example 70a (9.5 g, 27.4 mmol) and iron (7.64 g, 137 mmol) in ethanol (60 mL) and acetic acid (60 mL) was heated at 100 ℃ for 1 h. The solution changed from red to grey. The solid was filtered off and then washed with additional ethyl acetate. The solvent was removed under reduced pressure to 20% of the original volume and it was partitioned between water and ethyl acetate. The aqueous layer was extracted several times with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-40% ethyl acetate/hexanes to give 6.05g of the title compound.

Example 70c

1-benzyl-4-bromo-7-methoxy-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 70b (0.88 g, 2.94 mmol)/dimethylformamide (15 mL) was treated with 60% sodium hydride (0.106 g, 4.41 mmol, 0.117 g of a 60% oil dispersion). The solution was stirred at room temperature for 10 minutes. To this solution was added benzyl bromide (0.59 g, 3.45 mmol). The reaction mixture was stirred for an additional 2 hours. It was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-40% ethyl acetate/hexanes to give 1.07 g of the title compound.

Example 70d

Example 70d was prepared according to the procedure used to prepare example 1d, substituting example 70c for example 1c to provide the title compound.

Example 70e

1-benzyl-4-bromo-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 70e was prepared according to the procedure used to prepare example 1e, substituting example 70d for example 1d to provide the title compound.

Example 70f

1-benzyl-4- (2-fluoro-5-nitrophenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 70f was prepared according to the procedure used for the preparation of example 2a (method B) substituting example 70e for example 1e to provide the title compound.

Example 70g

1-benzyl-6-methyl-4- (5-nitro-2-phenoxyphenyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 70g was prepared according to the procedure used for the preparation of example 2b substituting example 70f for example 2a to provide the title compound.

Example 70h

4- (5-amino-2-phenoxyphenyl) -1-benzyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 70h was prepared according to the procedure used for the preparation of example 29b substituting example 70g for example 29a to provide the title compound.

Example 70i

1-benzyl-6-methyl-4- (5- (N- (methylsulfonyl) methylsulfonylamino) -2-phenoxyphenyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 70i was prepared according to the procedure used for method a of example 4 substituting example 70h for example 3 except 1M NaOH was used to provide the title compound.

Example 70j

6-methyl-4- (5- (N- (methylsulfonyl) methylsulfonylamino) -2-phenoxyphenyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 70i (0.53 g, 0.816 mmol), anisole (0.176 g, 1.631 mmol) and concentrated H were heated at 90 deg.C₂SO₄A mixture of (0.5 mL) TFA (10mL) was used for 4 hours.Excess TFA was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted several times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and then brine over MgSO₄Dried, filtered and concentrated to give 0.48 g of the title compound. The crude material was used directly for the next reaction.

Example 70k

Example 70j (0.4 g, 0.858 mmol)/dioxane (5 mL) was treated with 2.0N NaOH (1.72 mL, 3.43 mmol). The reaction mixture was heated at 65 ℃ for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). After addition of concentrated HCl (1mL), the mixture was extracted three times with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated to give 0.36 g (93%) of the title compound. A small amount of the sample was purified by preparative HPLC (C18, 10-70% acetonitrile/0.1% TFA/water) to provide the title compound as a TFA salt.

Example 71

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

With concentrated H₂SO₄Example 70k (0.2 g, 0.441 mmol)/ethanol (10mL) was treated (0.5 mL). The reaction mixture was heated at reflux overnight. The solvent was removed and the residue was partitioned between water and ethyl acetate. The organic layer was separated and extracted with additional ethyl acetateThe aqueous layer was washed several times. With saturated NaHCO₃The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated to give 0.19 g of the title compound. The small amount of crude product was purified by preparative HPLC to provide a clean product for biological testing.

Example 72

N-ethyl-6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide

Example 72a

6-methyl-4- (5- (methylsulfonamido) -2-phenoxyphenyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carbonyl chloride

Example 72a was prepared according to the procedure used to prepare example 13a, substituting example 70k for example 10 to provide the title compound.

Example 72b

Example 72b was prepared according to the procedure used to prepare example 13b, substituting example 72a for example 13a to provide the title compound.

Example 73

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide

Example 73 was prepared according to the procedure used for the preparation of example 13b, substituting example 72a for example 13a and aqueous ammonium hydroxide for ethylamine to provide the title compound, respectively.

Example 74

4- (5-amino-2-phenoxyphenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxylic acid ethyl ester

Example 74a

4-amino-6-chloro-2-methylpyridazin-3 (2H) -one

A mixture of 4, 6-dichloro-2-methylpyridazin-3 (2H) -one (5.0 g, 27.9 mmol) and ammonium hydroxide (55 mL, 1412 mmol) was heated at 150 ℃ for 2H and then cooled to room temperature. The solvent was removed and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was extracted three more times with additional ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography (silica gel, eluting with 40% ethyl acetate/hexanes to give 3.85 g (87%) of the title compound.

Example 74b

4-amino-6-chloro-5-iodo-2-methylpyridazin-3 (2H) -one

A mixture of example 74a (2.12 g, 13.3 mmol) and N-iodosuccinimide (5.38 g,23.9 mmol) in acetonitrile (30mL) was heated at reflux for 6 h. The reaction mixture was cooled to room temperature and allowed to separate between ethyl acetate and water. The aqueous layer was extracted twice with additional 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 on silica gel eluting with 20-40% ethyl acetate/hexanes to give 3.27 g (86%) of the title compound.

Example 74c

4-chloro-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [3,2-d ] pyridazine-2-carboxylic acid

A mixture of example 74b (0.59 g, 2.1 mmol), pyruvic acid (0.546 g, 6.2 mmol), 1, 4-diazabicyclo [2.2.2] octane (0.695 g, 6.2 mmol) and palladium (II) acetate (0.046 g, 10 mol%) in dimethylformamide (8 mL) was degassed and backfilled with nitrogen three times. The reaction mixture was then heated at 105 ℃ overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated in 30% ethyl acetate/hexanes to give 0.25 g (53%) of the title compound.

Example 74d

4-chloro-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [3,2-d ] pyridazine-2-carboxylic acid ethyl ester

Example 74c (0.45 g, 2.0 mmol)/ethanol (15 mL) was treated with concentrated sulfuric acid (1 mL). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 0.45 g (89%) of the title compound.

Example 74e

4-chloro-6-methyl-7-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [3,2-d ] pyridazine-2-carboxylic acid ethyl ester

A solution of example 74d (0.41 g, 1.6mmol) in dimethylformamide (15 mL) was treated with 60% sodium hydride (0.096 g, 2.4 mmol) at room temperature. The reaction mixture was stirred for 30 minutes and then treated with (2- (chloromethoxy) ethyl) trimethylsilane (0.40 g, 2.4 mmol). Then, the reaction mixture was stirred for 2 hours. It was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with additional 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 on silica gel eluting with 20% ethyl acetate to give 0.50 g (81%) of the title compound.

Example 74f

4- (2-fluoro-5-nitrophenyl) -6-methyl-7-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [3,2-d ] pyridazine-2-carboxylic acid ethyl ester

Example 74f was prepared according to the procedure used for the preparation of example 2a (method B) substituting example 74e for example 1e to provide the title compound.

Example 74g

6-methyl-4- (5-nitro-2-phenoxyphenyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [3,2-d ] pyridazine-2-carboxylic acid ethyl ester

A mixture of example 74f (0.26 g, 0.53 mmol), phenol (0.060 g, 0.64 mmol) and cesium carbonate (0.21 g, 0.63 mmol) in dimethyl sulfoxide (5 mL) was heated at 110 deg.C for 6 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three more times with additional ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. However, the device is not suitable for use in a kitchenAfter that, 15 mL of ethanol and 1mL of concentrated H were used₂SO₄The residue is treated. The mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40-80% ethyl acetate to give 0.14 g (61%) of the title compound.

Example 74h

Prepare example 74h according to the procedure used to prepare example 29b, replace example 29a with example 74g and ethyl acetate with ethanol, respectively, to provide the title compound.

Example 75

4- [5- (ethylamino) -2-phenoxyphenyl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxylic acid ethyl ester

Example 75 was obtained as a by-product from the preparation of example 74 h.

Example 76

4- {5- [ Ethyl (methylsulfonyl) amino ] -2-phenoxyphenyl } -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxylic acid ethyl ester

Example 76 was prepared according to the procedure used for method a of example 4 substituting example 75 for example 3 except NaOH was used to provide the title compound.

Example 77

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxylic acid

Example 77 was prepared according to the procedure used for method a of example 4 substituting example 74h for example 3 to provide the title compound.

Example 78

6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxamide

Example 78a

6-methyl-4- (5- (methylsulfonylamino) -2-phenoxyphenyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carbonyl chloride

Example 78a was prepared according to the procedure used to prepare example 13a, substituting example 77 for example 10 to provide the title compound.

Example 78b

Example 78b was prepared according to the procedure used to prepare example 13b, substituting example 78a for example 13a and aqueous ammonium hydroxide for ethylamine, respectively, to provide the title compound.

Example 79

6-methyl-N- [2- (4-methylpiperazin-1-yl) ethyl ] -4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxamide

Example 79 was prepared according to the procedure used for the preparation of example 13b, substituting example 78a for example 13a and 2- (4-methylpiperazin-1-yl) ethylamine for ethylamine to provide the title compound as a TFA salt, respectively.

Example 80

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-4-yl) -4-phenoxyphenyl ] methanesulfonamide

Example 80a

(E) -4-amino-6-chloro-5- (2-ethoxyvinyl) -2-methylpyridazin-3 (2H) -one

Example 80a was prepared according to the procedure used for the preparation of example 2a (method B), substituting example 74B for example 1E and (E) -2- (2-ethoxyvinyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan for 2-fluoro-5-nitrophenylboronic acid, respectively, to provide the title compound.

Example 80b

4-chloro-6-methyl-1H-pyrrolo [3,2-d ] pyridazin-7 (6H) -one

Example 80a (0.1g, 0.435 mmol) in acetic acid (5 mL) was heated at 90 deg.C overnight. The solvent was evaporated under reduced pressure to give 0.071 g of the title compound.

Example 80c

4-chloro-6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [3,2-d ] pyridazin-7 (6H) -one

Example 80c was prepared according to the procedure used to prepare example 74e, substituting example 80b for example 74c to provide the title compound.

Example 80d

4- (2-fluoro-5-nitrophenyl) -6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [3,2-d ] pyridazin-7 (6H) -one

Example 80d was prepared according to the procedure used for the preparation of example 2a (method B) substituting example 80c for example 1e to provide the title compound.

Example 80e

6-methyl-4- (5-nitro-2-phenoxyphenyl) -1H-pyrrolo [3,2-d ] pyridazin-7 (6H) -one

Example 80e was prepared according to the procedure used for the preparation of example 2b, substituting example 80d for example 2a to provide the title compound.

Example 80f

4- (5-amino-2-phenoxyphenyl) -6-methyl-1H-pyrrolo [3,2-d ] pyridazin-7 (6H) -one

Example 80f was prepared according to the procedure used to prepare example 29b, substituting example 80e for example 29a to provide the title compound.

Example 80g

Example 80g was prepared according to the procedure used in method a of example 4 substituting example 80f for example 3 to provide the title compound.

Example 81

N-ethyl-6-methyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxamide

Example 81 was prepared according to the procedure used to prepare example 13b, substituting example 78a for example 13a to provide the title compound.

Example 82

6-methyl-4- (2-phenoxyphenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one

Example 82 was prepared according to the procedure used for the preparation of example 1f, substituting example 80b for example 1e except that potassium carbonate was used and then purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound.

Example 83

N-ethyl-N, 6-dimethyl-4- {5- [ (methylsulfonyl) amino ] -2-phenoxyphenyl } -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazine-2-carboxamide

Example 83 was prepared according to the procedure used for the preparation of example 13b, substituting example 78a for example 13a and N-methylethylamine for ethylamine to provide the title compound, respectively.

Example 84

4- {4- [ (ethylsulfonyl) amino ] -2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy } benzamide

To a mixture of example 33b (50 mg, 0.14mmol) and triethylamine (0.043 g, 0.42 mmol) in dichloromethane (4 mL) was added dropwise ethanesulfonyl chloride (0.072 g, 0.56 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure, dioxane (4 mL) and sodium hydroxide (10% w/v, 3mL, 0.14mmol) were added and the reaction mixture was heated at 70 ℃ for 1 hour. The mixture was cooled to ambient temperature and then neutralized to pH 7 with saturated aqueous ammonium chloride (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was purified by preparative HPLC (C18,10-100% acetonitrile/water, 0.1% TFA) to give the title compound (22 mg, 35%).

Example 85

6-methyl-4- [5- (methylsulfonyl) -2-phenoxyphenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 85a

4- (methylsulfonyl) -2-nitro-1-phenoxybenzene

Example 85a was prepared according to the procedure used for the preparation of example 2b, substituting 1-fluoro-4- (methylsulfonyl) -2-nitrobenzene for example 2a to provide the title compound.

Example 85b

5- (methylsulfonyl) -2-phenoxyaniline

Example 85b was prepared according to the procedure used to prepare example 29b, substituting 85a for example 29a to provide the title compound.

Example 85c

2-iodo-4- (methylsulfonyl) -1-phenoxybenzene

Example 85b (0.27 g, 1.025 mmol) in dioxane (1mL) was treated with concentrated HCl (6 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 10 minutes. To this solution was added sodium nitrite (0.08)5g, 1.23 mmol) in water (1 mL). The reaction was stirred at 0 ℃ for another 1 hour. To this solution was added potassium iodide (0.34 g, 1.051 mmol) in water (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10-30% ethyl acetate/hexanes to give 0.28 g of the title product.

Example 85d

Preparation example 85d was prepared according to the procedure used for preparation example 1f, substituting example 85C for example 1e and substituting example 6a for 2-phenoxyphenylboronic acid, and then purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound.

Example 86

5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (tetrahydrofuran-3-yloxy) pyridine-3-sulfonamide

Example 86a

5-bromo-6-chloropyridine-3-sulfonamides

5-bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g)/methanol (20mL) was cooled to 0 ℃. To this solution was added 7NNH₃Methanol (80 mL). The reaction mixture was stirred at room temperature overnight. The solvent is removed at low temperature and the residue is taken up in acetic acidThe layers were separated between ethyl ester and water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO)₄) Filtered and concentrated. The solid was purified by flash column chromatography on silica gel to give 4.2 g of clean product.

Example 86b

5-bromo-6- (tetrahydrofuran-3-yloxy) pyridine-3-sulfonamide

Example 86b was prepared according to the procedure used for the preparation of example 29a, substituting example 2a with 86a and tetrahydro-2H-pyran-4-ol with tetrahydrofuran-3-ol to provide the title compound.

Example 86c

Example 86C was prepared according to the procedure used for the preparation of example 1f, substituting example 86b for example 1e and substituting example 6a for 2-phenoxyphenylboronic acid, and then purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound.

Example 87

N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (tetrahydrofuran-3-yloxy) pyridine-3-sulfonamide

Example 87 was obtained as a by-product from the preparation of example 86 c.

Example 88

6-methyl-4- (2-phenoxyphenyl) -2-phenyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

4-bromo-2-iodo-6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 88a

To a cold solution of example 1e (0.2 g, 0.525 mmol) in tetrahydrofuran (6 mL (-78 ℃, dry ice/acetone bath) was added a freshly prepared solution of lithium di-isopropylamide (1.2 equiv.). The reaction mixture was stirred at-78 ℃ for 45 minutes. A solution of iodine (0.054 mL, 1.049 mmol) in tetrahydrofuran (0.5 mL) was added at-78 ℃. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate (20 mL). The reaction mixture was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organics were washed with brine, anhydrous MgSO₄Dried, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 1-100% ethyl acetate/hexanes). The recovered material was further purified by reverse phase HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to give the title compound (55 mg, 21%).

Example 88b

4-bromo-6-methyl-2-phenyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 88a (0.1g, 0.197mmol), phenylboronic acid (0.024 g, 0.197mmol), Pd (PPh) were heated at 85 deg.C₃)₄Mixture of dimethylformamide (2mL) (0.011g, 0.0096 mmol) and sodium bicarbonate (0.041 g, 0.493 mmol) and water (0.6 mL) 4And (4) hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 30% ethyl acetate to give 0.084 g of the title compound.

Example 88c

Preparative example 88C was prepared according to the procedure used for preparative example 1f, substituting example 88b for example 1e, and then purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound.

Example 89

N- {3- [2- (hydroxymethyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c]Pyridin-4-yl]-4-phenoxyphenyl } methanesulfonamide

Example 89 was prepared according to the procedure used to prepare example 20b substituting example 71 for example 20a to provide the title compound.

Example 90

N- [4- (4-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Example 90a

4- (2-bromo-4-nitrophenoxy) benzonitrile

Preparation example 90a was prepared according to the procedure used for preparation example 7a, substituting 4-hydroxybenzonitrile for phenol to provide the title compound.

Example 90b

4- (4-amino-2-bromophenoxy) benzonitrile

A250 mL stainless steel pressure bottle was charged with example 90a (3.21 g, 10.1 mmol), platinum (IV) oxide (0.642 g, 2.83 mmol), and tetrahydrofuran (70 mL) under a stream of nitrogen. The reaction flask was charged with hydrogen to 30 psi and stirred at ambient temperature for 45 minutes. The mixture was filtered through a nylon membrane. The filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide the title compound (1.75 g, 60% yield).

Example 90c

4- (4-amino-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) benzonitrile

A mixture of example 90b (1.75 g, 6.05 mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (3.07 g, 12.1 mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoadamantane (0.159 g, 0.545 mmol), potassium acetate (1.31 g, 13.3 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.166 g, 0.182 mmol) in dioxane (30mL) was dehydrogenated and backfilled with nitrogen. The reaction mixture was heated at 80 ℃ for 20 hours and then cooled to ambient temperature. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate) to provide the title compound (2.0 g, 98% yield).

Example 90d

Preparative example 90d was prepared according to the procedure used for preparative example 1f, substituting example 90C for 2-phenoxyphenylboronic acid, and then purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound.

Example 90e

Prepare example 90e according to the procedure used for preparative example 4, method a, substituting ethanesulfonyl chloride for methanesulfonyl chloride and example 90d for example 3, respectively, to provide the title compound.

Example 91

2-fluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydrofuran-3-yloxy) phenyl ] ethanesulfonamide

Example 91a

Preparation example 91a was prepared according to the procedure used for preparation example 29a, substituting tetrahydrofuran-3-ol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 91b

Example 91b was prepared according to the procedure used to prepare example 29b, substituting example 91a for example 29a to provide the title compound.

Example 91c

To a mixture of example 91b (80.0 mg, 0.246 mmol) and triethylamine (74.6 mg, 0.738 mmol) in dichloromethane (4 mL) was added 2-fluoroethylsulfonyl chloride (144 mg, 0.984 mmol) dropwise and the reaction mixture was stirred at about ambient temperature for about 1 hour. The reaction mixture was neutralized with saturated aqueous ammonium chloride (50mL) and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile/0.1% TFA/water) to provide the title compound (7.0 mg, 6.5% yield).

Example 92

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydrofuran-3-yloxy) phenyl ] propane-1-sulfonamide

Example 92 was prepared according to the procedure used for the preparation of example 4 (method a) substituting example 91b for example 3 and propane-1-sulfonyl chloride for methanesulfonyl chloride to provide the title compound.¹H NMR (300 MHz, CDCl₃) ppm10.63 (bs, 1H), 7.25 (m, 3H), 6.90 (d, J = 8.7 Hz, 1H), 6.46 6.35 (m, 2H),4.88 (bs, 1H), 4.01 3.66 (m, 7H), 3.12 3.03 (m, 2H), 2.2 (bs, 1 H), 2.19 1.80(m, 4H), 1.06 (t, J = 7.4 Hz, 3H).MS (ESI+) m/z 432.2 (M+H)⁺。

Example 93

N- [4- (4-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] propane-1-sulfonamide

Example 93 was prepared according to the procedure used for the preparation of example 4 (method a) substituting example 33b for example 3 and propane-1-sulfonyl chloride for methanesulfonyl chloride to provide the title compound.¹H NMR (300 MHz, DMSO-d ₆) ppm12.03 (bs, 1H), 9.91 (s, 1H), 7.70-7.63 (m, 2H), 7.42 (d, J = 2.5 Hz, 1H),7.32-7.17 (m, 4H), 6.93-6.86 (m, 2H), 6.22 (dd, J = 2.8, 1.9 Hz, 1H), 3.46(s, 3H), 3.18-3.09 (m, 2H), 1.92-1.65 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).MS(ESI+) m/z 463.2 (M+H)⁺。

Example 94

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] propane-1-sulfonamide

Example 94a

Preparation of example 94a was carried out according to the procedure used for preparation of example 2b, substituting 2,4, 6-trifluorophenol for phenol to provide the title compound.

Example 94b

Example 94b was prepared according to the procedure used to prepare example 3, substituting example 94a for example 2b to provide the title compound.

Example 94c

Prepare example 94c according to the procedure used for prepare example 4 (method a), replace example 3 with example 94b and methanesulfonyl chloride with propane-1-sulfonyl chloride to provide the title compound.

Example 95

3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4-phenoxybenzenesulfonamide

Example 95a

3-nitro-4-phenoxybenzenesulfonamides

Phenol (1.282 g, 13.63 mmol)/dimethylformamide (20mL) was treated with 60% sodium hydride (0.545 g, 13.63 mmol). The reaction mixture was stirred for 10 minutes. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (0.75g, 3.41 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (1:1 ethyl acetate/hexane) to give 0.96 g of the title product.

Example 95b

3-amino-4-phenoxybenzenesulfonamides

Example 95b was prepared according to the procedure used to prepare example 29b, substituting example 95a for example 29a to provide the title compound.

Example 95c

3-iodo-4-phenoxybenzenesulfonamides

Example 95c was prepared according to the procedure used to prepare example 85c, substituting example 95b for example 85b to provide the title compound.

Example 95d

Example 6a (0.086 g, 0.20 mmol), example 95c (0.083 g, 0.22 mmol), Pd (PPh) were heated under microwave conditions (110 ℃ C., 30 minutes)₃)₄(0.012g, 5 mol%) and cesium fluoride (0.091 g, 0.6mmol) in a mixture of dimethoxyethane (2mL) and methanol (1 mL). The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (C18,10-100% acetonitrile/0.1% TFA/water) to provide the title compound (48 mg, 61% yield).

Example 96

6- (cyclohexylamino) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

Example 96a

5-bromo-6- (cyclohexylamino) pyridine-3-sulfonamides

A mixture of example 86a (0.136 g, 0.5 mmol) and cyclohexylamine (0.198 g, 2.0 mmol) in dioxane (2mL) was heated under microwave conditions (140 deg.C, 1 hour). The solvent was removed and the residue was purified by flash chromatography on silica gel (3:2 ethyl acetate/hexane) to give 0.164 g of the title product.

Example 96b

Example 96b was prepared according to the procedure used to prepare example 95d, substituting example 96a for example 95c to provide the title compound.

Example 97

6- (cyclohexylamino) -N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

Example 97 was isolated as a minimal product during the preparation of example 96 b.

Example 98

N-methyl-N' - [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] thiodiamide

To a mixture of example 94b (76.3 mg, 0.198 mmol) and triethylamine (60.1 mg, 0.594 mmol) in dichloromethane (4 mL) was added dropwise methylsulfamoyl chloride (103 mg, 0.792 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with dioxane (5 mL) and 1M aqueous sodium hydroxide solution (3 mL, 0.2 mmol) and heated at 70 ℃ for 1 hour. The reaction mixture was cooled to room temperature, then neutralized with saturated aqueous ammonium chloride (50mL) and the aqueous solution was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile/0.1% TFA/water) to provide the title compound (11 mg, 11% yield).

Example 99

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] propane-1-sulfonamide

Example 99a

To a solution of tetrahydro-2H-pyran-4-ol (231 mg, 2.265 mmol) in tetrahydrofuran (10mL) was added sodium hydride (181 mg, 4.53 mmol) in portions. After stirring for 10 min, example 2a (500 mg, 1.133mmol) was added. The mixture was heated at 50 ℃ for 2 hours. On cooling, the reaction mixture was quenched with saturated ammonium chloride solution (10mL), diluted with 50% aqueous sodium chloride (80 mL) and extracted with ethyl acetate (75 mL, 2 × 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0.5-4% methanol/dichloromethane) to provide the title compound (220 mg, 52.6% yield).

Example 99b

Example 99b was prepared according to the procedure used to prepare example 29b, substituting example 99a for example 29a to provide the title compound.

Example 99c

Preparation example 99c was prepared according to the procedure used for preparation example 4 (method a), substituting example 99b for example 3 and propane-1-sulfonyl chloride for methanesulfonyl chloride, except that the reaction mixture was first stirred at ambient temperature for 18 hours, then heated at 50 ℃ for 1 hour in the presence of sodium hydroxide to provide the title compound.

Example 100

2,2, 2-trifluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] ethanesulfonamide

To a solution of example 99b (43.2 mg, 0.127 mmol) in dichloromethane (2mL) was added 2,2, 2-trifluoroethanesulfonyl chloride (0.015 mL, 0.140 mmol) and triethylamine (0.053 mL, 0.382 mmol). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated and the residue was purified by flash column chromatography (silica gel, 0.5-5% methanol/dichloromethane) to provide the title compound (20.8 mg, 33.7% yield).

Example 101

N- {4- [ (4, 4-Difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } ethanesulfonamide

Example 101a

Example 101a was prepared according to the procedure used for the preparation of example 99a, substituting 4, 4-difluorocyclohexanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 101b

Example 101b was prepared according to the procedure used to prepare example 29b, substituting example 101a for example 29a to provide the title compound.

Example 101c

Example 101c was prepared according to the procedure used to prepare example 4 (method a), substituting example 101b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride, except that the reaction mixture was first stirred at ambient temperature for 18 hours and then heated at 50 ℃ for 1 hour in the presence of sodium hydroxide to provide the title compound.

Example 102

N- {4- [ (4, 4-difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } propane-1-sulfonamide

Example 102 was prepared according to the procedure used for preparation example 4 (method a) substituting example 101b for example 3 and propane-1-sulfonyl chloride for methanesulfonyl chloride, except that the reaction mixture was first stirred at ambient temperature for 18 hours and then heated at 50 ℃ for 1 hour in the presence of sodium hydroxide to provide the title compound.

Example 103

N- {4- [ (4, 4-Difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } -2,2, 2-trifluoroethanesulfonamide

Example 103 was prepared according to the procedure used to prepare example 100, substituting example 101b for example 99b to provide the title compound.

Example 104

N- {4- [ (4, 4-Difluorocyclohexyl) oxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } -N' -methylsulfamoamide

Prepare example 104 according to the procedure used to prepare example 100, replace example 99b with example 101b and 2,2, 2-trifluoroethanesulfonyl chloride with methylaminosulfonyl chloride to provide the title compound.

Example 105

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] ethanesulfonamide

Example 105a

Preparation of example 105a following the procedure used for preparation of example 99a, substituting tetrahydro-2H-pyran-3-ol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 105b

Example 105b was prepared according to the procedure used to prepare example 29b, substituting example 105a for example 29a to provide the title compound.

Example 105c

Example 105c was prepared according to the procedure used for preparation example 4 (method a), substituting example 105b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride, except that the reaction mixture was first stirred at ambient temperature for 18 hours and then heated at 50 ℃ for 1 hour in the presence of sodium hydroxide to provide the title compound.

Example 106

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] propane-1-sulfonamide

Example 106 was prepared according to the procedure used for the preparation of example 4 (method a) substituting example 105b for example 3 and propane-1-sulfonyl chloride for methanesulfonyl chloride, except that the reaction mixture was first stirred at ambient temperature for 18 hours and then heated at 50 ℃ for 1 hour in the presence of sodium hydroxide to provide the title compound.

Example 107

2,2, 2-trifluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] ethanesulfonamide

Example 107 was prepared according to the procedure used to prepare example 100, substituting example 105b for example 99b to provide the title compound.

Example 108

N-methyl-N' - [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-3-yloxy) phenyl ] sulfamide

Example 108 was prepared according to the procedure used to prepare example 100, substituting example 105b for example 99b and substituting methylsulfamoyl chloride for 2,2, 2-trifluoroethanesulfonyl chloride to provide the title compound.

Example 109

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (tetrahydro-2H-pyran-4-yloxy) phenyl ] ethanesulfonamide

Example 109 was prepared according to the procedure used for the preparation of example 4 (method a), substituting example 99b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride, except that the reaction mixture was first stirred at ambient temperature for 18 hours and then heated at 50 ℃ for 1 hour in the presence of sodium hydroxide to provide the title compound.

Example 110

N, N-dimethyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (tetrahydrofuran-3-yloxy) pyridine-3-sulfonamide

Example 110a

5-bromo-6-chloro-N, N-dimethylpyridine-3-sulfonamide

5-bromo-6-chloropyridine-3-sulfonyl chloride (1.455 g, 5mmol) in methanol (20mL) was treated with 2.0N dimethylamine (6.25 mL, 12.50 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed and the solid was washed several times with water. The solid was then purified by chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give 0.8g of the title compound.

Example 110b

5-bromo-N, N-dimethyl-6- (tetrahydrofuran-3-yloxy) pyridine-3-sulfonamide

Prepare example 110b according to the procedure used to prepare example 29a, replace example 2a with example 110a and tetrahydro-2H-pyran-4-ol with tetrahydrofuran-3-ol, respectively, to provide the title compound.

Example 110c

Example 110c was prepared according to the procedure used to prepare example 95d, substituting example 110b for example 95c to provide the title compound.

Example 111

5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (phenylamino) pyridine-3-sulfonamide

Example 111a

5-bromo-6- (phenylamino) pyridine-3-sulfonamides

A mixture of example 86a (0.136 g, 0.5 mmol), aniline (0.186 g, 2.0 mmol) and 60% sodium hydride (0.12 g, 3.0 mmol) in dioxane (2mL) was stirred and heated at 60 ℃ for 16 h. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (2:3 ethyl acetate/hexane) to give 0.095 g of the title product.

Example 111b

Example 111b was prepared according to the procedure used to prepare example 95d, substituting example 111a for example 95c to provide the title compound.

Example 112

N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -6- (phenylamino) pyridine-3-sulfonamide

During the preparation of example 111b, example 112 was isolated as the smallest product.

Example 113

N- [4- (4-cyanophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2-fluoroethanesulfonamide

Example 33b (50 mg, 0.140 mmol) and triethylamine (42.6mg, 0.421 mmol) were mixed in dichloromethane (4 mL). 2-fluoroethanesulfonyl chloride (82 mg, 0.561 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 1 hour. Then, the reaction mixture was extracted with saturated aqueous sodium chloride solution, separated, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (C18,10-100% acetonitrile/water, 0.1% TFA) to give the title compound (1.4 mg, 2% yield).

Example 114

2-fluoro-N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (2,4, 6-trifluorophenoxy) phenyl ] ethanesulfonamide

Example 114 was prepared according to the procedure used to prepare example 91c, substituting example 94b for example 91b to provide the title compound.

Example 115

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] propane-1-sulfonamide

Prepare example 115 according to the procedure used for prepare example 27c, substituting propane-1-sulfonyl chloride for methanesulfonyl chloride to provide the title compound.

Example 116

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyrimidin-2-yl) benzamide

A solution of example 50b (24 mg, 0.06 mmol) in a4 mL vial was dissolved in anhydrous tetrahydrofuran (1.0mL) and 1-chloro-N, N, 2-trimethyl-1-propenylamine (65 μ L, 0.48 mmol) was added. The vial was capped and shaken at ambient temperature for 2 hours. Then, a solution of pyrimidin-2-amine (9 mg, 0.09 mmol) in anhydrous tetrahydrofuran (0.3mL) was added, followed by a solution of 4- (dimethylamino) pyridine (37 mg, 0.3 mmol) in anhydrous tetrahydrofuran (0.5 mL). The mixture was stirred at 60 ℃ for 16 h, cooled and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (10-80% acetonitrile/0.1% TFA water).

Example 117

4- (2, 4-Difluorophenoxy) -N- (2, 6-dimethoxypyridin-3-yl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Preparation example 117 was prepared according to the procedure used for preparation example 116, substituting 2, 6-dimethoxypyridin-3-amine hydrochloride for pyrimidin-2-amine to provide the title compound as a TFA salt.

Example 118

4- (2, 4-Difluorophenoxy) -N- (1H-indazol-6-yl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Example 118 was prepared according to the procedure used to prepare example 116, substituting 1H-indazol-6-amine for pyrimidin-2-amine to provide the title compound.

Example 119

4- [2- (2, 4-Difluorophenoxy) -5- { [4- (pyrrolidin-1-ylcarbonyl) piperazin-1-yl ] carbonyl } phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 119 was prepared according to the procedure used for preparation example 116, substituting piperazin-1-yl (pyrrolidin-1-yl) methanone for pyrimidin-2-amine to provide the title compound.

Example 120

4- (2, 4-Difluorophenoxy) -N- [4- (dimethylamino) phenyl ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Example 120 was prepared according to the procedure used to prepare example 116, using N¹,N¹-dimethylbenzene-1, 4-diamine instead of pyrimidin-2-amine to provide the title compound as a TFA salt.

Example 121

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-4-ylmethyl) benzamide

Preparation of example 121 was performed according to the procedure used for preparation of example 116, substituting pyridin-4-ylmethylamine for pyrimidin-2-amine to provide the title compound as a TFA salt.

Example 122

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- [2- (2-oxopyrrolidin-1-yl) ethyl ] benzamide

Preparation example 122 was prepared according to the procedure used for preparation example 116, substituting 1- (2-aminoethyl) pyrrolidin-2-one for pyrimidin-2-amine to provide the title compound.

Example 123

4- (2, 4-Difluorophenoxy) -N- (2-hydroxy-2-methylpropyl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Preparation example 123 was prepared according to the procedure used for preparation example 116, substituting 1-amino-2-methylpropan-2-ol for pyrimidin-2-amine to provide the title compound.

Example 124

4- (2, 4-Difluorophenoxy) -N- [2- (5-methoxy-1H-indol-3-yl) ethyl ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Preparation example 124 was prepared according to the procedure used for preparation example 116, substituting 2- (5-methoxy-1H-indol-3-yl) ethylamine for pyrimidin-2-amine to provide the title compound.

Example 125

N- (3, 4-difluorobenzyl) -4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Example 125 was prepared according to the procedure used to prepare example 116 substituting (3, 4-difluorophenyl) methylamine for pyrimidin-2-amine to provide the title compound.

Example 126

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- [4- (trifluoromethoxy) benzyl ] benzamide

Example 126 was prepared according to the procedure used to prepare example 116, substituting (4- (trifluoromethoxy) phenyl) methylamine for pyrimidin-2-amine to provide the title compound.

Example 127

2- {4- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoyl ] piperazin-1-yl } -N, N-dimethylacetamide

Preparation example 127 was prepared according to the procedure used for preparation example 116, substituting N, N-dimethyl-2- (piperazin-1-yl) acetamide for pyrimidin-2-amine to provide the title compound as a TFA salt.

Example 128

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-3-ylmethyl) benzamide

Preparation example 128 was prepared according to the procedure used for preparation example 116, substituting pyridin-3-ylmethylamine for pyrimidin-2-amine to provide the title compound as a TFA salt.

Example 129

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-2-ylmethyl) benzamide

Preparation example 129 was prepared according to the procedure used for preparation example 116, substituting pyridin-2-ylmethylamine for pyrimidin-2-amine to provide the title compound as a TFA salt.

Example 130

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (3,4, 5-trimethoxybenzyl) benzamide

Prepare example 130 according to the procedure used to prepare example 116, substituting (3,4, 5-trimethoxyphenyl) methylamine for pyrimidin-2-amine to provide the title compound.

Example 131

4- (2, 4-Difluorophenoxy) -N- [2- (dimethylamino) ethyl ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Example 131 was prepared according to the procedure used to prepare example 116, using N¹,N¹-dimethylethylene-1, 2-diamine instead of pyrimidin-2-amine to provide the title compound as TFA salt.

Example 132

N- [2- (1, 3-benzodioxol-5-yl) ethyl ] -4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Preparation example 132 was prepared according to the procedure used for preparation example 116, substituting 2- (benzo [ d ] [1,3] dioxol-5-yl) ethylamine for pyrimidin-2-amine to provide the title compound.

Example 133

4- (2, 4-Difluorophenoxy) -N- [2- (1H-indol-3-yl) ethyl ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzamide

Preparation example 133 was prepared according to the procedure used for preparation example 116 substituting 2- (1H-indol-3-yl) ethylamine for pyrimidin-2-amine to provide the title compound.

Example 134

4- [2- (2, 4-Difluorophenoxy) -5- { [4- (furan-2-ylcarbonyl) piperazin-1-yl ] carbonyl } phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 134 was prepared according to the procedure used for preparation example 116, substituting furan-2-yl (piperazin-1-yl) methanone for pyrimidin-2-amine to provide the title compound.

Example 135

{1- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoyl ] piperidin-4-yl } carbamic acid tert-butyl ester

Preparation example 135 was prepared according to the procedure used for preparation example 116 substituting piperidin-4-ylcarbamic acid tert-butyl ester for pyrimidin-2-amine to provide the title compound.

Example 136

4- { [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzoyl ] amino } piperidine-1-carboxylic acid tert-butyl ester

Preparation example 136 was prepared according to the procedure used for preparation example 116 substituting 4-aminopiperidine-1-carboxylic acid tert-butyl ester for pyrimidin-2-amine to provide the title compound.

Example 137

4- [2- (2, 4-Difluorophenoxy) -5- { [4- (ethylsulfonyl) piperazin-1-yl ] carbonyl } phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 137 was prepared according to the procedure used for the preparation of example 116, substituting 1- (ethylsulfonyl) piperazine for pyrimidin-2-amine to provide the title compound.

Example 138

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 138a

4- (2-fluoro-5- (methylsulfonyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A mixture of dioxane (10mL) from example 6a (0.642 g,1.5 mmol), 2-bromo-1-fluoro-4- (methylsulfonyl) benzene (0.380 g,1.500 mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoadamantane (0.051 g, 0.176mmol), tris (dibenzylideneacetone) dipalladium (0) (0.041 g, 0.045 mmol) and potassium phosphate (0.796 g, 3.75mmol) and water (2.500 mL) was degassed and backfilled with nitrogen several times. The reaction was heated at 60 ℃ for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three more times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexanes to give the title compound (0.63 g, 1.328 mmol,89% yield).

Example 138b

A mixture of example 138a (0.05 g, 0.105 mmol), 2, 4-difluorophenol (0.016 g,0.126 mmol) and cesium carbonate (0.069 g, 0.211 mmol) in DMSO (1mL) was heated at 120 deg.C for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three more times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative HPLC (10-80% acetonitrile/0.1% TFA/water) to give the title compound (0.036 g, 0.084 mmol, 79% yield).

Example 139

4- [2- (4-chlorobenzoyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 139 was prepared according to the procedure used for preparation example 95d, substituting (2-bromophenyl) (4-chlorophenyl) methanone for example 95c to provide the title compound.

Example 140

4- {2- [ (4-chlorophenyl) (hydroxy) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

A mixture of example 139 (0.05 g,0.138 mmol) and sodium tetrahydroborate (2) (5.21 mg,0.138 mmol) in tetrahydrofuran (2mL) was heated at 60 ℃ for 3 h. The solvent was removed and the residue was purified by reverse phase preparative HPLC (10-80% acetonitrile/0.1% TFA/water) to give the title compound (0.042 g, 0.115 mmol, 84% yield).

Example 141

N- [3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (pyrimidin-5-yloxy) phenyl ] ethanesulfonamide

Example 141a

6-methyl-4- (5-nitro-2- (pyrimidin-5-yloxy) phenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparation example 141a was prepared according to the procedure used for preparation example 2b, substituting pyrimidin-5-ol for phenol to provide the title compound.

Example 141b

4- (5-amino-2- (pyrimidin-5-yloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 141b was prepared according to the procedure used to prepare example 3, substituting example 141a for example 2b to provide the title compound.

Example 141c

Example 141c was prepared according to the procedure used for the preparation of example 4 (method a), substituting example 141b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride to provide the title compound.

Example 142

N- {3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- [ (1-methyl-1H-pyrazol-5-yl) methoxy ] phenyl } ethanesulfonamide

Example 142a

6-methyl-4- (2- ((1-methyl-1H-pyrazol-5-yl) methoxy) -5-nitrophenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 142a was prepared according to the procedure used for the preparation of example 29a, substituting (1-methyl-1H-pyrazol-5-yl) methanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 142b

4- (5-amino-2- ((1-methyl-1H-pyrazol-5-yl) methoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 142b was prepared according to the procedure used to prepare example 3, substituting example 142a for example 2b to provide the title compound.

Example 142c

Example 142c was prepared according to the procedure used for the preparation of example 4 (method a), substituting example 142b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride to provide the title compound.

Example 143

N- {4- [ (1, 3-dimethyl-1H-pyrazol-5-yl) methoxy ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl } ethanesulfonamide

Example 143a

4- (2- ((1, 3-dimethyl-1H-pyrazol-5-yl) methoxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 143a was prepared according to the procedure used for the preparation of example 29a, substituting (1, 3-dimethyl-1H-pyrazol-5-yl) methanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 143b

4- (5-amino-2- ((1, 3-dimethyl-1H-pyrazol-5-yl) methoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 143b was prepared according to the procedure used to prepare example 3, substituting example 143a for example 2b to provide the title compound.

Example 143c

Example 143c was prepared according to the procedure used for the preparation of example 4 (method a), substituting example 143b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride to provide the title compound.

Example 144

N- [4- (2, 2-dimethylpropoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Example 144a

6-methyl-4- (2- (neopentyloxy) -5-nitrophenyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Preparation example 144a was prepared according to the procedure used for preparation example 29a, substituting 2, 2-dimethylpropan-1-ol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 144b

4- (5-amino-2- (neopentyloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 144b was prepared according to the procedure used to prepare example 3, substituting example 144a for example 2b to provide the title compound.

Example 144c

Example 144c was prepared according to the procedure used for the preparation of example 4 (method a), substituting example 144b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride to provide the title compound.

Example 145

N- [4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Example 145a

4- (2- (cyclopropylmethoxy) -5-nitrophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 145a was prepared according to the procedure used for the preparation of example 29a, substituting cyclopropylmethanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 145b

4- (5-amino-2- (cyclopropylmethoxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 145b was prepared according to the procedure used to prepare example 3, substituting example 145a for example 2b to provide the title compound.

Example 145c

Example 145c was prepared according to the procedure used for the preparation of example 4 (method a) substituting example 145b for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride to provide the title compound.

Example 146

4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide

Example 146a

4- (2, 4-Difluorophenoxy) -3-nitrobenzenesulfonamide

A solution of 2, 4-difluorophenol (5.39 g, 41.4 mmol) in N, N-dimethylformamide (34.5 mL) was cooled to 10 ℃ and treated portionwise with sodium hydride (1.66 g, 41.4 mmol). After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (2.28 g, 10.36 mmol) was added portionwise. The reaction mixture was stirred at ambient temperature for 1.5 h, diluted into ethyl acetate and quenched with 0.5M HCl to pH 6. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to provide the title compound (3.24 g, 95%).

Example 146b

3-amino-4- (2, 4-difluorophenoxy) benzenesulfonamide

Example 146a (3.24 g, 9.81 mmol), iron (2.74 g, 49.1 mmol) and ammonium chloride (0.787 g, 14.72 mmol) were stirred in a mixture of tetrahydrofuran (21 mL), ethanol (21 mL) and water (7 mL) at 95 ℃ for 3 h. The mixture was filtered through a nylon membrane and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.81 g, 95%).

Example 146c

4- (2, 4-Difluorophenoxy) -3-iodobenzenesulfonamide

To a solution of example 146b (2.8 g, 9.32 mmol) in dioxane (20mL) was added concentrated hydrochloric acid (40 mL, 9.32 mmol) at 0 ℃. The mixture was stirred for 15 minutes and a solution of sodium nitrite (0.772 g, 11.19 mmol) in water (10mL) was added. The mixture was stirred at 0 ℃ for 1 hour. A solution of potassium iodide (3.10 g, 18.7 mmol) in water (10mL) was added and stirring continued at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium thiosulfate, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-60% ethyl acetate/hexanes) to provide the title compound (2.24 g, 58.4% yield).

Example 146d

A suspension of example 146c (111 mg, 0.270 mmol), example 6a (150mg, 0.351 mmol), tetrakis (triphenylphosphine) palladium (0) (31.2 mg, 0.027 mmol) and cesium fluoride (123mg,0.810 mmol) in a mixture of 1,2 dimethoxyethane (4.6 mL) and methanol (2.3 mL) was heated at 150 ℃ under microwave conditions for 5 minutes. The reaction mixture was partitioned between ethyl acetate (75 mL) and 50% aqueous sodium chloride (75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. To the residue in dioxane (4 mL) was added a solution of lithium hydroxide hydrate (113 mg, 2.7mmol) in water (1mL) and the mixture was heated at 120 ℃ for 30 minutes under microwave conditions. The reaction mixture was partitioned between ethyl acetate (75 mL) and water (75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0.5-10% methanol/dichloromethane) to provide the title compound (74 mg, 63.5% yield).

Example 147

4- [2- (cyclohexylamino) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 147a

2-bromo-N-cyclohexyl-4- (methylsulfonyl) aniline

A mixture of 2-bromo-1-fluoro-4- (methylsulfonyl) benzene (0.05 g, 0.198 mmol) and cyclohexylamine (0.059 g, 0.593 mmol) in a vial in dioxane (1mL) was capped and heated at 110 ℃ for three days. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 40% ethyl acetate/hexanes to give the title compound (0.044 g, 0.132 mmol, 67.0% yield).

Example 147b

Example 147b was prepared according to the procedure used for the preparation of example 95d, substituting example 147a for example 95c to provide the title compound.

Example 148

4- [ 5-amino-2- (2, 4-difluorophenoxy) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one

Example 148a

Prepare example 148a according to the procedure used to prepare example 2b, substituting 2-bromo-1-fluoro-4-nitrobenzene for example 2a and 2, 4-difluorophenol for phenol, respectively, to provide the title compound.

Example 148b

3-bromo-4- (2, 4-difluorophenoxy) aniline

Example 148b was prepared according to the procedure used to prepare example 3, substituting example 148a for example 2b to provide the title compound.

Example 148c

4- (2, 4-Difluorophenoxy) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline

Example 148c was prepared according to the procedure used for the preparation of example 6a, substituting example 148b for example 1e to provide the title compound.

Example 148d

Prepare example 148d according to the procedure used for the preparation of example 95d, substituting example 80b for example 95c and example 148c for example 6a, respectively, to provide the title compound as a TFA salt.

Example 149

4- [2- (2-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 149 was prepared according to the procedure used for the preparation of example 138b substituting 2-fluorophenol for 2, 4-difluorophenol to provide the title compound.

Example 150

4- [2- (3-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 150 was prepared according to the procedure used to prepare example 138b substituting 3-fluorophenol for 2, 4-difluorophenol to provide the title compound.

Example 151

4- [2- (4-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 151 was prepared according to the procedure used to prepare example 138b substituting 4-fluorophenol for 2, 4-difluorophenol to provide the title compound.

Example 152

4- [2- (2-chlorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 152 was prepared according to the procedure used for the preparation of example 138b substituting 2-chlorophenol for 2, 4-difluorophenol to provide the title compound.

Example 153

4- [2- (3-chlorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparative example 153 was prepared according to the procedure used for preparative example 138b substituting 3-chlorophenol for 2, 4-difluorophenol to provide the title compound.

Example 154

4- [2- (4-chlorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 154 was prepared according to the procedure used for the preparation of example 138b, substituting 4-chlorophenol for 2, 4-difluorophenol to provide the title compound.

Example 155

3- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] benzonitrile

Preparation example 155 was prepared according to the procedure used for preparation example 138b substituting 3-cyanophenol for 2, 4-difluorophenol to provide the title compound.

Example 156

4- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] benzonitrile

Example 156 was prepared according to the procedure used for the preparation of example 138b substituting 4-cyanophenol for 2, 4-difluorophenol to provide the title compound.

Example 157

6-methyl-4- {5- (methylsulfonyl) -2- [3- (trifluoromethyl) phenoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 157 was prepared according to the procedure used for the preparation of example 138b, substituting 3-trifluoromethylphenol for 2, 4-difluorophenol to provide the title compound.

Example 158

4- [2- (cyclopropylmethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Cyclopropylmethanol (0.014 g, 0.19 mmol)/tetrahydrofuran (2mL) was treated with 60% sodium hydride (10.11 mg, 0.253 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes. To this solution was added example 138a (0.03 g, 0.063 mmol). The reaction mixture was heated at 60 ℃ for 16 hours. The solvent was removed and the residue was purified by preparative HPLC (C18, 10-80% CH)₃CN/water (0.1% TFA)) to give the title compound (0.012g, 0.032mmol, 51.0% yield).

Example 159

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-4-yl) phenyl ] methanesulfonamide

Example 159 was prepared according to the procedure used to prepare example 4 (method a) substituting example 148d for example 3 to provide the title compound.

Example 160

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-4-yl) phenyl ] ethanesulfonamide

Example 160 was prepared according to the procedure used for the preparation of example 4 (method a), substituting example 148d for example 3 and ethanesulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound.

Example 161

4- [2- (isoquinolin-5-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 161 was prepared according to the procedure used for preparation example 138b, substituting isoquinolin-5-ol for 2, 4-difluorophenol to provide the title compound as a TFA salt.

Example 162

6-methyl-4- [5- (methylsulfonyl) -2- (quinolin-6-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 162 according to the procedure used for prepare example 138b, substituting quinolin-6-ol for 2, 4-difluorophenol to provide the title compound as a TFA salt.

Example 163

4- {2- [ 2-chloro-5- (trifluoromethyl) phenoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 163 was prepared according to the procedure used for the preparation of example 138b, substituting 2-chloro-5-trifluoromethylphenol for 2, 4-difluorophenol to provide the title compound.

Example 164

4- {2- [ 2-fluoro-5- (trifluoromethyl) phenoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 164 was prepared according to the procedure used for the preparation of example 138b substituting 2-fluoro-5-trifluoromethylphenol for 2, 4-difluorophenol to provide the title compound.

Example 165

2- {4- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] phenyl } acetamide

Example 165 was prepared according to the procedure used for the preparation of example 138b substituting 2- (4-hydroxyphenyl) acetamide for 2, 4-difluorophenol to provide the title compound.

Example 166

4- [2- (3-Aminophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparative example 166 was prepared according to the procedure used for preparative example 138b substituting 3-aminophenol for 2, 4-difluorophenol to provide the title compound as a TFA salt.

Example 167

6-methyl-4- [5- (methylsulfonyl) -2- (tetrahydrofuran-3-ylamino) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 167a

N- (2-bromo-4- (methylsulfonyl) phenyl) tetrahydrofuran-3-amine

Preparation example 167a was prepared according to the procedure used for preparation example 147a, substituting tetrahydrofuran-3-amine for cyclohexylamine to provide the title compound.

Example 167b

Example 167b was prepared according to the procedure used for the preparation of example 95d, substituting example 167a for example 95c to provide the title compound.

Example 168

4- [2- (2, 4-Difluorophenoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 168a

(3-bromo-4-fluorophenyl) (ethyl) sulfane

A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.79 mmol) and sodium hydroxide (3.95 mL,19.73 mmol) in MeOH was stirred at 0 deg.C for 10 min. To this solution was added iodoethane (1.803 mL, 22.54 mmol). The reaction mixture was stirred at ambient temperature for 6 hours. The solvent was removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted three more times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (4.35 g, 18.50 mmol, 98% yield). It was used directly in the next reaction.

Example 168b

2-bromo-4- (ethylsulfonyl) -1-fluorobenzene

Example 168a (4.4 g, 18.71 mmol) in dichloromethane (250 mL) was cooled to 0 ℃. The solution was treated batchwise with mCPBA (10.15 g, 41.2 mmol). The reaction was stirred at ambient temperature for 6 hours. The solids from the reaction mixture were removed by filtration. The filtrate was washed several times with saturated aqueous sodium bicarbonate solution. The aqueous layer was then extracted three times with additional dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give the title compound (4.4 g,16.47 mmol, 88% yield).

Example 168c

4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 168c was prepared according to the procedure used for the preparation of example 138a, substituting example 168b for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene to provide the title compound.

Example 168d

Example 168d was prepared according to the procedure used to prepare example 138b, substituting example 168c for example 138a to provide the title compound.

Example 169

4- {2- [ (4, 4-Difluorocyclohexyl) oxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 169 according to the procedure used to prepare example 158, replace example 138a with example 168c and cyclopropylmethanol with 4, 4-difluorocyclohexanol, respectively, to provide the title compound.

Example 170

4- {5- (ethylsulfonyl) -2- [ (1-methylpiperidin-4-yl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 170 according to the procedure used for preparing example 158, substituting example 168c for example 138a and 1-methylpiperidin-4-ol for cyclopropylmethanol, respectively, to provide the title compound as a TFA salt.

Example 171

4- [2- (2,1, 3-benzothiadiazol-4-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 171 was prepared according to the procedure used for preparation example 138b, substituting benzo [ c ] [1,2,5] thiadiazol-5-ol for 2, 4-difluorophenol to provide the title compound.

Example 172

4- [2- (isoquinolin-7-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 172 was prepared according to the procedure used for the preparation of example 138b substituting isoquinolin-7-ol for 2, 4-difluorophenol to provide the title compound.

Example 173

4- [2- (2, 5-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 173 was prepared according to the procedure used for the preparation of example 138b substituting 2, 5-difluorophenol for 2, 4-difluorophenol to provide the title compound.

Example 174

4- [2- (3, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 174 was prepared according to the procedure used to prepare example 138b substituting 3, 4-difluorophenol for 2, 4-difluorophenol to provide the title compound.

Example 175

6-methyl-4- {5- (methylsulfonyl) -2- [ (1-oxo-2, 3-dihydro-1H-inden-4-yl) oxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 175 was prepared according to the procedure used for preparation example 138b, substituting 4-hydroxy-2, 3-dihydro-1H-inden-1-one for 2, 4-difluorophenol to provide the title compound.

Example 176

4- [2- (3, 5-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 176 was prepared according to the procedure used for the preparation of example 138b substituting 3, 5-difluorophenol for 2, 4-difluorophenol to provide the title compound.

Example 177

6-methyl-4- [2- (4-methylphenoxy) -5- (methylsulfonyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 177 was prepared according to the procedure used for the preparation of example 138b, substituting 4-methylphenol for 2, 4-difluorophenol to provide the title compound.

Example 178

4- [2- (2-methoxyphenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 178 was prepared according to the procedure used for the preparation of example 138b substituting 2-methoxyphenol for 2, 4-difluorophenol to provide the title compound.

Example 179

6-methyl-4- {2- [ (2-methylpyridin-3-yl) oxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 179 according to the procedure used for prepare example 138b, substituting 2-methylpyridin-3-ol for 2, 4-difluorophenol to provide the title compound.

Example 180

4- {2- [3- (dimethylamino) phenoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 180 was prepared according to the procedure used for the preparation of example 138b substituting 3- (dimethylamino) phenol for 2, 4-difluorophenol to provide the title compound.

Example 181

6-methyl-4- {5- (methylsulfonyl) -2- [ (1-oxo-2, 3-dihydro-1H-inden-5-yl) oxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 181 was prepared according to the procedure used for preparation example 138b substituting 5-hydroxy-2, 3-dihydro-1H-inden-1-one for 2, 4-difluorophenol to provide the title compound.

Example 182

6-methyl-4- {5- (methylsulfonyl) -2- [ (3-oxo-2, 3-dihydro-1H-inden-5-yl) oxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 182 according to the procedure used to prepare example 138b, substituting 6-hydroxy-2, 3-dihydro-1H-inden-1-one for 2, 4-difluorophenol to provide the title compound.

Example 183

2- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] benzonitrile

Example 183 was prepared according to the procedure used for the preparation of example 138b, substituting 2-cyanophenol for 2, 4-difluorophenol to provide the title compound.

Example 184

4- [2- (3-chloro-2-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 184 was prepared according to the procedure used for the preparation of example 138b substituting 2-fluoro-3 chlorophenol for 2, 4-difluorophenol to provide the title compound.

Example 185

6-methyl-4- [5- (methylsulfonyl) -2- (naphthalen-1-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 185 was prepared according to the procedure used for the preparation of example 138b substituting naphthalen-1-ol for 2, 4-difluorophenol to provide the title compound.

Example 186

4- [2- (2-fluoro-5-methylphenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparative example 186 was prepared according to the procedure used for preparative example 138b substituting 2-fluoro-5 methylphenol for 2, 4-difluorophenol to provide the title compound.

Example 187

4- [2- (5-fluoro-2-methylphenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 187 was prepared according to the procedure used to prepare example 138b substituting 5-fluoro-2-methylphenol for 2, 4-difluorophenol to provide the title compound.

Example 188

6-methyl-4- [5- (methylsulfonyl) -2- (quinolin-7-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 188 according to the procedure used to prepare example 138b, substituting quinolin-7-ol for 2, 4-difluorophenol to provide the title compound.

Example 189

4- [2- (4-chloro-3-fluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 189 was prepared according to the procedure used to prepare example 138b, substituting 3-fluoro-4-chlorophenol for 2, 4-difluorophenol to provide the title compound.

Example 190

6-methyl-4- [5- (methylsulfonyl) -2- (pyridin-3-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 190 was prepared according to the procedure used for the preparation of example 138b substituting pyridin-3-ol for 2, 4-difluorophenol to provide the title compound.

Example 191

4- [2- (2, 3-dihydro-1H-inden-5-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 191 was prepared according to the procedure used to prepare example 138b, substituting 2, 3-dihydro-1H-inden-5-ol for 2, 4-difluorophenol to provide the title compound.

Example 192

6-methyl-4- {5- (methylsulfonyl) -2- [4- (propan-2-yl) phenoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 192 was prepared according to the procedure used for the preparation of example 138b substituting 4-isopropylphenol for 2, 4-difluorophenol to provide the title compound.

Example 193

4- [2- (isoquinolin-8-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 193 according to the procedure used to prepare example 138b, substituting isoquinolin-8-ol for 2, 4-difluorophenol to provide the title compound.

Example 194

6-methyl-4- [5- (methylsulfonyl) -2- (3,4, 5-Trifluorophenoxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 194 was prepared according to the procedure used to prepare example 138b substituting 3,4, 5-trifluorophenol for 2, 4-difluorophenol to provide the title compound.

Example 195

4- (2-benzylphenyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 195 was prepared according to the procedure used for the preparation of example 95d, substituting 1-benzyl-2-bromobenzene for example 95c to provide the title compound.

Example 196

4- (Biphenyl-2-yl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 196 was prepared according to the procedure used for the preparation of example 95d, substituting biphenyl-2-ylboronic acid for example 6a and example 1e for example 95c to provide the title compound.

Example 197

4- [2- (1, 4-dioxaspiro [4.5] decan-8-yloxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 197 according to the procedure used to prepare example 158, substituting example 168c for example 138a and 1, 4-dioxaspiro [4.5] decan-8-ol for cyclopropylmethanol, respectively, to provide the title compound.

Example 198

4- [2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 198 was prepared according to the procedure used to prepare example 158 substituting example 168c for example 138a to provide the title compound.

Example 199

4- {5- (ethylsulfonyl) -2- [ (4-oxocyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 197 (0.192 g, 0.406 mmol) was treated with a 4.0N solution of hydrochloric acid in dioxane (1.016 mL, 4.06 mmol), tetrahydrofuran (10mL) and water (2 mL). The reaction mixture was heated at 60 ℃ for 2 hours. The solvent was removed and the product was purified by reverse phase HPLC (C18, 10-80% CH)₃CN/water (0.1% TFA)) to give the title compound (0.154 g, 0.359 mmol, 88% yield).

Example 200

4- {2- [ (cyclopropylmethyl) amino ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 200a

2-bromo-N- (cyclopropylmethyl) -4- (ethylsulfonyl) aniline

Example 200a was prepared according to the procedure used for the preparation of example 147a, substituting cyclopropylmethylamine for cyclohexylamine and substituting example 168b for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene to provide the title compound.

Example 200b

Example 200b was prepared according to the procedure used for the preparation of example 95d, substituting example 200a for example 95c to provide the title compound.

Example 201

6-methyl-4- {5- (methylsulfonyl) -2- [ (tetrahydrofuran-3-ylmethyl) amino ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 201a

2-bromo-4- (ethylsulfonyl) -N- ((tetrahydrofuran-3-yl) methyl) aniline

Example 200a was prepared according to the procedure used to prepare example 147a, substituting (tetrahydrofuran-3-yl) methylamine for cyclohexylamine and example 168b for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene to provide the title compound.

Example 201b

Example 201b was prepared according to the procedure used to prepare example 95d, substituting example 201a for example 95c to provide the title compound.

Example 202

4- {5- (ethylsulfonyl) -2- [ (cis-4-hydroxycyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

A mixture of example 199(0.052 g, 0.121 mmol) and sodium tetrahydroborate (6.89 mg,0.182 mmol) in tetrahydrofuran (5 mL) was heated at 60 deg.C for 2 hours. The solvent was removed and the solid was treated with MeOH and a few drops of TFA. By preparative HPLC (C18, 10-80% CH)₃CN/water (0.1% TFA)) to give the title compound (second elution peak, 0.036 g, 0.084 mmol, 68.9% yield).

Example 203

4- {5- (ethylsulfonyl) -2- [ (trans-4-hydroxycyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

During the preparation of example 202, the title compound was isolated as the minimum product (first eluting peak).

Example 204

4- [2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one

Example 204a

2-bromo-1- (cyclopropylmethoxy) -4- (ethylsulfonyl) benzene

Example 204a was prepared according to the procedure used to prepare example 158 substituting example 168b for example 138a to provide the title compound.

Example 204b

2- (2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane

Example 204b was prepared according to the procedure used for the preparation of example 6a, substituting example 204a for example 1e to provide the title compound.

Example 204c

Example 204c was prepared according to the procedure used for the preparation of example 95d, substituting example 80b for example 95c and example 204b for example 6a, respectively, to provide the title compound.

Example 205

6-methyl-4- [5- (methylsulfonyl) -2- (tetrahydrofuran-3-yloxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 205 was prepared according to the procedure used for preparation example 158, substituting tetrahydrofuran-3-ol for cyclopropylmethanol to provide the title compound.

Example 206

4- {2- [ (3-Fluorooxetan-3-yl) methoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 206 was prepared according to the procedure used for preparation example 158, substituting (3-fluorooxetan-3-yl) methanol for cyclopropylmethanol to provide the title compound.

Example 207

6- (cyclopropylmethoxy) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

Example 207a

5-bromo-6- (cyclopropylmethoxy) pyridine-3-sulfonamide

Example 207a was prepared according to the procedure used for the preparation of example 29a, substituting 86a for example 2a and cyclopropylmethanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 207b

Example 207b was prepared according to the procedure used for the preparation of example 95d, substituting example 207a for example 95c to provide the title compound.

Example 208

6- (cyclopropylmethoxy) -N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

During the preparation of example 207b, the title compound was isolated as minimal product.

Example 209

6- [ (cyclopropylmethyl) amino ] -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

Example 209a

5-bromo-6- (cyclopropylmethylamino) pyridine-3-sulfonamide

Preparation example 209a was prepared according to the procedure used for preparation example 96a, substituting cyclopropylmethylamine for cyclohexylamine to provide the title compound.

Example 209b

Example 209b was prepared according to the procedure used to prepare example 95d, substituting example 209a for example 95c to provide the title compound.

Example 210

6- [ (cyclopropylmethyl) amino ] -N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

During the preparation of example 209b, the title compound was isolated as minimal product.

Example 211

4- {5- (ethylsulfonyl) -2- [ (cis-4-hydroxy-4-methylcyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 199(0.052 g, 0.121 mmol)/tetrahydrofuran was treated with 3.0M methylmagnesium bromide/tetrahydrofuran (0.485 mL, 0.485 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed and the solid was treated with MeOH and a few drops of TFA. Preparative HPLC by reverse phase (C18, 10-80% CH)₃CN/water (0.1% TFA)) to give the title compound (first elution peak, 0.018 g, 0.040 mmol, 33.4% yield).

Example 212

4- {5- (ethylsulfonyl) -2- [ (trans-4-hydroxy-4-methylcyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

During the preparation of example 211, the title compound was isolated as the least product (second eluting peak).

Example 213

4- [2- (cyclobutyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

A4 mL vial was charged with a stir bar, a solution of example 138a (30 mg, 0.063 mmol) in tetrahydrofuran (1mL), a solution of cyclobutanol (32 mg,7 equiv., 0.46 mmol) in tetrahydrofuran (1mL), and pure sodium hydride (19 mg,7 equiv., 0.46 mmol). The reaction mixture was stirred at 60 ℃ for 16 hours. The crude material was filtered, concentrated and purified by reverse phase HPLC (C18, 10-100% CH)₃CN/water (0.1% TFA)) to afford the title compound.

Example 214

4- [2- (cyclopentylmethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation 214 was prepared according to the procedure used for preparation 213 substituting cyclobutanol with cyclopentylmethanol to provide the title compound.

Example 215

4- [2- (cyclohexyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 215 was prepared according to the procedure used for the preparation of example 213 substituting cyclohexanol for cyclobutanol to provide the title compound.

Example 216

4- [2- (cyclopentyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 216 was prepared according to the procedure used for preparation example 213 substituting cyclopentanol for cyclobutanol to provide the title compound.

Example 217

6-methyl-4- [5- (methylsulfonyl) -2- (tetrahydrofuran-3-ylmethoxy) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 217 was prepared according to the procedure used for preparation example 213 substituting cyclobutanol with (tetrahydrofuran-3-yl) methanol to provide the title compound.

Example 218

6-methyl-4- {5- (methylsulfonyl) -2- [2- (2-oxoimidazolidin-1-yl) ethoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation 218 was prepared according to the procedure used for preparation 213 substituting 1- (2-hydroxyethyl) imidazolidin-2-one for cyclobutanol to provide the title compound.

Example 219

4- [2- (2-Cyclopropylethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 219 was prepared according to the procedure used for the preparation of example 213 substituting 2-cyclopropylethanol for cyclobutanol to provide the title compound.

Example 220

4- [2- (cycloheptyloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 220 was prepared according to the procedure used for the preparation of example 213 substituting cycloheptanol for cyclobutanol to provide the title compound.

Example 221

6-methyl-4- [2- (2-methylpropoxy) -5- (methylsulfonyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 221 was prepared according to the procedure used for preparation example 213 substituting 2-methylpropan-1-ol for cyclobutanol to provide the title compound.

Example 222

6-methyl-4- [2- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } -5- (methylsulfonyl) phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 222 was prepared according to the procedure used for preparation example 213 substituting (S) - (1-methylpyrrolidin-2-yl) methanol for cyclobutanol to provide the title compound.

Example 223

6-methyl-4- {2- [ (2-methylcyclopropyl) methoxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 223 was prepared according to the procedure used for the preparation of example 213 substituting (2-methylcyclopropyl) methanol for cyclobutanol to provide the title compound.

Example 224

4- [2- (cyclohexylmethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 224 was prepared according to the procedure used for preparation example 213 substituting cyclobutanol with cyclohexylmethanol to provide the title compound.

Example 225

6-methyl-4- {2- [2- (1-methylpyrrolidin-2-yl) ethoxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 225 was prepared according to the procedure used for the preparation of example 213 substituting 2- (1-methylpyrrolidin-2-yl) ethanol for cyclobutanol to provide the title compound.

Example 226

6-methyl-4- [5- (methylsulfonyl) -2- { [ (2R) -5-oxopyrrolidin-2-yl ] methoxy } phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 226 was prepared according to the procedure used for preparation example 213 substituting (R) -5- (hydroxymethyl) pyrrolidin-2-one for cyclobutanol to provide the title compound.

Example 227

6-methyl-4- {5- (methylsulfonyl) -2- [2- (morpholin-4-yl) ethoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 227 was prepared according to the procedure used for preparation example 213 substituting 2-morpholinoethanol for cyclobutanol to provide the title compound.

Example 228

6-methyl-4- [5- (methylsulfonyl) -2- { [ (2S) -5-oxopyrrolidin-2-yl ] methoxy } phenyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 228 was prepared according to the procedure used for preparation example 213 substituting (S) -5- (hydroxymethyl) pyrrolidin-2-one for cyclobutanol to provide the title compound.

Example 229

4- {2- [ (1-tert-butoxyprop-2-yl) oxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 229 was prepared according to the procedure used for the preparation of example 213 substituting 1-tert-butoxypropan-2-ol for cyclobutanol to provide the title compound.

Example 230

4- {2- [ (1S,4R) -bicyclo [2.2.1] hept-2-ylmethoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 230 was prepared according to the procedure used for preparation example 213 substituting (1S,4R) -bicyclo [2.2.1] hept-2-ylmethanol for cyclobutanol to provide the title compound.

Example 231

6-methyl-4- {2- [ (1-methylcyclopropyl) methoxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 231 was prepared according to the procedure used for preparation example 213 substituting cyclobutanol with (1-methylcyclopropyl) methanol to provide the title compound.

Example 232

6-methyl-4- {5- (methylsulfonyl) -2- [2- (2-oxopyrrolidin-1-yl) ethoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 232 was prepared according to the procedure used for preparation example 213 substituting 1- (2-hydroxyethyl) pyrrolidin-2-one for cyclobutanol to provide the title compound.

Example 233

6-methyl-4- {2- [ (4-methylcyclohexyl) oxy ] -5- (methylsulfonyl) phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 233 was prepared according to the procedure used for the preparation of example 213 substituting cyclobutanol with 4-methylcyclohexanol to provide the title compound.

Example 234

4- [2- (cyclobutylmethoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 234 was prepared according to the procedure used for the preparation of example 213 substituting cyclobutylmethanol for cyclobutanol to provide the title compound.

Example 235

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] cyclopropanesulfonamide

Example 235 was prepared according to the procedure used for the preparation of example 4 (method a), substituting example 27c for example 3 and cyclopropanesulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound.

Example 236

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2-methoxyethanesulfonamide

Example 236 was prepared according to the procedure used to prepare example 4, method a, substituting example 27b for example 3 and 2-methoxyethanesulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound.

Example 237

6-methyl-4- {5- (methylsulfonyl) -2- [ tricyclo [3.3.1.1^3,7]Decyl-2-yloxy]Phenyl } -1, 6-dihydro-7H-pyrrolo [2, 3-c)]Pyridin-7-ones

Preparation example 237 was prepared according to the procedure used for preparation example 158 substituting 2-adamantanol for cyclopropylmethanol to provide the title compound.

Example 238

4- [ (cyclopropylmethyl) amino ] -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide

Example 238a

3-bromo-4- (cyclopropylmethylamino) benzenesulfonamide

Prepare example 238a according to the procedure used to prepare example 96a, substituting cyclopropylmethylamine for cyclohexylamine and 3-bromo-4-fluorobenzenesulfonamide for example 86a, respectively, to provide the title compound.

Example 238b

Example 238b was prepared according to the procedure used for the preparation of example 95d, substituting example 238a for example 95c to provide the title compound.

Example 239

4- [ (cyclopropylmethyl) amino ] -N-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide

In the preparation of example 238b, the title compound was isolated as the minimum product.

Example 240

4- {2- [ (2, 2-Difluorocyclopropyl) methoxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 240a

2-bromo-1- ((2, 2-difluorocyclopropyl) methoxy) -4- (ethylsulfonyl) benzene

Prepare example 240a according to the procedure used to prepare example 158, replace example 138a with example 168b and cyclopropylmethanol with (2, 2-difluorocyclopropyl) methanol, respectively, to provide the title compound.

Example 240b

Example 240b was prepared according to the procedure used for the preparation of example 95d, substituting example 240a for example 95c to provide the title compound.

Example 241

4- (4-bromo-2-methoxyphenyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 241a

4- (4-bromo-2-methoxyphenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

The product from example 6a (0.2 g, 0.467 mmol), 4-bromo-1-iodo-2-methoxybenzene (0.16g, 0.514 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.013 g, 0.014 mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoadamantane (0.3 g, 0.014 mmol) were combined014 g, 0.047 mmol) and tripotassium phosphate (0.347 g,1.634 mmol), and sparged with argon for 15 minutes. At the same time, a 4:1 dioxane/water (7.5 mL) solution was sparged with nitrogen for 15 minutes and transferred to the reaction vessel under argon via syringe. The mixture was stirred at ambient temperature for 20 minutes and the layers were separated between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution and dried (Na)₂SO₄) Treated with 3-mercaptopropyl-functionalized silica gel for twenty minutes, filtered and concentrated. Purification by chromatography (silica gel, 10-80% ethyl acetate/heptane) gave the title compound (0.2 g, 88%).

Example 241b

The product from example 241a (0.2 g, 0.410 mmol), potassium hydroxide (0.460 g, 8.21 mmol) and cetyltrimethylammonium bromide (7.48 mg, 0.021mmol) were mixed in dioxane (8 mL) and water (4 mL) and heated at 100 ℃ for 18 hours. The reaction mixture was partitioned between equal volumes of ethyl acetate and water and the pH was adjusted to pH 7 by careful addition of concentrated HCl. The organic layer was separated and washed three times with saturated aqueous sodium chloride solution and dried (Na)₂SO₄) Filtered and concentrated. Purification by trituration in dichloromethane afforded the title compound (0.1 g, 73%).

Example 242

6- (2, 4-Difluorophenoxy) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

Example 242a

5-bromo-6- (2, 4-difluorophenoxy) pyridine-3-sulfonamide

A mixture of example 86a (0.543 g, 2mmol), 2, 4-difluorophenol (0.390 g, 3.00mmol) and cesium carbonate (1.955 g, 6.00 mmol) in DMSO (10mL) was heated at 110 deg.C for 16 h. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (3:2 ethyl acetate/hexanes) to give the title compound (0.53 g, 1.451 mmol, 72.6% yield).

Example 242b

Example 242b was prepared according to the procedure used to prepare example 95d, substituting example 242a for example 95c to provide the title compound.

Example 243

4- {2- (cyclopropylmethoxy) -5- [ (trifluoromethyl) sulfonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 243a

(3-bromo-4-fluorophenyl) (trifluoromethyl) sulfane

3-bromo-4-fluorobenzenethiol (2.071 g,10 mmol)/dimethylformamide (10mL) was treated with 60% sodium hydride (0.480 g, 12.00 mmol). The solution was stirred at room temperature for 10 minutes. Trifluoroiodomethane (2.74g, 14.00 mmol) was released into the balloon using a three-way piston. A balloon was then placed on the flask and trifluoroiodomethane was released into the reaction. After 1 hour, all the contents of the balloon were released. And the balloon was again filled with 2.74g of trifluoroiodomethane. The reaction mixture was stirred for 16 hours. The reaction mixture was poured into water and extracted several times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The oil obtained was used directly in the next reaction.

Example 243b

2-bromo-1-fluoro-4- (trifluoromethylsulfonyl) benzene

Example 243a (2.75 g, 10.00 mmol) in acetonitrile (4 mL), carbon tetrachloride (4.00 mL) and water (16.00mL) were treated with sodium periodate (6.42 g, 30.0 mmol) and ruthenium (III) chloride hydrate (0.023 g,0.100 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. Dichloromethane (100 mL) was added to the reaction mixture, which was then filtered through a pad of filter. The filtrate was treated with saturated sodium bicarbonate (50 mL). The organic layer was separated. The aqueous layer was then extracted three times with additional dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with 5% ethyl acetate/hexanes to give 2.14 g of the title compound (7.85 mmol, 79% yield).

Example 243c

2-bromo-1- (cyclopropylmethoxy) -4- (trifluoromethylsulfonyl) benzene

Example 243c was prepared according to the procedure used to prepare example 158, substituting example 243b for example 138a to provide the title compound.

Example 243d

Example 243d was prepared according to the procedure used to prepare example 95d, substituting example 243c for example 95c to provide the title compound.

Example 244

4- {2- [ (cyclopropylmethyl) amino ] -5- [ (trifluoromethyl) sulfonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 244a

Prepare example 244a according to the procedure used for prepare example 96a, substituting cyclopropylmethylamine for cyclohexylamine and example 243b for example 86a, respectively, to provide the title compound.

Example 244b

Example 244b was prepared according to the procedure used to prepare example 95d, substituting example 244a for example 95c to provide the title compound.

Example 245

6- [ (cyclopropylmethyl) amino ] -N, N-dimethyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

Example 245a

5-bromo-6- (cyclopropylmethylamino) -N, N-dimethylpyridine-3-sulfonamide

Prepare example 245a according to the procedure used for prepare example 96a, substituting cyclopropylmethylamine for cyclohexylamine and example 110a for example 86a, respectively, to provide the title compound.

Example 245b

Example 245b was prepared according to the procedure used for the preparation of example 95d, substituting example 245a for example 95c to provide the title compound.

Example 246

6- (2, 4-Difluorophenoxy) -N-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

In preparing example 242b, the title compound was isolated as the minimum product.

Example 247

4- [2- (cyclopropylmethoxy) -6-methylphenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 247a

2-bromo-1- (cyclopropylmethoxy) -3-methylbenzene

A250 mL flask with stir bar was charged with 2-bromo-3-methylphenol (2.86 g, 15.3 mmol), (bromomethyl) cyclopropane (1.80 mL, 18.6 mmol), and cesium carbonate (7.46 g, 22.9 mmol) in dimethylformamide (50 mL). The mixture was stirred at room temperature for 16 hours and then heated at 50 ℃ for 3 hours. The mixture was cooled to ambient temperature and the layers were separated between ethyl acetate (200 mL) and saturated aqueous sodium chloride (200 mL). The organics were washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (3.7 g, 100%).

Example 247b

4- (2- (cyclopropylmethoxy) -6-methylphenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 247b was prepared according to the procedure used to prepare example 7d, substituting the product of example 247a for the product of example 7c and stirring at 65 ℃ for 2.5 hours to provide the title compound.

Example 247c

4- (2- (cyclopropylmethoxy) -6-methylphenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 247c was prepared according to the procedure used to prepare example 4b, substituting the product of example 247b for the product of example 4a to provide the title compound.

Example 248

4- {5- (ethylsulfonyl) -2- [ (cis-4-methoxycyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 248a

2-bromo-4- (ethylsulfonyl) -1- (4-methoxycyclohexyloxy) benzene

4-methoxycyclohexanol (mixture of 70% cis and 30% trans isomers) (0.521 g,4.00 mmol) in dioxane (20mL) was treated with sodium hydride (0.240 g, 6.00 mmol). The reaction mixture was stirred for 10 minutes. To this solution was added example 168b (0.534 g,2 mmol). The reaction was heated at 60 ℃ for 16 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted more than twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 70:30 ethyl acetate/hexanes) to give the title compound (0.29 g, 38.4% yield).

Example 248b

Example 248b (second eluting peak) was prepared according to the procedure used for the preparation of example 95d, substituting example 248a for example 95c to provide the title compound.

Example 249

4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide

Example 249a

3-bromo-4- (cyclopropylmethoxy) benzenesulfonamide

Example 249a was prepared according to the procedure used to prepare example 29a, substituting 3-bromo-4-fluorobenzenesulfonamide for example 2a and cyclopropylmethanol for tetrahydro-2H-pyran-4-ol to provide the title compound.

Example 249b

Example 249b was prepared according to the procedure used to prepare example 95d, substituting example 249a for example 95c to provide the title compound.

Example 250

4- (cyclopropylmethoxy) -N-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide

In preparing example 249b, the title compound was isolated as the minimum product.

Example 251

N- [4- (cyclopropylmethoxy) -2-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Example 251a

2-bromo-1- (cyclopropylmethoxy) -3-methyl-4-nitrobenzene

Example 251a was prepared according to the procedure used for the preparation of example 247a, substituting 2-bromo-3-methyl-4-nitrophenol for 2-bromo-3-methylphenol to provide the title compound.

Example 251b

4- (6- (cyclopropylmethoxy) -2-methyl-3-nitrophenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 251b was prepared according to the procedure used to prepare example 7d, substituting the product of example 251a for the product of example 7c and stirring at 65 ℃ for 2.5 hours to provide the title compound.

Example 251c

4- (3-amino-6- (cyclopropylmethoxy) -2-methylphenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 251c was prepared according to the procedure used to prepare example 3, substituting the product of example 251b for the product of example 2b to provide the title compound.

Example 251d

N- (4- (cyclopropylmethoxy) -2-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) ethanesulfonamide

Prepare example 251d according to the procedure used for prepare example 4 (method a), replace example 3 with example 251c and methanesulfonyl chloride with ethanesulfonyl chloride, respectively, to provide the title compound.

Example 252

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide

Example 252a

1- (2, 4-Difluorophenoxy) -4- (methylsulfonyl) -2-nitrobenzene

A mixture of 1-fluoro-4- (methylsulfonyl) -2-nitrobenzene (20 g, 91mmol), 2, 4-difluorophenol (11.87 g, 91mmol) and potassium carbonate (12.6 g, 91mmol) in DMSO (90 mL) was heated at 120 ℃ for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide the title compound (28 g, 89% yield).

Example 252b

2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) aniline

A solution of example 252a (10.0 g, 30.4 mmol) in tetrahydrofuran (150 mL) was added to 10% Pd/C (1.616 g, 15.18 mmol) in a 250 mL flask and the mixture stirred at 40 ℃ for 24h under a 30 psi hydrogen atmosphere. The mixture was filtered through a nylon membrane and concentrated. The residue was purified by flash chromatography (silica gel, 70:30 ethyl acetate/hexanes) to provide the title compound (8.6 g, 55% yield).

Example 252c

1- (2, 4-Difluorophenoxy) -2-iodo-4- (methylsulfonyl) benzene

Example 252b (5.00 g,16.7 mmol) in dioxane (30mL) was treated with concentrated HCl (150 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 10 minutes. To this solution was added sodium nitrite (1.383 g, 20.05 mmol) in water (6 mL). The reaction mixture was stirred at 0 ℃ for 1 hour. To this solution was added potassium iodide (5.55 g, 33.4 mmol) in water (20 mL). The reaction mixture was stirred at 10 ℃ for 2 hours. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2:3 ethyl acetate/hexanes) to provide the title compound (8.9 g, 89% yield).

Example 252d

1-benzyl-6-methyl-7-oxo-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

A mixture of example 70e (2 g, 5.14 mmol), diamonodiboron (2.61 g,10.3 mmol), potassium acetate (1.11 g, 11.3 mmol tris (dibenzylideneacetone) dipalladium (0) (0.235 g, 0.257mmol) and 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (0.245 g, 0.514 mmol) in dioxane (50mL) was stirred at 90 ℃ under argon atmosphere for 16 h the mixture was filtered through celite, washed several times with ethyl acetate and concentrated the residue was purified by flash chromatography (silica gel, 50-75% ethyl acetate/petroleum ether, gradient) to give the title compound (1.15 g, 40% yield).

Example 252e

1-benzyl-4- (2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 252d (2.3 g, 5.27 mmol), example 252c (2.270 g, 5.54 mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoadamantane (0.154 g, 0.527 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.121 g, 0.132 mmol) and potassium phosphate (1.119 g, 5.27 mmol) were combined and sparged with argon for 30 minutes. A mixture of degassed dioxane (30mL) and water (7.5 mL) was added and the reaction mixture was stirred at 60 ℃ for 16 h. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20-100% ethyl acetate/petroleum ether) to give the title compound (1.77 g, 33.4% yield).

Example 252f

4- (2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

A mixture of example 252e, anisole (1.585 mL, 14.51 mmol) and concentrated sulfuric acid (4.3 mL, 81mmol) in trifluoroacetic acid (20mL, 260 mmol) was heated at 90 deg.C for 4 h. Excess trifluoroacetic acid was removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was extracted with additional ethyl acetate (2 × 200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL), then with saturated aqueous sodium chloride (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was poured into methanol (50mL) and the resulting solid was filtered, washed with methanol and dried to provide the title compound (3.1 g, 63% yield).

Example 252g

4- (2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid

Example 252f (1.1 g, 2.2 mmol)/dioxane (60 mL) was treated with 2.0M aqueous lithium hydroxide (4.38 mL, 8.76 mmol). The reaction mixture was heated at 65 ℃ for 2 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in water (50mL) and the pH was adjusted to 5 with HCl (3M). The resulting solid was filtered and dissolved in ethyl acetate (200 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (0.85 g, 77% yield).

Example 252h

To a solution of example 252g (0.10g, 0.21 mmol) in dry dichloromethane (5 mL) was added oxalyl chloride (0.037 mL, 0.42 mmol) and dimethylformamide (0.816 μ l, 10.5 μmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated. The residue was again dissolved in dichloromethane (5 mL) and treated with ammonium hydroxide (2mL, 92mmol) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was partitioned between water (15mL) and ethyl acetate (25 mL). The aqueous layer was extracted with additional ethyl acetate (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate and the resulting solid filtered, washed with dichloromethane and dried under vacuum to provide the title compound (48 mg, 47% yield).

Example 253

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide

Example 253 was prepared according to the procedure used for the preparation of example 252h substituting ethylamine for ammonium hydroxide to provide the title compound.

Example 254

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-7-oxo-N- (2,2, 2-trifluoroethyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide

Example 254 was prepared according to the procedure used for the preparation of example 252h substituting 2,2, 2-trifluoroethylamine for ammonium hydroxide to provide the title compound.

Example 255

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- (morpholin-4-ylcarbonyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 255 was prepared according to the procedure used for the preparation of example 252h, substituting morpholine for ammonium hydroxide to provide the title compound.

Example 256

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (4-methylpiperazin-1-yl) carbonyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 256 was prepared according to the procedure used for preparation example 252h, substituting 1-methylpiperazine for ammonium hydroxide to provide the title compound.

Example 257

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-7-oxo-N- (1, 3-thiazol-2-yl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide

Preparation example 257 was prepared according to the procedure used for preparation example 252h, substituting thiazol-2-amine for ammonium hydroxide to provide the title compound.

Example 258

4- [2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -4- (methylsulfonyl) phenoxy ] piperidine-1-carboxylic acid ethyl ester

Preparation example 258 was prepared according to the procedure used for preparation example 158, substituting 4-hydroxypiperidine-1-carboxylic acid ethyl ester for cyclopropylmethanol to provide the title compound.

Example 259

4- [ 2-ethoxy-5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

In preparing example 258, the title compound was isolated as the minimum product.

Example 260

4- {5- (ethylsulfonyl) -2- [ (trans-4-methoxycyclohexyl) oxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

In the preparation of example 248b, the title compound was isolated as a second product (first eluting peak).

Example 261

4- {2- [ (cyclopropylmethyl) amino ] -5- (prop-2-ylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 261a

(3-bromo-4-fluorophenyl) (isopropyl) sulfane

Example 261a was prepared according to the procedure used to prepare example 168a substituting 2-iodopropane for iodoethane to provide the title compound.

Example 261b

2-bromo-1-fluoro-4- (isopropylsulfonyl) benzene

Example 261b was prepared according to the procedure used to prepare example 168b substituting example 261a for example 168a to provide the title compound.

Example 261c

2-bromo-N- (cyclopropylmethyl) -4- (isopropylsulfonyl) aniline

Example 261c was prepared according to the procedure used to prepare example 147a, substituting cyclopropylmethylamine for cyclohexylamine and example 261b for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene to provide the title compound.

Example 261d

Example 261d was prepared according to the procedure used to prepare example 95d, substituting example 261c for example 95c to provide the title compound.

Example 262

N- [4- (cyclopropylmethoxy) -2-methyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 262 was prepared according to the procedure used to prepare example 4 (method a) substituting example 251c for example 3 to provide the title compound.

Example 263

N- [4- (cyclopropylmethoxy) -2-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] methanesulfonamide

Example 263a

1-bromo-2- (cyclopropylmethoxy) -4-methyl-5-nitrobenzene

Example 263a was prepared according to the procedure used for the preparation of example 247a, substituting 2-bromo-5-methyl-4-nitrophenol for 2-bromo-3-methylphenol to provide the title compound.

Example 263b

4- (2- (cyclopropylmethoxy) -4-methyl-5-nitrophenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 263b was prepared according to the procedure used to prepare example 7d, substituting the product of example 263a for the product of example 7c and stirring at 65 ℃ for 2.5 hours to provide the title compound.

Example 263c

4- (5-amino-2- (cyclopropylmethoxy) -4-methylphenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 263c was prepared according to the procedure used to prepare example 3, substituting the product of example 263b for the product of example 2b to provide the title compound.

Example 263d

N- (4- (cyclopropylmethoxy) -2-methyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) methanesulfonamide

Example 263d was prepared according to the procedure used to prepare example 4 (method a) substituting example 263c for example 3 to provide the title compound.

Example 264

4- [5- (ethylsulfonyl) -2- (tetrahydro-2H-thiopyran-4-yloxy) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 264a

4- (2-bromo-4- (ethylsulfonyl) phenoxy) tetrahydro-2H-thiopyran

Prepare example 264a according to the procedure used to prepare example 158, replace example 138a with example 168b and cyclopropylmethanol with tetrahydro-2H-thiopyran-4-ol, respectively, to provide the title compound.

Example 264b

Example 264b was prepared according to the procedure used for the preparation of example 95d, substituting example 264a for example 95c to provide the title compound.

Example 265

4- {2- [ (1, 1-tetrahydro-2H-thiopyran-4-yl) -oxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 265 was prepared according to the procedure used to prepare example 168b substituting example 264b for example 168a to provide the title compound.

Example 266

6- (2, 4-Difluorophenoxy) -N, N-dimethyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

Example 266a

5-bromo-6- (2, 4-difluorophenoxy) -N, N-dimethylpyridine-3-sulfonamide

Example 242a (0.365 g,1 mmol)/dimethylformamide (5 mL) was treated with 60% sodium hydride (0.120 g, 3.00 mmol). The solution was stirred for 10 minutes. To this solution was added methyl iodide (0.355 g, 2.500 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted more than twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (0.365 g, 0.928 mmol, 93% yield).

Example 266b

Example 266b was prepared according to the procedure used to prepare example 95d, substituting example 266a for example 95c to provide the title compound.

Example 267

4- [2- (cyclopropylamino) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 267a

2-bromo-N-cyclopropyl-4- (ethylsulfonyl) aniline

Prepare example 267a according to the procedure used for prepare example 147a, substituting cyclopropylamine for cyclohexylamine and substituting example 168b for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene to provide the title compound.

Example 267b

Example 267b was prepared according to the procedure used for the preparation of example 95d, substituting example 267a for example 95c to provide the title compound.

Example 268

4- (5- (ethylsulfonyl) -2- (cis-4-methoxy-4-methylcyclohexyloxy) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 268a

8- (2-bromo-4- (ethylsulfonyl) phenoxy) -1, 4-dioxaspiro [4.5] decane

Prepare example 268a according to the procedure used to prepare example 158, replace example 138a with example 168b and cyclopropylmethanol with 1, 4-dioxaspiro [4.5] decan-8-ol, respectively, to provide the title compound.

Example 268b

4- (2-bromo-4- (ethylsulfonyl) phenoxy) cyclohexanone

Example 268b was prepared according to the procedure used to prepare example 199 substituting example 268a for example 197 to provide the title compound.

Example 268c

(cis) -4- (2-bromo-4- (ethylsulfonyl) phenoxy) -1-methylcyclohexanol

Cooling example 268b (0.95 g, 2.63 mmol) based on-THF (15mL) to 0 ℃. The solution was treated with 3.0M methylmagnesium bromide (2.63 ml, 7.89 mmol) and stirred at room temperature overnight. With saturated NH₄The reaction mixture was quenched with Cl solution and partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine over MgSO₄Dried, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 1:1 ethyl acetate/hexanes to give two fractions. Example 268c is the first fraction eluted from the column.

Example 268d

2-bromo-4- (ethylsulfonyl) -1- ((cis) -4-methoxy-4-methylcyclohexyloxy) benzene

Example 268c (0.43 g, 1.140 mmol)/tetrahydrofuran (5 mL) was treated with 60% sodium hydride (0.182 g, 4.5 mmol). The reaction was stirred at ambient temperature for 10 minutes. To this solution was added iodomethane (2) (0.65 g, 4.5 mmol). The reaction mixture was heated at 40 ℃ for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted more than twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (0.356 g, 0.910mmol, 80% yield).

Example 268e

Example 268e was prepared according to the procedure used to prepare example 95d, substituting example 268d for example 95c to provide the title compound.

Example 269

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -N, N, 6-trimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide

Example 269 was prepared according to the procedure used for preparation example 252h, substituting dimethylamine for ammonium hydroxide to provide the title compound.

Example 270

6-methyl-4- {5- (methylsulfonyl) -2- [4- (methylsulfonyl) phenoxy ] phenyl } -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 270 was prepared according to the procedure used for the preparation of example 138b, substituting 4- (methylsulfonyl) phenol for 2, 4-difluorophenol to provide the title compound.

Example 271

4- [2- (2, 4-Difluorophenoxy) -5- (propan-2-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 271a

2-bromo-1- (2, 4-difluorophenoxy) -4- (isopropylsulfonyl) benzene

Example 271a was prepared according to the procedure used to prepare example 138b, substituting example 261b for example 138a to provide the title compound.

Example 271b

Example 271b was prepared according to the procedure used for the preparation of example 95d, substituting example 271a for example 95c to provide the title compound.

Example 272

6- (cyclopropylmethoxy) -N, N-diethyl-5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridine-3-sulfonamide

Example 272a

5-bromo-6- (cyclopropylmethoxy) -N, N-diethylpyridine-3-sulfonamide

Example 272a was prepared according to the procedure used to prepare example 266a, substituting example 207a for example 242a and iodoethane for iodomethane, respectively, to provide the title compound.

Example 272b

Example 272b was prepared according to the procedure used to prepare example 95d, substituting example 272a for example 95c to provide the title compound.

Example 273

4- (cyclopropylmethoxy) -N, N-dimethyl-3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide

Example 273a

3-bromo-4- (cyclopropylmethoxy) -N, N-dimethylbenzenesulfonamide

Example 273a was prepared according to the procedure used to prepare example 266a, substituting example 249a for example 242a to provide the title compound.

Example 273b

Example 273b was prepared according to the procedure used to prepare example 95d, substituting example 273a for example 95c to provide the title compound.

Example 274

4- [2- (cyclopropylmethoxy) -5-fluorophenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 274a

2-bromo-1- (cyclopropylmethoxy) -4-fluorobenzene

To a solution of 2-bromo-4-fluorophenol (0.50 g, 2.6 mmol) in tetrahydrofuran (13 mL) was added cyclopropanemethanol (0.209 mL,2.62 mmol), triphenylphosphine (0.687 g, 2.62 mmol) and DIAD (0.509 mL,2.62 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure. The residue was triturated with hexanes. The mixture was filtered and the filtrate containing the product was concentrated by reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes) to provide the title compound (400 mg, 62% yield).

Example 274b

(2- (Cyclopropylmethoxy) -5-fluorophenyl) boronic acid

To a solution of example 274a (0.1 g, 0.408 mmol) in tetrahydrofuran (2 mL) was added nBuLi (0.180 mL of a 2.5M solution in hexane, 0.449mmol) at-20 ℃. The reaction mixture was stirred for 2 hours and then cooled to-40 ℃. 2-Isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.092 mL, 0.449mmol) was added dropwise. The reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with 1M citric acid at 0 ℃. The mixture was stirred at ambient temperature for 1 hour and then extracted with ethyl acetate. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 10-33% ethyl acetate/hexanes, gradient) to provide the title compound (23mg, 20% yield).

Example 274c

Nitrogen was bubbled through the 4:1 dimethoxyethane/ethanol solution for 20 minutes. A microwave vial was charged with example 1e (0.05 g, 0.1)31 mmol), example 274b (0.046 g, 0.144 mmol), Pd (Ph)₃P)₄(7.58 mg, 6.56 μmol) and cesium fluoride (0.060 g, 0.393 mmol). The vial was sealed and flushed with nitrogen. A4: 1 dimethoxyethane/ethanol mixture (0.5 mL) was added. The reaction mixture was heated in a microwave reactor at 120 ℃ for 40 minutes. The reaction mixture was partitioned between water and ethyl acetate. And (5) separating the layers. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 20-80% ethyl acetate/hexanes, gradient) to provide the title compound (5 mg, 23% yield).

Example 275

4- [2- (2, 4-Difluorophenoxy) -5- (trifluoromethyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 275a

2-bromo-1- (2, 4-difluorophenoxy) -4- (trifluoromethyl) benzene

A mixture of 3-bromo-4-fluorobenzotrifluoride (0.5 mL, 3.52 mmol), 2, 4-difluorophenol (0.337 mL, 3.52 mmol) and potassium carbonate (0.486 g, 3.52 mmol) in dimethylformamide (7 mL) was heated at 80 deg.C for 16 h. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 0-10% ethyl acetate/hexanes, gradient) to provide the title compound (1.0g, 80% yield).

Example 275b

(2- (2, 4-Difluorophenoxy) -5- (trifluoromethyl) phenyl) boronic acid

To a suspension of magnesium (0.083 g,3.42 mmol) in tetrahydrofuran (1.00 mL) was added 0.5 mL of the solution of example 275a (1.099 g, 3.11 mmol) in tetrahydrofuran (1.5 mL). The reaction mixture was warmed (about 40-50 ℃ C.) until the reaction started. The remaining solution of the starting bromide was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour. The resulting solution was added dropwise to a solution of trimethyl borate (0.696 mL, 6.23 mmol) in tetrahydrofuran (1.5 mL) at 0 ℃. The reaction mixture was stirred at ambient temperature for 1 hour, quenched with ice water, and then neutralized with 2M HCl. The mixture was quenched with ethyl acetate. The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 10-33% ethyl acetate/hexanes, gradient) to provide the title compound (650 mg, 66% yield).

Example 275c

Example 275c was prepared according to the procedure used to prepare example 274c substituting example 275b for example 274b to provide the title compound.

Example 276

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -2- (hydroxymethyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

To a stirred suspension of example 252f (0.20 g, 0.40 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (1M in tetrahydrofuran, 0.398 mL, 0.398 mmol) at 0 deg.C and the mixture was stirred at 0 deg.C for 2 h. The solvent was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (30mL) and water (20 mL). The mixture was filtered to remove undissolved material. The aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane and the resulting solid filtered and dried to provide the title compound (0.10g, 55% yield).

Example 277

4- [2- (2, 3-dihydro-1H-inden-2-yloxy) -5- (methylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 277 according to the procedure used to prepare example 158 substituting 2, 3-dihydro-1H-inden-2-ol for cyclopropylmethanol to provide the title compound.

Example 278

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -2- (1-hydroxyethyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 278a

4- (2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carbaldehyde

To a solution of example 276 (1.0g, 2.2mmol) in dichloromethane (50mL) was added dess-Martin periodinane (1.84 g, 4.34 mmol) at 0 deg.C and the reaction mixture was stirred at 0 deg.C for 30 min. The reaction mixture was then stirred at ambient temperature for 3 hours. Sodium hydrogen sulfite (0.9 g, 9mmol) in saturated aqueous sodium bicarbonate (5 mL) was added and the reaction mixture was stirred for 15 minutes and extracted with ethyl acetate. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated to provide the title compound (0.80 g, 70% yield).

Example 278b

To a solution of example 278a (0.20 g, 0.44 mmol) in tetrahydrofuran (6 mL) was added methylmagnesium bromide (1.0M in tetrahydrofuran, 0.873 mL, 0.873 mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, then 1M aqueous HCl (2 mL) was added. The reaction mixture was concentrated and partitioned between saturated aqueous sodium chloride (10mL) and ethyl acetate (2 × 30 mL). The combined organic phases were washed with saturated aqueous sodium chloride (30mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography (silica gel, dichloromethane/methanol, 15/1) to provide the title compound (51 mg, 24% yield).

Example 279

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -2- [ (dimethylamino) methyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

To a solution of example 278a (0.20 g, 0.44 mmol) and dimethylamine hydrochloride (0.071 g,0.873 mmol) in methanol (6 mL) was added zinc chloride (0.059 g, 0.436 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 hour, then sodium cyanoborohydride (0.055 g,0.873 mmol) was added and the reaction mixture was stirred at ambient temperature for 3 days. The resulting solid was filtered and washed with methanol (10mL) and the eluate was concentrated. The residue was purified by preparative thin layer chromatography (silica gel, dichloromethane/methanol, 15/1) to provide the title compound (75 mg, 34% yield).

Example 280

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- (morpholin-4-ylmethyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 280 was prepared according to the procedure used for the preparation of example 279, substituting morpholine for dimethylamine hydrochloride to provide the title compound.

Example 281

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (4-methylpiperazin-1-yl) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 281 was prepared according to the procedure used for the preparation of example 279 substituting 1-methylpiperazine for dimethylamine hydrochloride to provide the title compound.

Example 282

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (phenylamino) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 282 was prepared according to the procedure used to prepare example 279, substituting aniline for dimethylamine hydrochloride to provide the title compound.

Example 283

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (1, 3-thiazol-2-ylamino) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 283 was prepared according to the procedure used for the preparation of example 279, substituting thiazol-2-amine for dimethylamine hydrochloride to provide the title compound.

Example 284

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (tetrahydrofuran-3-ylamino) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 284 was prepared according to the procedure used for the preparation of example 279, substituting tetrahydrofuran-3-amine for dimethylamine hydrochloride to provide the title compound.

Example 285

4- [2- (cyclopropylmethoxy) -5- (phenylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 285a

1- (cyclopropylmethoxy) -4- (phenylsulfonyl) benzene

Example 285a was prepared according to the procedure used to prepare example 158, substituting 1-fluoro-4- (phenylsulfonyl) benzene for example 138a to provide the title compound.

Example 285b

2-bromo-1- (cyclopropylmethoxy) -4- (phenylsulfonyl) benzene

Example 285a (0.087 g, 0.3 mmol) in acetic acid (5 mL) was cooled to 0 ℃. To this solution was added 1-bromopyrrolidine-2, 5-dione (2) (0.059 g, 0.330 mmol). The reaction mixture was heated at 80 ℃ for 16 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted more than twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (0.032 g, 0.087 mmol, 29% yield).

Example 285c

Example 285c was prepared according to the procedure used to prepare example 95d, substituting example 285b for example 95c to provide the title compound.

Example 286

4- [2- (cyclopropylmethoxy) -5- (morpholin-4-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 286a

4- (3-bromo-4-fluorophenylsulphonyl) morpholine

3-bromo-4-fluorobenzene-1-sulfonyl chloride (0.44 g, 1.609mmol) in tetrahydrofuran (10mL) was treated with morpholine (0.294 g, 3.38 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed and the residue was loaded onto a silica gel column and eluted with 20% ethyl acetate/hexane to give the title compound (0.45 g, 1.388 mmol, 86% yield).

Example 286b

4- (3-bromo-4- (cyclopropylmethoxy) phenylsulfonyl) morpholine

Example 286b was prepared according to the procedure used to prepare example 158 substituting example 286a for example 138a to provide the title compound.

Example 286c

Example 286c was prepared according to the procedure used to prepare example 95d, substituting example 286b for example 95c to provide the title compound.

Example 287

4- {2- (2, 4-Difluorophenoxy) -5- [ (methylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 287a

3-bromo-4- (2, 4-difluorophenoxy) benzaldehyde

A mixture of 3-bromo-4-fluorobenzaldehyde (4.06 g, 20mmol), 2, 4-difluorophenol (2.60 g, 20mmol) and cesium carbonate (7.17 g, 22 mmol) in dimethyl sulfoxide (20mL) was heated at 100 deg.C for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate/heptane) to provide the title compound (5.94 g, 95%).

Example 287b

(3-bromo-4- (2, 4-difluorophenoxy) phenyl) methanol

To a solution of example 287a (3.76 g, 12mmol) in a mixture of ethanol (10mL) and tetrahydrofuran (10mL) was added sodium borohydride (0.136 g, 3.60 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (3.72 g, 98%).

Example 287c

2-bromo-4- (bromomethyl) -1- (2, 4-difluorophenoxy) benzene

To a solution of example 287b (3.70 g, 11.74 mmol) in dichloromethane (20mL) was added phosphorus tribromide (1.11 mL, 11.7 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 3 hours and poured into ice water. The pH was adjusted to basic by careful addition of saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (4.15 g, 93%).

Example 287d

(3-bromo-4- (2, 4-difluorophenoxy) benzyl) (methyl) sulfane

A mixture of example 287c (1.512 g,4.00 mmol) and sodium thiomethoxide (0.280 g,4.00 mmol) in dimethylformamide (8 mL) is stirred at ambient temperature for 6 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to provide the title compound (1.38 g, 100%).

Example 287e

2-bromo-1- (2, 4-difluorophenoxy) -4- (methylsulfonylmethyl) benzene

To a solution of example 287d (1.38 g,4.00 mmol) in methanol (15mL) at 0 deg.C was added oxone (5.16 g, 8.40 mmol) in water (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20-40% ethyl acetate/heptane) to provide the title compound (1.49 g, 98%).

Example 287f

4- (2- (2, 4-Difluorophenoxy) -5- (methylsulfonylmethyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 287e (94 mg, 0.25 mmol), example 6a (107 mg, 0.250mmol), potassium phosphate (186 mg, 0.875 mmol), tris (dibenzylideneacetone) dipalladium (6.9 mg, 7.5. mu. mol) and 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (6.6 mg, 0.023 mmol) were mixed in a microwave tube and flushed with nitrogen for 15 minutes. The mixture of dioxane (2 mL) and water (0.5 mL) was flushed with nitrogen for 15 minutes and transferred to a microwave tube. The reaction mixture was heated at 60 ℃ for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 1-2% methanol/dichloromethane) to provide the title compound (62 mg, 41%).

Example 287g

Example 287f (59.9 mg,0.100 mmol), potassium hydroxide (84 mg, 1.5 mmol) and cetyltrimethylammonium bromide (1.8 mg, 5.0 μmol) were mixed in a mixture of tetrahydrofuran (4 mL) and water (2 mL). The reaction mixture was heated at 100 ℃ for 44 hours and then cooled to ambient temperature. To this mixture was added water and the pH was adjusted to pH 7 by the addition of 1 MHCl. The mixture was extracted with ethyl acetate and the organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to provide the title compound (31 mg, 70%).

Example 288

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) pyridin-3-yl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 288a

2-fluoro-5- (methylthio) pyridine

5-bromo-2-fluoropyridine (2.05 g, 11.7 mmol) and N were purged with nitrogen¹,N¹,N²,N²A mixture of (2.27 mL, 15.1 mmol) of (tetramethylethylene-1, 2-diamine for 45 minutes. Toluene (116 mL) was added and the reaction mixture was cooled to-78 ℃. N-butyllithium (2.5M in hexane, 5.59 mL, 14.0 mmol) was added dropwise over 6 min. The reaction mixture was stirred at-78 ℃ for 1 hour. Dimethyldisulfide (1.26 mL, 14.0 mmol) was added. The reaction mixture was stirred at-78 ℃ for 1 hour. The reaction mixture was brought to 0 ℃ and then immediately quenched with saturated aqueous ammonium chloride. The layers were separated and the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/heptane) to provide the title compound (1.00g, 60%).

Example 288b

2-fluoro-5- (methylsulfonyl) pyridine

To a solution of example 288a (2.17 g, 15.2 mmol) in dichloromethane (50.5 mL) was added 3-chloroperoxybenzoic acid (3-chloroperoxyoic acid) (7.15 g, 31.1 mmol) in portions over 10 minutes. The reaction mixture was stirred at ambient temperature for 4 hours. Additional 3-chloroperoxybenzoic acid (2.62 g, 15.16 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium carbonate solution and the layers were separated. The aqueous layer was quenched with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-10% methanol in dichloromethane) to provide the title compound (1.81g, 68%).

Example 288c

5- (methylsulfonyl) pyridin-2 (1H) -ones

Example 288b (0.679 g, 3.88mmol) was treated with acetic acid (35.2 mL) and water (3.52 mL) at 110 deg.C for 16 h. The reaction mixture was cooled to ambient temperature and the solvent was removed to provide the title compound (0.700g, 100%).

Example 288d

3-bromo-5- (methylsulfonyl) pyridin-2 (1H) -one

To a solution of example 288c (0.671 g, 3.87 mmol) and sodium acetate (0.318 g, 3.87 mmol) in acetic acid (8.50 mL) was added dropwise a solution of bromine (0.201 mL, 3.91 mmol) in acetic acid (1.7 mL). The reaction mixture was stirred at 40 ℃ for 3 hours. Bromine (0.05 mL) was added and the reaction mixture was stirred at 40 ℃ for 2 h. The reaction mixture was cooled to ambient temperature and quenched with 100 mL of 10% aqueous sodium thiosulfate. The resulting suspension was filtered, and the solid was collected and dried for 16 hours to provide the title compound (0.64 g, 66%).

Example 288e

3-bromo-2-chloro-5- (methylsulfonyl) pyridine

Example 288d (0.6395 g, 2.54 mmol) was treated with phosphorus oxychloride (12.7 mL) at 110 ℃ for 4 hours. The reaction mixture was cooled to ambient temperature and poured into ice. The resulting suspension was filtered and washed with water, and an off-white solid was collected and dried in a vacuum oven at 60 ℃ for 16 hours to provide the title compound (0.244g, 35%).

Example 288f

3-bromo-2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) pyridine

Example 288f was prepared according to the procedure used for the preparation of example 2b, substituting 2, 4-difluorophenol for phenol and example 288e for example 2a, respectively, to provide the title compound.

Example 288g

4- (2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) pyridin-3-yl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 288g was prepared according to the procedure used to prepare example 4a, substituting example 288f for example 7c to provide the title compound.

Example 288h

4- (2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) pyridin-3-yl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 288h was prepared according to the procedure used for the preparation of example 4b, substituting example 288g for example 4a to provide the title compound.

Example 289

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- [ (pyridin-3-yloxy) methyl ] -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 289a

2- (chloromethyl) -4- (2- (2, 4-difluorophenoxy) -5- (methylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A mixture of example 276 (0.50 g, 1.09 mmol) and thionyl chloride (5.0 mL, 69 mmol) was heated at reflux for 2 h. The solvent was removed under reduced pressure and the residue was dried under vacuum for 1 hour to afford the title compound.

Example 289b

To a solution of pyridin-3-ol (0.039 g, 0.407 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (16 mg, 0.407 mmol) at 0 deg.C and the mixture was stirred for 30 minutes. To this solution was added example 289a (0.25 g, o.204 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was poured into a mixture of ethyl acetate (30mL) and saturated aqueous sodium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. By reverse phase HPLC (C18, water (10 mM NH)₄HCO₃) Acetonitrile, 25-50%, gradient) to provide the title compound (18 mg, 16% yield).

Example 290

4- [5- (cyclopropylsulfonyl) -2- (2, 4-difluorophenoxy) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 290a

(3-bromo-4-fluorophenyl) (cyclopropyl) sulfane

Example 290a was prepared according to the procedure used for the preparation of example 168a substituting bromocyclopropane for iodoethane to provide the title compound.

Example 290b

2-bromo-4- (cyclopropylsulfonyl) -1-fluorobenzene

Example 290b was prepared according to the procedure used to prepare example 168b, substituting example 290a for example 168a to provide the title compound.

Example 290c

2-bromo-4- (cyclopropylsulfonyl) -1- (2, 4-difluorophenoxy) benzene

Example 290c was prepared according to the procedure used to prepare example 138b, substituting example 290b for example 138a to provide the title compound.

Example 290d

Example 290d was prepared according to the procedure used to prepare example 95d, substituting example 290c for example 95c to provide the title compound.

Example 291

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- (prop-1-en-2-yl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

To a stirred solution of example 252f (0.10g, 0.20 mmol) in tetrahydrofuran (6 mL) was added methylmagnesium bromide (0.498 mL, 0.498 mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, then aqueous HCl (1M, 2 mL) was added. The reaction mixture was concentrated and partitioned between saturated aqueous sodium chloride (10mL) and ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride (30mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase-HPLC (C1840-90% gradient, acetonitrile: water (0.1% TFA)) to provide the title compound (25 mg,25% yield).

Example 292

4- [2- (2, 4-Difluorophenoxy) -5- (methylsulfonyl) phenyl ] -6-methyl-2- (phenoxymethyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 292 was prepared according to the procedure used for preparation example 289b, substituting phenol for pyridin-3-ol to provide the title compound.

Example 293

4- [2- (2, 4-Difluorophenoxy) -5- (morpholin-4-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 293a

4- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) morpholine

Example 293a was prepared according to the procedure used for the preparation of example 138b substituting example 286a for example 138a to provide the title compound.

Example 293b

Example 293b was prepared according to the procedure used for the preparation of example 95d substituting example 293a for example 95c to provide the title compound.

Example 294

4- [2- (2, 4-Difluorophenoxy) -5- (ethylsulfonyl) pyridin-3-yl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 294a

3-bromo-2-chloro-5- (ethylsulfonyl) pyridine

Sodium sulfite (1.755 g, 13.92 mmol) and sodium bicarbonate (1.231 g, 14.65 mmol) were dissolved in water (37 mL) to give a colorless solution. The mixture was heated at 75 ℃. 3-bromo-2-chloropyridine-5-sulfonyl chloride (2.132 g, 7.33mmol) was added portionwise over 1 hour. The reaction mixture was stirred at 75 ℃ for 1 hour. The mixture was concentrated and N, N-dimethylformamide (13.88 mL) was added. Sodium bicarbonate (1.231 g, 14.65 mmol) and iodoethane (0.589 mL, 7.33mmol) were added. The resulting mixture was heated to 75 ℃ for 2 hours and then cooled to ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to provide the title compound.

Example 294b

4- (2-chloro-5- (ethylsulfonyl) pyridin-3-yl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 294b was prepared according to the procedure used to prepare example 4a, substituting example 294a for example 7c to provide the title compound.

Example 294c

4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfonyl) pyridin-3-yl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 294c was prepared according to the procedure used for the preparation of example 2b, substituting 2, 4-difluorophenol for phenol and example 294b for example 2a, respectively, to provide the title compound.

Example 295

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2- (morpholin-4-yl) ethanesulfonamide

Example 295a

Example 295a was prepared according to the procedure used for the preparation of example 138a substituting example 1e for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene and example 148c for example 6a, respectively, to provide the title compound.

Example 295b

A mixture of example 295a, 2-chloroethanesulfonyl chloride (0.098 g, 0.600 mmol) and triethylamine (0.081 g, 0.800 mmol) in dichloromethane (3 mL) was stirred at ambient temperature for 2 h. The solvent was removed and the residue was redissolved in MeOH (5 mL). To this solution was added morpholine (0.697 g, 8.00 mmol). The reaction mixture was heated at 50 ℃ for 2 hours. To this solution was added 2.0N sodium hydroxide (2.00 mL, 4.00 mmol). The reaction mixture was heated at 85 ℃ for 2 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and 1.0N HCl. The aqueous layer was extracted several times with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (10-80% acetonitrile/0.1% TFA water) to give the title compound as a TFA salt (0.077 g,0.117 mmol, 58.5% yield).

Example 296

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- [2- (dimethylamino) ethyl ] ethanesulfonamide

A mixture of example 36e (0.15 g, 0.326 mmol), 2- (dimethylamino) ethanol (0.029 g, 0.326 mmol) and triphenylphosphine (0.128 g, 0.490 mmol) in tetrahydrofuran (3 mL) was stirred at ambient temperature for 10 min. To the solution was added (E) -di-tert-butyldiazene-1, 2-dicarboxylate (0.113 g, 0.490 mmol). The solution was stirred at ambient temperature for 3 hours. The solvent was removed and the residue was purified by preparative HPLC (10-80% acetonitrile/0.1% TFA water) to give the title compound (0.055 g, 0.104mmol, 31.8% yield).

Example 297

4- {2- (2, 4-Difluorophenoxy) -5- [ (ethylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 297a

(3-bromo-4- (2, 4-difluorophenoxy) benzyl) (ethyl) sulfane

Example 297a was prepared according to the procedure used for preparation 287d, substituting sodium ethanethiol for sodium methanethiol to provide the title compound (1.04 g, 99%).

Example 297b

2-bromo-1- (2, 4-difluorophenoxy) -4- (ethylsulfonylmethyl) benzene

Example 297b was prepared according to the procedure used to prepare example 287e, substituting example 297a for example 287d to provide the title compound (1.01g, 89%).

Example 297c

4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 297c was prepared according to the procedure used to prepare example 287f, substituting example 297b for example 287 e. Purification by flash chromatography (silica gel, 0-2% methanol in dichloromethane) gave the title compound (63 mg, 51%).

Example 297d

Example 297d was prepared according to the procedure used to prepare example 287g, substituting example 297c for example 287f to provide the title compound (34 mg, 75%).

Example 298

4- {2- (2, 4-Difluorophenoxy) -5- [2- (ethylsulfonyl) propan-2-yl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 298a

2-bromo-1- (2, 4-difluorophenoxy) -4- (2- (ethylsulfonyl) propan-2-yl) benzene

To a solution of example 297b (469 mg, 1.20 mmol) in tetrahydrofuran (10mL) was added 60% sodium hydride in mineral oil (240 mg, 6.00 mmol) at 0 ℃. The reaction mixture was stirred at ambient temperature under nitrogen for 10 minutes. Methyl iodide (0.750 mL, 12.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 20-40% ethyl acetate/heptane) to provide the title compound (442mg, 88%).

Example 298b

4- (2- (2, 4-Difluorophenoxy) -5- (2- (ethylsulfonyl) propan-2-yl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 298b was prepared according to the procedure used to prepare example 287f, substituting example 298a for example 287 e. Purification by flash chromatography (silica gel, 0-2% methanol in dichloromethane) gave the title compound (80 mg, 62%).

Example 298c

Example 298c was prepared according to the procedure used to prepare example 287g, substituting example 298b for example 287f and the reaction time was 16 hours instead of 44 hours to provide the title compound (52 mg, 88%).

Example 299

4- [2- (2, 4-Difluorophenoxy) -5- (pyrrolidin-1-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 299a

1- ((3-bromo-4-fluorophenyl) sulfonyl) pyrrolidine

To a solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (1.0g, 3.66 mmol) in 20mL of dichloromethane at 0 deg.C was added pyrrolidine (0.635 mL, 7.68 mmol). The mixture was stirred at 0 ℃ for 30 minutes and then at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with 1% HCl solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (0.86 g, 76% yield).

Example 299b

1- ((3-bromo-4- (2, 4-difluorophenoxy) phenyl) sulfonyl) pyrrolidine

A mixture of example 299a (250mg, 0.811 mmol), 2, 4-difluorophenol (106 mg,0.811 mmol) and cesium carbonate (317 mg, 0.973 mmol) in 5mL of dimethyl sulfoxide was heated at 110 ℃ for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water (2 ×), saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (278mg, 82% yield) which was used without further purification.

Example 299c

A mixture of example 299b (100 mg, 0.239mmol), example 6a (102 mg, 0.239mmol), tetrakis (triphenylphosphine) palladium (0) (13.81 mg, 0.012 mmol) and cesium fluoride (109 mg, 0.717 mmol) in 2mL dimethoxyethane and 1mL methanol was heated in a microwave oven (Biotage Initiator) at 120 ℃ for 40 minutes. The mixture was then treated with 4N NaOH (1mL) and stirred at ambient temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate (2 ×). The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 60-100% ethyl acetate/heptane, gradient) to give the title compound (75 mg, 64.6% yield).

Example 300

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -2- (dimethylamino) ethanesulfonamide

Preparation example 300 was prepared according to the procedure used for preparation example 295b, substituting N, N-dimethylamine for morpholine to provide the title compound as a TFA salt.

Example 301

4- [4- (ethylsulfonyl) -2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy ] piperidine-1-carboxylic acid ethyl ester

Example 301a

4- (2-bromo-4- (ethylsulfonyl) phenoxy) piperidine-1-carboxylic acid ethyl ester

Prepare example 301a according to the procedure used to prepare example 158, replace example 168b with example 138a and cyclopropylmethanol with ethyl 4-hydroxypiperidine-1-carboxylate, respectively, to provide the title compound.

Example 301b

Example 301b was prepared according to the procedure used for the preparation of example 95d, substituting example 301a for example 95c to provide the title compound.

Example 302

4- [2- (cyclopropylmethoxy) -5- (pyrrolidin-1-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 302a

1- ((3-bromo-4- (cyclopropylmethoxy) phenyl) sulfonyl) pyrrolidine

To a solution of cyclopropylmethanol (115 μ L, 1.460 mmol) in dioxane (8 mL) was added sodium hydride (78 mg, 1.947 mmol) at room temperature. After stirring at ambient temperature for 10 min, example 299a (300 mg, 0.973 mmol) was added as a solid. The mixture was then heated at 65 ℃ overnight. Water was added. The mixture was extracted with ethyl acetate, washed with water (2 ×), saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate in heptane, gradient) to give the title compound (156mg, 44.5% yield).

Example 302b

A mixture of 2mL of dimethoxyethane and 1mL of methanol of example 302a (84 mg, 0.233mmol), example 6a (100 mg, 0.233mmol), tetrakis (triphenylphosphine) palladium (0) (13.49 mg, 0.012 mmol) and cesium fluoride (106 mg, 0.700 mmol) was flushed with nitrogen and heated at 130 ℃ under microwave conditions (Biotage Initiator) for 40 minutes. The mixture was then treated with 4N NaOH (1mL) and stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was adsorbed on silica gel and purified by flash chromatography (silica gel, 0-10% methanol/dichloromethane, gradient) to give the title compound (64 mg, 64.1% yield).

Example 303

4- {2- [ (1-acetylpiperidin-4-yl) oxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 303a

1- (4- (2-bromo-4- (ethylsulfonyl) phenoxy) piperidin-1-yl) ethanone

Prepare example 303a according to the procedure used to prepare example 158, replace example 138a with example 168b and cyclopropylmethanol with 1- (4-hydroxypiperidin-1-yl) ethanone, respectively, to provide the title compound.

Example 303b

Example 303b was prepared according to the procedure used for the preparation of example 95d, substituting example 303a for example 95c to provide the title compound.

Example 304

4- [4- (ethylsulfonyl) -2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy ] benzonitrile

Prepare example 304 according to the procedure used to prepare example 138b, replace example 138a with example 168c and 2, 4-difluorophenol with 4-cyanophenol to provide the title compound, respectively.

Example 305

4- [2- (cyclopropylmethoxy) -5- (2, 3-dihydro-1H-indol-1-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 305a

1- (3-bromo-4-fluorophenylsulfonyl) indoline

A solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (Aldrich) (2.53 g, 8.33 mmol), indoline (0.99 g, 8.33 mmol), N-diisopropylethylamine (1.60 mL, 9.16 mmol) and tetrahydrofuran (20mL) was stirred at ambient temperature for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give a brown oil which solidified upon standing. The crude product was recrystallized from ether/heptane to give the title compound (1.99g, 5.59 mmol,67% yield).

Example 305b

1- (3-bromo-4- (cyclopropylmethoxy) phenylsulfonyl) indoline

Example 305b was prepared according to the procedure used for the preparation of example 29a substituting cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and example 305a for example 2a to provide the title compound.

Example 305c

4- (2- (cyclopropylmethoxy) -5- (indolin-1-ylsulfonyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 305c was prepared according to the procedure used to prepare example 6c, substituting example 305b for example 6b to provide the title compound.

Example 305d

4- (2- (cyclopropylmethoxy) -5- (indolin-1-ylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 305d was prepared according to the procedure used to prepare example 6d, substituting example 305c for example 6c to provide the title compound.

Example 306

4- {2- (2, 4-Difluorophenoxy) -5- [ (phenylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 306a

(3-bromo-4- (2, 4-difluorophenoxy) benzyl) (phenyl) sulfane

Example 306a was prepared according to the procedure used for the preparation of example 287d, substituting sodium thiophenolate for sodium methionate to provide the title compound (815 mg, 100%).

Example 306b

2-bromo-1- (2, 4-difluorophenoxy) -4- (phenylsulfonylmethyl) benzene

Example 306b was prepared according to the procedure used to prepare example 287e, substituting example 306a for example 287d to provide the title compound (867 mg, 99%).

Example 306c

4- (2- (2, 4-Difluorophenoxy) -5- (phenylsulfonylmethyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 306c was prepared according to the procedure used to prepare example 287f, substituting example 306b for example 287 e. Purification by flash chromatography (silica gel, 0-2% methanol in dichloromethane) gave the title compound (51 mg, 52%).

Example 306d

Example 306d was prepared according to the procedure used to prepare example 287g, substituting example 306c for example 287f to provide the title compound (30 mg, 80%).

Example 307

4- {2- [ (2, 2-Difluorocyclopropyl) methoxy ] -5- (pyrrolidin-1-ylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 307a

1- ((3-bromo-4- ((2, 2-difluorocyclopropyl) methoxy) phenyl) sulfonyl) pyrrolidine

Preparation example 307a was prepared according to the procedure used for preparation example 302a, substituting (2, 2-difluorocyclopropyl) methanol for cyclopropylmethanol to provide the title compound.

Example 307b

Example 307b was prepared according to the procedure used for the preparation of example 302b substituting 307a for 302a to provide the title compound.

Example 308

4- {2- (cyclopropylmethoxy) -5- [ (3, 3-difluoroazetidin-1-yl) sulfonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 308a

1- ((3-bromo-4-fluorophenyl) sulfonyl) -3, 3-difluoroazetidine

To a suspension of 3, 3-difluoroazetidine hydrochloride (0.947 g, 7.31 mmol) in 20mL of dichloromethane at 0 deg.C was added N-ethyl-N-isopropylpropan-2-amine (2.80 mL, 16.1 mmol) followed by 3-bromo-4-fluorobenzene-1-sulfonyl chloride (2.0 g, 7.3mmol) in 4mL of dichloromethane. The mixture was stirred at room temperature overnight, then heated at 55 ℃ for 5 hours, diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 10-50% ethyl acetate/heptane, gradient) to give the title compound (1.5g, 62.1% yield).

Example 308b

1- ((3-bromo-4- (cyclopropylmethoxy) phenyl) sulfonyl) -3, 3-difluoroazetidine

Example 308b was prepared according to the procedure used for the preparation of example 302a, substituting example 308a for example 299a to provide the title compound.

Example 308c

Example 308c was prepared according to the procedure used to prepare example 302b, substituting example 308b for example 302a to provide the title compound.

Example 309

4- {2- [2- (2-hydroxyethyl) phenoxy ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 304 was prepared according to the procedure used to prepare example 138b, substituting 2- (2-hydroxyethyl) phenol for 2, 4-difluorophenol to provide the title compound.

Example 310

4- [2- (cyclopropylmethoxy) -5- { [3- (dimethylamino) pyrrolidin-1-yl ] sulfonyl } phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 310a

1- (3-bromo-4-fluorophenylsulphonyl) -N, N-dimethylpyrrolidin-3-amine

A solution of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (Combi-blocks) (250mg, 0.91mmol), N-dimethylpyrrolidin-3-amine (218mg, 1.9 mmol) in tetrahydrofuran (5.7 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, dichloromethane/MeOH with gradient) to give the title compound (220 mg, 69% yield).

Example 310b

1- (3-bromo-4- (cyclopropylmethoxy) phenylsulfonyl-N, N-dimethyl-3-amine

Example 310b was prepared according to the procedure used for the preparation of example 29a substituting cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and example 310a for example 2a to provide the title compound.

Example 310c

4- (2- (cyclopropylmethoxy) -5- (3- (dimethylamino) pyrrolidin-1-ylsulfonyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 310c was prepared according to the procedure used to prepare example 6c, substituting example 310b for example 6b to provide the title compound.

Example 310d

4- (2- (cyclopropylmethoxy) -5- (3- (dimethylamino) pyrrolidin-1-ylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 310d was prepared according to the procedure used to prepare example 6d, substituting example 310c for example 6c to provide the title compound.

Example 311

4- {2- (2, 4-Difluorophenoxy) -5- [ (methylsulfonyl) methyl ] pyridin-3-yl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 311a

5-bromo-6- (2, 4-difluorophenoxy) nicotinic acid

5-bromo-6-chloronicotinic acid (3 g, 12.69 mmol), 2, 4-difluorophenol (3.30 g, 25.4 mmol) and cesium carbonate (16.54 g, 50.8 mmol) were mixed in DMSO (25.4 mL), heated at 100 ℃ for 6 hours, cooled, diluted with 150mL of ice water, and the pH adjusted to pH 3 with 12M HCl. The resulting solid was collected by filtration, washed with cold water, and dried to constant weight to give the title compound (2.84 g, 64%).

Example 311b

(5-bromo-6- (2, 4-difluorophenoxy) pyridin-3-yl) methanol

The product from example 311a (1.0g, 3.03 mmol) and borane tetrahydrofuran complex (6.06 mL, 6.06 mmol) were combined in tetrahydrofuran (15.15 mL) and heated at 50 ℃ for 2h, cooled, treated with 10mL methanol, heated at 50 ℃ for 1h, cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution and dried (Na)₂SO₄) Filtered and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/heptane) gave the title compound (0.73g, 76%).

Example 311c

3-bromo-5- (bromomethyl) -2- (2, 4-difluorophenoxy) pyridine

A solution of the product from example 311b (0.73g, 2.309 mmol) in dichloromethane (11.55 mL) was treated dropwise with phosphine tribromide (0.218 mL, 2.309 mmol) under nitrogen, stirred at ambient temperature for 1 hour and poured into ice water, and the pH adjusted to pH 9 by the batchwise addition of solid sodium bicarbonate. The formed emulsion was partially removed by filtration. The aqueous layer was extracted with dichloromethane and the organics were combined, washed with saturated aqueous sodium chloride and dried (Na)₂SO₄) Filtered and concentrated to give the title compound (0.75 g, 86%).

Example 311d

3-bromo-2- (2, 4-difluorophenoxy) -5- (methylthiomethyl) pyridine

The product from example 311c (0.75 g, 1.979 mmol) and sodium thiomethoxide (0.139 g, 1.979 mmol) were combined in dimethylformamide (3.96 mL), stirred at ambient temperature for 4 hours and partitioned between ethyl acetate and cold water. The organic layer was washed with saturated aqueous sodium chloride solution and dried (Na)₂SO₄) Filtered and concentrated to give the title compound (0.66 g, 96%).

Example 311e

3-bromo-2- (2, 4-difluorophenoxy) -5- (methylsulfonylmethyl) pyridine

The product from example 311d (0.66 g, 1.906 mmol) was treated with oxone (2.461 g,4.00 mmol) in methanol (7.33mL) at 0 deg.C with a solution of water (7.33mL), stirred at ambient temperature for 2h and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution and dried (Na)₂SO₄) Filtered and concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) gave the title compound (0.433 g, 60%).

Example 311f

4- (2- (2, 4-Difluorophenoxy) -5- ((methylsulfonyl) methyl) pyridin-3-yl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

The product from example 311e (0.075 g,0.198 mmol), the product from example 6a (0.085 g,0.198 mmol)), tris (dibenzylideneacetone) dipalladium (0) (5.45 mg, 5.95. mu. mol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoadamantane (5.80 mg, 0.020 mmol) and potassium phosphate (0.126 g,0.595 mmol) were combined and sparged with argon for 15 minutes. At the same time, a 4:1 dioxane/water (2 mL) solution was sparged with nitrogen for 15 minutes and transferred to the reaction vessel by syringe under argon. The mixture was stirred at 60 ℃ for 2 hours and partitioned between ethyl acetate and water. Washing with saturated aqueous sodium chloride solutionMechanical layer, drying (Na)₂SO₄) Treated with 3-mercaptopropyl-functionalized silica gel, filtered and concentrated. Purification by trituration in dichloromethane afforded the title compound (0.083 g, 70%).

Example 311g

The product from example 311f (0.083 g, 0.138mmol), potassium hydroxide (0.194 g, 3.46 mmol) and N, N-trimethylhexadecane-1-ammonium bromide (2.52mg, 6.92 μmol) were mixed in dioxane (1.8 mL)/water (0.9 mL) and heated at 100 ℃ for 4 hours, cooled and partitioned between ethyl acetate with pH adjusted to 7 with 1M HCl. The organic layer was washed with saturated aqueous sodium chloride solution and dried (Na)₂SO₄) Filtered and concentrated. Purification by chromatography (silica gel, 0-4% methanol/dichloromethane) gave the title compound (0.035 g, 57%).

Example 312

4- [4- (ethylsulfonyl) -2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenoxy ] piperidine-1-carboxylic acid tert-butyl ester

Example 312a

4- (2-bromo-4- (ethylsulfonyl) phenoxy) piperidine-1-carboxylic acid tert-butyl ester

Prepare example 312a according to the procedure used to prepare example 158, replace example 138a with example 168b and cyclopropylmethanol with tert-butyl 4-hydroxypiperidine-1-carboxylate, respectively, to provide the title compound.

Example 312b

Example 312b was prepared according to the procedure used for the preparation of example 95d, substituting example 312a for example 95c to provide the title compound.

Example 313

4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N-phenylbenzenesulfonamide

Example 313a

3-bromo-4-fluoro-N-phenylbenzenesulfonamides

Example 313a was prepared according to the procedure used to prepare example 305a, substituting aniline for indoline. The crude product was purified by flash chromatography (silica gel, eluting with 10% ethyl acetate in heptane) to give the title compound.

Example 313b

3-bromo-4- (cyclopropylmethoxy) -N-phenylbenzenesulfonamide

Example 313b was prepared according to the procedure used for the preparation of example 29a substituting cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and example 313a for example 2a to provide the title compound.

Example 313c

4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N-phenylbenzenesulfonamide

Example 313c was prepared according to the procedure used to prepare example 6c, substituting example 313b for example 6b to provide the title compound.

Example 313d

Example 313d was prepared according to the procedure used to prepare example 6d, substituting example 313c for example 6c to provide the title compound.

Example 314

4- [2- (cyclopropylmethoxy) -5- (pyrrolidin-1-ylmethyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 314a

4-bromo-1- (cyclopropylmethoxy) -2-iodobenzene

A mixture of 4-bromo-2-iodophenol (5.00 g,16.7 mmol), bromomethylcyclopropane (2.26 g,16.7 mmol) and cesium carbonate (6.54 g, 20.1 mmol) in 15mL dimethylformamide was stirred at 50 deg.C overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to provide the title compound (5.84 g, 99% yield).

Example 314b

4- (5-bromo-2- (cyclopropylmethoxy) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A mixture of 15mL dioxane and 5mL water of example 6a (1.1 g, 2.57mmol), example 314a (0.907 g, 2.57mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (0.060 g, 0.21 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.094 g, 0.103 mmol) and potassium phosphate (1.635 g, 7.70 mmol) was purged with nitrogen and then heated at 55 ℃ for 3 hours. Saturated aqueous sodium chloride was added and the mixture was extracted with ethyl acetate (2 ×). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-80% ethyl acetate/heptane, gradient) to give the title compound (1.24 g, 92% yield).

Example 314c

A 4mL dioxane/water (9:1) mixture of example 314b (100 mg,0.190 mmol), potassium trifluoro (pyrrolidin-1-ylmethyl) borate (36.2 mg,0.190 mmol), palladium (II) acetate (2.55 mg, 0.011 mmol), dicyclohexyl (2',4',6' -triisopropylbiphenyl-2-yl) phosphine (10.85 mg, 0.023 mmol) and cesium carbonate (185 mg, 0.569 mmol) was flushed with nitrogen and then heated under microwave conditions at 140 ℃ (Biotage Initiator) for 40 minutes. The reaction mixture was then treated with 2mL of 4N NaOH and heated in a microwave oven (Biotage Initiator) at 100 ℃ for 30 minutes. Water was added. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 2-14% methanol in dichloromethane, gradient) to give the title compound (8.0 mg, 11% yield).

Example 315

4- [2- (cyclopropylmethoxy) -5- (pyridin-3-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

A suspension of example 314b (100 mg,0.190 mmol), pyridin-3-ylboronic acid (23.31 mg,0.190 mmol), sodium carbonate (60.3 mg, 0.569 mmol) and tris (dibenzylideneacetone) -dipalladium (0) (15.48 mg, 0.019 mmol) in 4mL dioxane-water (3:1) was heated under nitrogen at 120 ℃ for 30 minutes. The reaction mixture was treated with 1mL of 4N aqueous NaOH solution and heated again at 120 ℃ for 30 minutes under microwave conditions. The mixture was diluted with water and extracted with ethyl acetate (2 ×), washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 0-10% methanol/dichloromethane, gradient) to give the title compound (53mg, 75% yield).

Example 316

4- [2- (cyclopropylmethoxy) -5- (morpholin-4-ylmethyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 316 was prepared according to the procedure used for the preparation of example 314c, substituting potassium trifluoro (morpholinylmethyl) borate for potassium trifluoro (pyrrolidin-1-ylmethyl) borate to provide the title compound.

Example 317

4- {5- (ethylsulfonyl) -2- [3- (hydroxymethyl) phenoxy ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Prepare example 317 according to the procedure used for prepare example 138b substituting 3- (hydroxymethyl) phenol for 2, 4-difluorophenol and example 168c for example 138a, respectively, to provide the title compound.

Example 318

4- [2- (cyclopropylmethoxy) -5- (1-methyl-1H-pyrazol-4-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 318 was prepared according to the procedure used for the preparation of example 315 substituting 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole for pyridin-3-ylboronic acid to provide the title compound.

Example 319

4- [2- (2, 4-Difluorophenoxy) -5- (2, 3-dihydro-1H-indol-1-ylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 319a

1- (3-bromo-4- (2, 4-difluorophenoxy) phenylsulfonyl) indoline

Example 319a was prepared according to the procedure used for the preparation of example 2b substituting 2, 4-difluorophenol for phenol and example 305a for example 2a to provide the title compound.

Example 319b

4- (2- (2, 4-Difluorophenoxy) -5- (indolin-1-ylsulfonyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 319b was prepared according to the procedure used for the preparation of example 6c substituting example 319a for example 6b to provide the title compound.

Example 319c

Example 319c was prepared according to the procedure used for the preparation of example 6d, substituting example 319b for example 6c to provide the title compound.

Example 320

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrazolo [3,4-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Example 320a

5-bromo-1, 4-dimethyl-3-nitropyridin-2 (1H) -one

Example 320a was prepared according to the procedure used for preparation example 1e, substituting example 1d for 5-bromo-4-methyl-3-nitropyridin-2-ol to provide the title compound.

Example 320b

3-amino-5-bromo-1, 4-dimethylpyridin-2 (1H) -one

Example 320b was prepared according to the procedure used to prepare example 7b, substituting example 320a for example 7a to provide the title compound.

Example 320c

4-bromo-6-methyl-1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Example 320b (1 g, 4.61 mmol), acetic anhydride (1.304 mL, 13.82mmol) and potassium acetate (0.543 g, 5.53 mmol) were stirred in toluene (25mL) for 18 h. Isoamyl nitrite (0.930 mL, 6.91mmol) was added dropwise and the solution was heated at 80 ℃ for 24 hours. The solution was cooled, water was added, and the aqueous solution was extracted with ethyl acetate. The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated. The residue was triturated with 30% ethyl acetate/hexane to give 0.415 g of the title compound.

Example 320d

4-bromo-6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Dimethylformamide (5 mL) from example 320c (0.228 g, 1.000 mmol) was treated with sodium hydride (0.060 g, 1.500 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes. To the solution was added (2- (chloromethoxy) ethyl) trimethylsilane (0.200 g, 1.200 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane, gradient) to give the title compound (0.301 g, 0.840 mmol, 84% yield).

Example 320e

4- (5-amino-2- (2, 4-difluorophenoxy) phenyl) -6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Prepare example 320e according to the procedure used to prepare example 138a, substituting example 320d for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene and example 148c for example 6a, respectively, to provide the title compound.

Example 320f

N- (4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrazolo [3,4-c ] pyridin-4-yl) phenyl) -N- (ethylsulfonyl) ethanesulfonamide

A mixture of example 320e (0.1 g, 0.201 mmol), ethanesulfonyl chloride (0.077 g, 0.602mmol) and triethylamine (0.081 g, 0.802 mmol) in dichloromethane was stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by flash chromatography on silica gel (4:1 ethyl acetate/hexane) to give the title compound (0.11 g, 0.161 mmol,80% yield).

Example 320g

Example 320 f/dichloromethane (3 mL) was treated with 2,2, 2-trifluoroacetic acid (1.837 g, 16.11 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed and the residue was placed under high vacuum for 1 hour. Then treated with dioxane (5 mL) and 2.0N sodium hydroxide (1.611 mL, 3.22 mmol). The reaction mixture was heated at 85 ℃ for 2 hours. After cooling, the reaction mixture was partitioned between 0.1% HCl and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was then purified by reverse phase preparative HPLC (10-80% acetonitrile/0.1% TFA water) to give the title compound as a TFA salt (0.055 g, 0.119 mmol, 74.1% yield).

Example 321

4- {2- (2, 4-Difluorophenoxy) -5- [ (methylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrazolo [3,4-c ] pyridin-7-one

Example 321a

2- (2- (2, 4-Difluorophenoxy) -5- ((methylsulfonyl) methyl) phenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane

Example 287e (1.13 g, 3mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (1.52 g, 6mmol), potassium acetate (1.18 g, 12mmol) and bis (triphenylphosphine) palladium (II) chloride (0.126 g,0.18 mmol) were mixed in a 20-mL microwave vial and sparged with nitrogen for 30 minutes. To this mixture was added nitrogen sparged dioxane (15 mL). The reaction mixture was heated at 90 ℃ for 8 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, treated with 3-mercaptopropyl-functionalized silica gel, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-10% ethyl acetate/dichloromethane) then triturated with heptane to provide the title compound (0.64 g, 50%).

Example 321b

4- (2- (2, 4-Difluorophenoxy) -5- ((methylsulfonyl) methyl) phenyl) -6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Example 320d (0.04 g, 0.112 mmol), example 321a (0.052g, 0.123 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.0031 g, 3.35. mu. mol), (1S,3R,5R,7S) -1,3,5, 7-tetramethyl-8-phenyl-2, 4, 6-trioxa-8-phosphamantane (0.0033 g, 0.011 mmol) and sodium carbonate (0.051 g, 0.48 mmol) were mixed in a 5-mL microwave vial and sparged with nitrogen for 30 minutes. To this mixture was added nitrogen sparged dioxane (0.8mL) and water (0.2 mL). The reaction mixture was stirred at 60 ℃ for 4.5 hours. The reaction mixture was cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, treated with 3-mercaptopropyl-functionalized silica gel, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-10% methanol in dichloromethane) to provide the title compound (0.06 g, 93%).

Example 321c

Example 321b (0.06 g, 0.104mmol) was treated with 2,2, 2-trifluoroacetic acid (2mL, 26.1 mmol), stirred at ambient temperature for 30 min, then concentrated to dryness. By reverse phase HPLC (C18, CH)₃CN/water (0.1% TFA), 20-80%) to provide the title compound (0.03 g, 65%).

Example 322

4- [2- (2, 4-Difluorophenoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrazolo [3,4-c ] pyridin-7-one

Example 322a

Ethyl (4-fluorophenyl) sulfane

Triethylamine (5.44 mL, 39mmol) was added to a solution of 4-fluorobenzenethiol (5 g, 39mmol) and iodoethane (3.78 mL, 46.8 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at ambient temperature for 2 hours and then filtered. The filtrate was concentrated, triturated with hexane, and dried under vacuum to give the title compound (4.8 g, 76%).

Example 322b

1- (ethylsulfonyl) -4-fluorobenzene

Example 322a (5 g, 32 mmol)/dichloromethane (200 mL) was treated with 3-chloroperoxybenzoic acid (14.3 g, 70.4 mmol) and stirred at ambient temperature for 6 hours. The solid formed during the reaction mixture was removed by filtration and washed with additional dichloromethane. The combined filtrate was washed with 10% aqueous sodium hydroxide (50mL, twice) and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 15% ethyl acetate/petroleum ether) to give the title compound (4.6 g, 76%).

Example 322c

2-bromo-4- (ethylsulfonyl) -1-fluorobenzene

By usingNExample 322b (1 g, 5.31 mmol)/sulfuric acid (6 mL, 113 mmol) was treated with bromosuccinimide (1.04 g, 5.84 mmol), stirred at ambient temperature for 6 hours, then at 50 ℃ for 16 hours. The reaction mixture was then poured into ice water and the resulting solid was collected by filtration, washed three times with ice water and dried in a vacuum oven for 16 hours. The solid was then purified by flash chromatography (silica gel, 9-20% ethyl acetate/petroleum ether) to give the title compound (1.1 g, 78%).

Example 322d

2- (5- (ethylsulfonyl) -2-fluorophenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane

4,4,4',4',5,5,5',5' -octamethyl-2, 2 '-bis (1,3, 2-dioxaborolane) (0.665 g, 2.62 mmol), example 322c (0.5 g, 1.9 mmol), potassium acetate (0.367 g, 3.74 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.041 g, 0.056 mmol) were mixed in an argon sparged dioxane (10 mL)/dimethylsulfoxide (0.3 mL) mixture and heated at 90 ℃ under argon for 24 hours. The reaction mixture was partitioned between ethyl acetate and water and filtered through a plug of celite to remove elemental palladium. The layers were separated and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl-functionalized silica gel for 15 minutes, filtered and concentrated. The residue was triturated in a minimum amount of heptane/diethyl ether (20:1) and filtered to give the crude product. The material was then dissolved in ethyl acetate, treated again with 3-mercaptopropyl-functionalized silica gel, filtered and concentrated. The residue was recrystallized from heptane/ethyl acetate (9:1) to give the title compound (0.3 g, 77%).

Example 322e

4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Example 322e was prepared according to the procedure used for the preparation of example 321b, substituting example 322d for example 321a to provide the title compound (0.0635 g, 55%).

Example 322f

4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Example 322e (0.0635 g, 0.136mmol), 2, 4-difluorophenol (0.021 g, 0.164mmol) and cesium carbonate (0.089 g, 0.273 mmol) were combined in a 4-mL vial containing dimethylsulfoxide (1.5 mL), stirred at 60 ℃ for 8 hours then at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-8% methanol/dichloromethane) to provide the title compound (0.0574 g, 73%).

Example 322g

4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Example 322g was prepared according to the procedure used to prepare example 321c, substituting example 322f for example 321b to provide the title compound (0.0299 g, 67%).

Example 323

4- [2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrazolo [3,4-c ] pyridin-7-one

Example 323a

4- (2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Cyclopropylmethanol (0.018 g,0.25 mmol)/dioxane (0.75 mL) was treated with sodium hydride (60% oil dispersion) (0.023 g, 0.587 mmol) and stirred at ambient temperature for 10 min. A solution of example 322e (0.0683g, 0.147 mmol) in dioxane (0.75 mL) was added and the mixture was stirred at 60 ℃ for 8 hours and then at ambient temperature for 16 hours. Additional cyclopropylmethanol (0.018 g, 0.249 mmol) and sodium hydride (60% oil dispersion) (0.023 g, 0.587 mmol) were added and the mixture was heated at 70 ℃ for 9 h. The reaction mixture was cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate/dichloromethane) to provide the title compound (0.0685 g, 90%).

Example 323b

4- (2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-1H-pyrazolo [3,4-c ] pyridin-7 (6H) -one

Example 323b was prepared according to the procedure used to prepare example 321c, substituting example 323a for example 321b to provide the title compound (0.0302 g, 59%).

Example 324

N- [ 2-cyano-4- (2, 4-difluorophenoxy) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Example 324a

4-bromo-5- (2, 4-difluorophenoxy) -2-nitrobenzoic acid

Example 324a was prepared according to the procedure used for preparation example 7a, substituting 4-bromo-5-fluoro-2-nitrobenzoic acid for 2-bromo-1-fluoro-4-nitrobenzene (Combi Blocks) and 2, 4-difluorophenol for phenol to provide the title compound.

Example 324b

4-bromo-5- (2, 4-difluorophenoxy) -2-nitrobenzoic acid methyl ester

Oxalyl chloride (1.4 mL, 16.6 mmol) was added dropwise to a suspension of example 324a (5.47 g, 14.6 mmol) and dichloromethane (65 mL) at 0 ℃.3 drops of dimethylformamide were added and the reaction mixture was stirred at ambient temperature for 2 hours. After cooling to 0 ℃ methanol (12 mL, 296 mmol) was added dropwise. The solution was stirred at 0 ℃ for 15 minutes and at ambient temperature for 2.5 hours. The solution was diluted with dichloromethane and washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (5.42 g, 96% yield).

Example 324c

2-amino-4-bromo-5- (2, 4-difluorophenoxy) benzoic acid methyl ester

Example 324c was prepared according to the procedure used to prepare example 7b, substituting example 324b for example 7a to provide the title compound.

Example 324d

4-bromo-5- (2, 4-difluorophenoxy) -2- (ethylsulfonylamino) benzoic acid

Example 324d was prepared according to the procedure used to prepare example 7c, substituting example 324c for example 7b to provide the title compound.

Example 324e

4-bromo-5- (2, 4-difluorophenoxy) -2- (ethylsulfonamido) benzamide

Oxalyl chloride (0.046 mL, 0.54 mmol) was added dropwise to the suspension of example 324d (214mg, 0.49 mmol) and dichloromethane (2.2 mL). 1 drop of dimethylformamide was added and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated and the residue was dried (vacuum). The resulting acid chloride was suspended in tetrahydrofuran (1.0 mL) and cooled to 0 ℃ while ammonium hydroxide (0.65 mL, 4.7 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. Ethyl acetate was added, and the solution was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-8% methanol/dichloromethane, gradient) to give the title compound (176 mg, 82% yield).

Example 324f

N- (5-bromo-2-cyano-4- (2, 4-difluorophenoxy) phenyl) ethanesulfonamide

To the suspension of example 324e (230 mg, 0.53 mmol) and dioxane (1.5 mL) was added pyridine (0.14 mL, 1.7 mmol) followed by 2,2, 2-trifluoroacetic anhydride (0.14 mL, 0.99 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 5-40% ethyl acetate/heptane, gradient) to give the title compound (135 mg, 61% yield).

Example 324g

N- (2-cyano-4- (2, 4-difluorophenoxy) -5- (6-methyl-7-oxo-1-toluenesulfonyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) ethanesulfonamide

Example 324g was prepared according to the procedure used to prepare example 6c, substituting example 324f for example 6b to provide the title compound.

Example 324h

N- (2-cyano-4- (2, 4-difluorophenoxy) -5- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl) ethanesulfonamide

Example 324h was prepared according to the procedure used for the preparation of example 6d, substituting example 324g for example 6c to provide the title compound.

Example 325

4- [4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester

Preparation example 325 was prepared according to the procedure used for preparation example 315 substituting 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester for pyridin-3-ylboronic acid to provide the title compound.

Example 326

4- [5- (6-Aminopyridin-3-yl) -2- (cyclopropylmethoxy) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 326 was prepared according to the procedure used for the preparation of example 315 substituting 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine for pyridin-3-ylboronic acid to provide the title compound.

Example 327

4- {2- [ (2, 2-Difluorocyclopropyl) methoxy ] -5- (ethylsulfonyl) phenyl } -6-methyl-7-oxo-N- (2,2, 2-trifluoroethyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxamide

Example 327a

Example 327a was prepared according to the procedure used for the preparation of example 6a, substituting example 70e for example 1e to provide the title compound.

Example 327b

1-benzyl-4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 327b was prepared according to the procedure used for the preparation of example 138a, substituting example 327a for example 6a and example 168b for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene, respectively, to provide the title compound.

Example 327c

4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 327c was prepared according to the procedure used to prepare example 70j, substituting example 327b for example 70i to provide the title compound.

Example 327d

4- (2- ((2, 2-difluorocyclopropyl) methoxy) -5- (ethylsulfonyl) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid

To a solution of example 327c (1 g, 2.460 mmol) and (2, 2-difluorocyclopropyl) methanol (0.532 g, 4.92mmol) in dimethyl sulfoxide (10mL) was added cesium carbonate (1.203 g, 3.69 mmol). The reaction mixture was sealed in a microwave tube and heated at 110 ℃ for 5 days. Three additional batches of (2, 2-difluorocyclopropyl) methanol (0.532 g, 4.92mmol) were added to the reaction mixture over 5 days. The reaction mixture was poured into ethyl acetate (150 mL) and water (150 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the corresponding ethyl ester (1.2 g, 1.869 mmol, 76% yield). The pH of the aqueous layer was adjusted to about 3 with 1N HCl, and the resulting solid was filtered and dried to give the title compound (0.30 g, 0.64 mmol).

Example 327e

To the dry dichloromethane of example 327d (0.070g, 0.15 mmol)Oxalyl chloride (0.026 mL, 0.300 mmol) and dimethylformamide (0.581 μ l, 7.50 μmol) were added to a solution of alkane (5 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was dissolved in dichloromethane (5 mL) and treated with 2,2, 2-trifluoroethylamine (0.048 mL, 0.600 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between water (15mL) and ethyl acetate (25 mL). The aqueous layer was extracted twice with additional ethyl acetate (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. By reverse phase HPLC (C18, mobile phase A: water (10 mM NH)₄HCO₃) (ii) a B acetonitrile, gradient 25-60% B/a) to purify the residue to give the title compound (70 mg, 85%).

Example 328

4- {2- [ (cyclopropylmethyl) amino ] -5- [ (methylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 328a

1- ((methylsulfonyl) methyl) -4-nitrobenzene

To a solution of 4-nitrobenzyl bromide (10.02 g, 46.4 mmol) in N, N-dimethylformamide (25mL) was added sodium methanesulfinate (7.10 g, 69.6 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with water. The resulting suspension was stirred for 10 minutes and filtered through a medium frit to provide the title compound.

Example 328b

4- ((methylsulfonyl) methyl) aniline

Example 328a (8.2 g, 38.1 mmol) and tetrahydrofuran (200 mL) were added to a 5% Pd/C, humidified (1.6 g, 0.376 mmol) 50mL pressure bottle and stirred at 30 psi and 50 ℃ for 2 hours. The mixture was filtered through a nylon membrane and washed with small amounts of tetrahydrofuran and methanol. The solvent was evaporated to afford the title compound.

Example 328c

2-iodo-4- ((methylsulfonyl) methyl) aniline

To a solution of example 328b (3.80 g, 20.5 mmol) in N, N-dimethylformamide (103 mL) was added N-iodosuccinimide (5.08 g, 22.56 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with 150mL 10% aqueous sodium thiosulfate and 100 mL saturated aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and concentrated. Water was added and the resulting suspension was stirred at ambient temperature for 10 minutes. The suspension was filtered and the collected solids were washed with water and dried overnight to provide the title compound.

Example 328d

N- (cyclopropylmethyl) -2-iodo-4- ((methylsulfonyl) methyl) aniline

Example 328c (0.200 g, 0.643 mmol) and cyclopropanecarboxaldehyde (0.062 mL,0.836 mmol) were suspended in dichloromethane (3.21 mL) and methanol (3.21 mL). Acetic acid (0.368 mL, 6.43 mmol) was added. The reaction mixture was heated at 50 ℃ for 30 minutes and then cooled to ambient temperature. Polymer-supported cyanoborohydride (0.817 g, 1.928 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. Cyclopropanecarboxaldehyde (0.062 mL,0.836 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered, washed thoroughly with dichloromethane, and concentrated. The residue was purified by flash chromatography (silica gel, 20-100% ethyl acetate in heptane, gradient) to provide the title compound.

Example 328e

4- (2- ((cyclopropylmethyl) amino) -5- ((methylsulfonyl) methyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 328e was prepared according to the procedure used for the preparation of example 4a, substituting example 328d for example 7c to provide the title compound.

Example 328f

Example 328f was prepared according to the procedure used for the preparation of example 4b, substituting example 328e for example 4a to provide the title compound.

Example 329

4- {2- [ (cyclopropylmethyl) amino ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 329a

2-bromo-N- (cyclopropylmethyl) -4- (methylsulfonyl) aniline

Example 329a was prepared according to the procedure used for preparation example 147a, substituting cyclopropylmethylamine for cyclohexylamine to provide the title compound.

Example 329b

4- (2- ((cyclopropylmethyl) amino) -5- (methylsulfonyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 329b was prepared according to the procedure used to prepare example 7d, substituting the product of example 329a for the product of example 7c and stirring at 100 ℃ for 30 minutes to provide the title compound.

Example 329c

Example 329C was prepared according to the procedure used for the preparation of example 4 (method B), the product of example 329B was substituted for the product of example 7d and purified by preparative HPLC (C18, 10-100% acetonitrile/0.1% TFA/water) to provide the title compound as a TFA salt.

Example 330

4- [5- (ethylsulfonyl) -2- (pyrrolidin-1-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 330a

4- (5- (ethylsulfonyl) -2-fluorophenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 168b (0.935 g, 3.50 mmol), example 6a (1.5g, 3.5 mmol), tetrakis (triphenylphosphine) palladium (0) (0.202 g, 0.175 mmol) and cesium fluoride were heated at 120 ℃ under microwave conditions(1.596 g, 10.51mmol) of a mixture of 12 mL of dimethoxyethane and 4mL of methanol for 40 minutes. The mixture was concentrated and the residue was adsorbed on silica gel and purified by flash chromatography (SiO)₂0-10% methanol in dichloromethane, gradient) to give the title compound (1.01g, 86% yield).

Example 330b

A1 mL DMSO mixture of example 330a (90 mg, 0.27 mmol) and pyrrolidine (668 μ L,8.08 mmol) was heated under microwave conditions at 160 ℃ for 30 minutes. By preparative HPLC (C18, 10-80% CH)₃CN/water (0.1% TFA)) to give the title compound (37 mg, 35.7% yield).

Example 331

4- [5- (ethylsulfonyl) -2- (4-methylpiperazin-1-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Preparation example 331 was prepared according to the procedure used for preparation example 330b, substituting N-methylpiperazine for pyrrolidine to provide the title compound as a TFA salt.

Example 332

4- {2- [ (4-fluorophenyl) amino ] -5- (methylsulfonyl) phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 332a

4- (2-amino-5- (methylsulfonyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 6a (1.71 g,4.00 mmol), 2-bromo-4- (methylsulfonyl) aniline (1.00g, 4.00 mmol), tris (dibenzylideneacetone) dipalladium (0.110 g, 0.120 mmol), 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (0.117 g, 0.400 mmol) and sodium carbonate (1.48 g, 14.0 mmol) were combined and flushed with argon for 15 minutes. The mixture of dioxane (21.3 mL) and water (5.3 mL) was flushed with nitrogen for 15 minutes and transferred to the reaction vessel. The reaction mixture was heated at 60 ℃ for 3 hours, cooled to ambient temperature and diluted with water. The resulting solid was filtered, washed with water, and dried to give the title compound (2.06 g, quantitative yield).

Example 332b

4- (2- ((4-fluorophenyl) amino) -5- (methylsulfonyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 332a (47.2 mg,0.100 mmol), 1-bromo-4-fluorobenzene (17.5 mg,0.100 mmol), palladium acetate (diacyloxyalladium) (0.9mg, 4. mu. mol), dicyclohexyl (2',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl) phosphine (3.8 mg, 8.0. mu. mol) and cesium carbonate (45.6 mg, 0.140 mmol) were mixed in a mixture of toluene (1.6 mL) and tert-butanol (0.4 mL). The reaction mixture was heated in a microwave reactor at 150 ℃ for 15 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl functionalized silica gel, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2-4% methanol/dichloromethane) to provide the title compound (30 mg, 53%).

Example 332c

Example 332b (28 mg, 0.050mmol), potassium hydroxide (41.7 mg, 0.743 mmol) and hexadecyltrimethylammonium bromide (0.90 mg, 2.5 μmol) were mixed in a mixture of tetrahydrofuran (2 mL) and water (1 mL). The reaction mixture was heated at 100 ℃ for 20 hours and then cooled to ambient temperature. To the mixture was added water and the pH was adjusted to pH 7 by addition of 1M HCl. The mixture was extracted with ethyl acetate and the organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 2-4% methanol in dichloromethane) to provide the title compound (13 mg, 64%).

Example 333

4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-3-ylmethyl) benzenesulfonamide

Example 333a

3-bromo-4-fluoro-N- (pyridin-3-ylmethyl) benzenesulfonamide

Example 333a was prepared according to the procedure used to prepare example 305a, substituting pyridin-3-ylmethylamine for indoline. The crude product was purified by recrystallization from ethyl acetate/diethyl ether to give the title compound.

Example 333b

3-bromo-4- (cyclopropylmethoxy) -N- (pyridin-3-ylmethyl) benzenesulfonamide

Preparation example 333b was prepared according to the procedure used for the preparation of example 29a, substituting cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and example 333a for example 2a to give the title compound.

Example 333c

4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -N- (pyridin-3-ylmethyl) benzenesulfonamide

Example 333c was prepared according to the procedure used for the preparation of example 6c, substituting example 333b for example 6b to give the title compound.

Example 333d

Example 333d was prepared according to the procedure used for preparation of example 6d, substituting example 333C for example 6C and purified by preparative HPLC (C18, 10-100% acetonitrile/0.1% TFA/water) to provide the title compound as a TFA salt.

Example 334

4- [4- (cyclopropylmethoxy) -3' -fluorobiphenyl-3-yl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 334a

Example 334a was prepared according to the procedure used for the preparation of example 6c, substituting example 314a for example 6b to give the title compound.

Example 334b

4- (4- (cyclopropylmethoxy) -3' -fluorobiphenyl-3-yl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 334b was prepared according to the procedure used for the preparation of example 6c, substituting example 334a for example 6b and (3-fluorophenyl) boronic acid for example 6a to give the title compound.

Example 334c

4- (4- (cyclopropylmethoxy) -3' -fluorobiphenyl-3-yl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 334c was prepared according to the procedure used for the preparation of example 6d, substituting example 334b for example 6c to give the title compound.

Example 335

4- {2- [ (4-fluorophenyl) amino ] -5- [ (methylsulfonyl) methyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 335a

4- (2-amino-5- ((methylsulfonyl) methyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 335a was prepared according to the procedure used for the preparation of example 4a, substituting example 328c for example 7c to give the title compound.

Example 335b

4- (2- ((4-fluorophenyl) amino) -5- ((methylsulfonyl) methyl) phenyl) -6-methyl-1-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

4-bromofluorobenzene (0.027 mL, 0.25 mmol), example 335a (0.100 g, 0.206 mmol), palladium (II) acetate (1.849 mg, 8.24. mu. mol), dicyclohexyl (2',4',6 '-triisopropyl- [1,1' -biphenyl ] -2-yl) phosphine (7.85 mg, 0.016 mmol), and cesium carbonate (0.094 g, 0.29 mmol) were suspended in toluene (1.37 mL) and tert-butanol (0.69 mL). The reaction mixture was heated at 150 ℃ for 30 minutes under microwave conditions. The reaction mixture was filtered through a column of 2.5g celite and washed thoroughly with ethyl acetate. The filtrate was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and mercaptopropyl silica gel, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-4% methanol in dichloromethane, gradient) to provide the title compound.

Example 335c

Example 335c was prepared according to the procedure used for the preparation of example 4b, substituting example 335b for example 4a to give the title compound.

Example 336

[4- (cyclopropylmethoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] acetonitrile

A mixture of example 314b (100 mg,0.190 mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoxazole (44.4 mg, 0.228 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] -dichloropalladium (II) complex with dichloromethane (1:1) (15.5 mg, 0.019 mmol) and potassium fluoride (44.1 mg,0.758 mmol) in dimethylsulfoxide (1.9 mL) and water (0.75 mL) was flushed with nitrogen and heated at 130 ℃ for 1.5 hours under microwave conditions. The mixture was then treated with 1mL of 4N NaOH and stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water (2 ×), saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 0-8% methanol/dichloromethane, gradient) to give the title compound (30 mg, 48% yield).

Example 337

N- {4- (2, 4-Difluorophenoxy) -3- [2- (hydroxymethyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl ] phenyl } ethanesulfonamide

Example 337a

4- (5-amino-2- (2, 4-difluorophenoxy) phenyl) -1-benzyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Prepare example 337a according to the procedure used for the preparation of example 138a, substituting example 70e for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene and example 148c for example 6a, respectively, to give the title compound.

Example 337b

1-benzyl-4- (2- (2, 4-Difluorophenoxy) -5- (N- (ethylsulfonyl) ethylsulfonylamino) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 337b was prepared according to the procedure used for the preparation of example 320f substituting example 337a for example 320e to give the title compound.

Example 337c

4- (2- (2, 4-Difluorophenoxy) -5- (N- (ethylsulfonyl) ethanesulfonamide) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid ethyl ester

Example 337c was prepared according to the procedure used for the preparation of example 70j, substituting example 337b for example 70i to give the title compound.

Example 337d

4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfonylamino) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carboxylic acid

Example 337d was prepared according to the procedure used for the preparation of example 70k, substituting example 337c for example 70j to give the title compound.

Example 337e

Example 337d (0.060 g, 0.12 mmol)/tetrahydrofuran (5 mL) was treated with 1.0N borane (0.119 mL, 0.119 mmol). The reaction mixture was heated at 60 ℃ for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC (C18, 10-100% acetonitrile/0.1% TFA/water) to give the title product (0.035 g, 60% yield).

Example 338

N- [4- (2, 4-Difluorophenoxy) -3- { 6-methyl-2- [ (4-methylpiperazin-1-yl) carbonyl ] -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl } phenyl ] ethanesulfonamide

Example 338a

4- (2- (2, 4-Difluorophenoxy) -5- (ethylsulfonylamino) phenyl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-2-carbonyl chloride

Example 338a was prepared according to the procedure used for the preparation of example 13a substituting example 337d for example 10 to give the title compound.

Example 338b

Prepare example 338b according to the procedure used for the preparation of example 13b, substituting example 338a for example 13a and 1-methylpiperazine for ethylamine to give the title compound as TFA salt, respectively.

Example 339

N- [4- (2, 4-Difluorophenoxy) -3- { 6-methyl-2- [ (4-methylpiperazin-1-yl) methyl ] -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl } phenyl ] ethanesulfonamide

Example 339 was prepared according to the procedure used for the preparation of example 337e, substituting example 338b for example 337d to give the title compound as a TFA salt.

Example 340

4- [2- (cyclopropylmethoxy) -5- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 325 (100 mg, 0.210 mmol) in 2mL of dichloromethane was treated with 1mL of trifluoroacetic acid. The mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated. The residue was treated with saturated aqueous sodium carbonate solution and then extracted with ethyl acetate (4 ×). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (26 mg, 32.9% yield).

Example 341

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- (2-methoxyethyl) ethanesulfonamide

To a 4mL vial was added (azidocarbonyl) dipiperidine (ADDP) (25.9 mg, 0.102 mmol) in dry toluene. The vial was placed in a drying box and tributylphosphine (41.5 mg, 3 eq, 0.205 mmol) was added to the vial. The mixture was shaken until the solution became clear. To this solution was added a solution of 2-methoxyethanol in anhydrous tetrahydrofuran (1.2 eq, 0.082 mmol, 6.24 mg). The solution was stirred at ambient temperature for 10 minutes. To the mixture was added a solution of example 36e (0.068mmol, 31.4 mg) in anhydrous toluene/anhydrous tetrahydrofuran (1:1 v/v) (1 mL). The reaction mixture was stirred at room temperature in a dry box overnight. The reaction mixture was concentrated to dryness and the residue was purified by reverse phase HPLC (C18, 10-100% acetonitrile/0.1% TFA/water) to provide the title compound (4.24%, 1.5 mg).

Example 342

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- (pyridin-2-ylmethyl) ethanesulfonamide

Preparation example 342 was prepared according to the procedure used for preparation example 341, substituting pyridin-2-ylmethanol for 2-methoxyethanol to give the title compound as the TFA salt.

Example 343

N- (cyclopropylmethyl) -N- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Preparation example 343 was prepared according to the procedure used for the preparation of example 341, substituting cyclopropylmethanol for 2-methoxyethanol to give the title compound.

Example 344

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- [2- (2-oxopyrrolidin-1-yl) ethyl ] ethanesulfonamide

Preparation example 344 was prepared according to the procedure used for preparation example 341, substituting 1- (2-hydroxyethyl) pyrrolidin-2-one for 2-methoxyethanol to give the title compound.

Example 345

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- (tetrahydrofuran-2-ylmethyl) ethanesulfonamide

Preparation example 345 was prepared according to the procedure used for preparation example 341, substituting (tetrahydrofuran-2-yl) methanol for 2-methoxyethanol to give the title compound.

Example 346

N- [4- (2, 4-Difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] -N- (3,3, 3-trifluoropropyl) ethanesulfonamide

Preparation example 346 was prepared according to the procedure used for the preparation of example 341, substituting 3,3, 3-trifluoropropan-1-ol for 2-methoxyethanol to give the title compound.

Example 347

4- (cyclopropylmethoxy) -N- (4-fluorophenyl) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide

Example 347a

3-bromo-4-fluoro-N- (4-fluorophenyl) benzenesulfonamide

Example 347a was prepared according to the procedure used to prepare example 305a, substituting 4-fluoroaniline for indoline. The crude product was purified by flash chromatography (silica gel, 10% ethyl acetate/heptane) to afford the title compound.

Example 347b

3-bromo-4- (cyclopropylmethoxy) -N- (4-fluorophenyl) benzenesulfonamide

Preparation example 347b was prepared according to the procedure used for the preparation of example 29a, substituting cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and example 347a for example 2a to give the title compound.

Example 347c

4- (cyclopropylmethoxy) -N- (4-fluorophenyl) -3- (6-methyl-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) benzenesulfonamide

Example 347c was prepared according to the procedure used for the preparation of example 6c, substituting example 347b for example 6b to give the title compound.

Example 347d

Example 347d was prepared according to the procedure used for the preparation of example 6d, substituting example 347c for example 6c to give the title compound.

Example 348

4- [2- (cyclopropylmethoxy) -5- (6-fluoropyridin-3-yl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 348a

4- (2- (cyclopropylmethoxy) -5- (6-fluoropyridin-3-yl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Prepare example 348a according to the procedure used to prepare example 6c, replace example 6b with example 334a and example 6a with (6-fluoropyridin-3-yl) boronic acid to give the title compound.

Example 348b

4- (2- (cyclopropylmethoxy) -5- (6-fluoropyridin-3-yl) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 348b was prepared according to the procedure used for the preparation of example 6d, substituting example 348a for example 6c to give the title compound.

Example 349

N- [4- (2, 4-Difluorophenoxy) -3- (3-formyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) phenyl ] ethanesulfonamide

Example 349a

4-bromo-6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A mixture of example 1e (7 g, 18.36 mmol) and lithium hydroxide monohydrate (3.08 g, 73.4mmol) in tetrahydrofuran (50mL) and water (20mL) was heated at 80 deg.C overnight. After cooling to ambient temperature, the reaction mixture was poured into 300 mL of water. The resulting solid was collected by vacuum filtration to give the title compound (3.92 g, 17.26 mmol, 94% yield).

Example 349b

4-bromo-6-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 349a (3.92 g, 17.26 mmol)/tetrahydrofuran (100 mL) was treated with 60% sodium hydride (1.036 g, 25.9 mmol). The reaction was stirred at ambient temperature for 10 minutes. To this solution was added (2- (chloromethoxy) ethyl) trimethylsilane (4.58 mL, 25.9 mmol). The reaction mixture was stirred overnight. The resulting solid was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate/heptane) to give the title compound (5.84 g,95% yield).

Example 349c

4-bromo-6-methyl-7-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-3-carbaldehyde

Example 349b (3.92 g, 17.3mmol) in dimethylformamide (15mL) was treated dropwise with phosphorus oxychloride (9.66 mL, 104mmol) at 0 ℃. After the addition was complete, the solution was heated at 80 ℃ for 6 hours. After cooling to ambient temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 50-100% ethyl acetate/heptane) to give the title compound (1.35 g, 20.3% yield).

Example 349d

4- (5-amino-2- (2, 4-difluorophenoxy) phenyl) -6-methyl-7-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridine-3-carbaldehyde

Prepare example 349d according to the procedure used to prepare example 138a substituting example 349c for 2-bromo-1-fluoro-4- (methylsulfonyl) benzene and example 148c for example 6a, respectively, to provide the title compound. After aqueous work-up, the crude product was used for the next reaction without purification.

Example 349e

A mixture of example 349d (0.5 g, 0.951 mmol), ethanesulfonyl chloride (0.226 mL,2.38 mmol) and triethylamine (0.817 mL, 5.71 mmol) in dichloromethane (10mL) was stirred at ambient temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was treated with dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure and the residue was treated with dioxane (10mL) and 2.0N NaOH (5 mL). The reaction mixture was heated at 90 ℃ for 2 hours. After cooling to ambient temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate) to give the title compound (0.42 g, 0.862 mmol, 91% yield).

Example 350

N- {4- (2, 4-Difluorophenoxy) -3- [ 6-methyl-3- (morpholin-4-ylmethyl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl ] phenyl } ethanesulfonamide

A mixture of example 349e (0.04 g, 0.082 mmol), morpholine (0.014 g, 0.164mmol) and sodium triacetoxyborohydride (0.035 g, 0.164mmol) in 1, 2-dichloroethane (2 mL) was stirred at ambient temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC (C18, 10-100% acetonitrile/0.1% TFA/water) to give the title compound as a TFA salt (0.035 g, 0.052 mmol, 63.4% yield).

Example 351

N- [4- (2, 4-Difluorophenoxy) -3- { 6-methyl-3- [ (4-methylpiperazin-1-yl) methyl ] -7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl } phenyl ] ethanesulfonamide

Preparation example 351 was prepared according to the procedure used for preparation example 350, substituting 1-methylpiperazine for morpholine to give the title compound as a TFA salt.

Example 352

4- {2- [ (cyclopropylmethyl) amino ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 352a

2-bromo-N- (cyclopropylmethyl) aniline

A solution of 2-bromoaniline (1.720 g, 10.00 mmol), cyclopropanecarboxaldehyde (0.374 mL, 5.00mmol) and acetic acid (2.86 mL, 50.0 mmol) in dichloromethane (50mL) was heated at 50 deg.C for 1 hour. The solution was cooled in an ice bath and sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added. The mixture was stirred for 2 hours while heating to ambient temperature, then partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate/heptane) to provide the title compound (1.05 g, 93% yield).

Example 352b

4- (2- ((cyclopropylmethyl) amino) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 352b was prepared according to the procedure used for preparation example 4a, substituting example 352a for example 7c, except that the reaction mixture was heated at 90 ℃ for 2.5 hours and the material was purified by flash column chromatography (silica gel, 0-5% methanol/dichloromethane) to provide the title compound.

Example 352c

Example 352c was prepared according to the procedure used for preparation example 4b, example 352b was used instead of example 4a, except that the reaction was heated at 90 ℃ for 2.5 hours and the material was purified by flash column chromatography (silica gel, 0-5% methanol/dichloromethane) to provide the title compound.

Example 353

4'- (cyclopropylmethoxy) -3' - (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) biphenyl-3-carbonitrile

Example 353a

4'- (cyclopropylmethoxy) -3' - (6-methyl-7-oxo-1-toluenesulfonyl-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) biphenyl-3-carbonitrile

Example 353a was prepared according to the procedure used to prepare example 6c, example 334a was used instead of example 6b, and (3-cyanophenyl) boronic acid was used instead of example 6a to provide the title compound.

Example 353b

Example 353b was prepared according to the procedure used for the preparation of example 6d, substituting example 353a for example 6c to give the title compound.

Example 354

4- {2- (cyclopropylmethoxy) -5- [ (4-hydroxypiperidin-1-yl) sulfonyl ] phenyl } -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one

Example 354a

1- (3-bromo-4-fluorophenylsulphonyl) piperidin-4-ol

Preparation example 354a was prepared according to the procedure used for preparation example 310a, substituting piperidin-4-ol for N, N-dimethylpyrrolidin-3-amine to give the title compound.

Example 354b

1- (3-bromo-4-fluorophenylsulfonyl) -4- (tetrahydro-2H-pyran-2-yloxy) piperidine

3, 4-dihydro-2H-pyran (0.28 mL, 3.1 mmol) was added dropwise to a 0 deg.C solution of example 354a (0.51 g,1.5 mmol), 4-methylphenylsulfuric acid hydrate (0.59 g, 3.1 mmol) and dichloromethane (28 mL). The reaction mixture was stirred at ambient temperature for 5 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol, gradient) to give the title compound (420 mg, 65.9% yield).

Example 354c

1- (3-bromo-4- (cyclopropylmethoxy) phenylsulfonyl) -4- (tetrahydro-2H-pyran-2-yloxy) piperidine

Example 354c was prepared according to the procedure used for the preparation of example 29a substituting cyclopropylmethanol for tetrahydro-2H-pyran-4-ol and example 354b for example 2a to give the title compound.

Example 354d

4- (2- (cyclopropylmethoxy) -5- (4- (tetrahydro-2H-pyran-2-yloxy) piperidin-1-ylsulfonyl) phenyl) -6-methyl-1-tosyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 354d was prepared according to the procedure used for the preparation of example 6c substituting example 354c for example 6b to give the title compound.

Example 354e

4- (2- (cyclopropylmethoxy) -5- (4- (tetrahydro-2H-pyran-2-yloxy) piperidin-1-ylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Example 354e was prepared according to the procedure used for the preparation of example 6d, substituting example 354d for example 6c to give the title compound.

Example 354f

4- (2- (cyclopropylmethoxy) -5- (4-hydroxypiperidin-1-ylsulfonyl) phenyl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

A solution of example 354e (54 mg,0.10 mmol), acetic acid (4 mL, 69.9 mmol), tetrahydrofuran (2 mL) and water (1mL) was stirred at 45 ℃ for 2.5 h. The reaction mixture was concentrated to dryness and the residue was dried overnight (vacuum). The crude product was triturated with ether, filtered and dried (vacuum) to give the title compound (30 mg, 66% yield).

Biological examples

Bromodomain ligation assay

Time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used to determine the binding of the example compounds listed in table 1 to each bromodomain of human BRD 4. His-tagged first (BD1: amino acids K57-E168) and second (BD2: amino acids E352-E168) bromodomains of human BRD4 were expressed and purified. Alexa 647-labeled BET-inhibitors were used as fluorescent probes for this assay. Synthesis of Alexa 647-labeled bromodomain inhibitor compounds

2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazepan-6-yl) acetic acid. 2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazepan-6-yl) methyl acetate (see, e.g., WO2006129623) (100.95 mg, 0.243 mmol) was suspended in 1mL of methanol to which a freshly prepared solution of lithium hydroxide monohydrate (0.973 mL, 0.5M, 0.487 mmol) was added and shaken at ambient temperature for 3 hours. Methanol was evaporated and the pH was adjusted with aqueous hydrochloric acid (1M, 0.5 mL, 0.5 mmol) and extracted four times with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and concentrated to give 2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazepan-6-yl) acetic acid (85.3 mg, 87.0%); ESI-MS M/z = 401.1 [ (M + H)⁺]It was used directly for the next reaction.

N- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazacyclotrien-6-yl) acetamide bis (2,2, 2-trifluoroacetate). 2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazepan-6-yl) acetic acid (85.3 mg, 0.213 mmol) was combined with 2,2' - (ethyl-1, 2-diylbis (oxy)) diethylamine (Sigma-Aldrich, 0.315 mg, 2.13 mmol) in 5mL anhydrous dimethylformamide. Adding (1H-benzo [ d ]][1,2,3]Triazol-1-yloxy) tripyrrolidin-1-ylphosphine hexafluorophosphate (V) (PyBOB, CSBio, Menlo Park CA; 332 mg, 0.638 mmol) and shaking the reaction at ambient temperature for 16 h. The reaction mixture was diluted to 6 mL with dimethylsulfoxide water (9:1, v: v) and collected for purification over time in two injections, Waters Deltapak C18200X 25 mm column, eluting with a gradient of 0.1% trifluoroacetic acid (v/v)/water and acetonitrile. The fractions containing the two purified products were lyophilized to give N- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazacyclotrien-6-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 (S, Z) -N, N '- (2,2' - (ethane-1, 2-diylbis (oxy)) bis (ethane-2, 1-diyl)) bis (2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazepan-6-yl) acetamide) bis (2,2, 2-trifluoroacetate) (3.0 mg, 1.5%); ESI-MS M/z =913.2 [ (M + H)⁺]；911.0 [(M-H)^-]。

N- (2- (2- (2-amido- (Alexa647) -ethoxy) ethyl) -2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazacyclotrien-6-yl) acetamide (2,2, 2-trifluoroacetate). Reacting N- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a][1,4]Diazepatrien-6-yl) acetamide bis (2,2, 2-trifluoroacetate) (5.4 mg, 0.0071 mmol) with Alexa Fluor 647 succinimidyl formate (Life Techno)logies, Grand Island, NY; 3mg, 0.0024 mmol) were mixed in 1mL of anhydrous dimethyl sulfoxide with diisopropylethylamine (1% v/v) and shaken at ambient temperature for 16 h. The reaction was diluted to 3mL with dimethylsulfoxide water (9:1, v: v) and the purifications were collected over time in one injection, Waters Deltapak C18200X 25 mm column, eluting with a gradient of 0.1% trifluoroacetic acid (v/v)/water and acetonitrile. The fractions containing the purified product were lyophilized to give N- (2- (2- (2-amido- (Alexa647) -ethoxy) ethyl) -2- ((6S, Z) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f) as a dark blue powder][1,2,4]Triazolo [4,3-a][1,4]Diazacyclotrien-6-yl) acetamide (2,2, 2-trifluoroacetate) (1.8 mg); MALDI-MS M/z =1371.1, 1373.1 [ (M + H)⁺]。

Test of

Compound dilution series were prepared in DMSO by 3-fold serial dilutions from 2.5 mM to 42 nM. Then, the compound was diluted 6:100 in assay buffer (20 mM sodium phosphate, pH 6.0, 50mM NaCl, 1mM ethylenediaminetetraacetic acid disodium salt dihydrate, 0.01% Triton X-100, 1mM DL-dithiothreitol) to give a 3X working solution. Then, six microliters (μ L) of the working solution was transferred to a white, low-volume assay plate (Costar # 3673). A1.5X assay mixture containing His-tagged bromodomain, europium-conjugated anti-His antibody (Invitrogen PV5596), and Alexa-647-conjugated probe molecules was also prepared. 12 μ L of this solution was added to the assay plate to reach a final volume of 18 μ L. The final concentration of 1 × assay buffer contained 2% DMSO, 50 μ M-0.85 nM compound, 8 nM His-tagged bromodomain, 1 nM europium-conjugated anti-His-tag antibody and 100 nM or 30 nM probe (to BDI or BDII, respectively). After one hour incubation at room temperature, the TR-FRET ratio was determined using an Envision multi-label plate reader (Ex 340, Em 495/520).

TR-FRET data were normalized to the mean of 24 no compound controls ("high") and 8 controls containing 1 μ M unlabeled probe ("low"). Percent inhibition was plotted as a function of compound concentration and the data was fitted with a 4-parameter logistic equation to obtain IC₅₀. Slave IC₅₀Probe K_dAnd probe concentration calculation inhibition constant (K)_i). Typical values of Z' are from 0.65 to 0.75. The minimum significance ratio was determined to evaluate test reproducibility (Eastwood et al, (2006) J Biomol Screen,11: 253-261). The MSR is determined to be 2.03 for BDI, 1.93 for BDII, and the Mobile MSR (last six sets of MSRs timeout) is typically used for both BDI and BDII<3. K is reported in Table 1_iThe value is obtained.

MX-1 cell line proliferation assay

The effect of the example compounds on cancer cell proliferation was determined in a 3-day proliferation assay using the breast cancer cell line MX-1 (ATCC). At 37 ℃ and 5% CO₂Under atmosphere, MX-1 cells were maintained in RPMI1640 medium (Sigma) supplemented with 10% FBS (fetal bovine serum). For compound detection, MX-1 cells were placed at a density of 5000 cells/well in 90 μ L culture medium in a 96-well black-bottom plate and incubated overnight at 37 ℃ for cell adhesion and spreading. Compound dilution series were prepared in DMSO by 3-fold serial dilutions from 3mM to 0.1 μ M. Then, the DMSO dilution sequence was diluted 1:100 in phosphate buffered saline and 10 μ L of the resulting solution was added to the appropriate wells of the MX-1 cell plate. Final compound concentrations in wells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003 and 0.0001 μ M. After addition of the compound, cells were incubated for more than 72 hours and the amount of viable cells was determined using the Cell Titer Glo assay kit (Promega) according to the manufacturer's recommended protocol.

Fluorescence readings from the Cell Titer Glo assay were normalized to DMSO-treated cells and analyzed using GraphPad Prism software with sigmoidal curve fitting to obtain EC₅₀. The Minimum Significant Ratio (MSR) was determined to evaluate test reproducibility (Eastwood et al, (2006) J Biomol Screen,11: 253-. Determine total MSR as 2.1 and mobile MSR (last six MSR timeout) as<2。

Proliferation plate assay

The effect of the compounds of examples 4 and 78 on proliferation of plates of the cancer cell line types listed in table 2 (with the particular cell lines tested) was examined.Cells were plated at 1500 cells/well in 96-well plates in appropriate culture media without test compound and at 37 ℃ and 5% CO₂Was incubated overnight under the atmosphere of (1). A dilution series of the compound was prepared and added to the same wells as the MX-1 proliferation assay. After addition of the compound, at 37 ℃ and 5% CO₂Incubate wells for an additional 3 days. The amount of viable cells was determined using the CellTiter Glo assay kit (Promega) according to the manufacturer's recommended protocol. Analysis of cell proliferation data to obtain EC for Compounds of examples 4 and 78 as described in MX-1 proliferation assay above₅₀And reported in table 2.

TABLE 1

Means of multiple experiments

NA means not determined.

TABLE 2

Human, rat and mouse microsome stability test

Microsomal stability testing was performed on the example compounds ("test compounds") listed in table 3. Liver microsome incubation of humans, rats and mice was performed at 37 ℃ with a final incubation volume of 135 μ L. Human liver microsomes were obtained from XenoTech (male and female cocktail, catalog No. H2610). Rat liver microsomes were obtained from BD Gentest (Male Sprague-Dawley, catalogNumber 42501). Mouse liver microsomes were obtained from BD Gentest (male CD1, catalog No. 452701). Incubations were performed at pH 7.4 using test compound at a concentration of 0.5 μ M (initially dissolved in DMSO, at a concentration of 5 μ M) and 0.25 mg/mL of microsomal protein in 50mM phosphate buffer. The zero time sample was prepared by transferring 13.5 μ L of the compound-microsome mixture to a quench plate containing 45 μ L of a quench solution with 10 nM buspirone (Sigma) or 50nM butamsuron (Princeton Bio) as internal standards at 1:1 methanol: and (3) preparing in acetonitrile. A1.5 μ L aliquot of reduced coenzyme II tetrasodium salt (NADPH) was also added to the zero hour plate. Then, the reaction was started by adding 13.5 μ L of NADPH to the compound-microsome mixture. At each remaining time point (5, 10, 15, 20 and 30 min), 15 μ L of the incubation mixture was added to 45 μ L of the quench solution. The samples were centrifuged at 3800 rpm for 15-30 minutes. The samples were then mixed, six parts each. A60 μ L aliquot of the supernatant was transferred to a 384-well plate and a 5 μ L aliquot was injected and analyzed by LC-MS/MS (applied biosystems API 5500 QTrap). Intrinsic clearance of the compound was calculated by converting the peak area ratio (analyte peak area/IS peak area) to% of the remaining parent compound, the zero time area ratio used being 100%. Slope (k) was determined from the plot of% parent compound remaining versus incubation time, where half-life (t) is_1/2(ii) a Minutes), intrinsic Clearance (CL)_int(ii) a For liver microsomes muL/min/mg protein, for hepatocytes muL/min/million cells), and then derive a proportional intrinsic clearance (proportional CL)_int(ii) a L/h/kg). In Table 3, t is reported_1/2The value is obtained. The term "N/A" means not determined.

TABLE 3

LPS (lipopolysaccharide) -induced IL-6 production mouse assay

The example compounds listed in table 4 were tested for their ability to inhibit LPS (lipopolysaccharide) -induced IL-6 production in mice. One hour after oral administration of the compound, Fox Chase SCID^®Female mice (Charles river Labs, 8 per group) received intraperitoneal challenge of lipopolysaccharide (2.5 mg/kg, L2630 E.coli (E.coli) 0111: B4). Mice were euthanized 2 hours after lipopolysaccharide injection, blood was removed by cardiac puncture, and serum collected from blood samples was frozen at-80 ℃. On the day of testing, the serum samples were allowed to warm to room temperature and then diluted 1:20 in phosphate buffered saline containing 2% bovine serum albumin. Using cytokine assays from the Meso Scale Discovery (Gaithersburg, Maryland), interleukin-6 detection was performed according to the manufacturer's protocol for mouse serum analysis and read on a SECTOR Imager 6000(Meso Scale Discovery, Gaithersburg, Maryland) instrument. Statistical analysis was performed using Prism software (version 5.0) including Dunnett's one-way ANOVA. The mean and standard deviation of IL-6 for the vehicle-treated animal groups was compared to the mean and standard deviation of IL-6 for the groups treated with the test compound. p value<0.05 means that there is less than a 5% probability of equality for the mean of the two groups. The percent inhibition values in Table 4 all show p values<0.05。

TABLE 4

Inhibition of LPS-induced IL-6 production in mice

Denotes the average of multiple experiments.

Xenograft tumor growth inhibition assay

The compound of example 36 was evaluated for its effect on inhibiting the growth of OPM-2 and MX-1 xenograft tumors implanted in mice. Briefly, on study day 0, 5x 10 was examined⁶Human cancer cells (OPM-2) or the 1:10 tumor brie (MX-1) (in S-MEM (MEM, suspension, calcium-free, glutamate-free)) (Life Technologies Corporation) were subcutaneously seeded in female SCID-beige or female Fox Chase SCID, respectively^®Administration of compound (in (2% EtOH, 5% Tween-80, 20% PEG-400, 73% HPMC)) starting on day 17 (OPM-2) or day 12 (MX-1) at size-match (PO, QDx14) starting twice weekly at size-match, tumors were detected by a pair of calipers and according to formula V = L × W²2 (V: volume, mm)³(ii) a L: length, mm; w: width, mm) tumor volume was calculated. Tumor volumes were measured during the experiment, for OPM-2 until the mean tumor volume of each group was reached>1000 mm³Or for MX-1 until day 27 post inoculation. The results are shown in tables 5 and 6.

TABLE 5 OPM-2 human multiple myeloma cancer xenograft model

Group of	Treatment of	Route of administration, regimen	% TGI^a	% TGD^b
					1	Medium	0 mg/kg/day IP, QDx14	---	---
2	Compound of example 36	PO, QDx14, 3 mg/kg/day	90***	78***

a. Tumor growth inhibition,% TGI = 100-mean tumor volume of treated group/mean tumor volume of control group x 100. The number of mice per control group = 10. p-values (as indicated by asterisks) were derived from student T-test comparisons of treatment groups to control groups. Based on day 31. P <0.05, p <0.01, p < 0.001.

b. Tumor growth was retarded,% TGD = (T-C)/C x100, where T = median time to endpoint of treatment group and C = median time to endpoint of control group. The p-value (as indicated by the asterisk) is derived from the Kaplan Meier log-rank comparison of the treatment groups to the treatment control groups. Based on 1000 mm³The endpoint of (1). P<0.05, ** p<0.01, *** p<0.001。

TABLE 6 efficacy of BET inhibitors in MX-1 human Breast cancer xenograft model

Group of	Treatment of	Route of administrationScheme (2)	%TGI^a
				1	Medium	PO, QDx14, 0 mg/kg/day	---
2	Compound of example 36	PO, QDx14, 0.3 mg/kg/day	43**
				3	Compound of example 36	1 mg/kg/day PO, QDx14	60***
4	Compound of example 36	PO, QDx14, 3 mg/kg/day	76***

a. Tumor growth inhibition,% TGI = 100-mean tumor volume of treated group/tumor volume of control group x 100. p-values (as indicated by asterisks) were derived from student T-test comparisons of treatment groups to control groups. Based on day 27. P <0.05, p <0.01, p < 0.001.

Xenograft efficacy studies were performed with additional example compounds using OPM-2, MX-1, HT1080, MV4-11, SKM1, and Ramos human cancer cells. Cancer cells were prepared from culture broth or the above-mentioned tumor brie (MX-1) and subcutaneously inoculated into female SCID-beige mice (OPM-2, HT1080, MV4-11) or female Fox Chase SCID^®Right posterior of (Charles river Labs) mouse (MX-1, SKM1, Ramos)Tumor was detected twice weekly by a pair of calipers starting at size matching and according to the formula V = L × W²2 (V: volume, mm)³(ii) a L: length, mm; w: width, mm) tumor volume was calculated. Tumor volumes were measured during the experiment until the mean tumor volume of each group reached 500-³Model dependency end points of (1). The results are shown in table 7.

TABLE 7 efficacy of BET inhibitors in human xenograft models

a. The compounds were formulated in the following medium:

A: 10% EtOH, 30% PEG 400, 60% Phosol 53 MCT (Lipoid AG)

b10% EtOH, 30% PEG400, 60% Phosol 53 MCT (lipoid AG)/0.9% saline

C0.9% saline

D: 10% EtOH, 27.5% PEG 400, 60% Phosol 53 MCT (Lipoid AG)

E10% EtOH, 27.5% PEG400, 60% Phosol 53 MCT (lipoid AG)/0.9% saline

F: 2% EtOH, 5% Tween-80, 20% PEG400, 73% 0.2% HPMC

G2% EtOH, 5% Tween-80, 20% PEG400, 73% 0.2% HPMC/0.9% saline and

H: 5% EtOH, 30% PEG 400, 60% Phosol 53 MCT (Lipoid AG)。

b. tumor growth inhibition,% TGI = 100-mean tumor volume of treated group/mean tumor volume of control group x 100. The number of mice per treatment group = 8(MX-1, MV4-11, SKM1) or 10 (OPM-2). p-values (as indicated by asterisks) were derived from student T-test comparisons of treatment groups to control groups. Based on day 31. P <0.05, p <0.01, p < 0.001. If the mortality rate is ≧ 40%, the TGI% value is not shown.

c. Tumor growth was retarded,% TGD = (T-C)/C x100, where T = median time to endpoint of treatment group and C = median time to endpoint of control group. The p-value (as indicated by the asterisk) is derived from the Kaplan Meier log-rank comparison of the treatment groups to the treatment control groups. P <0.05, p <0.01, p < 0.001. If the mortality rate is ≧ 40%, the TGI% value is not shown.

ND = not determined.

In vivo rat collagen-induced arthritis model

The compound of example 36 inhibits paw distension in a rat collagen-induced arthritis (rCIA) inflammation model. On day 0 of rCIA model, 600 is usedMu.g of bovine type II collagen emulsion containing Freund's incomplete adjuvant (IFA) immunized female Lewis rats (n = 9/group) intradermally (id). Immunizations were given at three sites, and 100 μ L of intradermal injection was received at each site. On day 6, rats were boosted (boost) with 600 μ g of bovine type II collagen in the same manner as the immunization protocol was initiated. Control rats also received the same volume of IFA alone on day 0 and day 6. Paw volumes were measured on day 7 (baseline measurement) and on days 10, 12, 14 and 17 using a plethysmograph water displacement system. The dosing groups included IFA immunized non-arthritic rats, PBS vehicle treatment, prednisolone treatment (3 mg/kg positive control), compound vehicle treatment (10% EtOH/30% PEG 400/60% Phosal 53), and example 36 administered orally at 1.0, 0.3, 0.1, and 0.03 mg/kg. Dosing began on day 10, and animals were treated once daily by oral administration of 1.0mL volumes over 17 days. Paw swelling was reported as the change in paw volume from baseline, and the area under the paw swelling curve (AUC) was calculated for each dosing group. Example 36 inhibition of arthritis paw inflammation, ED, in a dose-dependent manner₅₀0.21 mg/kg and ED₈₀0.69 mg/kg, respectively relative to ED₅₀And ED₈₀6.8 ng/mL and 22.3 ng/mL.

TABLE 8

One-way factor Anova (for compound media) p <0.05 p < 0.001.

It should be understood that the foregoing detailed description and accompanying examples are exemplary only and should not be taken as limiting the scope of the invention, which is defined only by the appended claims and equivalents thereof. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to 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 of the invention. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein

R^xIs hydrogen or C₁-C₃An alkyl group;

R^yis C₁-C₃Alkyl, - (C)₂-C₃Alkylene) -OH, or C₁-C₃HalogenatedAn alkyl group;

X¹is N or CR^x1Wherein

X²Is N or CR^x2(ii) a Wherein

R^x2Is hydrogen, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -C (O) OR^ax2、-C(O)NR^bx2R^cx2、-C(O)R^dx2、-C(O)H、S(O)₂R^dx2、-S(O)₂NR^bx2R^cx2、G^x2、C₁-C₆Haloalkyl, or C₁-C₆An alkyl group; wherein C is₁-C₆The alkyl group is optionally substituted with one substituent selected from OR^ax2、SR^ax2、S(O)R^dx2、S(O)₂R^dx2、NR^bx2R^cx2、-C(O)R^ax2、-C(O)OR^ax2、-C(O)NR^bx2R^cx2、-S(O)₂NR^bx2R^cx2And G^x2；

G^x1、G^x2、G^a、G^b、G^2aand G^2bEach independently at each occurrence is aryl, heterocycle, cycloalkyl, or cycloalkenyl, and each independently is unsubstituted or substituted with 1,2,3, 4, or 5R^vSubstitution;

m is 0 or 1;

G¹is C₁-C₆Alkyl, alkoxyalkyl, G^1aOr- (C)₁-C₆Alkylene) -G^1a(ii) a Wherein each G^1aIndependently is aryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G^1aIndependently unsubstituted or substituted by 1,2,3, 4, or 5R^wSubstitution;

R^vand R^wEach occurrence independently is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, C₁-C₆Haloalkyl, -CN, oxo, -OR^h、-OC(O)Rⁱ、-OC(O)NR^jR^k、-SR^h、-S(O)₂R^h、-S(O)₂NR^jR^k、-C(O)R^h-C (O) -monocyclic heterocycle, -C (O) OR^h、-C(O)NR^jR^k、-NR^jR^k、-N(R^h)C(O)Rⁱ、-N(R^h)S(O)₂Rⁱ、-N(R^h)C(O)O(Rⁱ)、-N(R^h)C(O)NR^jR^k、–(C₁-C₆Alkylene) -OR^h、–(C₁-C₆Alkylene) -OC (O) Rⁱ、-(C₁-C₆Alkylene) -OC (O) NR^jR^k、–(C₁-C₆Alkylene) -S (O)₂R^h、–(C₁-C₆Alkylene) -S (O)₂NR^jR^k、-(C₁-C₆Alkylene) -C (O) R^h、–(C₁-C₆Alkylene) -C (O) OR^h、-(C₁-C₆Alkylene) -C (O) NR^jR^k、–(C₁-C₆Alkylene) -NR^jR^k、–(C₁-C₆Alkylene) -N (R)^h)C(O)Rⁱ、-(C₁-C₆Alkylene) -N (R)^h)S(O)₂Rⁱ、–(C₁-C₆Alkylene) -N (R)^h)C(O)O(Rⁱ)、–(C₁-C₆Alkylene) -N (R)^h)C(O)NR^jR^kOr is- (C)₁-C₆Alkylene) -CN;

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein

R^xIs hydrogen or C₁-C₃An alkyl group;

X¹is N or CR^x1Wherein

X²Is N or CR^x2(ii) a Wherein

m is 0 or 1;

G¹is G^1aOr (a)C₁-C₆Alkylene) -G^1a(ii) a Wherein each G^1aIndependently is aryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G^1aIndependently unsubstituted or substituted by 1,2,3, 4, or 5R^wSubstitution;

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^yIs C₁-C₃An alkyl group.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^yIs methyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X¹Is CR^x1(ii) a And is

X²Is CR^x2。

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y¹Is N.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y¹Is CR^u。

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R^uIs hydrogen or C₁-C₃An alkyl group.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L¹Is CH₂、C(O)、(CH₂)_mO or (CH)₂)_mN(R^z)。

10The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L¹Is (CH)₂)_mO and G¹Is G^1a。

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a¹Is CR¹；

A²Is CR²；

A³Is CR³(ii) a And

A⁴is CR⁴。

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a¹、A²、A³And A⁴One of which is N.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, C₁-C₆Alkyl radical, NO₂、G^2a、-S(O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)OR^2a、-C(O)NR^2bR^2c、-NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)S(O)₂NR^2bR^2c、–(C₁-C₆Alkylene) -G^2a、–(C₁-C₆Alkylene) -OR^2a、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、–(C₁-C₆Alkylene) -C (O) OR^2a、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2c。

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)S(O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2c。

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dor-N (R)^2e)S(O)₂NR^2bR^2c。

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

Y¹Is N;

X¹is CR^x1(ii) a And is

X²Is CR^x2。

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

n- [4- (2, 4-difluorophenoxy) -3- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-d ] pyridazin-4-yl) phenyl ] ethanesulfonamide; and

4- [2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one.

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R^yIs methyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein L¹Is CH₂、C(O)、(CH₂)_mO or (CH)₂)_mN(R^z)。

20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein L¹Is (CH)₂)_mO。

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein G¹Is G^1a。

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted aryl group.

23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted phenyl group.

24. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted cycloalkyl group.

25. As claimed inA compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wSubstituted monocyclic cycloalkyl.

26. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted heterocycle.

27. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted monocyclic heterocycle.

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

Y¹Is CR^u；

X¹Is CR^x1(ii) a And

X²is CR^x2。

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

6-methyl-4- (2-phenoxyphenyl) -1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (2-benzylphenyl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

4- (biphenyl-2-yl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one;

30. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R^yIs methyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein L¹Is CH₂、C(O)、(CH₂)_mO or (CH)₂)_mN(R^z)。

32. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein L¹Is (CH)₂)_mO。

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein G¹Is G^1a。

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted aryl group.

35. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted phenyl group.

36. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted cycloalkyl group.

37. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wSubstituted monocyclic cycloalkyl.

38. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted heterocycle.

39. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein G^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted monocyclic heterocycle.

40. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

Y¹Is CR^u；

X¹Is N;

X²is CR^x2(ii) a And

R^yis methyl.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

4- [2- (2, 4-difluorophenoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrazolo [3,4-c ] pyridin-7-one; and

4- [2- (cyclopropylmethoxy) -5- (ethylsulfonyl) phenyl ] -6-methyl-1, 6-dihydro-7H-pyrazolo [3,4-c ] pyridin-7-one; or a pharmaceutically acceptable salt thereof.

42. The compound of any one of claims 16, 18-28, and 30-40, or a pharmaceutically acceptable salt thereof, wherein:

A¹is CR¹、A²Is CR²、A³Is CR³And A is⁴Is CR⁴(ii) a Or

A¹、A²、A³And A⁴One of which is N.

43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, C₁-C₆Alkyl radical, NO₂、G^2a、-S(O)₂R^2d、-S(O)₂NR^2bR^2c、-C(O)R^2d、-C(O)OR^2a、-C(O)NR^2bR^2c、-NR^2bR^2c、-N(R^2e)C(O)R^2d、-N(R^2e)S(O)₂R^2d、-N(R^2e)S(O)₂NR^2bR^2c、–(C₁-C₆Alkylene) -G^2a、–(C₁-C₆Alkylene) -OR^2a、-(C₁-C₆Alkylene) -S (O)₂R^2d、-(C₁-C₆Alkylene) -S (O)₂NR^2bR^2c、-(C₁-C₆Alkylene) -C (O) R^2d、–(C₁-C₆Alkylene) -C (O) OR^2a、-(C₁-C₆Alkylene) -C (O) NR^2bR^2c、-(C₁-C₆Alkylene) -NR^2bR^2c、-(C₁-C₆Alkylene) -N (R)^2e)C(O)R^2d、-(C₁-C₆Alkylene) -N (R)^2e)S(O)₂R^2dOr is- (C)₁-C₆Alkylene) -N (R)^2e)S(O)₂NR^2bR^2c。

44. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein R²is-S (O)₂R^2d、-S(O)₂NR^2bR^2c、-N(R^2e)S(O)₂R^2dor-N (R)^2e)S(O)₂NR^2bR^2c。

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R^xIs hydrogen or methyl.

46. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R^xIs hydrogen.

47. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R^x1Is hydrogen, -C (O) OR^ax1、-C(O)NR^bx1R^cx1、G^x1Or C₁-C₆Alkyl radical, wherein C₁-C₆Alkyl is OR^ax1Optionally substituted.

48. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R^x1Is hydrogen, -C (O) OR^ax1or-C (O) NR^bx1R^cx1。

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R^x2Is hydrogen.

50. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

R^xIs hydrogen;

R^yis methyl;

Y¹is CR^uWherein R is^uIs hydrogen;

X¹is CR^x1Wherein R is^x1Is hydrogen or-C (O) NR^bx1R^cx1；

X²Is CR^x2Wherein R is^x2Is hydrogen;

L¹is (CH)₂)_mO, wherein m is 0;

G¹is G^1aOr- (C)₁-C₆Alkylene) -G^1aWherein G is^1aIs optionally substituted by 1,2,3, 4, or 5R^wSubstituted phenyl or optionally substituted with 1,2,3, 4, or 5R^wA substituted cycloalkyl group; and

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein A¹Is CR¹、A²Is CR²、A³Is CR³And A is⁴Is CR⁴。

52. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein A¹Is CR¹、A²Is CR²、A³Is CR³And A is⁴Is N.

53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

R^xIs hydrogen;

R^yis methyl;

Y¹is CR^uWherein R is^uIs hydrogen;

X¹is CR^x1Wherein R is^x1Is hydrogen;

X²is CR^x2Wherein R is^x2Is hydrogen;

L¹is (CH)₂)_mN(R^z) Wherein m is 0 and R^zIs hydrogen;

G¹is- (C)₁-C₆Alkylene) -G^1aWherein G is^1aIs optionally substituted by 1,2,3, 4, or 5R^wA substituted cycloalkyl group; and

54. The compound of claim 53, or a pharmaceutically acceptable salt thereof, wherein A¹Is CR¹、A²Is CR²、A³Is CR³And A⁴Is CR⁴。

55. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

56. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for treating cancer in a subject.

57. The use of claim 56, wherein the cancer is selected from the group consisting of: acoustic neuroma, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, brain carcinoma, breast carcinoma, bronchial carcinoma, cervical carcinoma, chordoma, choriocarcinoma, colorectal carcinoma, craniopharyngioma, cystadenocarcinoma, undesirable proliferative changes, embryonic carcinoma, ependymoma, epithelial carcinoma, esophageal carcinoma, essential thrombocythemia, glioma, glioblastoma, heavy chain disease, hemangioblastoma, liver carcinoma, leukemia, lung carcinoma, bladder, breast, colon, lung, ovary, pancreas, prostate, hyperproliferative disorders of the skin and uterus, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myeloma, neuroblastoma, NUT midline carcinoma, oral cancer, ovarian cancer, pancreatic cancer, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, renal cell carcinoma, retinoblastoma, sarcoma, neuroblastoma, prostate cancer, pancreatic cancer, papillary carcinoma, adenocarcinomas of the breast, retinoblastoma, prostate cancer, renal cell carcinoma, retinoblastoma, neuroblastoma, melanoma, Sebaceous gland carcinoma, seminoma, skin carcinoma, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid carcinoma, primary macroglobulinemia, testicular tumor, uterine cancer, and nephroblastoma.

58. The use of claim 56, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute myelogenous leukemia, acute T-cell leukemia, chondrosarcoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon carcinoma, diffuse large B-cell lymphoma, endometrial carcinoma, endotheliosarcoma, erythroleukemia, estrogen receptor positive breast cancer, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma sarcoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphoblastic leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, T-cell or B-cell derived lymphoid malignancies, multiple myeloma, myelogenous leukemia, myxosarcoma, non-small cell lung cancer, oligodendroglioma, Osteogenic sarcoma, papillary adenocarcinoma, rectal cancer, rhabdomyosarcoma, small cell lung cancer.

59. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and at least one additional therapeutic agent in the manufacture of a medicament for treating cancer in a subject, wherein the additional therapeutic agent is selected from cytarabine, bortezomib and 5-azacitidine.

60. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 in the manufacture of a medicament for treating a disease or condition in a subject, wherein the disease or condition is selected from: addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, behcet's disease, bullous skin disease, Chronic Obstructive Pulmonary Disease (COPD), crohn's disease, dermatitis, eczema, giant cell arteritis, hepatitis, ptosis, inflammatory bowel disease, kawasaki disease, multiple sclerosis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and wegener's granulomatosis.

61. The use of claim 60, wherein the nephritis is glomerulonephritis or lupus nephritis.

62. The use of claim 60, wherein the myositis is myocarditis.

63. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 in the manufacture of a medicament for treating a disease or condition in a subject, wherein the disease or condition is selected from: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal disease, polycystic kidney disease and tubulointerstitial nephritis.

64. The use of claim 63, wherein the glomerulonephritis is membranous glomerulonephritis.

65. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 in the manufacture of a medicament for treating an acute kidney disease or condition in a subject, wherein the acute kidney disease or condition is selected from: ischemia-reperfusion-induced, cardiotonic and major surgery-induced, percutaneous coronary intervention-induced, radiocontrast-induced, sepsis-induced, pneumonia-induced, and drug intoxication-induced acute kidney disease or condition.

66. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Acquired Immune Deficiency Syndrome (AIDS) in a subject.

67. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 in the manufacture of a medicament for treating a disease or condition in a subject, wherein the disease or condition is selected from: obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy and diabetic neuropathy.

68. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for contraception in a male subject.