NZ725267B2 - Bromodomain inhibitors - Google Patents

Bromodomain inhibitors Download PDF

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Publication number
NZ725267B2
NZ725267B2 NZ725267A NZ72526712A NZ725267B2 NZ 725267 B2 NZ725267 B2 NZ 725267B2 NZ 725267 A NZ725267 A NZ 725267A NZ 72526712 A NZ72526712 A NZ 72526712A NZ 725267 B2 NZ725267 B2 NZ 725267B2
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NZ
New Zealand
Prior art keywords
dihydro
pyrrolo
phenyl
methyl
methyloxo
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NZ725267A
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NZ725267A (en
Inventor
Yujia Dai
Steven D Fidanze
Lisa Hasvold
James H Holms
Warren M Kati
Dachun Liu
Robert A Mantei
William J Mcclellan
Keith F Mcdaniel
John K Pratt
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Abbvie Inc
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Priority claimed from PCT/CN2011/002224 external-priority patent/WO2013097052A1/en
Application filed by Abbvie Inc filed Critical Abbvie Inc
Publication of NZ725267A publication Critical patent/NZ725267A/en
Publication of NZ725267B2 publication Critical patent/NZ725267B2/en

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Abstract

Provided are compounds of the general formula (I), including pyrrolopyridazines and pyrrolopyridines, wherein the variables are as defined in the specification. Examples of the compounds include 6-methyl-4-(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c ]pyridin-7–one and ethyl 4-(5-amino-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate. The compounds are inhibitors of bromodomains. The compounds may be useful in the treatment of a variety of diseases including cancer, AIDS and inflammatory diseases. enyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate. The compounds are inhibitors of bromodomains. The compounds may be useful in the treatment of a variety of diseases including cancer, AIDS and inflammatory diseases.

Description

BROMODOMAIN INHIBITORS BACKGROUND Bromodomains refer to conserved protein structural folds which bind to N-acetylated lysine residues that are found in some proteins. The BET family of bromodomain containing proteins is comprised of four members (BRD2, BRD3, BRD4 and BRDt). Each member of the BET family employs two bromodomains to recognize N-acetylated lysine residues found ily, but not exclusively, on the amino-terminal tails of e proteins. These interactions modulate gene expression by recruiting transcription factors to specific genome locations within chromatin. For example, histone-bound BRD4 recruits the transcription factor P-TEFb to ers, resulting in the expression of a subset of genes involved in cell cycle progression (Yang et 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 were recently ished as being important for the maintenance of l cancer types (Zuber et al., Nature 478: 524-528 (2011); Mertz et al; Proc. Nat’l.
Acad. Sci. 108: 16669-16674 (2011); Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478: 3 (2011)). BET family members have also been ated in mediating acute matory responses through the canonical NF-KB pathway (Huang et al., Mol. Cell.
Biol. 29: 1375-1387 (2009)) resulting in the upregulation of genes ated with the production of cytokines (Nicodeme et al., Nature 468: 1119-1123, (2010)). In addition, bromodomain function has been implicated in kidney disease (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)). BRD2 function has also been linked to a predisposition for dyslipidemia or improper regulation of adipogenesis, elevated inflammatory profiles and increased susceptibility to autoimmune diseases (Denis, Discovery Medicine 10: 9 (2010)). The human immunodeficiency virus utilizes BRD4 to te transcription of viral RNA from stably ated viral DNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomain inhibitors have also been shown to reactivate HIV transcription in models of latent T cell infection and latent monocyte infection jee, et al, J. Leukocyte Biol. .1189/jlb.0312165). BRDt has an important role in spermatogenesis (Matzuk, et al., Cell 150: 673-684 (2012)). Accordingly, there is an ongoing medical need to develop new drugs to treat diseases and indications involving bromodomain function, including BET bromodomain function.
SUMMARY According to a first aspect of the present invention there is provided compounds of formula (I) or pharmaceutically acceptable thereof, wherein Rx is hydrogen or C1-C3 alkyl; Ry is C1-C3 alkyl, —(C2-C3 alkylenyl)-OH, or C1-C3 kyl; X1 is N or CR"l wherein R"1 is hydrogen, C2—C6 alkenyl, C2-C6 alkynyl, -C(O)OR‘”", —C(0)NR"“R°"', -C(O)Rd"', S(O)2Rd“, -S(O)2NR'”"R°"', G“, C.—c.5 haloalkyl, or C.-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of OR“, SRa“, S(O)Rd"', S(O)2Rd“, Nbe‘Rc“, —C(0)R‘”", —C(0)0R‘“', -C(O)NRb“R°“, -S(O)2NR'”"R°"', and 6x1; Ra“, Rb“, and RC“, at each occurrence, are each ndently hydrogen, C]- C6 alkyl, C1—C5 haloalkyl, G“, or -(C1—C6 alkylenyl)-Ga; Rd“, at each ence, are each independently C1-C6 alkyl, C1-C6 haloalkyl, 6“, or -(C1-C6 alkylenyl)—Ga; X2 is N or Csz; wherein R"2 is en, C2-C6 alkenyl, C2-C6 alkynyl, —C(0)0R”2, —C(0)NR""2R°‘2, -C(0)Rd"2, -C(O)H, S(O)2Rd"2, -S(O)2NR""2R°"2, G”, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is ally substituted with one tuent ed from the group consisting of 0R3”, SR“, S(0)Rd"2, S(O)2Rd"2, NRmRm, -C(O)R‘”‘2, -C(O)0R’”‘2, -C(O)Nbe2Rc"2, -S(O)2NRb"2R°"2, and 6x2; Rad, bez, and ch2, at each occurrence, are each independently hydrogen, C1- C6 alkyl, C1—C6 haloalkyl, G”, or 6 alkylenyl)-Gb; Rdxz, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, 6", or ’(Cl'Cé alkylenyl)-Gb; Y1 is N or CR"; wherein Ru is hydrogen, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; A1 is N or CR1, A2 is N or CR2, A3 is N or CR3; and A4 is N or CR4; with the proviso that zero, one, two, or three of A1, A2, A3, and A4 are N; R1, R3, and R4 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, or NO2; R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 l, halogen, C1-C6 kyl, -CN, NO2, G2a, -OR2a, -OC(O)R2d, -OC(O)NR2bR2c, -SR2a, -S(O)2R2d, NR2bR2c, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)C(O)O(R2d), -N(R2e)C(O)NR2bR2c, -N(R2e)S(O)2NR2bR2c, –(C1-C6 alkylenyl)-G2a, –(C1-C6 alkylenyl)-OR2a, -(C1- C6 alkylenyl)-OC(O)R2d, –(C1-C6 nyl)-OC(O)NR2bR2c, -(C1-C6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, –(C1-C6 alkylenyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 nyl)-N(R2e)C(O)R2d, -(C1-C6 nyl)-N(R2e)S(O)2R2d, –(C1-C6 alkylenyl)-N(R2e)C(O)O(R2a), –(C1-C6 alkylenyl)-N(R2e)C(O)NR2bR2c, –(C1- C6 alkylenyl)-N(R2e)S(O)2NR2bR2c, and –(C1-C6 alkylenyl)-CN; R2a, R2b, R2c, and R2e, at each occurrence, are each independently hydrogen, C2-C6 alkenyl, C2-C6 l, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group ting of –ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b; R2d, at each occurrence, is ndently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b; Rz1 and Rz2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1- C6 haloalkyl; Gx1, Gx2, Ga, Gb, G2a, and G2b, at each occurrence, are each independently aryl, heteroaryl, heterocycle, lkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rv; L1 is absent, CH2, C(O), C(H)(OH), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or 1; Gx1, Gx2, Ga, Gb, G2a, and G2b, at each ence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently tituted or substituted with 1, 2, 3, 4, or 5 of Rv; L1 is absent, CH2, C(O), C(H)(OH), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) n Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or 1; G1 is C1-C6 alkyl, alkoxyalkyl, G1a or -(C1-C6 alkylenyl)-G1a; wherein each G1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rw; Rv and Rw, at each occurrence, are each ndently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri, NRjRk, -SRh, -S(O)2Rh, -S(O)2NRjRk, -C(O)Rh, -C(O)-monocyclic heterocycle, -C(O)- monocyclic heteroaryl,-C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, -N(Rh)S(O)2Ri, -N(Rh)C(O)O(Ri), -N(Rh)C(O)NRjRk, –(C1-C6 nyl)-ORh, – (C1-C6 alkylenyl)-OC(O)Ri, -(C1-C6 alkylenyl)-OC(O)NRjRk, –(C1-C6 alkylenyl)-S(O)2Rh, 6 alkylenyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)-C(O)Rh, –(C1-C6 alkylenyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, –(C1-C6 alkylenyl)-NRjRk, –(C1-C6 alkylenyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, –(C1-C6 alkylenyl)-N(Rh)C(O)O(Ri), –(C1-C6 alkylenyl)-N(Rh)C(O)NRjRk, or –(C1-C6 alkylenyl)-CN; Rh, Rj, Rk, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and Ri, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl.
Also disclosed herein are nds of formula (I) or pharmaceutically acceptable thereof, alkyl; n the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax1, SRax1, x1, dx1, NRbx1Rcx1, -C(O)Rax1, -C(O)ORax1, -C(O)NRbx1Rcx1, -S(O)2NRbx1Rcx1, and Gx1; Rax1, Rbx1, and Rcx1, at each occurrence, are each independently en, C1- C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga; Rdx1, at each occurrence, are each independently C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga; X2 is N or CRx2; wherein Rx2 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax2, -C(O)NRbx2Rcx2, -C(O)Rdx2, S(O)2Rdx2, -S(O)2NRbx2Rcx2, Gx2, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent ed from the group consisting of ORax2, SRax2, S(O)Rdx2, dx2, NRbx2Rcx2, -C(O)Rax2, -C(O)ORax2, -C(O)NRbx2Rcx2, -S(O)2NRbx2Rcx2, and Gx2; Rax2, Rbx2, and Rcx2, at each occurrence, are each independently hydrogen, C1- C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb; Rdx2, at each occurrence, is independently C1-C6 alkyl, C1-C6 kyl, Gb, or -(C1-C6 alkylenyl)-Gb; Y1 is N or CRu; wherein Ru is hydrogen, C1-C6 alkyl, n, or C1-C6 haloalkyl; A1 is N or CR1, A2 is N or CR2, A3 is N or CR3; and A4 is N or CR4; with the proviso that zero, one, two, or three of A1, A2, A3, and A4 are N; R1, R3, and R4 are each independently hydrogen, C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, n, C1-C6 haloalkyl, CN, or NO2; R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, G2a, -OR2a, -OC(O)R2d, -OC(O)NR2bR2c, -SR2a, -S(O)2R2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)C(O)O(R2d), -N(R2e)C(O)NR2bR2c, -N(R2e)S(O)2NR2bR2c, –(C1-C6 alkylenyl)-G2a, –(C1-C6 alkylenyl)-OR2a, -(C1- C6 alkylenyl)-OC(O)R2d, –(C1-C6 alkylenyl)-OC(O)NR2bR2c, -(C1-C6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, 6 alkylenyl)-C(O)R2d, –(C1-C6 alkylenyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, -(C1-C6 alkylenyl)-N(R2e)S(O)2R2d, –(C1-C6 nyl)-N(R2e)C(O)O(R2a), –(C1-C6 alkylenyl)-N(R2e)C(O)NR2bR2c, –(C1- C6 alkylenyl)-N(R2e)S(O)2NR2bR2c, and –(C1-C6 alkylenyl)-CN; R2a, R2b, R2c, and R2e, at each occurrence, are each independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of –ORz1, NRz1Rz2, Rz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b; R2d, at each ence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent ed from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b; Rz1 and Rz2, at each occurrence, are each independently en, C1-C6 alkyl, or C1- C6 haloalkyl; Gx1, Gx2, Ga, Gb, G2a, and G2b, at each occurrence, are each independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently tituted or substituted with 1, 2, 3, 4, or 5 of Rv; L1 is absent, CH2, C(O), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or 1; G1 is G1a or -(C1-C6 alkylenyl)-G1a; wherein each G1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or lkenyl, and each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rw; Rv and Rw, at each ence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri, -OC(O)NRjRk, -SRh, -S(O)2Rh, -S(O)2NRjRk, -C(O)Rh, -C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, -N(Rh)S(O)2Ri, -N(Rh)C(O)O(Ri), C(O)NRjRk, –(C1-C6 alkylenyl)-ORh, –(C1-C6 alkylenyl)-OC(O)Ri, -(C1-C6 alkylenyl)-OC(O)NRjRk, –(C1-C6 alkylenyl)-S(O)2Rh, 6 alkylenyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)-C(O)Rh, –(C1-C6 nyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, –(C1-C6 alkylenyl)-NRjRk, –(C1-C6 alkylenyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, 6 alkylenyl)-N(Rh)C(O)O(Ri), –(C1-C6 alkylenyl)-N(Rh)C(O)NRjRk, or –(C1-C6 alkylenyl)-CN; L1 is absent, CH2, C(O), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or 1; G1 is G1a or -(C1-C6 alkylenyl)-G1a; wherein each G1a is independently aryl, heteroaryl, heterocycle, lkyl, or cycloalkenyl, and each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rw; Rv and Rw, at each occurrence, are each ndently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 l, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri, -OC(O)NRjRk, -SRh, -S(O)2Rh, -S(O)2NRjRk, -C(O)Rh, -C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, S(O)2Ri, -N(Rh)C(O)O(Ri), -N(Rh)C(O)NRjRk, –(C1-C6 alkylenyl)-ORh, –(C1-C6 alkylenyl)-OC(O)Ri, -(C1-C6 alkylenyl)-OC(O)NRjRk, – (C1-C6 alkylenyl)-S(O)2Rh, –(C1-C6 alkylenyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)-C(O)Rh, –(C1-C6 alkylenyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, –(C1-C6 alkylenyl)-NRjRk, –(C1-C6 alkylenyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, –(C1-C6 alkylenyl)-N(Rh)C(O)O(Ri), –(C1-C6 alkylenyl)-N(Rh)C(O)NRjRk, or –(C1-C6 alkylenyl)-CN; Rh, Rj, Rk, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 kyl; and Ri, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl.
Also disclosed are methods for treating or preventing ers that are ameliorated by inhibition of BET. Such methods comprise of administering to the subject a therapeutically effective amount of a compound of a (I), alone, or in combination with a pharmaceutically able carrier.
Some of the methods are directed to ng or preventing an inflammatory disease or cancer or AIDS.
Also disclosed are methods of treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt f, to a subject in need thereof. In n embodiments, the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, arcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic locytic) ia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, e large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, geal cancer, en-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular ma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung , lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, ma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, a, myxosarcoma, neuroblastoma, NUT midline oma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, oma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and as), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenström’s lobulinemia, testicular tumors, uterine cancer and Wilms’ tumor. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the additional eutic agent is an ancer agent. In particular embodiments, the additional therapeutic agents are selected from the group ting of cytarabine, bortezomib, and 5-azacitidine.
Also disclosed are methods of treating a disease or condition in a subject comprising administering a eutically effective amount of a compound of a (I) or a pharmaceutically acceptable salt thereof, to a subject in need thereof, n said disease or condition is selected from the group consisting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell tis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ lant rejection, rthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic tis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, go, vasculitis, and r's granulomatosis. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In n embodiments, the methods further se administering a therapeutically effective amount of at least one additional therapeutic agent.
Also disclosed are methods of ng a chronic kidney disease or condition in a subject comprising stering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a subject in need f, wherein said disease or condition is selected from the group consisting of: diabetic nephropathy, hypertensive nephropathy, sociated pathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous ulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis. In certain embodiments, the methods further comprise administering a eutically effective amount of at least one additional therapeutic agent. In certain embodiments, the methods further comprise administering a therapeutically ive amount of at least one additional therapeutic agent.
Also disclosed are methods of treating an acute kidney injury or disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said acute kidney injury or disease or condition is selected from the group consisting of: ischemiareperfusion induced, cardiac and major y induced, percutaneous ry intervention induced, radio-contrast agent induced, sepsis induced, pneumonia d, and drug toxicity induced. In certain embodiments, the methods r comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
Also disclosed are methods of treating AIDS in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a subject in need f. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
Also disclosed are methods of treating obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, lic syndrome, hepatic steatosis, type II es, insulin resistance, diabetic retinopathy or diabetic neuropathy in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a ceutically able salt f, to a subject in need thereof. In certain embodiments, the methods further comprise administering a eutically effective amount of at least one additional therapeutic agent.
According to a second aspect of the t invention there is provided use of a compound of formula (I) according to the first aspect or a pharmaceutically acceptable salt f in the manufacture of a medicament for treatment of cancer in the manufacture of a medicament for treatment of cancer.
According to a third aspect of the present invention there is provided use of a compound of formula (I) according to the first aspect or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a disease or condition selected from the group ting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's e,dermatitis, eczema,giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease,), Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis,myositis, nephritis, organ transplant ion, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, toid arthritis, tis, sclerosing cholangitis, sepsis systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis. ing to a fourth aspect of the present invention there is provided use of a compound of a (I) according to the first aspect or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a disease or condition selected from the group consisting of: diabetic nephropathy, hypertensive pathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, stic kidney disease and tubular interstitial tis.
According to a fifth aspect of the present ion there is provided use of a compound of formula (I) according to the first aspect or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of an acute kidney disease, wherein said acute kidney disease or condition is selected from the group consisting of: ischemia-reperfusion induced, cardiac and major surgery induced, percutaneous coronary intervention induced, radiocontrast agent induced, sepsis induced, pneumonia induced, and drug ty induced.
According to a sixth aspect of the present invention there is provided use of a compound of formula (I) according to the first aspect or a pharmaceutically acceptable salt f in the manufacture of a ment for treatment of acquired immunodeficiency syndrome (AIDS).
According to a seventh aspect of the present invention there is provided use of a compound of formula (I) according to the first aspect or a pharmaceutically acceptable salt thereof, in the manufacture of a ment for treatment of a disease or condition selected from the group consisting of: obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic me, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy and diabetic neuropathy.
According to an eighth aspect of the present invention there is provided use of a nd of formula (I) according to the first aspect or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for male contraception.
Also disclosed are methods of ting conception by inhibiting spermatogenesis in a subject comprising administering a therapeutically effective amount of a nd of formula (I) or a ceutically acceptable salt thereof, to a subject in need thereof. In certain ments, the methods further se administering a therapeutically effective amount of at least one additional therapeutic agent.
Also disclosed is the use of a nd of formula (I), alone or in combination with a second active pharmaceutical agent, in the manufacture of a medicament for treating or preventing conditions and disorders disclosed , with or without a pharmaceutically acceptable carrier.
Pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, alone or in combination with a second active pharmaceutical agent, are also ed.
According to a ninth aspect of the present invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to the first aspect, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically able carrier.
DETAILED DESCRIPTION Disclosed herein are compounds of formula (I) Ry N G1 A1 A4 A2 wherein A1, A2, A3, A4, X1, X2, Y1, L1, G1, Rx, and Ry are defined above in the Summary of the Invention and below in the ed Description. Further, compositions comprising such alkenyl group containing 2-6 carbon atoms. Non-limiting examples of alkenyl include buta- 1,3-dienyl, ethenyl, 2-propenyl, 2-methylpropenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2- heptenyl, 2-methylheptenyl, and 3-decenyl.
The term ylene” means a divalent group derived from a straight or branched chain hydrocarbon of 2 to 4 carbon atoms and contains at least one carbon-carbon double bond. entative examples of alkenylene include, but are not limited to, -CH=CH- and -CH2CH=CH-.
The term “alkyl” as used herein, means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is indicated by the prefix “Cx-Cy”, n x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C6 alkyl” refers to an alkyl substituent containing from 1 to 6 carbon atoms and “C1-C3 alkyl” refers to an alkyl substituent ning from 1 to 3 carbon atoms. Representative es of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, l, tyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, ylbutyl, 1,1- 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, noctyl , n-nonyl, and n-decyl.
The term “alkylene” or “alkylenyl” means a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms (C1-C6 alkylenyl) or of 1 to 4 carbon atoms or of 2 to 3 carbon atoms (C2-C3 alkylenyl). Examples of alkylene and alkylenyl include, but are not limited to, -CH2-, - CH2CH2-, -CH2CH2CH2-, 2CH2CH2-, and -CH2CH(CH3)CH2-.
The term “alkynyl” as used herein, means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one -carbon triple bond, optionally substituted with 1, 2, or 3 halogen atoms. The term “C2-C6 alkynyl” means an alkynyl group of 2 to 6 carbon atoms. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, ynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term “aryl” as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples of the aryl groups include dihydroindenyl, indenyl, naphthyl, onaphthalenyl, and ydronaphthalenyl. The bicyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring systems and can be unsubstituted or substituted.
The term “cycloalkyl” as used herein, refers to a radical that is a monocyclic cyclic alkyl, a bicyclic lkyl, or a spiro cycloalkyl. The monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, zero heteroatoms and zero double bonds.
Examples of monocyclic ring s include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic lkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring. The monocyclic and the bicyclic cycloalkyl groups may contain one or two alkylene bridges, each consisting of one, two, three, or four carbon atoms in length, and each bridge links 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]nonane, and bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane (octahydro-2,5-methanopentalene or noradamantane), and tricyclo[3.3.1.13,7]decane (adamantane). A spiro cycloalkyl is a monocyclic lkyl wherein two substituents on the same carbon atom of the monocyclic cycloalkyl ring together with said carbon atom form a second monocyclic cycloalkyl ring.
The monocyclic, the bicyclic, and the spiro cycloalkyl groups can be unsubstituted or substituted, and are ed 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 a bicyclic hydrocarbon ring radical. The monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms. The four-membered ring systems have one double bond, the five-or six-membered ring systems have one or two double bonds, and the seven- or membered ring s have one, two, or three double bonds. Representative examples of monocyclic cycloalkenyl groups e, but are not limited to, cyclobutenyl, entenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic lkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. The monocyclic or bicyclic cycloalkenyl ring may n one or two alkylene bridges, each consisting of one, two, or three carbon atoms, and each linking two non-adjacent carbon atoms of the ring system.
Representative examples of the bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and 1,6-dihydro-pentalene. The clic and bicyclic cycloalkenyls can be attached to the parent molecular moiety through any substitutable atom ned within the ring systems, and can be unsubstituted or substituted.
The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.
The term “haloalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are ed by halogen. The term “C1-C6 haloalkyl” means a C1-C6 alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term “C1-C3 haloalkyl” means a C1-C3 alkyl group, as defined herein, in which one, two, or three hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, trifluoroethyl, trifluoromethyl, difluoromethyl, luoroethyl, 2-chlorofluoropentyl, trifluorobutyl, and trifluoropropyl.
The term “heterocycle” or ocyclic” as used herein, means a radical of a monocyclic heterocycle, a bicyclic heterocycle, and a spiro heterocycle. A monocyclic heterocycle is a , four-, five-, six-, seven-, or eight-membered yclic ring also containing at least one atom ndently selected from the group consisting of O, N, and S. A three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group ting of O, N, and S. When two O atoms or one O atom and one S atom are present in a cyclic ring, then the two O atoms or one O atom and one S atom are not bonded directly to each other. A five-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. es of five-membered heterocyclic rings include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N.
Examples of ered heterocyclic groups include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, and 3-pyrrolinyl. A six-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of six-membered heterocyclic rings include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 Q and 1 N; and 1 O and 2 N. Examples of 6-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, 1,1-dioxo- hexahydrothiopyranyl, 1,1-dioxo-1λ6-thiomorpholinyl, thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, yl, aziridinyl, diazepanyl, oxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, ydropyridinyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a clic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle. entative 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- zinyl, hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl. The monocyclic heterocycle and the ic cycle may contain one or two ne bridges or an alkenylene bridge, or mixture thereof, each consisting of no more than four carbon atoms and each linking two non adjacent atoms of the ring . Examples of such bridged heterocycle include, but are not limited to, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept yl), 8-azabicyclo[3.2.1]octyl, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[b]furan, dro-1H-1,4-methanocyclopenta[c]furan, aza-admantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). A spiro heterocycle is a monocyclic heterocycle wherein two substituents on the same carbon atom of the clic heterocycle ring together with said carbon atom form a second ring system selected from a clic cycloalkyl, a bicyclic cycloalkyl, a monocyclic heterocycle, or a bicyclic heterocycle. Examples of spiro heterocycle include, but not limited to, 6-azaspiro[2.5]octyl, 1’H, ro[1,3-benzodioxine-2,4’-piperidin]-1’-yl, 1’H, 3H- spiro[2-benzofuran-1,4’-piperidin]-1’-yl, and 1,4-dioxaazaspiro[4.5]decyl. The monocyclic, the bicyclic, and the spiro heterocycles can be unsubstituted or substituted. The monocyclic, the bicyclic and the spiro heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring systems.
The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally be quarternized.
The term oaryl” as used herein, means a monocyclic heteroaryl and a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or mbered ring. The five-membered ring contains two double bonds. The five membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom. The mbered ring contains three double bonds and one, two, three or four nitrogen atoms. Representative examples of monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, l, triazolyl, and triazinyl. The bicyclic heteroaryl ts of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a clic aryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle.
Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 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, o[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 2,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[5,4-d]pyrimidinyl, and ,6,7,8-tetrahydroquinolinyl. The monocyclic and bicyclic heteroaryl groups can be substituted or unsubstituted and are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable en atom contained within the ring s. The nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be quarternized.
The term “heteroatom” as used herein, means a nitrogen, , and sulfur.
The term “oxo” as used herein, means a =O group.
If a moiety is described as ituted”, a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the . Thus, for example, a substituted heterocycle moiety is a heterocycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be ized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless otherwise stated).
If a moiety is described as being “optionally substituted,” the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either (1) not substituted; or (2) tuted by up to that particular number of drogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is bed as a heteroaryl optionally substituted with up to 3 non- hydrogen radicals, then any heteroaryl with less than 3 substitutable ons would be optionally substituted by up to only as many drogen radicals as the heteroaryl has substitutable positions. To illustrate, olyl (which has only one substitutable position) would be optionally substituted with up to one drogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 nonhydrogen ls, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
The terms “treat”, “treating”, and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
The terms “prevent”, “preventing”, and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a t from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
The phrase “therapeutically effective amount” means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another pharmaceutical agent or treatment in a particular subject or subject population. For example in a human or other , a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the ines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular e and subject being treated.
The term “subject” is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human. b. Compounds Compounds of the invention have the l formula (I) as described above.
Particular values of variable groups in compounds of formula (I) are as follows. Such values may be used where riate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
In compounds of formula (I), Rx is as d in the Summary. For example, in certain embodiments, Rx is hydrogen or methyl. In certain embodiments, Rx is hydrogen.
Ry, in compounds of formula (I), is as disclosed in the Summary. For example, in certain embodiments, Ry is C1-C3 alkyl (e.g. methyl, ethyl). In certain embodiments, Ry is X1 is as disclosed in the Summary. For example, in n ments, X1 is N. In certain embodiments, X1 is CRx1. R x1 is as defined in the Summary or embodiments herein.
In certain embodiments, Rx1 is hydrogen, C2-C6 alkenyl, -C(O)ORax1, Rbx1Rcx1, dx1, Gx1, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group ting of ORax1, NRbx1Rcx1, and Gx1. In certain embodiments, Rx1 is hydrogen, -C(O)ORax1, -C(O)NRbx1Rcx1, Gx1, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with ORax1. In certain embodiments, R x1 is hydrogen, -C(O)ORax1, Rbx1Rcx1, optionally substituted phenyl, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with ORax1 In certain embodiments, Rx1 is en, -C(O)ORax1, or -C(O)NRbx1Rcx1. In certain embodiments, R x1 is hydrogen or unsubstituted C1-C6 alkyl. In certain embodiments, Rx1 is -C(O)ORax1, -C(O)NRbx1Rcx1, or C1-C6 alkyl substituted with ORax1. In certain embodiments, R x1 is en or -C(O)NRbx1Rcx1. In certain ments, Rx1 is hydrogen. Rax1, Rbx1, Rcx1, Rdx1, and Gx1, are as disclosed in the Summary. For example, Rax1 and Rbx1, are each independently hydrogen, C1-C6 alkyl (e.g. , ethyl, isopropyl), or C1-C6 haloalkyl (e.g. trifluoromethyl). In certain embodiments, Rax1 and Rbx1, are each independently hydrogen or C1-C6 alkyl (e.g. methyl, ethyl, isopropyl).
In certain embodiments, Rax1 and Rbx1, are each independently en, methyl, or ethyl.
Rcx1, for example, is hydrogen, C1-C6 alkyl (e.g. methyl, ethyl, isopropyl), or C1-C6 haloalkyl (e.g. trifluoromethyl, 2,2,2 trifluoroethyl), wherein the C1-C6 alkyl is optionally substituted with Gx1. In certain embodiments, R cx1, for example, is hydrogen or C 1-C6 alkyl (e.g. methyl, ethyl, isopropyl). In certain embodiments, Rcx1, for example, is Gx1 or C1-C6 alkyl substituted with Gx1; n Gx1 is lyl, morpholinyl, piperazinyl, tetrahydrofuranyl, or phenyl, each of which is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C1-C3 alkyl and C1-C3 haloalkyl.
X2 is as sed in the Summary. For example, in certain embodiments, X2 is N. In certain embodiments, X2 is CRx2. R x2 is as defined in the Summary or embodiments herein.
In certain embodiments, X2 is C(O)H or C1-C6 alkyl substituted with one Gx2. In certain embodiments, X2 is C(O)H or C1-C3 alkyl substituted with one Gx2 wherein Gx2 is piperidinyl, piperazinyl, or morpholinyl, each of which is optionally substituted with 1, 2, or 3 C1-C3 alkyl. In certain embodiments, Rx2 is hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl). In certain embodiments, Rx2 is hydrogen.
Y1 is N or CRu. For example, in certain embodiments, Y 1 is N. In certain embodiments, Y1 is CRu. R u is as defined in the Summary and embodiments herein. For example, in certain embodiments, Ru is hydrogen or C1-C6 alkyl (e.g. ). In certain embodiments, Ru is hydrogen or C1-C3 alkyl (e.g. methyl). In certain embodiments, Ru is hydrogen or methyl. In certain embodiments, Ru is en.
A1, A2, A3, and A4 are as defined in the Summary. In certain embodiments, A1 is CR1, A2 is CR2, A3 is CR3, and A4 is CR4; or one of A1, A2, A3, and A4 is N. In certain embodiments, A1 is CR1, A2 is CR2, A3 is CR3, and A4 is CR4. In certain embodiments, one of A1, A2, A3, and A4 is N. In the embodiments that one of A1, A2, A3, and A4 is N, example of a group of compound includes, but is not limited to, those wherein A1 is CR1, A2 is CR2, A3 is CR3, and A4 is N. In certain embodiments, two of A1, A2, A3, and A4 are N, for example, A1 is N, A2 is CR2, A3 is N, and A4 is CR4; or for example, A1 is N, A2 is CR2, A3 is CR3, and A4 is N. In certain embodiments, three of A1, A2, A3, and A4 are N, for example, A1 is N, A2 is CR2, A3 is N, and A4 is N.
R1, R3, and R4, are as defined in the Summary. For example, in certain embodiments, R1, R3, and R4, are each independently en, C1-C6 alkyl (e.g. methyl, ethyl), halogen (e.g. Br, F, or Cl), or CN. For e, in certain embodiments, R1, R3, and R4, are each independently hydrogen, C1-C6 alkyl (e.g. methyl, ethyl), or C1-C6 haloalkyl (e.g. trifluoromethyl). In certain embodiments, R1, R3, and R4, are each independently hydrogen or . In n embodiments, R1, R3, and R4 are hydrogen.
R2 is as disclosed in the Summary. In certain ment, R2, for example, is halogen, haloalkyl (e.g. CF3), or -(C1-C3 alkylenyl)-CN. In certain embodiments, R2, for example, is hydrogen, C1-C6 alkyl, NO2, G2a, -S(O)2R2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)OR2a, R2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)S(O)2NR2bR2c, –(C1-C6 alkylenyl)-G2a, –(C1-C6 alkylenyl)-OR2a, -(C1-C6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, –(C1-C6 nyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, 6 nyl)-N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c. In certain embodiments, R 2, for example, is hydrogen, or NO2. In c ertain embodiments, R2, for example, is G2a, R2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)OR2a, R2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)S(O)2NR2bR2c, –(C1-C6 nyl)-G2a, –(C1-C6 alkylenyl)-OR2a, -(C1-C6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, –(C1-C6 alkylenyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 nyl)-N(R2e)C(O)R2d, -(C1-C6 nyl)-N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c. In certain embodiments, R 2, for example, is -S(O) 2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)S(O)2NR2bR2c, -(C1-C6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, -(C1- C6 alkylenyl)-C(O)R2d, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, -(C1-C6 alkylenyl)-N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c. In certain embodiments, R2, for example, is -S(O)2R2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or -N(R2e)S(O)2NR2bR2c. In certain ment, R 2, for example, is -S(O) 2d, -S(O) 2bR2c, 2R 2NR -N(R2e)S(O)2R2d, or 6 alkylenyl)-S(O)2R2d. In certain embodiment, R 2, for example, is -(C1-C3 alkylenyl)-S(O)2R2d wherein R2d is C1-C3 alkyl. In certain ment, R2, for example, is -(CH2)-S(O)2R2d wherein R2d is methyl or ethyl.
G2a, R2a, R2b, R2c, R2d, and R2e are as disclosed in the Summary and embodiments herein below.
In the embodiments wherein R2 is G2a, G2a is as disclosed in the Summary and embodiments herein. For example, in certain embodiments, G2a is an optionally substituted heterocycle. In certain embodiments, G2a is an optionally tuted monocyclic heterocycle. In certain embodiments, G2a is 1,2-dioxido-1,2-thiazolidinyl or tetrahydropyridinyl, each of which is optionally substituted. In certain embodiments, G2a is optionally substituted 1,2-dioxido-1,2-thiazolidinyl. In certain embodiment, G2a is aryl or heteroaryl, each of which is optionally substituted. In certain embodiments, G2a is ally tuted phenyl. In certain embodiments, G2a is pyridinyl or pyrazolyl, each of which is optionally substituted. In certain embodiments, G2a is unsubstituted.
In the embodiments n R2 is –(C1-C6 alkylenyl)-G2a, G2a is as disclosed in the Summary and embodiments herein. For example, in certain embodiments, G2a is a heterocycle or a heteroaryl, each of which is optionally substituted. In certain ments, G2a is a monocyclic heterocycle or a monocyclic heteroaryl, each of which is optionally substituted. In certain ments, G2a is 1,1-dioxido-1,2-thiazolidinyl, pyrrolidinyl, morpholinyl, or pyrazolyl, each of which is optionally substituted. In certain embodiments, G2a is unsubstituted. In n ments, G2a is optionally substituted phenyl.
Where G2a group is optionally substituted, it is, for example, optionally substituted with 1, 2, 3, 4, or 5 Rv. R v is as described in the Summary and herein, for example, Rv is C 1- C6 alkyl (e.g. methyl), halogen (e.g. F, Cl), C1-C6 haloalkyl, -CN, -NRjRk, or -C(O)ORh; or for e, Rv is C1-C6 alkyl (e.g. methyl), halogen (e.g. F, Cl), or C1-C6 haloalkyl.
In the embodiments wherein R2 is -S(O)2R2d, R2d is as disclosed in the Summary and embodiments herein. In certain embodiments, R2d is C1-C6 haloalkyl (e.g. CF3), G2b, unsubstituted C1-C6 alkyl (e.g. methyl, ethyl, isopropyl), or C1-C6 alkyl substituted with one G2b group; n G2b is , monocyclic lkyl, or monocyclic heterocycle, each of which is optionally substituted. In some such embodiments, the G2b group is optionally substituted with 1, 2, or 3 Rv groups wherein Rv is as described in the Summary and herein, for example, each Rv is independently C1-C6 alkyl (e.g. methyl), halogen (e.g. F, Cl), C1-C6 haloalkyl, -ORh, -CN, or -NRjRk, In n embodiments, R2d is C1-C6 haloalkyl or unsubstituted C1-C6 alkyl. In certain ments, R2d is methyl or ethyl.
In the embodiments wherein R2 is -S(O)2NR2bR2c, R2b and R2c are as disclosed in the Summary and embodiments herein. For example, in certain embodiments, R2b is hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl, ethyl), and R2c is hydrogen, tituted C1-C6 alkyl (e.g. methyl, ethyl), or C1-C6 haloalkyl (e.g. 2,2,2-trifluoroethyl, 2-fluoroethyl). In certain embodiments, R2b is hydrogen, and R2c is optionally substituted phenyl, or R2c is –C1-C3 alkyl substituted with one G2b group wherein G2b is optionally substituted pyridinyl.
In the embodiments wherein R2 is -C(O)R2d, R2d is as disclosed in the Summary and embodiments herein. For example, in certain ments, R2d is G2b n G2b is as sed in the Summary and embodiments herein. For example, in certain embodiments, G2b is an optionally substituted heterocycle. In n embodiments, G2b is an optionally substituted monocyclic heterocycle. In certain embodiments, G2b is 1,1- dioxidothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, or morpholinyl, each of which is optionally substituted. Each G2b is optionally substituted as described in the y and embodiments herein. For example, each G2b is independently unsubstituted or substituted with 1, 2, or 3 Rv. R v is as described in the Summary and embodiments .
For e, each Rv is independently C1-C6 alkyl (e.g. methyl), oxo, N(H)C(O)O(C1-C6 alkyl), -CH2-C(O)NRjRk, -C(O)-monocyclic heterocycle, or –C(O)-monocyclic heteroaryl. In certain ments, each Rv is independently C1-C6 alkyl (e.g. methyl), oxo, or N(H)C(O)O(C1-C6 alkyl).
In the embodiments wherein R2 is -C(O)OR2a, R2a is as disclosed in the Summary and embodiments herein. For example, in certain embodiments, R2a is hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl, ethyl).
In the ments wherein R2 is -C(O)NR2bR2c, R2b and R2c are as disclosed in the Summary and embodiments herein. For example, in certain embodiments, R2b is hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl), and R2c is hydrogen, G2b, C1-C6 haloalkyl (e.g. 2,2- difluoroethyl), C1-C6 alkyl (e.g. , ethyl) wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of –ORz1, NRz1Rz2, and G2b. R z1, Rz2, and G2b are as defined in the Summary and embodiments herein. For example, in certain embodiments, G2b is optionally substituted phenyl. In certain embodiments, G2b is a cycloalkyl, a aryl, or a heterocycle, each of which is optionally substituted. In certain embodiments, G2b is a clic cycloalkyl, a monocyclic heteroaryl, or a monocyclic heterocycle, each of which is optionally substituted. In certain embodiments, G2b is pyridinyl, dinyl, indazolyl, indolyl, entyl, thiazolyl, 1,1- dioxidotetrahydrothienyl, ydrofuranyl, piperazinyl, piperidinyl, or pyrrolidinyl, each of which is optionally substituted. Each G2b is optionally substituted as described in the y and embodiments herein. For example, each G2b is ndently unsubstituted or substituted with 1, 2, or 3 Rv. R v is as described in the Summary and embodiments herein.
For example, each Rv is independently C1-C6 alkyl (e.g. ), C1-C6 haloalkyl, -ORh, -C(O)ORh, -S(O)2Rh, halogen, or oxo. In certain embodiments, each Rv is independently C1- C6 alkyl (e.g. methyl) or oxo.
In the embodiments wherein R2 is -NR2bR2c, R2b and R2c are as disclosed in the Summary and embodiments herein. For example, in certain embodiments, R2b and R2c are each independently hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl, ethyl).
In the embodiments wherein R2 is -N(R2e)C(O)R2d, R2d and R2e are as disclosed in the Summary and embodiments herein. For example, in certain embodiments, R2e hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl, ethyl), and R2d is unsubstituted C1-C6 alkyl (e.g. methyl, ethyl, utyl) or C1-C6 haloalkyl (e.g. 2,2,2-trifluoroethyl).
In the embodiments wherein R2 is )S(O)2R2d, R2d and R2e are as sed in the Summary and embodiments herein. For e, in n embodiments, R2e is hydrogen or unsubstituted C1-C6 alkyl (e.g. , ethyl), and R2d is unsubstituted C1-C6 alkyl (e.g. methyl, ethyl) or C1-C6 haloalkyl (e.g. 2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2-dfluoroethyl).
In certain embodiments, R2e is hydrogen and R2d is unsubstituted C1-C6 alkyl (e.g. methyl, ethyl). In certain embodiments, R2e is C1-C6 haloalkyl, or C1-C6 alkyl substituted with one substituent selected from the group consisting of –ORz1, -NRz1Rz2, and G2b, and R2d is unsubstituted C1-C6 alkyl (e.g. methyl, ethyl). In certain embodiments, R2e is C1-C6 haloalkyl (e.g. 3,3,3-trifluoropropyl), or C1-C3 alkyl substituted with one substituent selected from the group consisting of –ORz1, -NRz1Rz2, and G2b, and R2d is unsubstituted C1-C6 alkyl (e.g. methyl, ethyl), wherein G2b is monocyclic cycloalkyl (e.g. ropyl), monocyclic heterocycle (e.g. idinylor tetrahydrofuranyl), or monocyclic heteroaryl (e.g. pyridinyl), each of which is optionally substituted.
In the embodiments wherein R2 is -N(R2e)S(O)2NR2bR2c, R2b, R2c, and R2e are as disclosed in the Summary and embodiments . For example, in certain embodiments, R2b, R2c, and R2e are each independently hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl, ethyl).
In the embodiments wherein R2 is –(C1-C6 alkylenyl)-OR2a, R2a is as described in the Summary and embodiments herein. In certain embodiments R2a is hydrogen. In certain embodiments, R2 is –CH2-OH or –CH2CH2-OH.
In the embodiments wherein R2 is –(C1-C6 alkylenyl)-C(O)OR2a, R2a is as described in the Summary and embodiments herein. For example, R2a is hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl, ethyl).
In the embodiments wherein R2 is -(C1-C6 alkylenyl)-C(O)NR2bR2c, R2b and R2c are as sed in the Summary and embodiments herein. For example, in certain ments, R2b and R2c are each ndently hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl, ethyl).
In the embodiments n R2 is -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, R2d and R2e are as disclosed in the Summary and embodiments herein. For example, in certain embodiments, R2e is hydrogen or unsubstituted C1-C6 alkyl (e.g. methyl, ethyl), and R2d is C1-C6 alkyl (e.g. methyl) optionally substituted with C(O)ORz1.
In the embodiments wherein R2 is -(C1-C6 alkylenyl)-S(O)2R2d, R2d is as disclosed in the Summary and embodiments . For example, in certain embodiments, R2d is optionally substituted phenyl or unsubstituted C1-C6 alkyl. In certain embodiments, R2d is unsubstituted C1-C3 alkyl. In certain embodiments, R2d is methyl or ethyl. In certain embodiments, R2d is optionally substituted phenyl.
L1 is as set forth in the Summary and ments herein. For e, in certain embodiments, L1 is absent, CH2, C(H)(OH), C(O), O, or (CH2)mN(Rz). For example, in n embodiments, L1 is CH2, C(O), (CH2)mO, or (CH2)mN(Rz). In certain embodiments, L1 is (CH2)mO or (CH2)mN(Rz). In certain embodiments, L 1 is (CH 2)mO. In certain embodiments, L1 is (CH2)mN(Rz).
The variable, m, is 0 or 1. In certain embodiments, m is 0. In n embodiments, m is 1.
Rz, is as set forth in the y and embodiments herein. For example, Rz is hydrogen or C1-C3 alkyl. In certain ments, Rz is hydrogen.
G1 is as set forth in the Summary and embodiments . For example, G1 is G”.
In certain embodiments, Gl is -(C1-C6 nyl)—G'a. In n embodiments, Gl is C1—C6 alkyl or alkoxyalkyl. In certain embodiments, G1 is C1-C6 alkyl (e.g. methyl, ethyl, isobutyl, or 2,2—dimethylpropyl). In certain embodiments, Gl is alkoxyalkyl.
Gla is as defined in the Summary and embodiments herein. For example, in certain ments G” is aryl, heterocycle, or cycloalkyl, each of which is optionally substituted.
In certain embodiments Gla is aryl, heterocycle, heteroaryl, or cycloalkyl, each of which is optionally substituted. In certain embodiments Glal is optionally substituted aryl. In certain embodiments Gla is optionally substituted heterocycle. In certain embodiments Gla is optionally substituted heteroaryl. In certain embodiments G1" is optionally substituted cycloalkyl.
In the ments wherein Gla is optionally substituted aryl, G”, for example, is , naphthyl, or indanyl, each of which is optionally substituted. In n embodiments, G”, for example, is optionally substituted phenyl. In certain embodiments, G”, for example, is phenyl optionally substituted with one or two halogen (e.g. F). In n embodiments, G1:! is F F \(55 : \é-S F F F In certain embodiments, Gla is unsubstituted phenyl or \éSF In the embodiments wherein Gla is optionally substituted heterocycle, examples of the heterocycle include, but are not limited to, yl, tetrahydrofuranyl (e.g. tetrahydrofuran- 2—yl, tetrahydrofuran—3-yl), pyrrolidinyl, morpholinyl, dinyl, tetrahydrothiopyranyl, and ydropyranyl (e.g. tetrahydropyran-4—yl, tetrahydropyranyl), each of which (including the exemplary rings) is optionally substituted.
In the embodiments wherein G"il is optionally substituted heteroaryl, G”, for example, is pyrazolyl, pyridinyl, pyrimidinyl, 2,1,3-benzothiadiazolyl, quinolinyl, or isoquinolinyl, each of which is optionally tuted.
In the embodiments wherein Gla is optionally substituted cycloalkyl (e.g. optionally substituted monocyclic cycloalkyl), examples of the cycloalkyl e, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, exyl, cycloheptyl, o[2.2.1]heptyl, and adamantyl, each of which is optionally substituted. In n embodiments, G1a is optionally tuted cycloalkyl. In certain embodiments, G1a is unsubstituted cycloalkyl. In certain embodiments, G1a is a tuted lkyl. In certain embodiments, G1a is cyclohexyl optionally tuted with 1 or two substituents selected from the group ting of C1-C3 alkyl (e.g. methyl), O(C1-C3 alkyl), and halogen. In certain embodiments, G1a is cyclohexyl ally substituted with 1 or two substituents selected from the group consisting of methyl and O(CH3). In certain embodiments, G1a is 4,4-difluorocyclohexyl. In certain embodiments, G1a is optionally substituted cyclopropyl. In certain embodiments, G1a is unsubstituted cyclopropyl.
The optional substituents of G1a are as set forth in the Summary and embodiments herein. For example, each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or Rw. In certain embodiments, R w is, for example, C 1-C6 alkyl -CN, n (e.g. F, Cl), oxo, C1-C6 haloalkyl (e.g. trifluoromethyl), -ORh, NRjRk, -S(O)2Rh, -C(O)Rh, -C(O)ORh, -C(O)NRjRk, -(C1-C3 alkylenyl)-ORh, or -(C1-C3 alkylenyl)C(O)NRjRk. In certain embodiments, Rw is, for example, C1-C6 alkyl, -CN, n (e.g. F, Cl), or C1-C6 haloalkyl (e.g. trifluoromethyl). In certain embodiments, Rw is halogen, -ORh, or C1-C6 alkyl. In certain embodiments, Rw is halogen. In certain ments, Rw is F.
It is appreciated that compounds of formula (I) with combinations of the above embodiments, including particular, more particular and preferred embodiments are contemplated. All embodiments of compounds of formula (I) formed by combining the substituent embodiments discussed above are within the scope of Applicants’ invention, and some illustrative embodiments of the compounds of formula (I) are provided below.
Accordingly, one aspect of the invention is directed to a group of compounds of formula (I) wherein L1 is (CH2)mO and G1 is G1a and G1a is as disclosed in the Summary and embodiments herein above.
Other examples of a group of compounds of formula (I) is ed to those wherein Y1 is N; X1 is CRx1; and X2 is CRx2.
Yet other examples of a group of compounds of formula (I) is directed to those wherein Y1 is N; X1 is CRx1; X2 is CRx2, and Ry is methyl.
Other examples of a group of compounds of formula (I) is directed to those n Y1 is N; X1 is CRx1; X2 is CRx2, Ry is methyl, and L1 is CH2, C(O), (CH2)mO, or (CH2)mN(Rz). In certain embodiments, L 1 is (CH 2)mO. In yet othe embodiments, L1 is (CH2)mO and m is 0. In yet othe embodiments, L1 is (CH2)mO and m is 1. In certain embodiments, L1 is N(Rz). In n embodiments, L 1 is (CH z) and m is 0. 2)mN(R In yet othe embodiments, L1 is (CH2)mN(Rz) and m is 1. Rz has values as described in the Summary and embodiments herein above.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is N; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, and G1 is –(C1-C6 alkylenyl)-G1a wherein G1a is optionally substituted phenyl.
Other examples of a group of compounds of formula (I) is ed to those wherein Y1 is N; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, and G1 is –(C1-C6 alkylenyl)-G1a wherein G1a is optionally substituted cycloalkyl. In some embodiments, G1a is unsubstituted cyclopropyl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is N; X1 is CRx1; X2 is CRx2, Ry is , L1 is (CH2)mO, and G1 is G1a.
Other examples of a group of compounds of formula (I) is directed to those n Y1 is N; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is O, G1 is G1a, and G1a is optionally substituted aryl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is N; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is O, G1 is G1a, and G1a is optionally substituted phenyl.
Other examples of a group of compounds of a (I) is directed to those wherein Y1 is N; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is optionally substituted cycloalkyl (e.g. optionally substituted monocyclic lkyl).
Other examples of a group of compounds of formula (I) is ed to those wherein Y1 is N; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is optionally substituted heterocycle (e.g. optionally substituted monocyclic heterocycle).
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; and X2 is CRx2.
Yet other examples of a group of compounds of formula (I) is directed to those n Y1 is CRu; X1 is CRx1; X2 is CRx2, and Ry is methyl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, and L1 is CH2, C(O), (CH2)mO, or (CH2)mN(Rz). In certain embodiments, L 1 is (CH 2)mO. In yet othe embodiments, L1 is (CH2)mO and m is 0. In yet othe embodiments, L1 is (CH2)mO and m is 1. In certain embodiments, L1 is (CH2)mN(Rz). In certain embodiments, L 1 is (CH z) and m is 0. 2)mN(R In yet othe embodiments, L1 is (CH2)mN(Rz) and m is 1. Rz has meaning as described in the Summary and embodiments herein above.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mN(Rz), and G1 is G1a or –(C1-C6 alkylenyl)-G1a n G1a is phenyl, monocyclic cycle (e.g. tetrahydrofuranyl), or monocyclic cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl), each of which (including the exemplary rings) is optionally substituted.
Other examples of a group of compounds of a (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mN(Rz), m is 0, Rz is hydrogen, and G1 is G1a wherein G1a is phenyl, monocyclic cycle (e.g. tetrahydrofuranyl), or monocyclic cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl), each of which (including the exemplary rings) is optionally substituted.
Other examples of a group of compounds of formula (I) is directed to those n Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mN(Rz), m is 0, Rz is hydrogen, and G1 is –(C1-C6 alkylenyl)-G1a wherein G1a is monocyclic heterocycle (e.g. tetrahydrofuranyl), or monocyclic cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl), each of which (including the exemplary rings) is optionally tuted. In some embodiments, G1 is –(C1-C3 alkylenyl)-G1a wherein G1a is optionally tuted monocyclic cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl, each of which is ally substituted). In some embodiments, G1 is –(CH2)-G1a wherein G1a is optionally substituted monocyclic cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl, each of which is ally substituted). In certain embodiments, G1a is optionally substituted is clic heterocycle (e.g. optionally substituted tetrahydrofuranyl). In certain embodiments, G1a is optionally substituted cyclopropyl. In some embodiments, G1a is unsubstituted cyclopropyl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, and G1 is C1-C6 alkyl or alkoxyalkyl. In certain ments, G1 is C1-C6 alkyl (e.g. methyl, ethyl, isobutyl, or 2,2- dimethylpropyl). In certain embodiments, G1 is alkoxyalkyl.
Other examples of a group of compounds of formula (I) is ed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, and G1 is –(C1-C6 alkylenyl)-G1a wherein G1a is optionally substituted .
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is O, and G1 is –(C1-C6 alkylenyl)-G1a wherein G1a is optionally tuted cycloalkyl. In some embodiments, G1a is optionally substituted cyclopropyl. In some embodiments, G1a is unsubstituted cyclopropyl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, and G1 is G1a.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is optionally tuted aryl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is optionally substituted phenyl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is ally tuted cycloalkyl (e.g. ally substituted monocyclic cycloalkyl).
Other examples of a group of compounds of formula (I) is ed to those wherein Y1 is CRu; X1 is CRx1; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is optionally substituted heterocycle (e.g. optionally tuted clic heterocycle).
Yet other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is N; X2 is CRx2, and Ry is methyl.
Other examples of a group of compounds of formula (I) is ed to those wherein Y1 is CRu; X1 is N; X2 is CRx2, Ry is methyl, and L1 is CH2, C(O), O, or (CH2)mN(Rz).
In certain embodiments, L1 is (CH2)mO. In yet othe embodiments, L1 is (CH2)mO and m is 0.
In yet othe embodiments, L1 is (CH2)mO and m is 1. In n embodiments, L1 is (CH2)mN(Rz). In certain embodiments, L 1 is (CH z) and m is 0. 2)mN(R In yet othe embodiments, L1 is (CH2)mN(Rz) and m is 1. Rz has meaning as described in the Summary and embodiments herein above.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is N; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, and G1 is G1a.
Other examples of a group of compounds of a (I) is directed to those wherein Y1 is CRu; X1 is N; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is optionally substituted aryl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is N; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is optionally substituted phenyl.
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is N; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is ally substituted cycloalkyl (e.g. optionally substituted monocyclic cycloalkyl).
Other examples of a group of compounds of formula (I) is directed to those wherein Y1 is CRu; X1 is N; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, G1 is G1a, and G1a is optionally substituted heterocycle (e.g. optionally substituted monocyclic heterocycle).
Other examples of a group of compounds of formula (I) is directed to those n Y1 is CRu; X1 is N; X2 is CRx2, Ry is methyl, L1 is (CH2)mO, and G1 is –(C1-C6 alkylenyl)-G1a wherein G1a is optionally substituted cycloalkyl. In some embodiments, G1a is optionally substituted cyclopropyl. In some embodiments, G1a is unsubstituted cyclopropyl.
Within each group of compounds of formula (I) bed herein above, A1, A2, A3, and A4 have meanings as disclosed in the Summary and embodiments herein above.
For example, within each group of compounds of formula (I) described herein above, es of a subgroup include those wherein A1 is CR1, A2 is CR2, A3 is CR3, and A4 is CR4; or one of A1, A2, A3, and A4 is N.
Other examples of a subgroup include, but are not limited to, those wherein A1 is CR1, A2 is CR2, A3 is CR3, and A4 is CR4.
Other examples of a subgroup include, but are not limited to, those wherein one of A1, A2, A3, and A4 is N.
Yet other examples of a subgroup include, but are not limited to, those wherein A1 is CR1, A2 is CR2, A3 is CR3, and A4 is N.
Yet other examples of a subgroup include, but are not d to, those wherein two of A1, A2, A3, and A4 are N.
Yet other examples of a up include, but are not limited to, those n A1 is N, A2 is CR2, A3 is N, and A4 is CR4.
Yet other examples of a subgroup include, but are not d to, those wherein A1 is N, A2 is CR2, A3 is CR3, and A4 is N.
Yet other es of a subgroup include, but are not limited to, those wherein three of A1, A2, A3, and A4 are N.
Yet other examples of a subgroup include, but are not limited to, those wherein A1 is N, A2 is CR2, A3 is N, and A4 is N.
Of all the groups and subgroups of compounds of formula (I) disclosed in the preceding aphs, R1, R2, R3, R4, Rx, Ru; Rx1, Rx2, m, and the optional substituents of G1 are as described in the Summary and embodiments herein above.
For e, of all the groups and subgroups of compounds of formula (I) disclosed in the preceding paragraphs, R2 is hydrogen, C1-C6 alkyl, NO2, G2a, R2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)S(O)2NR2bR2c, –(C1-C6 alkylenyl)-G2a, –(C1-C6 nyl)-OR2a, -(C1-C6 alkylenyl)-S(O)2R2d, 6 nyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, -(C1-C6 alkylenyl)-C(O)OR2a, -(C1-C6 nyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, -(C1-C6 alkylenyl)-N(R2e)S(O)2R2d, or 6 nyl)-N(R2e)S(O)2NR2bR2c. In certain embodiments, R 2 is -S(O) 2d, -S(O) 2bR2c, 2R 2NR )S(O)2R2d, or -N(R2e)S(O)2NR2bR2c. In some embodiments, R 2 is -S(O) 2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)-S(O)2R2d.
For example, of all the groups and subgroups of compounds of formula (I) disclosed in the preceding paragraphs, R2 is -S(O)2R2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or -N(R2e)S(O)2NR2bR2c, and Rx is hydrogen or methyl. In certain embodiments, Rx is hydrogen.
For example, of all the groups and subgroups of compounds of formula (I) disclosed in the preceding paragraphs, R2 is -S(O)2R2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or -N(R2e)S(O)2NR2bR2c, Rx is hydrogen, and Rx1 is hydrogen, -C(O)ORax1, -C(O)NRbx1Rcx1, Gx1, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with ORax1. In certain embodiments, Rx1 is hydrogen, Rax1, or -C(O)NRbx1Rcx1.
For example, of all the groups and ups of compounds of formula (I) disclosed in the ing paragraphs, R2 is -S(O)2R2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or -N(R2e)S(O)2NR2bR2c, Rx is hydrogen, Rx1 is hydrogen, -C(O)ORax1, or -C(O)NRbx1Rcx1, and Rx2 is hydrogen.
For example, of all the groups and subgroups of compounds of formula (I) disclosed in the preceding paragraphs, R2 is -S(O)2R2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)S(O)2R2d, Rx is hydrogen, Rx1 is hydrogen or -C(O)NRbx1Rcx1, and Rx2 is hydrogen.
One aspect of the invention is directed to compounds of a (I) or pharmaceutically acceptable salts thereof, wherein Rx is hydrogen; Ry is methyl; Y1 is CRu wherein Ru is hydrogen; X1 is CRx1 wherein Rx1 is hydrogen or –C(O)NRbx1Rcx1; X2 is CRx2 wherein Rx2 is hydrogen; L1 is (CH2)mO wherein m is 0; G1 is Gla or —(C1-C6 alkylenyl)—G'a, wherein Gla is optionally substituted phenyl or optionally substituted cycloalkyl; and R2 is -S(O)2R2d, —S(0)2NR2"R2°, -N(R2°)S(O)2R2d, or —(C.—C6 nyl)—S(O)2Rm.
In some such embodiments, Al is CR1, A2 is CR2, A3 is CR3, and A4 is CR4. In some further embodiments, A‘ is CR', A2 is CR2, A3 is CR3, and A4 is N.
Another aspect of the invention is directed to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Rx is hydrogen; Ry is methyl; Y1 is CRu wherein Ru is hydrogen; x' is CR"l wherein R“ is hydrogen; X2 is CR"2 wherein sz is hydrogen; LI is (CH2)mN(RZ) or wherein m is 0 and RZ is hydrogen; G1 is —(C.-C6 alkylenyl)—Gla, wherein G1a is optionally substituted lkyl; and R2 is R2", —S(0)2NR2"R2°, -N(R2°)S(O)2R2d, or —(C.—C6 alkylenyl)—S(0)2R2d.
In some such embodiments, Al is CR1, A2 is CR2, A3 is CR3, and A4 is CR4. In some further embodiments, A‘ is CR', A2 is CR2, A3 is CR3, and A4 is N.
In one aspect the present invention provides for compounds of formula (I) or pharmaceutically acceptable thereof, wherein Rx is hydrogen or C1-C3 alkyl; Ry is C1-C3 alkyl, -(C2—C3 alkylenyl)-OH, or C1-C3 kyl; x' is N or CR“ wherein R“ is hydrogen, C2—C6 alkenyl, C2—C6 alkynyl, —C(O)OR““, R"“R°"', —C(0)R""', S(O)2Rd"', —S(0)2NR""‘R°“, G", C1-C6 haloalkyl, or C1-C6 alkyl; wherein the Cl’Cfi alkyl is optionally substituted with one substituent ed from the group consisting of ORm, SR3“, S(O)Rdx1, S(O)2Rdx1, NRbx1Rcx1, -C(O)Rax1, -C(O)ORax1, -C(O)NRbx1Rcx1, -S(O)2NRbx1Rcx1, and Gx1; Rax1, Rbx1, and Rcx1, at each occurrence, are each ndently hydrogen, C1- C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga; Rdx1, at each ence, are each independently C1-C6 alkyl, C1-C6 haloalkyl, Ga, or 6 alkylenyl)-Ga; X2 is N or CRx2; wherein Rx2 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax2, Rbx2Rcx2, -C(O)Rdx2, S(O)2Rdx2, -S(O)2NRbx2Rcx2, Gx2, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is ally substituted with one substituent selected from the group consisting of ORax2, SRax2, S(O)Rdx2, S(O)2Rdx2, NRbx2Rcx2, -C(O)Rax2, -C(O)ORax2, -C(O)NRbx2Rcx2, -S(O)2NRbx2Rcx2, and Gx2; Rax2, Rbx2, and Rcx2, at each occurrence, are each independently hydrogen, C1- C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb; Rdx2, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb; Y1 is N or CRu; wherein Ru is hydrogen, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; A1 is N or CR1, A2 is N or CR2, A3 is N or CR3; and A4 is N or CR4; with the proviso that zero, one, two, or three of A1, A2, A3, and A4 are N; R1, R3, and R4 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, or NO2; R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, G2a, -OR2a, -OC(O)R2d, -OC(O)NR2bR2c, -SR2a, -S(O)2R2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)C(O)O(R2d), -N(R2e)C(O)NR2bR2c, )S(O)2NR2bR2c, –(C1-C6 nyl)-G2a, 6 alkylenyl)-OR2a, -(C1- C6 alkylenyl)-OC(O)R2d, –(C1-C6 alkylenyl)-OC(O)NR2bR2c, 6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, –(C1-C6 nyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 nyl)-N(R2e)C(O)R2d, -(C1-C6 alkylenyl)-N(R2e)S(O)2R2d, –(C1-C6 alkylenyl)-N(R2e)C(O)O(R2a), –(C1-C6 alkylenyl)-N(R2e)C(O)NR2bR2c, –(C1- C6 alkylenyl)-N(R2e)S(O)2NR2bR2c, and –(C1-C6 alkylenyl)-CN; R2a, R2b, R2c, and R2e, at each occurrence, are each independently hydrogen, C2-C6 alkenyl, C2-C6 l, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of –ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b; R2d, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b; Rz1 and Rz2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1- C6 haloalkyl; Gx1, Gx2, Ga, Gb, G2a, and G2b, at each occurrence, are each independently aryl, heteroaryl, heterocycle, lkyl, or cycloalkenyl, and each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rv; L1 is absent, CH2, C(O), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or 1; G1 is G1a or -(C1-C6 alkylenyl)-G1a; wherein each G1a is independently aryl, aryl, cycle, cycloalkyl, or cycloalkenyl, and each G1a is independently tituted or substituted with 1, 2, 3, 4, or 5 of Rw; Rv and Rw, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri, -OC(O)NRjRk, -SRh, -S(O)2Rh, -S(O)2NRjRk, h, -C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, -N(Rh)S(O)2Ri, -N(Rh)C(O)O(Ri), -N(Rh)C(O)NRjRk, –(C1-C6 alkylenyl)-ORh, –(C1-C6 alkylenyl)-OC(O)Ri, -(C1-C6 alkylenyl)-OC(O)NRjRk, 6 alkylenyl)-S(O)2Rh, –(C1-C6 alkylenyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)-C(O)Rh, –(C1-C6 nyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, –(C1-C6 alkylenyl)-NRjRk, –(C1-C6 alkylenyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, –(C1-C6 alkylenyl)-N(Rh)C(O)O(Ri), –(C1-C6 nyl)-N(Rh)C(O)NRjRk, or 6 alkylenyl)-CN; Rh, Rj, Rk, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and Ri, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl.
Compounds of formula (I) may contain one or more asymmetrically substituted atoms. Compounds of formula I may also exist as dual stereoisomers (including enantiomers and diastereomers) and mixtures thereof. Individual stereoisomers of compounds of formula I may be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers or by preparation of racemic mixtures followed by tion of the individual stereoisomer using methods that are known to those of ordinary skill in the art. Examples of resolution are, for e, (i) ment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, followed by liberation of the optically pure product; or (ii) separation of the mixture of enantiomers or diastereomers on chiral chromatographic columns.
Compounds of formula I may also include the various ric isomers and es thereof resulting from the disposition of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle group.
Substituents around a carbon-carbon double bond or a carbon-nitrogen double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycle are designated as being of cis or trans configuration.
Within the present ion it is to be understood that compounds disclosed herein may exhibit the phenomenon of tautomerism and all tautomeric isomers are included in the scope of the invention.
Thus, the formula drawings within this specification can ent only one of the possible tautomeric, geometric, or stereoisomeric forms. It is to be understood that the invention encompasses any tautomeric, geometric, or isomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric, geometric, or stereoisomeric form utilized within the a drawings. ary nds of formula (I) include, but are not limited to: 6-methyl(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl(5-nitrophenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(5-aminophenoxyphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; 2,2,2-trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]ethanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]acetamide; N-methyl-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; ethyl 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzoate; 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzoic acid; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(pyridin yloxy)phenyl]methanesulfonamide; yl[2-(morpholinylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one; l(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzamide; 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxy-N- (tetrahydrofuranylmethyl)benzamide; N-cyclopentyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzamide; N-(2,2-difluoroethyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- 4-phenoxybenzamide; 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxy-N-(1,3- thiazolyl)benzamide; N-(1,1-dioxidotetrahydrothiophenyl)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenoxybenzamide; 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzamide; 4-[5-(hydroxymethyl)phenoxyphenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]ethanesulfonamide; N,N-dimethyl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]sulfuric diamide; 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxypyridin- 3-yl]methanesulfonamide; N-[3-fluoro(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; N-[4-(2-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[4-(4-fluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin nyl]methanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide; N-[3-chloro(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]methanesulfonamide; 6-methyl[2-phenoxy(1H-pyrazolylmethyl)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran- 3-yloxy)phenyl]methanesulfonamide; N-{3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)[2- (trifluoromethyl)phenoxy]phenyl}methanesulfonamide; N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[4-(2-chlorofluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide; [4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetic acid; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-3,3,3-trifluoropropanamide; 2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-2,2-dimethylpropanamide; ethyl 4-(cyclopentylamino)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)benzoate; 4-{5-[(1,1-dioxido-1,2-thiazolidinyl)methyl]phenoxyphenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; (6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzyl]amino}oxobutanoic acid; 4-[2-(2,4-difluorophenoxy)(1,1-dioxido-1,2-thiazolidinyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; benzyloxy)(2-hydroxyethyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; methyl [4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetate; benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-ethylacetamide; 2-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N,N-dimethylacetamide; N-[4-(3,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]methanesulfonamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(tetrahydrofuranyl)benzamide; 4-{2-(2,4-difluorophenoxy)[(1,1-dioxidothiomorpholinyl)carbonyl]phenyl} methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(1-methyloxopyrrolidinyl)benzamide; tert-butyl {1-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzoyl]pyrrolidinyl}carbamate; 4-[2-(2,4-difluorophenoxy)(pyrrolidinylcarbonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(morpholinylcarbonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; N-[4-(cyclohexyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[4-(cyclopentyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}methanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]methanesulfonamide; 6-methyl[2-(morpholinylcarbonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]ethanesulfonamide; N-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]fluoroethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)phenyl]-N'-methylsulfuric e; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran- 3-yloxy)phenyl]ethanesulfonamide; methyl 6-methyloxo(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- oxylate; methyl 1,6-dimethyloxo(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinecarboxylate; ethyl 4-(5-aminophenoxyphenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinecarboxylate; 6-methyl(5-(methylsulfonamido)phenoxyphenyl)oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylic acid; ethyl 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxylate; N-ethylmethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide; ethyl 4-(5-aminophenoxyphenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3- d]pyridazinecarboxylate; ethyl 4-[5-(ethylamino)phenoxyphenyl]methyloxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxylate; ethyl ethyl(methylsulfonyl)amino]phenoxyphenyl}methyloxo-6,7- dihydro-1H-pyrrolo[2,3-d]pyridazinecarboxylate; 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- o[2,3-d]pyridazinecarboxylic acid; 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxamide; yl-N-[2-(4-methylpiperazinyl)ethyl]{5-[(methylsulfonyl)amino] phenoxyphenyl}oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazine carboxamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazinyl) phenoxyphenyl]methanesulfonamide; N-ethylmethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7- dihydro-1H-pyrrolo[2,3-d]pyridazinecarboxamide; 6-methyl(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazinone; N-ethyl-N,6-dimethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7- dihydro-1H-pyrrolo[2,3-d]pyridazinecarboxamide; 4-{4-[(ethylsulfonyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenoxy}benzamide; 6-methyl[5-(methylsulfonyl)phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; -(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)pyridinesulfonamide; N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)pyridinesulfonamide; 6-methyl(2-phenoxyphenyl)phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin one; N-{3-[2-(hydroxymethyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl]phenoxyphenyl}methanesulfonamide; N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide; 2-fluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)phenyl]ethanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran- 3-yloxy)phenyl]propanesulfonamide; N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]propanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- orophenoxy)phenyl]propanesulfonamide; 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) ybenzenesulfonamide; 6-(cyclohexylamino)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide; 6-(cyclohexylamino)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; yl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (2,4,6-trifluorophenoxy)phenyl]sulfuric diamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]propanesulfonamide; 2,2,2-trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydro-2H-pyranyloxy)phenyl]ethanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}ethanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}propanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}-2,2,2-trifluoroethanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}-N'-methylsulfuric diamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]ethanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]propanesulfonamide; 2,2,2-trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydro-2H-pyranyloxy)phenyl]ethanesulfonamide; N-methyl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydro-2H-pyranyloxy)phenyl]sulfuric diamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]ethanesulfonamide; N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)pyridinesulfonamide; 5-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (phenylamino)pyridinesulfonamide; N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (phenylamino)pyridinesulfonamide; N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]fluoroethanesulfonamide; 2-fluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- orophenoxy)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]propanesulfonamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(pyrimidinyl)benzamide; 4-(2,4-difluorophenoxy)-N-(2,6-dimethoxypyridinyl)(6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)-N-(1H-indazolyl)(6-methyloxo-6,7-dihydro-1H- o[2,3-c]pyridinyl)benzamide; 4-[2-(2,4-difluorophenoxy){[4-(pyrrolidinylcarbonyl)piperazin yl]carbonyl}phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(2,4-difluorophenoxy)-N-[4-(dimethylamino)phenyl](6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(pyridinylmethyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-[2-(2-oxopyrrolidinyl)ethyl]benzamide; 4-(2,4-difluorophenoxy)-N-(2-hydroxymethylpropyl)(6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzamide; -difluorophenoxy)-N-[2-(5-methoxy-1H-indolyl)ethyl](6-methyloxo- 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzamide; N-(3,4-difluorobenzyl)(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-[4-(trifluoromethoxy)benzyl]benzamide; 2-{4-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)benzoyl]piperazinyl}-N,N-dimethylacetamide; -difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(pyridinylmethyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(pyridinylmethyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(3,4,5-trimethoxybenzyl)benzamide; 4-(2,4-difluorophenoxy)-N-[2-(dimethylamino)ethyl](6-methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinyl)benzamide; N-[2-(1,3-benzodioxolyl)ethyl](2,4-difluorophenoxy)(6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)-N-[2-(1H-indolyl)ethyl](6-methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinyl)benzamide; 4-[2-(2,4-difluorophenoxy){[4-(furanylcarbonyl)piperazin yl]carbonyl}phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; tert-butyl {1-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzoyl]piperidinyl}carbamate; tert-butyl 4-{[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzoyl]amino}piperidinecarboxylate; 4-[2-(2,4-difluorophenoxy){[4-(ethylsulfonyl)piperazinyl]carbonyl}phenyl] methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; 4-[2-(4-chlorobenzoyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(pyrimidin yloxy)phenyl]ethanesulfonamide; N-{3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)[(1-methyl-1H- pyrazolyl)methoxy]phenyl}ethanesulfonamide; N-{4-[(1,3-dimethyl-1H-pyrazolyl)methoxy](6-methyloxo-6,7-dihydro-1H- o[2,3-c]pyridinyl)phenyl}ethanesulfonamide; N-[4-(2,2-dimethylpropoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; N-[4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide; 4-[2-(cyclohexylamino)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[5-amino(2,4-difluorophenoxy)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- d]pyridazinone; 4-[2-(2-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(3-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(4-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 2-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(3-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(4-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; 3-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]benzonitrile; 4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]benzonitrile; 6-methyl{5-(methylsulfonyl)[3-(trifluoromethyl)phenoxy]phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- d]pyridazinyl)phenyl]methanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- d]pyridazinyl)phenyl]ethanesulfonamide; isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(quinolinyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[2-chloro(trifluoromethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[2-fluoro(trifluoromethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 2-{4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]phenyl}acetamide; 4-[2-(3-aminophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(tetrahydrofuranylamino)phenyl]-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(4,4-difluorocyclohexyl)oxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(1-methylpiperidinyl)oxy]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,1,3-benzothiadiazolyloxy)(methylsulfonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 2,5-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; 4-[2-(3,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[(1-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(3,5-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[2-(4-methylphenoxy)(methylsulfonyl)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2-methoxyphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; yl{2-[(2-methylpyridinyl)oxy](methylsulfonyl)phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{2-[3-(dimethylamino)phenoxy](methylsulfonyl)phenyl}methyl-1,6-dihydro- rolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[(1-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[(3-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 2-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]benzonitrile; 4-[2-(3-chlorofluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(naphthalenyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2-fluoromethylphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(5-fluoromethylphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(quinolinyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(4-chlorofluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(pyridinyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2,3-dihydro-1H-indenyloxy)(methylsulfonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[4-(propanyl)phenoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(3,4,5-trifluorophenoxy)phenyl]-1,6-dihydro-7H- o[2,3-c]pyridinone; 4-(2-benzylphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(biphenylyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(1,4-dioxaspiro[4.5]decyloxy)(ethylsulfonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(4-oxocyclohexyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino](ethylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[(tetrahydrofuranylmethyl)amino]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(cishydroxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(transhydroxycyclohexyl)oxy]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-d]pyridazinone; 6-methyl[5-(methylsulfonyl)(tetrahydrofuranyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; (3-fluorooxetanyl)methoxy](methylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide; 6-(cyclopropylmethoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; 6-[(cyclopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; clopropylmethyl)amino]-N-methyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)pyridinesulfonamide; 4-{5-(ethylsulfonyl)[(cishydroxymethylcyclohexyl)oxy]phenyl}methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(transhydroxymethylcyclohexyl)oxy]phenyl}methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; cyclobutyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopentylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclohexyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopentyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(tetrahydrofuranylmethoxy)phenyl]-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[2-(2-oxoimidazolidinyl)ethoxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2-cyclopropylethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; 4-[2-(cycloheptyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[2-(2-methylpropoxy)(methylsulfonyl)phenyl]-1,6-dihydro-7H- o[2,3-c]pyridinone; 6-methyl[2-{[(2S)methylpyrrolidinyl]methoxy}(methylsulfonyl)phenyl]- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{2-[(2-methylcyclopropyl)methoxy](methylsulfonyl)phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclohexylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl{2-[2-(1-methylpyrrolidinyl)ethoxy](methylsulfonyl)phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl){[(2R)oxopyrrolidinyl]methoxy}phenyl]-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[2-(morpholinyl)ethoxy]phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl){[(2S)oxopyrrolidinyl]methoxy}phenyl]-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(1-tert-butoxypropanyl)oxy](methylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(1S,4R)-bicyclo[2.2.1]heptylmethoxy](methylsulfonyl)phenyl}methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{2-[(1-methylcyclopropyl)methoxy](methylsulfonyl)phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[2-(2-oxopyrrolidinyl)ethoxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{2-[(4-methylcyclohexyl)oxy](methylsulfonyl)phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; cyclobutylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]cyclopropanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methoxyethanesulfonamide; 6-methyl{5-(methylsulfonyl)[tricyclo[3.3.1.13,7]decyloxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[(cyclopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide; 4-[(cyclopropylmethyl)amino]-N-methyl(6-methyloxo-6,7-dihydro-1H- o[2,3-c]pyridinyl)benzenesulfonamide; 4-{2-[(2,2-difluorocyclopropyl)methoxy](ethylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(4-bromomethoxyphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide; 4-{2-(cyclopropylmethoxy)[(trifluoromethyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino][(trifluoromethyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-[(cyclopropylmethyl)amino]-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)pyridinesulfonamide; 6-(2,4-difluorophenoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)pyridinesulfonamide; 4-[2-(cyclopropylmethoxy)methylphenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-{5-(ethylsulfonyl)[(cismethoxycyclohexyl)oxy]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide; 4-(cyclopropylmethoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide; N-[4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenyl]ethanesulfonamide; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]-N-ethylmethyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-N-(2,2,2- trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(morpholin ylcarbonyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(4- piperazinyl)carbonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-N-(1,3- thiazolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; ethyl 4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]piperidinecarboxylate; 4-[2-ethoxy(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-{5-(ethylsulfonyl)[(transmethoxycyclohexyl)oxy]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino](propanylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenyl]methanesulfonamide; N-[4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenyl]methanesulfonamide; 4-[5-(ethylsulfonyl)(tetrahydro-2H-thiopyranyloxy)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(1,1-dioxidotetrahydro-2H-thiopyranyl)oxy](ethylsulfonyl)phenyl} methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; -difluorophenoxy)-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)pyridinesulfonamide; 4-[2-(cyclopropylamino)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-(5-(ethylsulfonyl)(cismethoxymethylcyclohexyloxy)phenyl)methyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]-N,N,6-trimethyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; 6-methyl{5-(methylsulfonyl)[4-(methylsulfonyl)phenoxy]phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(propanylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; lopropylmethoxy)-N,N-diethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)pyridinesulfonamide; 4-(cyclopropylmethoxy)-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzenesulfonamide; 4-[2-(cyclopropylmethoxy)fluorophenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-[2-(2,4-difluorophenoxy)(trifluoromethyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl](hydroxymethyl)methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,3-dihydro-1H-indenyloxy)(methylsulfonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl](1-hydroxyethyl)methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl][(dimethylamino)methyl] methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(morpholin ylmethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(4- methylpiperazinyl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl [(phenylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(1,3-thiazol ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(tetrahydrofuran- 3-ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(phenylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; cyclopropylmethoxy)(morpholinylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)pyridinyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(pyridin yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[5-(cyclopropylsulfonyl)(2,4-difluorophenoxy)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(propenyl)- hydro-7H-pyrrolo[2,3-c]pyridinone; 2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(phenoxymethyl)- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(morpholinylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)pyridinyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl](morpholinyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-N-[2-(dimethylamino)ethyl]ethanesulfonamide; 4-{2-(2,4-difluorophenoxy)[(ethylsulfonyl)methyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{2-(2,4-difluorophenoxy)[2-(ethylsulfonyl)propanyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(pyrrolidinylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl](dimethylamino)ethanesulfonamide; ethyl 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy]piperidinecarboxylate; 4-[2-(cyclopropylmethoxy)(pyrrolidinylsulfonyl)phenyl]methyl-1,6-dihydro- rolo[2,3-c]pyridinone; 4-{2-[(1-acetylpiperidinyl)oxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy]benzonitrile; 4-[2-(cyclopropylmethoxy)(2,3-dihydro-1H-indolylsulfonyl)phenyl]methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-(2,4-difluorophenoxy)[(phenylsulfonyl)methyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(2,2-difluorocyclopropyl)methoxy](pyrrolidinylsulfonyl)phenyl} methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-(cyclopropylmethoxy)[(3,3-difluoroazetidinyl)sulfonyl]phenyl}methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[2-(2-hydroxyethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy){[3-(dimethylamino)pyrrolidinyl]sulfonyl}phenyl]- 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]pyridinyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; tert-butyl 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)phenoxy]piperidinecarboxylate; 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-phenylbenzenesulfonamide; 4-[2-(cyclopropylmethoxy)(pyrrolidinylmethyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(pyridinyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(morpholinylmethyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[3-(hydroxymethyl)phenoxy]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; cyclopropylmethoxy)(1-methyl-1H-pyrazolyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(2,3-dihydro-1H-indolylsulfonyl)phenyl]methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrazolo[3,4- c]pyridinyl)phenyl]ethanesulfonamide; 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6- dihydro-7H-pyrazolo[3,4-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrazolo[3,4-c]pyridinone; 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrazolo[3,4-c]pyridinone; N-[2-cyano(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; tert-butyl cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate; 4-[5-(6-aminopyridinyl)(cyclopropylmethoxy)phenyl]methyl-1,6-dihydro- rolo[2,3-c]pyridinone; 4-{2-[(2,2-difluorocyclopropyl)methoxy](ethylsulfonyl)phenyl}methyloxo- N-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine carboxamide; 4-{2-[(cyclopropylmethyl)amino][(methylsulfonyl)methyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino](methylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[5-(ethylsulfonyl)(pyrrolidinyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-[5-(ethylsulfonyl)(4-methylpiperazinyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(4-fluorophenyl)amino](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(pyridinylmethyl)benzenesulfonamide; 4-[4-(cyclopropylmethoxy)-3'-fluorobiphenylyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(4-fluorophenyl)amino][(methylsulfonyl)methyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; [4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetonitrile; N-{4-(2,4-difluorophenoxy)[2-(hydroxymethyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl]phenyl}ethanesulfonamide; N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)carbonyl] oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)methyl]oxo- 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide; 4-[2-(cyclopropylmethoxy)(1,2,3,6-tetrahydropyridinyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-N-(pyridinylmethyl)ethanesulfonamide; lopropylmethyl)-N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinyl)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-N-[2-(2-oxopyrrolidinyl)ethyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-N-(tetrahydrofuranylmethyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-N-(3,3,3-trifluoropropyl)ethanesulfonamide; 4-(cyclopropylmethoxy)-N-(4-fluorophenyl)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzenesulfonamide; 4-[2-(cyclopropylmethoxy)(6-fluoropyridinyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(3-formylmethyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; N-{4-(2,4-difluorophenoxy)[6-methyl(morpholinylmethyl)oxo-6,7- o-1H-pyrrolo[2,3-c]pyridinyl]phenyl}ethanesulfonamide; N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)methyl]oxo- 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide; 4-{2-[(cyclopropylmethyl)amino]phenyl}methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4'-(cyclopropylmethoxy)-3'-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)biphenylcarbonitrile; and 4-{2-(cyclopropylmethoxy)[(4-hydroxypiperidinyl)sulfonyl]phenyl}methyl- hydro-7H-pyrrolo[2,3-c]pyridinone.
In certain embodiments, a compound of formula I is selected from the group consisting of: N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide; 6-methyl[5-(methylsulfonyl)phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) hydrofuranyloxy)pyridinesulfonamide; N-[4-(2-chlorofluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide; 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]ethanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)phenyl}methanesulfonamide; and N-[4-(4-fluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; or a pharmaceutically acceptable salt thereof.
In certain ments, a compound of formula I is selected from the group consisting of: 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]pyridinyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; 4-(cyclopropylmethoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide; 4-{2-[(4,4-difluorocyclohexyl)oxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-(5-(ethylsulfonyl)(cismethoxymethylcyclohexyloxy)phenyl)methyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one; 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide; 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6- o-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(transmethoxycyclohexyl)oxy]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino](ethylsulfonyl)phenyl}methyl-1,6-dihydro- rolo[2,3-c]pyridinone; 4-[(cyclopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide; 4-[2-(cyclopropylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclohexyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; and 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]ethanesulfonamide; or a pharmaceutically acceptable salt thereof.
In certain embodiments, a compound of the present invention is N-[4-(2,4- difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide, or a pharmaceutically able salt thereof.
Compounds of formula I can be used in the form of pharmaceutically acceptable salts.
The phrase aceutically acceptable salt” means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, tion, ic 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.
Compounds of formula (I) may contain either a basic or an acidic functionality, or both, and can be converted to a pharmaceutically acceptable salt, when desired, by using a suitable acid or base. The salts may be prepared in situ during the final isolation and cation 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, camphorsulfonate, digluconate, ophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, onate, p-toluenesulfonate and undecanoate.
Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not d to, methyl, ethyl, propyl, and butyl chlorides, es and iodides; dialkyl sulfates like dimethyl, diethyl, l and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and s; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or sible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts e such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
Basic addition salts may be prepared in situ during the final ion and cation of nds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other examples of organic amines useful for the formation of base on salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, zine and the like.
The term “pharmaceutically acceptable prodrug” or “prodrug”as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
The present invention contemplates compounds of formula (I) formed by tic means or formed by in vivo biotransformation of a prodrug. nds described herein can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the ion.
General Synthesis The compounds described herein, including compounds of general formula (I) and specific examples, may be ed, for example, through the reaction routes depicted in schemes 1-5. The variables A1, A2, A3, A4, X1, X2, Y1, L1, G1, Rx, and Ry used in the following schemes have the gs as set forth in the summary and detailed description sections unless otherwise noted.
Abbreviations used in the descriptions of the schemes and the specific es have the following gs: n-BuLi or BuLi for n-butyl lithium, DBU for 1,8- diazabicyclo[5.4.0]undecene, DIAD for diisopropyl arboxylate; DME for 1,2- dimethoxyethane, DMF for dimethylformamide, DMSO for dimethyl sulfoxide, EtOAc for ethyl acetate; mCPBA for 3-chloroperbenzoic acid, MeOH for ol; Pd(PPh3)4 for tetrakis(triphenylphosphine)palladium(0), ative HPLC for preparative HPLC; THF for tetrahydrofuran, TFA for trifluoroacetic acid, and HPLC for high performance liquid chromatography.
Compounds of general formula (I) may be prepared (a) by ng an aryl halide, an aryl te, or an aryl triflate with an aryl c acid or derivatives thereof (e.g. boronic esters) under Suzuki coupling condition (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999, 576:147-148), and (b) removal of the protecting group (PG), as illustrated in Scheme 1. Thus coupling of compounds of formula (1) wherein R101 is Br, Cl, mesylate, or triflate with compounds of formula (2) wherein R102 is boronic acid or derivatives thereof (e.g. boronic esters), or coupling of (1) wherein R101 is boronic acid or derivatives thereof (e.g. boronic ) with compounds (2) wherein R102 is Br, Cl, mesylate, or triflate, provides intermediates of formula (3). Generally, the coupling reaction is effected in the presence of a palladium st and a base, and optionally in the presence of a ligand, and in a le solvent at elevated temperature (for example, at about 80 oC to about 150 oC). The reaction may be facilitated by microwave irradiation. es of the palladium catalyst 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 employed include, but are not limited to, carbonates or phosphates of sodium, potassium, and cesium; and cesium de. Examples of suitable ligands include, but are not limited to, 1,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamante, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), and 1,1'- bis( diphenylphosphanyl) ene. Non-limiting examples of suitable solvent include methanol, dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydropyran, and water, or a e thereof.
Alternatively, treatment of formula (1) wherein R101 is Br, Cl, or triflate with boronic acid of formula (4), followed by displacement of the fluoride atom in (4) with an appropriate alcohol or amine of formula G1-L1-H wherein L1 is O or NH, provides compounds of a (3) or a (I) wherein Rx is hydrogen.
Displacement of the fluorine with an l or amine may be achieved in a solvent such as, but not limited to, dimethylsulfoxide, dimethylformamide, dioxane, or tetrahydrofuran, and in the presence of a base such as, but not limited to, cesium carbonate, potassium carbonate, or sodium hydride and at a temperature from about 40°C to about 120 The protecting group (PG) may be removed in situ during the displacement on or the coupling conditions described above.
Alternatively, l of the protecting group (PG) to afford compounds of general formula (I) wherein Rx is hydrogen can be accomplished using reaction conditions known generally to one skilled in the art, or modifications thereof. For example, the tosyl protecting group can be removed in the presence of a base such as, but not limited to, cesium carbonate, sodium hydroxide, or sodium hydride. The on is generally performed in the presence of a suitable solvent such as, but not limited to, dimethylsulfoxide, methanol, or tetrahydrofuran, and at a ature of about 40 °C to about 120 °C. The benzyl protecting group may be removed by hydrogenation in the presence of a st such as, but not d to, palladium on carbon and under hydrogen atmosphere. The reaction is typically performed 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 de reagent such as, but not limited to, TBAF (tetrabutylammonium fluoride). The reaction is generally performed in the presence of a suitable solvent such as, but not d to, dimethylsulfoxide, ethanol, or ydrofuran, and at a temperature of about 40 °C to about 120 °C. Removal of the (trimethylsilyl)ethoxy)methyl protecting group can also be achieved by treatment with an mild acid such as but not limited to, aqueous hydrochloric acid. The reaction is generally performed in the ce of a suitable solvent such as, but not limited to, ethanol, or methanol, and at a temperature of about 25 °C to about 80 °C.
Conversion of compounds of formula (I) wherein Rx is hydrogen to (I) wherein Rx is C1-C3 alkyl can be achieved with an alkylating agent of formula RxR103 wherein R103 is halogen, triflate, or mesylate. Generally, the reaction may be conducted in the presence of a base such as, but not limited to, sodium hyride or potassium carbonate, and in a solvent such as, but not limited to, tetrhydrofuran or dimethylformamide, and at a temperature of about 40 °C to about 120 °C.
Scheme 1 R102 o A‘QYLVG PG PG I | BK n’ Ry\ ,1] Ag 3, A4 if N \ A (2) Y]\ Yl}\ l I’x1 (L1 / R101 G1 HO OH A\A34 (1) B A%A3,A2 4 0 (4) “KT A§A3,A4 2 Compounds of formula (1) wherein Y1 is CR“, XI and X2 are CH, and R" is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl may be prepared by general synthetic methods as shown in Scheme 2.
Treatment of compounds of formula (6) wherein halo is Br, C1, or I, with 1,1- dimethoxy-N,N-dimethylmethanamine at elevated temperature (e.g. about 60 °C to about 100 °C), in the absence or presence of a base, and in a t such as, but not limited to, DMF, e compounds of formula (7). Examples of suitable bases e, but not d to, lithium or sodium methanolate. Catalytic hydrogenation of (7) in the presence of a catalyst such as, but not limited to, Raney-Nickel and under hydrogen atmosphere (about 30 psi) and in a solvent such as, but not limited to, ethyl acetate, at about room temperature lly affords compounds of formula (8). tion of the nitrogen atom with protecting group such as, but not limited to, benzyl, tosyl, and (trimethylsilyl)ethoxy)methyl group can be derived from reaction with an appropriate halide in the presence of a strong base such as, but not limited to, sodium hydride, to provide compounds of formula (9).
Treatment of (9) with an acid such as, but not limited to, hydrochloric acid or hydrobromic acid and in a solvent such as, but not limited to, dioxane or water, at about 40 0C to about 100 °C, typically provides nds of formula ([0).
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 ate, and in a solvent such as, but not limited to, dimethylforrnamide or dimethylsulfoxide at a temperature of about 0 °C to about 50 °C typically provides compounds of a (1 1).
Treatment of the compounds of formula (I l) with 4,4,4',4',5,5,5',5'—octamethyl-2,2'— ,2—dioxaborolane) generally affords compounds of formula (12). In general, the conversion may be facilitated by a palladium catalyst such as, but not limited to, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), or palladium(II)acetate, an optional ligand such as, but not limited to, clohexylphosphino— 2’,4’,6’-triisopropylbiphenyl, 2-dicyclohexylphosphino—2',4',6'—triisopropylbiphenyl (X— phos), or] , l '- bis( diphenylphosphanyl) ferrocene, and a base such as, but not limited to, carbonates, acetates, or phosphatesof sodium, potassium, and cesium; and cesium e.
Non-limiting examples of suitable solvents include methanol, dimethoxyethane, N,N- ylformamide, dimethylsulfoxide, dioxane, tetrahydropyran, and water, or a mixture thereof.
Scheme 2 0/ 0/ 0/ H / NO N —> I _> / _> \ / R" \ R“ \ / R" \ R" halo | halo halo halo (7) (8) (9) o 1 RV O l [PG /B\ Ru \ 0 O (12) halo 3 l halo (l 1) (10) An approach to prepare compounds of a (1) wherein Y1 is N, R101 is Cl, and X1 and X2 are CH, is outlined in Scheme 3.
Treatment of (13) with ammonium hydroxide at about 100 °C to about 150 °C can afford 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 °C to about 85 °C, typically yields compounds of formula (15). Subsequent coupling with (E)—2—(2—ethoxyvinyl)—4,4,5,5— tetramethyl-1,3,2-dioxaborolane utilizing Suzuki coupling reaction conditions as described in Scheme 1 provides compounds of formula (16). Cyclization of (16) followed by protection of the nitrogen atom typically affords compounds of formula (17).
Cyclization of (16) may be lished in the ce of an acid such as, but not limited to, acetic acid or hydrochloric acid and at an elevated temperature (e.g. about 50 °C to about 100 0C).
Scheme 3 O O o O Rv Cl 1 RV R NH2 RY\N \li‘ I —> \T I —> I \T I \ N I _ N N \ \ \ Cl Cl c| Cl (13) (I4) (15) (16) 0?) nds of formula (1) wherein Y1 is N, R'01 is Cl, X1 is -COOR21x1 or —C(0)NR""'R°"', Ra“, Rb“, and RC“ are hydrogen or C1-C6 alkyl, and x2 is CH may be prepared using the synthetic route exemplified 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 d to, DMF and at elevated ature (e.g. at about 80 °C to about 150 °C) generally results in acids of formula (18). Esten'fication of (18) to (19) may be accomplished by reaction conditions known to one skilled in the art, for e, by treatment with an alcohol under acidic condition. Subsequent protection of (19) using reaction conditions described in Scheme 2 for the conversion of (8) to (9) can provide for compounds of formula (20). Transformation of (20) to (2]) may be accomplished by step- wise reaction of (a) hydrolysis of the ester to the corresponding acid and (b) conversion of the acid to the corresponding amides.
The acid can be transformed to the riate acid chloride by ment with oxalyl chloride in the presence of catalytic amount of DMF at about room temperature, and in a suitable solvent such as, but not limited to, tetrahydrofuran or dichloromethane.
The resulting acid chloride may be converted to amides of formula (21) by treatment with an amine of formula Rm in a solvent such as, but not limited to, tetrahydrofuran, dimethylformamide, or dichloromethane at a temperature from about room ature to about 50 °C, optionally in the ce of a base such as, but not limited to, triethylamine, diisopropylethylamine, or potassium carbonate, and optionally in the presence of a catalyst such as 4wdimethylaminopyridine. Alternatively, the acid can be reacted with the amine of formula HNbe‘Rm in a solvent such as, but not limited to, tetrahydrofuran or dimethylformamide in the presence of a coupling reagent such as l, l ’-carbonyldiimidazole (CD1), bis(2-ox0—3-oxazolidinyl)phosphinic chloride (BOPCl), l,3—dicyclohexylcarbodiimide (DCC), polymer ted l,3—dicyclohexylcarbodiimide (PS—DCC), 0—(7—azabenzotriazol-l— yl)-N,N,N’,N’—tetramethyluronium orophosphate (HATU), or O—benzotriazol- l-yl- ,N’-tetramethyluronium tetrafluoroborate (TBTU), in the presence or absence of a coupling auxiliary such as, but not limited to, l-hydroxyazabenzotriazole (HOAT) or [- hydroxybenzotriazole hydrate (HOBT). The reaction may be generally conducted in the ce or absence of a base such as, but not limited to, yl morpholine, triethylamine, or diisopropylethylamine.
Scheme 4 O O H H RY\ NH2 RL N N N N 0 RL N O '1'\ —> kw“ _’iwmmm Cl c| Cl (15) (18) (19) 0 xPG 0 R‘Ny 1 /PG O Rsz N | I bx1 cx1 <— l (21) (20) Scheme 5 demonstrates a general approach to the preparation of compounds of formula (1) wherein Y' is CR“, R'°‘ is halogen, x' is -COOR‘”" or -C(0)NR"’“R°"', Ra“, Rb“, and Rm are hydrogen or C1-C6 alkyl, and x2 is CH.
An ester of formula (23) may be obtained from (a) ent of (6) 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, potassium ethoxide or sodium ethoxide, in a solvent such as, but not limited to, ethanol, e, or diethyl ether, and at a temperature of about 40 0C to about 80 °C; and (b) ation of the resulting (22) in the presence of iron and in ethanol and acetic acid, at a temperature of about 80 °C to about 100 °C. Conversion of (23) to (26) can be achieved by employing reaction conditions discussed above.
An ethyl ester of formula (26) may subsequently be hydrolysed to the corresponding acids. The resulting acids may be ormed to an appropriate ester or amide as described in Scheme 4. o/ o/ \ \ R“ R“ halo halo (6) (22) Optimum reaction conditions and reaction times for each individual step may vary ing on the particular reactants employed and substituents present in the reactants used.
Unless ise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Reactions may be further processed in the conventional manner, e.g. by eliminating the solvent from the residue and r purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either cially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical onality that may not be ible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; es of which may be found in T. Greene and P. Wuts, Protecting Groups in al Synthesis (3rd ed.), John Wiley & Sons, NY , which is incorporated herein by reference in its ty. Synthesis of the compounds of the invention may be accomplished by methods ous to those described in the synthetic schemes described hereinabove and in specific examples.
Starting materials, if not commercially available, may be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described s or the procedures described in the synthetic examples section.
When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric ion of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or tic resolution).
Similarly, when a pure geometric isomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting al, or by tion of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
Pharmaceutical Compositions This invention also provides for pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt f together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. The phrase “pharmaceutical composition” refers to a composition suitable for administration in medical or veterinary use.
The ceutical compositions that se a compound of formula (I), alone or or in combination with a second active pharmaceutical agent, may be administered to the subjects orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or , bucally or as an oral or nasal spray. The term “parenterally” as used , refers to modes of administration which include intravenous, uscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
The term “pharmaceutically acceptable carrier” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, ulating al or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not d 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 ose, 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 a 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 ide; alginic acid; n-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, g agents, ning, flavoring and perfuming agents, preservatives and antioxidants can also be present in the ition, according to the judgment of the ator.
Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile s for titution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and eous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of g materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These itions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. tion of the action of microorganisms can be ensured by the inclusion of various antibacterial and ngal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, which delay absorption such as aluminum earate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and lline form. Alternatively, delayed absorption of a parenterally-administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming ncapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be lled. 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.
The injectable ations can be sterilized, for e, by filtration h a bacterial-retaining filter or by incorporating sterilizing agents in the form of e solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In certain ments, solid dosage forms may contain from 1% to 95% (w/w) of a compound of formula I. In certain embodiments, the compound of formula I may be present in the solid dosage form in a range of from 5% to 70% (w/w). In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or r, such as sodium citrate or ium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or a starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid hylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
The pharmaceutical composition may be a unit dosage form. In such form the ation 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 ed tablets, capsules, and powders in vials or ampules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the riate number of any of these in packaged form. The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w/w) of a unit dose, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
The dose to be stered to a t may be determined by the efficacy of the particular compound ed and the condition of the subject, as well as the body weight or surface area of the subject to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that any the administration of a particular compound in a particular subject. In ining the effective amount of the compound to be administered in the treatment or prophylaxis of the disorder being treated, the physician can evaluate s such as the circulating plasma levels of the compound, compound toxicities, and/or the progression of the disease, etc. In l, the dose equivalent of a compound is from about 1 µg/kg to 100 mg/kg for a typical subject.
For administration, compounds of the formula I can be administered at a rate determined by factors that can include, but are not limited to, the LD50 of the compound, the pharmacokinetic profile of the nd, contraindicated drugs, and the side-effects of the compound at various concentrations, as applied to the mass and overall health of the subject.
Administration can be accomplished via single or divided doses.
The compounds utilized in the pharmaceutical method of the invention can be administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily. In certain embodiments, the daily dose range is from about 0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varied depending upon the requirements of the subject, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a ular situation is within the skill of the practitioner. Treatment may be initiated with smaller dosages, which are less than the optimum dose of the compound.
Thereafter, the dosage is sed by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
Solid compositions of a r type may also be employed as fillers in soft and hardfilled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings nown in the ceutical formulating art. They may optionally contain opacifying agents and may also be of a ition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned rs.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for e, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, ydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as g agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain ding agents as, for e, ethoxylated isostearyl alcohols, yethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
Compositions for rectal or l administration are preferably suppositories which can be prepared by mixing the compounds of this ion with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and ore melt in the rectum or vaginal cavity and release the active compound.
Compounds of formula I may also be administered in the form of liposomes.
Liposomes generally may be derived from olipids or other lipid nces.
Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, logically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may contain, in addition to a compound of formula (I), izers, preservatives, excipients and the like. Examples of lipids include, but are not limited to, natural and synthetic phospholipids and phosphatidyl es (lecithins), used separately or together.
Methods to form liposomes have been described, see e, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (l976), p. 33 et seq.
Dosage forms for topical administration of a compound described herein include powders, , ointments and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable r and any needed preservatives, buffers or propellants which may be ed. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Methods of Use The compounds of formula I, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions sing a compound of formula I, or a pharmaceutically acceptable salt thereof, can be stered to a subject suffering from a bromodomainmediated er or condition. The term “administering” refers to the method of contacting a compound with a subject. Thus, the compounds of formula I can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, parentally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of formula I can be stered transdermally, topically, via implantation, transdermally, topically, and via implantation. In certain embodiments, the compounds of the formula I may be delivered orally. The nds can also be delivered rectally, bucally, aginally, ocularly, andially, or by insufflation. Bromodomain-mediated disorders and conditions can be treated prophylactically, acutely, and chronically using compounds of formula I, depending on the nature of the disorder or condition. lly, the host or subject in each of these methods is human, although other s can also benefit from the administration of a compound of formula I.
A “bromodomain-mediated disorder or ion” is characterized by the participation of one or more bromodomains (e.g., BRD4) in the inception, manifestation of one or more symptoms or disease markers, severity, or progression of a disorder or condition.
Accordingly, compounds of formula I may be used to treat cancer, including, but not limited to acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell oma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical , chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, c myelocytic (granulocytic) leukemia, c enous leukemia, colon cancer, colorectal cancer, craniopharyngioma, enocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, moma, epithelial carcinoma, erythroleukemia, geal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, osarcoma, ia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic ia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, id malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, oblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung , oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, atic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell oma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenström’s macroglobulinemia, testicular tumors, uterine cancer and Wilms’ tumor. r, compounds of formula I may be used to treat inflammatory diseases, inflammatory ions, and autoimmune diseases, including, but not limited to: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, c obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema,giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel e, Kawasaki e, lupus nephritis, multiple sclerosis, myocarditis,myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis , pneumonitis, primary biliary cirrhosis, sis, 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.
Compounds of formula I, or pharmaceutically able salts thereof, may be used to treat AIDS. nds of formula I, or pharmaceutically acceptable salts thereof, may be used to treat c kidney disease or condition including, but are not limited to: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis.
Compounds of formula I, or pharmaceutically able salts thereof, may be used to treat acute kidney injury or disease or condition including, but are not limited to: ischemiareperfusion d, cardiac and major surgery induced, percutaneous coronary intervention induced, radio-contrast agent d, sepsis induced, nia induced, and drug toxicity induced.
Compounds of a I, or pharmaceutically acceptable salts thereof, may be used to treat obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic me, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy.
Compounds of formula I, or pharmaceutically acceptable salts thereof, may be used to provide for male contraception in a male t comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to a male subject in need thereof.
The compounds of formula I can be co-administered to a subject. The term “coadministered” means the administration of two or more different pharmaceutical agents or treatments (e.g., radiation treatment) that are administered to a subject by combination in the same pharmaceutical composition or separate pharmaceutical itions. Thus coadministration involves administration at the same time of a single ceutical composition sing two or more pharmaceutical agents or administration of two or more different compositions to the same subject at the same or different times.
The compounds of the invention can be co-administered with a therapeutically effective amount of one or more agents to treat a cancer, where examples of the agents include, such as radiation, alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, apoptosis ers (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 tors, DVDs (dual variable domain antibodies), leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone ylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinase tors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNA’s, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (bromodomain) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors, tin ligase inhibitors, and the like, and in combination with one or more of these agents.
BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.
Examples of BiTE antibodies include adecatumumab (Micromet , blinatumomab (Micromet MT103) and the like. t being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which e perforin and granzyme B. In this regard, Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B. These data suggest that inhibition of Bcl-2 could enhance the cytotoxic effects elicited by T-cells when targeted to cancer cells (V.R. Sutton, D.L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).
SiRNAs are les having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased ar potency. Examples of chemical modifications include phosphorothioate groups, xynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F- cleotides, 2'-methoxyethyl cleotides, combinations thereof and the like. The siRNA can have g lengths (e.g., 10-200 bps) and ures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the '- and/ or the s of a given strand.
Multivalent binding proteins are binding proteins comprising two or more antigen g sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies. The term “multispecific binding n” means a binding protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding ns binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of g one antigen) or multispecific (i.e., capable of g two or more antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site. 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, llicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, AZINE® (laromustine, VNP ), hosphamide, decarbazine, estramustine, stine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, en mustard e, ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamide and the like.
Angiogenesis inhibitors e endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor 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), -azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), abine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR ynylβ ofuranosylimidazole carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with orin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN®(melphalan), mercaptopurine, aptopurine riboside, methotrexate, mycophenolic acid, bine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.
Antivirals include ritonavir, hydroxychloroquine and the like.
Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors and the like.
Bcl-2 protein inhibitors include AT-101 ((-)gossypol), GENASENSE® (G3139 or rsen (Bcltargeting antisense oligonucleotide)), IPI-194, IPI-565, N-(4-(4-((4'- chloro(1,1'-biphenyl)yl)methyl)piperazinyl)benzoyl)(((1R)(dimethylamino) ((phenylsulfanyl)methyl)propyl)amino)nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2- (4-chlorophenyl)-5,5-dimethylcyclohexenyl)methyl)piperazinyl)benzoyl) (((1R)(morpholinyl)((phenylsulfanyl)methyl)propyl)amino) ((trifluoromethyl)sulfonyl)benzenesulfonamide 63), GX-070 clax), ABT-199, and the like.
Bcr-Abl kinase inhibitors include NIB® 54825), GLEEVEC® (imatinib) and the like.
CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, 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 acoxib), CT-3, DERAMAXX® oxib), JTE-522, yl(3,4-dimethylphenyl)(4- sulfamoylphenyl-1H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, , T-614, VIOXX® (rofecoxib) and the like.
EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFR immunoliposomes, 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 CP714, CI-1033 (canertinib), HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, , dHER2 (HER2 e), APC-8024 (HER-2 vaccine), anti-HER/2neu ific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, 3, MYCOGRAB® (human recombinant antibody to ), 3664, PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
Inhibitors of tors of apoptosis ns include HGS1029, GDC-0145, GDC- 0152, LCL-161, LBW-242 and the like.
Antibody drug conjugates include anti-CD22-MC-MMAF, D22-MC-MMAE, anti-CD22-MCC-DM1, CRvcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 and the like Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab, conatumumab, T01, GDC0145, (lexatumumab), 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 (lesaurtinib), XL019 and INCB018424 and the like.
MEK tors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like. mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, mpetitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and the like.
Non-steroidal anti-inflammatory drugs include IC® (salsalate), DOLOBID® (diflunisal), ® (ibuprofen), ® (ketoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE® (naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® lac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.
PDGFR inhibitors include C-451, , CP-868596 and the like. um chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, picoplatin and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Phosphoinositide-3 kinase (PI3K) 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 N® (bevacizumab), ABT-869, AEE-788, YME™ (a ribozyme that ts angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA)), axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib), R® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT® (sunitinib, SU- 11248), VEGF trap, ZACTIMA™ (vandetanib, ZD-6474), GA101, umab, ABT-806 06), ErbB3 specific antibodies, BSG2 specific antibodies, DLL4 specific dies and C-met specific dies, and the like.
Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or MYOCET® (liposomal bicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, zinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.
Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® zoxine), diflomotecan, edotecarin, ELLENCE® or RUBICIN® (epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.
Antibodies include N® (bevacizumab), CD40-specific antibodies, chTNT- 1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), IGF1R-specific antibodies, lintuzumab, PANOREX® olomab), RENCAREX® (WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20 antibodies types I and II and the like.
Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutamide), IDE® (cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane), dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™ (fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA® zole), formestane, orticoids, HECTOROL® (doxercalciferol), RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate, MEGACE® (megesterol), MIFEPREX® ristone), NILANDRON™ (nilutamide), NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone, PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR® (luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelin implant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin, goserelin) and the like.
Deltoids and retinoids e seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), 50 and the like.
PARP inhibitors include 8 (veliparib), olaparib, KU-59436, AZD-2281, AG- 014699, 1, BGP-15, INO-1001, ONO-2231 and the like.
Plant alkaloids include, but are not limited to, vincristine, stine, vindesine, vinorelbine and the like.
Proteasome inhibitors e VELCADE® (bortezomib), MG132, NPI-0052, PR-171 and the like.
Examples of immunologicals include interferons and other immune-enhancing agents. erons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, UNE® (interferon gamma-1b) or interferon gamma-n1, combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® ermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyte n 4), decarbazine, denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma e, mitumomab, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T), sargaramostim, sizofilan, teceleukin, YS® lus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific nce of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® zumab), ZEVALIN® (90Y-Ibritumomab an) and the like.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, ran, picibanil PF- 3512676 (CpG-8954), ubenimex and the like.
Pyrimidine s include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU orouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX® (ratitrexed), TROXATYL™ etyluridine troxacitabine) and the like.
Purine analogs include ® uanine) and PURI-NETHOL® (mercaptopurine).
Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4- hydroxyphenyl)amino)pyridinyl)methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.
Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like. nds of this invention can also be used as radiosensitizers that enhance the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like. onally, compounds having Formula (I) may be combined with other chemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA), APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin, L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4- diene), AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC® r vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN® (hydroxydoxorubicin); O: Vincristine IN®); P: prednisone), CYPAT™ (cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a a linker to human epidermal growth factor) or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6- dimethylxanthenoneacetic acid ), eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 me ), ermolide, DX-8951f (exatecan mesylate), aurin, EPO906 (epithilone B), IL® (quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®, GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin, ycarbamide, ibandronic acid, IGN-101, ILPE38, ILPE38QQR (cintredekin besudotox), ILpseudomonas in, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib, 5,10-methylenetetrahydrofolate, osine (hexadecylphosphocholine), NEOVASTAT®(AE-941), XIN® trexate glucuronate), NIPENT® statin), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® (melanoma vaccine treatment), X® (IL-2 Vaccine), ORATHECIN™ ecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb (murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® axomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA otide), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN® (DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn- KLH), thymitaq (2-amino-3,4-dihydromethyloxo(4-pyridylthio)quinazoline dihydrochloride), TNFERADE™ (adenovector: DNA carrier ning the gene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® afin gadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex), YONDELIS® ctedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA® (zolendronic acid), zorubicin and the like.
The compounds of the invention can also be co-administered with a therapeutically effective amount of one or more agents to treat an inflammatory disease or condition, or autoimmune disease, where examples of the agents include, such as methotrexate, tofacitinib, 6-mercaptopurine, azathioprine salazine, mesalazine, olsalazine chloroquinine/ hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, omil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as solone, odiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors, T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, alazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (etanercept) and p55TNFRIgG (Lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, cept, infliximab, adalimumab, certolizumab, tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine, methylprednisolone, cam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, ate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium, prednisolone, one, betamethasone, morphine sulfate, ine hydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, hosphamide, rituximab, IL- 1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469, VX-702, 8, VX-740, ilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), PKC family inhibitors (such as Ruboxistaurin or AEB-071) and Mesopram. In certain embodiments, combinations include methotrexate or leflunomide and in moderate or severe rheumatoid arthritis cases, cyclosporine and anti-TNF antibodies as noted above.
Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a nd of a (I) of the invention may be co-administered include the following: budenoside; epidermal growth ; corticosteroids; cyclosporin, alazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor nists; anti-IL-1β monoclonal antibodies; anti-IL-6 onal antibodies; growth factors; se inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, I, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, for e, ibuprofen; corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic AH26(14386215_1):RTK agents; complement inhibitors; adrenergic agents; agents which interfere with signalling by proinflammatory cytokines such as TNFα or IL-1 (e.g. NIK, IKK, or MAP kinase tors); IL-1β converting enzyme inhibitors; TNFα converting enzyme inhibitors; T-cell signalling inhibitors such as kinase inhibitors; metalloproteinase tors; sulfasalazine; azathioprine; aptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, II, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ). Preferred exam ples of therapeutic agents for Crohn's disease with which a nd of Formula (I) can be combined include the following: TNF antagonists, for e, anti- TNF antibodies, D2E7 (adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, FRIgG (etanercept) and p55TNFRIgG (LENERCEPTTM) inhibitors and PDE4 inhibitors. A compound of Formula (I) can be combined with corticosteroids, for example, budenoside and thasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents which interfere with synthesis or action of proinflammatory cytokines such as IL-1, for example, IL-1β converting enzyme inhibitors and ; T cell signaling inhibitors, for example, tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; oxylate/atrop sulfate; loperamide hloride; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen; hazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; azide disodium; codeine phosphate/apap; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab and eron-gamma.
Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound of Formula (I) may be co-administered include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-β1a (AVONEX®; ); interferon-β1b (BETASERON®; Chiron/Berlex); interferon α-n3) (Interferon Sciences/Fujimoto), interferon-α (Alfa mann/J&J), interferon β1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; enous immunoglobulin; cladribine; antibodies to or antagonists of other human cytokines or growth factors and their receptors, for example, 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. A compound of a (I) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound of Formula (I) may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate l, leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, AH26(14386215_1):RTK adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase tors), IL-1β ting enzyme inhibitors, TACE inhibitors, T-cell signaling inhibitors such as kinase tors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme tors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, IL-13 and TGFβ).
A compound of Formula (I) may also be co-administered with agents, such as zumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, idol, α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM ome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 or antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, ta2, tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.
Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a nd of a (I) can be co-administered include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, and anti-TNF antibodies, D2E7 (HUMIRA®), CA2 (infliximab), CDP 571, TNFR-Ig ucts, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (LENERCEPT®). miting examples of therapeutic agents for asthma with which a compound of Formula (I) may be co-administered include the following: albuterol, salmeterol/fluticasone, AH26(14386215_1):RTK montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate/ipratropium, solone sodium ate, inolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, erol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, ukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hloride, flunisolide/menthol, illin/clavulanate, levofloxacin, inhaler assist device, guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate, guaifenesin/d-methorphan, p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, rocodone/chlorphenir, cetirizine HCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, L-13 antibody, and metaproterenol sulfate.
Non-limiting examples of therapeutic agents for COPD with which a compound of a (I) may be inistered include the following: albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, uterol HCl, flunisolide, ceftriaxone , amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir, pirbuterol acetate, pephedrine /loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.
Non-limiting examples of therapeutic agents for psoriasis with which a compound of Formula (I) may be inistered include the following: otriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone te, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor, methylprednisolone acetate, sone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, ent, fluocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, en, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, alazine, ABT-874 and ustekinamab. miting examples of therapeutic agents for psoriatic arthritis with which a compound of Formula (I) may be co-administered include the following: methotrexate, cept, rofecoxib, celecoxib, folic acid, alazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, ylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), and efalizumab.
Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of Formula (I) may be co-administered include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for e, hydroxychloroquine; steroids, for example, prednisone, prednisolone, budenoside, thasone; cytotoxics, for example, oprine, cyclophosphamide, mycophenolate mofetil, rexate; inhibitors of PDE4 or purine synthesis tor, for example Cellcept®. A compound of a (I) may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL-1, for example, caspase inhibitors like IL-1β converting enzyme inhibitors and IL-1ra. A nd of Formula (I) may also be used with T cell ing inhibitors, for example, tyrosine kinase inhibitors; or molecules that target T cell activation les, for example, CTLAIgG or anti-B7 family dies, anti-PD-1 family antibodies. A compound of Formula (I) can be combined with IL-11 or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg antibody), or anti-receptor or antibodies, for example, anti-IL-6 receptor dy and antibodies to B-cell surface molecules. A compound of Formula (I) may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS AH26(14386215_1):RTK antibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 mumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, FRIgG (etanercept) and p55TNFRIgG (LENERCEPTTM).
The compounds of the invention can also be co-administered with a therapeutically effective amount of one or more agents used in the prevention or treatment of AIDS, where examples of the agents e, HIV reverse riptase inhibitors, HIV protease inhibitors, immunomodulators, and other retroviral drugs. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir, adefovir, sine, dipivoxil rdine, efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine, ine, tenofovir, zalcitabine, and zidovudine. Examples of se inhibitors include, but are not limited to, amprenavir, avir, darunavir, indinavir, fosamprenavir, lopinavir, avir, ritonavir, saquinavir, and tipranavir. Examples of other retroviral drugs include, but are not d to, elvitegravir, rtide, maraviroc and raltegravir.
The compounds of the ion can be co-administered with a therapeutically effective amount of one or more agents to prevent or treat type II diabetes, hepatic steatosis, insulin resistance, metabolic syndrome and related disorders, where examples of the agents include, but are not limited to, insulin and insulins that have been modified to improve the duration of action in the body; agents that stimulate insulin secretion such as acetohexamide, chlorpropamide, glyburide, glimepiride, glipizide, glicazide, glycopyramide, done, rapaglinide, nataglinide, mide and tolbutamide; agents that are glucagon-like peptide agonists such as exanatide, liraglutide and taspoglutide; agents that inhibit dipeptidylpeptidase IV such as vildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin and septagliptin; agents that bind to the peroxisome proliferator-activated receptor gamma such as rosiglitazone and pioglitazone; agents that decrease insulin resistance such as metformin; agents that reduce glucose absorbance in the small intestine such as acarbose, miglitol and voglibose.
The compounds of the invention can be co-administered with a therapeutically ive amount of one or more agents to prevent or treat acute kidney disorders and chronic kidney es, where examples of the agents include, but are not limited to, dopamine, diuretics such as furosemide, bumetanide, thiazide and the like, mannitol, calcium gluconate, sodium bicarbonate, albuterol, paricalcitol, doxercalciferol, cinacalcet and bardoxalone methyl.
The compounds of the invention can be co-administered with a therapeutically effective amount of one or more agents to a male subject to provide for male contraception.
The following Examples may be used for rative purposes and should not be deemed to narrow the scope of the invention.
Examples Example 1 6-methyl(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 1a (E)(5-bromomethoxynitropyridinyl)-N,N-dimethylethenamine -Bromomethoxymethylnitropyridine (15.0 g, 60.7 mmol) was dissolved in dimethylformamide (300 mL), and lithium methanolate (6.07 mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated to 100 °C. To this mixture was added 1,1- oxy-N,N-dimethylmethanamine (64.5 mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95 °C for 16 hours. The reaction mixture was cooled to room ature and water was added carefully (300 mL, exothermic). The resulting precipitate was collected by vacuum filtration, washed with water, and dried to provide the title nd (13.9 g, 45.9 mmol, 76 % yield).
Example 1b 4-bromomethoxy-1H-pyrrolo[2,3-c]pyridine Example 1a (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added to Ra-Ni 2800 (pre-washed with ethanol), water slurry (6.9 g, 118 mmol) in a stainless steel pressure bottle and d for 30 minutes at 30 psi and room temperature. The reaction e was filtered, and concentrated. The residue was triturated with dichloromethane, and the solid filtered to provide the title compound (5.82 g). The mother liquor was evaporated and the residue triturated again with dichloromethane and filtered to provide an onal 1.63 g of the title compound. Total yield = 7.45 g, 72% yield.
Example 1c 4-bromomethoxytosyl-1H-pyrrolo[2,3-c]pyridine A solution of Example 1b (7.42 g, 32.7 mmol) in dimethylformamide (235 mL) was d at room temperature. To this solution was added sodium hydride (1.18 g, 1.96 g of 60% dispersion in oil, 49.0 mmol), and the reaction mixture was stirred for 10 min. P- toluenesulfonyl chloride (9.35 g, 49.0 mmol) was then added portion-wise, and the mixture was d at room temperature under nitrogen for 16 hours. The reaction mixture was quenched carefully with water and the resulting beige solid collected by vacuum filtration on a Buchner funnel, and washed with water. The solid was collected and dried in a vacuum oven at 50 °C to provide 12.4 g (100%) of the title compound. e 1d otosyl-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 on was added 4M HCl in dioxane (140 mL). The reaction mixture was stirred at 40 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with diethylether, filtered, and rinsed with additional diethylether and dried to e the title compound (11.23 g, 30.6 mmol, 94 % yield) as a beige solid. e 1e 4-bromomethyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion) was added to a stirring solution of Example 1d (11.2 g, 30.4 mmol) in dimethylformamide (217 mL) under nitrogen. After 30 s, iodomethane (2.27 mL, 36.5 mmol) 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, rinsed with water (50 mL) and dried in a vacuum oven at 55 °C overnight to provide 11.2 g of the title compound (96%).
Example 1f 6-methyl(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone A mixture of Example 1e (152 mg, 0.40 mmol), oxyphenylboronic acid (0.111 g, 0.520 mmol, 1.3 equivalents), Pd(PPh3)4 (0.023 g, 5 mol%) and cesium fluoride (0.182 g, 1.2 mmol) in DME (3 mL) and methanol (1.5 mL) was heated under ave condition (120 ºC, 30 minutes). To this mixture was added potassium carbonate (0.055 g, 0.40 mmol) and water (1 mL) and the reaction mixture was reheated in the microwave oven at 120 ºC for another 2 hours. The organic layer was separated and purified by flash tography (silica gel, ethyl acetate). The resulting material was triturated with acetone and filtered to provide 0.075 g of the title compound (59%). 1H NMR (500 MHz, DMSO-d 6) δ 3.50 (s, 3 H), 6.21-6.23 (m, 1 H), 6.88 (d, J=7.62 Hz, 2 H), 6.99-7.04 (m, 2 H), 7.24-7.30 (m, 5 H), 7.36-7.40 (m, 1 H), 7.50 (dd, J=7.48, 1.68 Hz, 1H), 11.98 (s, 1 H). MS (ESI+) m/z 317 (M+H)+.
Example 2 6-methyl(5-nitrophenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 2a luoronitrophenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Method A: Example 1e (0.687 g, 1.802 mmol), 2-fluoronitrophenylboronic acid (0.500 g, 2.70 mmol), Pd(PPh3)4 (0.104 g, 0.090 mmol) and sodium carbonate (2.70 mL, 5.41 mmol) were combined in DME (7 mL) and water (7 mL) in a 20 mL microwave tube, sealed, sparged with nitrogen and heated under microwave at 120 ºC for 30 minutes. The mixture was ioned between EtAOc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and trated. The crude product was purified by flash chromatography (silica gel, 0-100% ethyl acetate in hexanes) to provide 0.41 g (52%) of the title compound.
Method B: Example 1e (6.00 g, 15.7 mmol), ronitrophenylboronic acid (5.82 g, 31.5 mmol), Pd(PPh3)4 (0.909 g, 0.787 mmol) and sodium carbonate (3.34 g, 31.5 mmol) were ed in toluene (60 mL), ethanol (15 mL) and water (15 mL) and the mixture was degassed and left under nitrogen. The reaction mixture was heated at 90 °C overnight, and then cooled to room temperature. The mixture was ioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated.
The crude product was purified by flash chromatography (silica gel, 20-50% ethyl acetate in hexanes) to provide 6.95 g (61%) of the title compound.
Example 2b 6-methyl(5-nitrophenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Phenol (0.094 g, 0.997 mmol), Example 2a (0.4 g, 0.906 mmol) and cesium ate (0.325 g, 0.997 mmol) were combined in DMSO (4.53 mL) and heated at 100 ºC for 2 hours.
The reaction mixture was partitioned between ethyl acetate and water and pH was adjusted to pH 7. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated.
Purification by flash chromatography (silica gel, 0-4 % methanol in dichloromethane) afforded 0.28 g (84%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.57 (s, 3 H) 6.28 - 6.34 (m, 1 H) 6.98 (d, J=9.12 Hz, 1 H) 7.16 (d, J=7.54 Hz, 2 H) 7.21 - 7.32 (m, 2 H) 7.40 - 7.49 (m, 3 H) 8.22 (dd, J=9.12, 2.78 Hz, 1 H) 8.32 (d, J=2.78 Hz, 1 H) 12.07 - 12.11 (m, 1 H). MS (ESI+) m/z 362 [M+H]+ Example 3 4-(5-aminophenoxyphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone e 2b (0.25 g, 0.692 mmol), iron powder (0.193 g, 3.46 mmol), and ammonium chloride (0.056 g, 1.038 mmol) were ed in tetrahydrofuran (6 mL), ethanol (6 mL) and water (2 mL). The mixture was heated at 95 ºC with vigorous stirring for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through a plug of Celite to remove solids. The plug was rinsed repeatedly with methanol and tetrahydrofuran. The filtrate was concentrated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-4 % methanol in dichloromethane) to afford 0.21 g (82 %) of the title compound. 1H NMR (300 MHz, 6) δ 3.43 (s, 3 H) 5.07 (s, 2 H) 6.22 - 6.25 (m, 1 H) 6.59 (dd, J=8.48, 2.71 Hz, 1 H) 6.68 (d, J=7.80 Hz, 2 H) 6.74 (d, J=2.71 Hz, 1 H) 6.80 - 6.88 (m, 2 H) 7.11 - 7.19 (m, 3 H) 7.24 (t, J=2.71 Hz, 1 H) 11.91 (s, 1 H). MS (ESI+) m/z 362 [M+H]+.
Example 4 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide Method A: To a solution of e 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 e was stirred for 2 hours at ambient temperature and then concentrated. The residue was dissolved in a mixture of dioxane (5 mL) and 1M sodium ide (2 mL) and heated for 1 hour at 90 ºC. The reaction mixture was cooled and diluted with ethyl acetate, brought to pH 7 with 1 M HCl and partitioned.
The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-4 % methanol in dichloromethane) to afford 0.20 g (77 %) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.02 (s, 3 H) 3.48 (s, 3 H) 6.23 - 6.30 (m, 1 H) 6.85 (d, J=7.46 Hz, 2 H) 6.99 (t, J=7.29 Hz, 1 H) 7.04 (d, J=8.82 Hz, 1 H) 7.20 - 7.29 (m, 5 H) 7.39 (d, J=2.71 Hz, 1 H) 9.72 (s, 1 H) 12.01 (s, 1 H). MS (ESI+) m/z 410 [M+H]+.
Method B: The product of Example 7d (1.127 g, 2 mmol), potassium hydroxide (1.82 g, 52.5 mmol) and rimethylammonium bromide (0.036 g, 0.100 mmol) were combined in ydrofuran (15.00 mL) and water (5.00 mL) and the mixture heated at 100 °C for 14 hours. The reaction mixture was partitioned between equal s 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, dried (Na2SO4) and concentrated.
Purification by ation in dichloromethane afforded the title compound (0.76 g, 93%). 2,2,2-trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]ethanesulfonamide To a solution of e 3 (0.05 g, 0.151 mmol) and ylamine (0.053 mL, 0.377 mmol) in dichloromethane (1.0 mL) was added dropwise 2,2,2-trifluoroethanesulfonyl chloride (0.036 g, 0.196 mmol). The reaction mixture was stirred for 1 hour at room temperature and then purified by flash chromatography (silica gel, 0-5% methanol in dichloromethane) to afford 0.050 g (68 %) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.49 (s, 3 H) 4.55 (q, J=9.91 Hz, 2 H) 6.28 (t, J=2.38 Hz, 1 H) 6.86 (d, J=7.54 Hz, 2 H) 6.95 - 7.07 (m, 2 H) 7.20 - 7.31 (m, 5 H) 7.40 (d, J=2.78 Hz, 1 H) 10.43 (s, 1 H) 12.02 (s, 1 H). MS (APCI+) m/z 478 [M+H]+.
Example 6 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]acetamide Example 6a 6-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)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'-bi(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- dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (X-PHOS, 0.819 g, 1.72 mmol) were ed and sparged with argon for 1 hour with ng. Dioxane (86 mL) was sparged with nitrogen for 1 hour, transferred via canula under nitrogen to the solid components, and the mixture was heated under argon at 80 °C for 5 hours. The on 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, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 25-80% ethyl acetate in hexane). The resulting material from tography was triturated with a minimal amount of hexanes (30 mL) and the particulate solid was collected by filtration, rinsed with a minimal amount of hexanes and dried to constant mass to afford the title compound (5.4 g, 73%).
Example 6b N-(3-bromophenoxyphenyl)acetamide Example 7b (0.2 g, 0.757 mmol), and acetic anhydride (1 mL, 10.60 mmol) were combined in a 5 mL microwave tube, sealed and heated under microwave at 100 °C for 30 minutes. The mixture was concentrated and the residue was purified by tography (silica gel, 0-50% ethyl acetate in hexanes) to afford the title compound (0.22 g, 95%). e 6c 6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) 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 (2.0 M, 0.245 mL, 0.490 mmol) were combined in DME (0.817 mL) and water (0.817 mL) in a 5 mL microwave tube, sealed, sparged with nitrogen and heated under microwave at 120 °C for minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. Purification by chromatography (silica gel, 0-5% methanol in dichloromethane) afforded the title nd (0.048 g, 56%).
Example 6d N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]acetamide Example 6c (0.048 g, 0.091 mmol) and potassium ate (0.044 g, 0.318 mmol) were combined in methanol (2 mL) and water (0.200 mL) in a 2 mL ave tube, sealed, and heated under microwave at 110 ºC for 30 minutes. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water, ing the pH to 6 with 1M HCl. The organic layer was separated and concentrated. Purification by flash chromatography (silica gel, 0-4 % methanol in dichloromethane) afforded 0.018 g (53%) of the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 2.05 (s, 3 H) 3.48 (s, 3 H) 6.25 - 6.30 (m, 1 H) 6.80 (d, J=7.46 Hz, 2 H) 6.96 (t, J=7.29 Hz, 1 H) 7.01 (d, J=8.82 Hz, 1 H) 7.18 - 7.31 (m, 4 H) 7.56 (dd, J=8.65, 2.54 Hz, 1 H) 7.79 (d, J=2.71 Hz, 1 H) 10.04 (s, 1 H) 11.97 (s, 1 H). MS (ESI+) m/z 374 [M+H]+.
Example 7 N-(3-{6-methyl[(4-methylphenyl)sulfonyl]oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl}phenoxyphenyl)methanesulfonamide Example 7a 2-bromonitrophenoxybenzene 2-Bromofluoronitrobenzene (2.5 g, 11.4 mmol), phenol (1.28 g, 13.6 mmol), and cesium carbonate (4.44 g, 13.6 mmol) were combined in dimethylsulfoxide (140 mL) and heated to 110 °C for 1 hour. The reaction mixture was partitioned between ethyl acetate and brine. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound.
Example 7b 3-bromophenoxyaniline 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 (50 mL),tetrahydrofuran (50 mL), and water (16.7 mL), and heated at 100 °C for 2 hour. The reaction e was cooled to just below reflux, vacuum filtered through diatomaceous earth, the filter cake washed with warm methanol (3x35 mL), and the filtrate trated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate (3 x 125 mL). The combined organics were washed with brine, dried ), gravity filtered then trated to afford the title nd.
Example 7c N-(3-bromophenoxyphenyl)methanesulfonamide Example 7b (2.86 g, 10.8 mmol) and ylamine (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, 12 mL, 0.427 mmol) were added, and the solution was heated to 70 ºC for 1 h. The on was neutralized to a pH of 7 with saturated aqueous NH4Cl (200 mL).
The aqueous phase was extracted with ethyl acetate (3x125 mL). The combined organics were washed with brine, dried (MgSO4), filtered, then concentrated. The residue was purified by flash chromatography (silica gel, 0-25% ethyl acetate/hexane gradient,) to afford the title compound.
Example 7d N-(3-{6-methyl[(4-methylphenyl)sulfonyl]oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl}phenoxyphenyl)methanesulfonamide e 6a (0.670 g, 1.564 mmol), e 7c (0.562 g, 1.643 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.036 g, 0.039 mmol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamante (0.023 g, 0.078 mmol) and potassium phosphate tribasic (1.03 g, 4.85 mmol) were combined and sparged with argon for 30 s. A solution of 4:1 dioxane/water (10 mL total volume) was sparged with nitrogen for 30 minutes and transferred by syringe into the reaction vessel under argon. The reaction e was d at 60 ºC for 2 hours, cooled to room ature and partitioned n ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), 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 in hexanes) afforded 0.68 g (74 %) of the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 2.38 (s, 3 H) 3.02 (s, 3 H) 3.38 (s, 3 H) 6.52 (d, J=3.39 Hz, 1 H) 6.82 (d, J=7.80 Hz, 2 H) 6.96 - 7.04 (m, 2 H) 7.19 - 7.28 (m, 4 H) 7.41 (d, J=8.14 Hz, 2 H) 7.48 (s, 1 H) 7.89 - 7.97 (m, 3 H) 9.73 (s, 1 H). MS (ESI+) m/z 564 [M+H]+.
Example 8 N-methyl-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide A mixture of Example 7d (0.113 g, 0.2 mmol) and potassium carbonate (0.111 g, 0.800 mmol) in methanol (0.9 mL) and water (0.1 mL) was heated at 100 ºC for 1 hour. The reaction was partitioned between ethyl acetate and water adjusting the pH to 7. The organic layer was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by e phase HPLC (C18, 10-100 % CH3CN/water (0.1% TFA)) to afford the title compound (0.012 g, 14%). 1H NMR (300 MHz, DMSO-d 6) δ 2.99 (s, 3 H) 3.27 (s, 3 H) 3.51 (s, 3 H) 6.27 - 6.32 (m, 1 H) 6.93 (d, J=7.80 Hz, 2 H) 6.99 (d, J=8.82 Hz, 1 H) 7.03 - 7.10 (m, 1 H) 7.25 - 7.34 (m, 4 H) 7.40 (dd, J=8.65, 2.88 Hz, 1 H) 7.55 (d, J=2.71 Hz, 1 H) 12.01 (s, 1 H). MS (ESI+) m/z 424 [M+H]+.
Example 9 ethyl 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzoate Example 9a ethyl 4-fluoro(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzoate A mixture of Example 1e (1.33 g, 3.5 mmol), 5-(ethoxycarbonyl) fluorophenylboronic acid (1.04 g, 4.9 mmol), Pd(PPh3)4 (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 d under a nitrogen here. The on mixture was heated at 90 ºC for 24 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The s layer was extracted with onal ethyl acetate twice.
The ed organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20-50% ethyl acetate in hexanes) to afford 1.43 g (87%) of the title compound.
Example 9b ethyl 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzoate 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 ºC for 12 hours.
After g to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 30-80% ethyl acetate/hexane) to afford 0.85 g (72%) of the title compound. 1H NMR (500 MHz, DMSO- d6) δ 1.31 (t, J=7.02 Hz, 3H), 3.55 (s, 3H), 4.32 (q, J=7.22 Hz, 2H), 6.23 (t, J=2.29 Hz,1H), 6.97 (d, J=8.54 Hz, 1H), 7.06 (d, J=8.24 Hz, 2H), 7.17 (t, J=7.32 Hz, 1H), 7.28 (t, J=2.75 Hz,1H), 7.36-7.51 (m, 3H), 7.94 (dd, J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14 Hz, 1H), 12.02 (s, 1 H). MS (ESI+) m/z 389.2 (M+H)+.
Example 10 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzoic acid A e of Example 9b (0.23 g, 0.59 mmol) and sodium hydroxide (0.89 mL of 2.0 M aqueous solution) in dioxane (10 mL) was heated at 60 °C for 2 hours. The reaction e 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 x 40 mL). The combined c layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford 0.21 g (98 %) of the title compound. 1H NMR (500 MHz, DMSO-d δ 3.55 (s, 3H), 6.24-6.25 (m,1H), 6.94 (d, J=8.54 Hz, 1H), 7.05 (d, J=7.63 Hz, 2H), 7.16 (t, J=7.32 Hz, 1H), 7.27 (t, J=2.9 Hz,1H), 7.35-7.40 (m, 3H), 7.92 (dd, J=8.7, 2.29 Hz, 1H), 8.04 (d, J=2.14 Hz, 1H), 12.03 (s, 1 H). MS (ESI+) m/z 361.2 (M+H)+.
Example 11 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(pyridin yloxy)phenyl]methanesulfonamide Example 11a 6-methyl(5-nitro(pyridinyloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one e 11a was prepared according to the procedure used for the preparation of Example 2b, substituting nol for phenol, to provide the title compound. e 11b 4-(5-amino(pyridinyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 11b was ed according to the procedure used for the preparation of Example 3, substituting Example 11a for Example 2b, to provide the title compound.
Example 11c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(pyridin yloxy)phenyl]methanesulfonamide Example 11c was prepared according to the procedure used in method A of Example 4, substituting Example 11b for Example 3, and purified by Preparative HPLC (C18, 10- 100% acetonitrile in 0.1 % TFA/water) to provide the TFA salt of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.49 (s, 3H), 3.05 (s, 3H), 6.25 (dd, J = 2.8, 1.9 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 7.34 - 7.21 (m, 5H), 7.40 (d, J = 2.6 Hz, 1H), 8.23 - 8.16 (m, 2H), 9.80 (s, 1H), 12.02 (bs, 1H). MS (ESI+) m/z 411.1 (M+H)+.
Example 12 6-methyl[2-(morpholinylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 12 was prepared according to the procedure used for the ation of Example 1f, substituting 2-(morpholinomethyl)phenylboronic acid for 2- phenoxyphenylboronic acid, followed by cation by preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 2.85 (br, 2H), 3.09 (br, 2H), 3.56 (s, 3H), 3.74 (br, 2H), 4.26 (br, 2H), 5.89-5.90 (m, 1H), 7.20 (s,1H), 7.29 (t, J=2.75 Hz, 1H), 7.39-7.43 (m, 1H), 7.53-7.55 (m, 2H), 7.75-7.77 (m, 1H),9.73 (br, 1H), 12.12 (s, 1H). MS (ESI+) m/z 324.0 (M+H)+.
Example 13 N-ethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzamide Example 13a 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzoyl chloride A solution of Example 10 (0.24 g, 0.67 mmol) in dichloromethane (10 mL) was d with oxalyl chloride (0.17g, 1.33 mmol) and dimethylformamide (5 mg, 10 mol %).
The reaction mixture was d at room temperature for 2 hours. The solvent was removed under reduced pressure to afford the title compound (0.25 g, quantitative).
Example 13b N-ethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzamide A solution of Example 13a (0.040 g, 0.11 mmol) in tetrahydrofuran (1 mL) was treated with ethylamine (0.21 mL of a 2 M solution in tetrahydrofuran, 0.42 mmol) for 2 h.
The reaction mixture was concentrated and the residue purified by preparative HPLC (C18, -90% acetonitrile in 0.1% TFA in water) to afford the title compound (0.025 g, 61%). 1H NMR (500 MHz, DMSO-d6) δ 1.12 (t, J=7.32 Hz, 3H), 3.25-3.32 (m, 2H), 3.54 (s, 3H), 6.23- 6.24 (m, 1H), 6.95-6.99 (m,3H), 7.11 (t, J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz, 1H), .37 (m, 3H), 7.84 (dd, J=8.54, 2.44 Hz, 1H), 7.98 (d, J=2.44 Hz, 1H), 8.46 (t, J=5.49 Hz, 1H), 11.99 (s, 1 H). MS (ESI+) m/z 388.2 (M+H)+.
Example 14 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxy-N- (tetrahydrofuranylmethyl)benzamide Example 14 was prepared according to the procedure used for the preparation of Example 13b, substituting (tetrahydrofuranyl)methanamine for ethylamine, and dichloromethane for tetrahydrofuran, tively, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.56-1.57 (m, 1H), 1.79-1.89 (m, 3H), 3.26-3.32 (m, 3H), 3.53 (s, 3H), 3.58-3.63 (m, 1H), .78 (m, 1H), 3.94-3.97 (m, 1H), 6.21-6.22 (m, 1H), 6.93-6.98 (m,3H), 7.10 (t, J=7.48 Hz, 1H), 7.25 (t, J=2.9 Hz, 1H), 7.30-7.35 (m, 3H), 7.84 (dd, J=8.54, 2.44 Hz, 1H), 7.98 (d, J=2.14 Hz, 1H), 8.52 (t, J=5.8 Hz, 1H), 12.00 (s, 1 H). MS (ESI+) m/z 444.2 (M+H)+.
Example 15 N-cyclopentyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzamide Example 15 was ed according to the procedure used for the preparation of Example 13b, substituting cyclopentylamine for ethylamine, and romethane for tetrahydrofuran, respectively, to e the title compound. 1H NMR (500 MHz, DMSO-d δ 1.49-1.66 (m, 4H), 1.65-1.69 (m, 2H), 1.85-1.91 (m, 2H), 3.54 (s, 3H), 4.20-4.26 (m, 1H), 6.20-6.22 (m, 1H), 6.95-6.98 , 7.01 (t, J=7.32 Hz, 1H), 7.26 (t, J=2.75 Hz, 1H), 7.30- 7.36 (m, 3H), 7.85 (dd, J=8.54, 2.14 Hz, 1H), 7.99 (d, J=2.44 Hz, 1H), 8.52 (t, J=5.8 Hz, 1H), 12.01 (s, 1 H). MS (ESI+) m/z 428.3 (M+H)+.
Example 16 N-(2,2-difluoroethyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzamide Example 16 was ed ing to the procedure used for the preparation of Example 13b, substituting 2,2-difluoroethanamine for ethylamine, and dichloromethane for tetrahydrofuran, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d δ 3.55 (s, 3H), .72 (m, 3H), 5.97 (t, J=3.97 Hz, 0.25H), 6.11 (t, J=4.12 Hz, 0.5H), 6.23- 6.26 (m, 1.25H), 6.98 (d, J=8.54 Hz, 1H), 7.01 (d, J=7.63 Hz, 2H), 7.13 (t, J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz, 1H), 7.33-7.36 (m, 3H), 7.88 (dd, J=8.54, 2.44 Hz, 1H), 8.03 (d, J=2.14 Hz, 1H), 8.85 (t, J=5.8 Hz, 1H), 12.03 (s, 1 H). MS (ESI+) m/z 424.2 (M+H)+.
Example 17 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxy-N-(1,3-thiazol zamide Example 17 was prepared according to the procedure used for the preparation of Example 13b, substituting thiazolamine for mine, and dichloromethane for tetrahydrofuran, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d δ 3.58 (s, 3H), 6.30-6.31 (m, 1H), 6.23-6.26 (m, 1H), 6.98 (d, J=8.54 Hz, 1H), 7.07 (d, J=7.63 Hz, 2H), 7.17 (t, J=7.32 Hz, 1H), 7.27-7.29 (m, 2H), 7.38-7.42 (m, 3H), 7.56 (d, J=3.36 Hz, 1H), 8.09 (dd, J=8.55, 2.44 Hz, 1H), 8.28 (d, J=2.44 Hz, 1H), 12.04 (s, 1H), 12.61 (s, 1H).
MS (ESI+) m/z 443.1 (M+H)+.
Example 18 N-(1,1-dioxidotetrahydrothiophenyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenoxybenzamide Example 18 was ed according to the procedure used for the preparation of Example 13b, substituting 1,1-dioxidotetrahydrothienylamine for ethylamine, and dichloromethane for ydrofuran, respectively, to provide the title compound. 1H NMR (500 MHz, 6) δ 2.20-2.23 (m, 1H), 2.41-2.45 (m, 1H), 3.04-3.09 (m, 1H), 3.19-3.23 (m, 1H), 3.34-3.37 (m, 1H), 3.48-3.53 (m, 1H), 3.55 (s, 3H), 4.66-4.76 (m, 1H), 6.30-6.31 (m, 1H), 6.21-6.22 (m, 1H), 6.99 (dd, J=8.09, 2.59 Hz, 2H), 7.12 (t, J=7.48 Hz, 1H), 7.27 (t, J=2.75 Hz, 1H), 7.31-7.37 (m, 3H), 7.87 (dd, J=8.54, 2.14 Hz, 1H), 8.02 (d, J=2.14 Hz, 1H), 8.72 (d, J=7.02 Hz, 1H), 12.03 (s, 1 H). MS (ESI+) m/z 478.2 (M+H)+.
Example 19 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzamide Example 19 was prepared according to the procedure used for the ation of e 13b, substituting aqueous ammonium hydroxide for ethylamine to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 3.54 (s, 3H), 6.23-6.24 (m, 1H), 6.94 (d, J=8.54 Hz, 1H), 6.98-7.00 (m, 2H), 7.11 (t, J=7.48 Hz, 1H), 7.26 (t, J=2.75 Hz, 1H), 7.31- 7.37 (m, 4H), 7.86 (dd, J=8.54, 2.44 Hz, 1H), 7.96 (s, 1H), 8.02 (d, J=2.44 Hz, 1H), 12.01 (s, 1 H). MS (ESI+) m/z 360.2 (M+H)+.
Example 20 4-[5-(hydroxymethyl)phenoxyphenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin Example 20a ethyl 3-(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzoate Example 20a was prepared according to the procedure used for the preparation of Example 1c, substituting Example 9b for Example 1b to provide the title compound.
Example 20b 4-[5-(hydroxymethyl)phenoxyphenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin Example 20a (0.32 g, 0.59 mmol) in tetrahydrofuran (5 mL) was cooled to 0 °C. To this solution was added 1.0 N aluminum lithium hydride (0.59 mL, 0.59 mmol). The on mixture was stirred at room temperature for 1 hour. The on e was quenched with 2.0 N HCl (5 mL), and then partitioned between water and ethyl e. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with % ethyl acetate in hexanes to afford 0.08 g (39%) of the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 3.49 (s, 3H), 4.54 (d, J=5.49 Hz, 2H), 5.21 (t, J=5.8 Hz, 1H), 6.23-6.24 (m, 1H), 6.94 (d, J=7.93 Hz, 2H), 6.97-7.01 (m, 2 H), 7.22-7.28 (m, 4H), 7.32 (dd, J=8.39, 2.29 Hz, 1H), 7.16 (d, J=1.83 Hz, 1H), 11.97 (s, 1H).
MS (ESI+) m/z 347.3 (M+H)+.
Example 21 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]ethanesulfonamide Example 21 was prepared according to the procedure used in method A of Example 4, substituting ethanesulfonyl chloride for methanesulfonyl chloride, to provide the title nd. 1H NMR (300 MHz, DMSO-d 6) δ 1.24 (t, J = 7.3 Hz, 3H), 3.13 (q, J = 7.3 Hz, 2H), 3.48 (s, 3H), 6.26 (t, J = 2.3 Hz, 1H), 6.88 - 6.80 (m, 2H), 7.07 - 6.95 (m, 2H), 7.31 - 7.18 (m, 5H), 7.40 (d, J = 2.7 Hz, 1H), 9.79 (s, 1H), 12.02 (bs, 1H). MS (ESI+) m/z 424.2 (M+H)+.
Example 22 N,N-dimethyl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]sulfuric diamide Example 22 was prepared according to the procedure used in method A of Example 4, substituting dimethylsulfamoyl chloride for methanesulfonyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 2.74 (s, 6H), 3.48 (s, 3H), 6.28 - 6.23 (m, 1H), 6.85 - 6.78 (m, 2H), 7.06 - 6.93 (m, 2H), 7.31 - 7.17 (m, 5H), 7.40 (d, J = 2.7 Hz, 1H), 9.91 (s, 1H), 12.04 - 12.00 (m, 1H). MS (ESI+) m/z 439.1 (M+H)+.
Example 23 N-[5-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxypyridin yl]methanesulfonamide Example 23a 3-bromonitrophenoxypyridine Phenol (0.416 g, 4.42 mmol), 3-bromochloronitropyridine (Combi-Blocks, CAS 17-7], 1 g, 4.21 mmol) and cesium carbonate (1.372 g, 4.21 mmol) were combined in DMSO (8 mL) and heated at 80 °C for 30 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and water. The c layer was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by chromatography a gel, 0-30 % ethyl acetate in hexanes) afforded the title compound (1.13 g, 91%). e 23b 6-methyl(5-nitrophenoxypyridinyl)tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 23b was prepared ing to the procedure used for the preparation of Example 7d, substituting the product of Example 23a for the product of Example 7c and stirring at 60 °C for 24 hours, to provide the title compound.
Example 23c 4-(5-aminophenoxypyridinyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 23c was prepared according to the procedure used for the ation of Example 3, substituting the product of Example 23b for the product of Example 2, to provide the title compound. e 23d N-[5-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxypyridin yl]methanesulfonamide Example 23d was prepared according to the procedure used in method A of Example 4, substituting the product of e 23c for the product of Example 3, to provide the title compound (0.035 g, 36%). 1H NMR (300 MHz, DMSO-d 6) δ 3.05 (s, 3 H) 3.57 (s, 3 H) 6.28 - 6.36 (m, 1 H) 7.10 (d, J=7.54 Hz, 2 H) 7.16 (t, J=7.54 Hz, 1 H) 7.28 - 7.41 (m, 3 H) 7.48 (s, 1 H) 7.78 (d, J=2.78 Hz, 1 H) 7.96 (d, J=2.38 Hz, 1 H) 9.79 (s, 1 H) 12.11 (s, 1 H). MS (ESI+) m/z 411.0 .
Example 24 N-[3-fluoro(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide Example 24a 4-(2,3-difluoronitrophenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 24a was prepared ing to the procedure used for the preparation of Example 7d, substituting 1-bromo-2,3-difluoronitrobenzene (Oakwood Products) for the product of Example 7c, to provide the title compound.
Example 24b 4-(3-fluoronitrophenoxyphenyl)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 combined in DMSO (2.177 mL) and heated at 80 °C for 30 minutes. The reaction mix was cooled and partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound. e 24c 4-(5-aminofluorophenoxyphenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 24c was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 24b for the product of e 2, to provide the title compound. e 24d luoro(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide 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%). 1H NMR (300 MHz, DMSO-d 6) δ 3.05 (s, 3 H) 3.57 (s, 3 H) 6.28 - 6.36 (m, 1 H) 7.10 (d, J=7.54 Hz, 2 H) 7.16 (t, J=7.54 Hz, 1 H) 7.28 - 7.41 (m, 3 H) 7.48 (s, 1 H) 7.78 (d, J=2.78 Hz, 1 H) 7.96 (d, J=2.38 Hz, 1 H) 9.79 (s, 1 H) 12.11 (s, 1 H).
Example 25 N-[4-(2-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 25a 2-(2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) nitrophenoxy)benzonitrile Example 25a was prepared according to the procedure used for the preparation of Example 2b, substituting 2-hydroxybenzonitrile for phenol, to provide the title compound.
Example 25b 2-(4-amino(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy)benzonitrile Example 25b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 25a for the t of Example 2b, to provide the title compound. e 25c N-[4-(2-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 25c was prepared according to the procedure used in method A of Example 4, substituting the product of e 25b for the product of Example 3, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 3.07 (s, 3H), 3.50 (s, 3H), 6.26 (dd, J = 2.8, 1.9 Hz, 1H), 6.73 (dd, J = 8.6, 0.9 Hz, 1H), 7.07 (td, J = 7.6, 0.9 Hz, 1H), 7.34 - 7.23 (m, 4H), 7.53 - 7.40 (m, 2H), 7.71 (dd, J = 7.7, 1.7 Hz, 1H), 9.89 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z 435.2 (M+H)+.
Example 26 N-[4-(4-fluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide e 26a 4-fluorophenoxy)nitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one e 26a was prepared according to the procedure used for the preparation of Example 2b, substituting 4-fluorophenol for phenol, to provide the title compound.
Example 26b 4-(5-amino(4-fluorophenoxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 26b was ed according to the procedure used for the preparation of Example 3, substituting the product of Example 26a for the product of Example 2b, to provide the title compound.
Example 26c N-[4-(4-fluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 26c was prepared according to the procedure used in method A of e 4, substituting the product of Example 26b for the product of Example 3, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 3.02 (s, 3H), 3.50 (s, 3H), 6.29 - 6.23 (m, 1H), 6.94 - 6.82 (m, 2H), 7.14 - 6.96 (m, 3H), 7.21 (dd, J = 8.7, 2.7 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.38 (d, J = 2.7 Hz, 1H), 9.71 (s, 1H), 12.02 (bs, 1H). MS (ESI+) m/z 428.1 (M+H)+.
Example 27 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 27a 4-(2-(2,4-difluorophenoxy)nitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 27a was ed according to the procedure used for the preparation of Example 2b, tuting 2,4-difluorophenol for phenol, to provide the title compound.
Example 27b 4-(5-amino(2,4-difluorophenoxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 27b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 27a for the product of Example 2b, to provide the title compound. e 27c N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 27b (50 mg, 0.136 mmol) and triethylamine (0.057 mL, 0.408 mmol) were combined in CH2Cl2 (9 mL). Methanesulfonyl chloride (0.042 mL, 0.544 mmol) was added dropwise and the solution stirred at ambient temperature for 1 hour. The solution was concentrated under reduced pressure, dioxane (5 mL) and sodium hydroxide (10% w/v, 3 mL, 0.136 mmol) were added and the solution heated at 70 ºC for 1 hour. The e was cooled to ambient temperature and then neutralized with saturated NH4Cl (100 mL) to a pH of 8.
The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3x25 mL). The combined organic layers were washed with brine, dried ), filtered, and concentrated. Purification by reverse phase HPLC (C18, 10-100 % acetonitrile/water, 0.1 % TFA) ed 27.5 mg (45.4 %) of the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 3.01 (s, 3H), 3.53 (s, 3H), 6.29-6.23 (m, 1H), 7.04-6.90 (m, 2H), 7.09 (td, J = 9.1, 5.6 Hz, 1H), 7.44-7.14 (m, 5H), 9.70 (s, 1H), 12.04 (bs, 1H). MS (ESI+) m/z 446.1 .
Example 28 N-[3-chloro(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) yphenyl]methanesulfonamide Example 28a 4-(3-chlorofluoronitrophenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 28a was prepared according to the procedure used for the ation of Example 6c, substituting 1,3-dichlorofluoronitrobenzene (0.176 g, 0.841 mmol) for the product of Example 6b, to provide the title compound.
Example 28b N-[3-chloro(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide Example 28b was ed according to the procedures used for the preparation of Examples 24b-24d, substituting Example 28a for the product of Example 24a, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 3.12 (s, 3 H) 3.43 (s, 3 H) 6.25 - 6.29 (m, 1 H) 6.63 (d, J=7.93 Hz, 2 H) 6.87 (t, J=7.34 Hz, 1 H) 7.10 - 7.18 (m, 2 H) 7.27 - 7.31 (m, 2 H) 7.39 (s, 2 H) 10.05 (s, 1 H) 12.04 (s, 1 H). MS (ESI+) m/z 444 (M+H)+.
Example 29 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran yloxy)phenyl]methanesulfonamide Example 29a 6-methyl(5-nitro(tetrahydro-2H-pyranyloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Tetrahydro-2H-pyranol (0.046 g, 0.453 mmol) in ydrofuran (2 mL) was d with sodium hydride (0.022g, 0.906 mmol, 0.036 g of 60% dispersion in oil) 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 °C 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 c layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to afford 0.055 g of the title compound.
Example 29b mino(tetrahydro-2H-pyranyloxy)phenyl)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 (10 mL) was treated with a balloon of hydrogen ght. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to provide 0.042 g of the title compound.
Example 29c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran yloxy)phenyl]methanesulfonamide e 29c was prepared according to the procedure used in method A of Example 4, substituting the product of Example 29b for the t of Example 3, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.45-1.51 (m, 2H), 1.82-1.87 (m, 2H), 2.94 (s, 3H), 3.35-3.41 (m, 2), 3.56 (s, 3H), .68 (m, 2H), 4.45-4.49 (m, 1H), 6.20 (t, J=2.29 Hz, 1H), 7.14-7.16 (m, 2H), 7.28-7.29 (m, 3H), 9.45 (s, 1H), 12.01 (s, 1H). (ESI+) m/z 418.2 (M+H)+.
Example 30 6-methyl[2-phenoxy(1H-pyrazolylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone 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 (1 mL) was stirred for 2 minutes. To this solution was added di-t-butyl azodicarboxylate (DTBAD, 0.053 g, 0.231 mmol). The on mixture was d at room temperature for 3 hours. The solvent was removed under d pressure, and the residue was purified by preparative HPLC (C18, -80% acetonitrile/water with 0.1% TFA) to afford 0.006 g of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.49 (s, 3H), 5.37 (s, 2H), 5.21 (t, J=5.8 Hz, 1H), 6.17-6.18 (m, 1H), 6.28 (t, J=1.98 Hz, 1H), 6.86 (d, J=7.63 Hz, 2H), 6.97 (d, J=8.24 Hz, 1H), 7.02 (t, J=7.32 Hz, 4H), 7.22-7.29 (m, 5H), 7.39 (d, J=2.14 Hz, 1H), 7.47 (d, J=1.83 Hz, 1H), 7.53-7.46 (m, 3H), 7.86 (d, J= 2.44 Hz, 1H), 11.97 (s, 1 H). (ESI+) m/z 397.2 (M+H)+.
Example 31 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)phenyl]methanesulfonamide Example 31a 6-methyl(5-nitro(tetrahydrofuranyloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 31a was prepared according to the procedure used for the preparation of Example 29a, substituting tetrahydrofuranol for tetrahydro-2H-pyranol, to provide the title compound.
Example 31b 4-(5-amino(tetrahydrofuranyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 31b was prepared according to the procedure used for the preparation of Example 29b, substituting the product of Example 31a for the t of Example 29a, to provide the title compound.
Example 31c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)phenyl]methanesulfonamide Example 31 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, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.84-1.90 (m, 1H), 2.08-2.17 (m, 1H), 2.95 (s, 3H), 3.35-3.41 (m, 2), 3.56 (s, 3H), .69 (M, 2H), 3.80-3.84 (m, 1H), 4.96-4.98 (m, 1H), .18 (m, 1H), 7.06-7.08 (m, 1H), 7.16-7.18 (m, 1H), 7.25 (s, 1H), 7.27-7.29 (m, 2H), 9.45 (s, 1H), 12.00 (s, 1H). (ESI+) m/z 404.2 (M+H)+.
Example 32 N-{3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)[2- (trifluoromethyl)phenoxy]phenyl}methanesulfonamide Example 32a 6-methyl(5-nitro(2-(trifluoromethyl)phenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 32a was prepared according to the procedure used for the preparation of Example 2b, substituting fluoromethyl)phenol for phenol, to provide the title compound.
Example 32b 4-(5-amino(2-(trifluoromethyl)phenoxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 32b was prepared according to the procedure used for the preparation of Example 3, substituting the product of e 32a for the product of Example 2b, to provide the title compound.
Example 32c N-{3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)[2- (trifluoromethyl)phenoxy]phenyl}methanesulfonamide Example 32c was prepared according to the ure used in method A of Example 4, substituting the product of Example 32b for the product of Example 3, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 3.05 (s, 3H), 3.44 (s, 3H), 6.32 - 6.26 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 7.17 - 7.07 (m, 2H), 7.34 - 7.18 (m, 3H), 7.53 - 7.38 (m, 2H), 7.65 (dd, J = 7.8, 1.6 Hz, 1H), 9.84 (s, 1H), 12.09 - 11.99 (m, 1H). MS (ESI+) m/z 478.1 (M+H)+.
Example 33 4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 33a 4-(2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) nitrophenoxy)benzonitrile Example 33a was prepared according to the procedure used for the preparation of Example 2b, tuting oxybenzonitrile for phenol, to provide the title compound.
Example 33b 4-(4-amino(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy)benzonitrile Example 33b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 33a for the product of Example 2b, to e the title compound.
Example 33c N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 33c was prepared according to the procedure used in method A of Example 4, substituting the product of Example 33b for the product of Example 3, to provide the title nd. 1H NMR (300 MHz, DMSO-d 6) δ 3.07 (s, 3H), 3.46 (s, 3H), 6.27 - 6.21 (m, 1H), 6.94 - 6.87 (m, 2H), 7.32 - 7.20 (m, 4H), 7.42 (d, J = 2.5 Hz, 1H), 7.70 - 7.63 (m, 2H), 9.87 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z 435.2 (M+H)+.
Example 34 N-[4-(2-chlorofluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)phenyl]methanesulfonamide Example 34a 4-(2-(2-chlorofluorophenoxy)nitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 34a was prepared ing to the procedure used for the preparation of Example 2b, substituting 2-chlorofluorophenol for phenol, to provide the title compound.
Example 34b 4-(5-amino(2-chlorofluorophenoxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 34b was prepared according to the procedure used for the ation of e 3, substituting the product of Example 34a for the product of Example 2b, to provide the title compound.
Example 34c N-[4-(2-chlorofluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)phenyl]methanesulfonamide Example 34c was prepared according to the procedure used in method A of Example 4, substituting the product of Example 34b for the product of Example 3, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 3.02 (s, 3H), 3.52 (s, 3H), 6.29 (t, J = 2.3 Hz, 1H), 6.99 - 6.88 (m, 2H), 7.14 - 7.03 (m, 1H), 7.21 (dd, J = 8.7, 2.7 Hz, 1H), 7.28 (t, J = 2.8 Hz, 1H), 7.34 (s, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.49 (dd, J = 8.3, 3.0 Hz, 1H), 9.75 (s, 1H), 12.05 (bs, 1H). MS (ESI+) m/z 462.1 (M+H)+.
Example 35 [4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl]acetic acid Example 35a ethyl 2-(3-bromohydroxyphenyl)acetate To a solution of ethyl 2-(4-hydroxyphenyl)acetate (Alfa, 2.70 g, 15 mmol) in acetic acid (20 mL) was added drop wise over 15 minutes a solution of bromine (0.773 mL, 15.00 mmol) in acetic acid (15 mL). The mixture was stirred at ambient temperature for 30 minutes and evaporated. Purification by chromatography (silica gel, 10-20% ethyl acetate in hexane) ed the title compound (3.66 g, 94%).
Example 35b ethyl 2-(4-(benzyloxy)bromophenyl)acetate 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 with ethyl acetate and water. The c layer was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by tography a gel, 0-20% ethyl acetate in hexane) afforded the title compound (4.84 g, 98%).
Example 35c ethyl 2-(4-(benzyloxy)(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl)acetate Example 35c was prepared according to the procedure used for the preparation of Example 7d, substituting the product of Example 35b for the product of Example 7c to provide the title compound.
Example 35d [4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl]acetic acid e 35c (0.4 g, 0.701 mmol), ium hydroxide (0.787 g, 14.02 mmol) and cetyltrimethylammonium bromide (0.013 g, 0.035 mmol) were combined in dioxane (10 mL) and water (5 mL) and heated at 100 °C for 3 hours, cooled and partitioned between equal volumes of ethyl acetate and water (20 mL each). The pH was adjusted to pH 2 by careful addition of concentrated HCl. The organic layer was separated and washed with saturated brine, dried (Na2SO4), filtered and concentrated. Trituration of the residue in hexane afforded the title compound (0.27 g, 98%). 1H NMR (300 MHz, DMSO-d 6) δ 3.52 (s, 3 H) 3.55 (s, 2 H) 5.09 (s, 2 H) 6.14 - 6.21 (m, 1 H) 7.10 - 7.33 (m, 10 H) 11.97 (s, 1 H) 12.25 (s, 1 H). MS (ESI+) m/z 389.0 (M+H)+.
Example 36 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide Example 36a 2-bromo(2,4-difluorophenoxy)nitrobenzene A mixture of 2-bromofluoronitrobenzene (15 g, 68 mmol), 2,4-difluorophenol (7.82 ml, 82 mmol), and cesium carbonate (26.7 g, 82 mmol) in ylsulfoxide (75 mL) was heated to 110 °C for 1 hour. Th e on 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 (3x200 mL). The combined organics were washed with saturated aqueous sodium chloride, dired (anhydrous ium sulfate), filtered, and concentrated under reduced pressure to e the title nd (22.5 g, quantitative).
Example 36b 3-bromo(2,4-difluorophenoxy)aniline A mixture of Example 36a (22.5 g, 68.2 mmol), iron powder (19.04 g, 341 mmol), and ammonium chloride (7.30 g, 136 mmol) in ydrofuran (117 mL), ethanol (117 mL), and water (39.0 mL) was heated under reflux at 100 °C for 2 hours. The reaction mixture was cooled to just below reflux temperature, filtered through celite, and the filter cake washed with warm ol (3 x 50 mL). The resulting solution was concentrated under reduced pressure and then neutralized to a pH of 8 with saturated sodium hydrogen carbonate (150 mL). The mixture was ted with ethyl acetate (3 x 100 mL). The ed organics were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, ed, and concentrated. The residue was purified by flash tography (silica gel, ethyl acetate/hexane gradient 0-15%) to provide the title nd (16.8 g, 82% yield).
Example 36c 4-(5-amino(2,4-difluorophenoxy)phenyl)methyltosyl-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-tetramethylphenyl-2,4,8-trioxaphosphaadamantane (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 (50 mL) and water (12.5 mL) was degassed and back-filled with nitrigen several times. The reaction mixture was heated at 60 °C for 16 hours and then cooled to ambient temperature. The reaction mixture was partitioned between water and ethly acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined c 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)(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide A solution of Example 36c (4.35 g, 8.34 mmol) in dichloromethane (50 mL) was cooled to 0 °C. To this solution was added ethanesulfonyl chloride (2.37 mL, 25.0 mmol).
The reaction mixture was d 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 with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium de, dried over anhydrous magnesium sulfate, filtered, and trated. The residue was purified by flash chromatography (silica gel, 80% ethyl e/hexanes) to e the title compound (5.34 g, 91 % yield).
Example 36e N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide A mixture of Example 36d (5.3 g, 7.5 mmol), potassium hydroxide (8.43 g, 150 mmol), and N,N,N-trimethylhexadecanaminium bromide (0.137 g, 0.375 mmol) in tetrahydrofuran (60 mL) and water (30 mL) was heated at 90 °C for 16 hours.
Tetrahydrofuran was removed under reduced pressure, and the residue was ioned between water and ethyl acetate. The aqueous layer was neutalized to pH =7 using 10% HCl.
The aqueous layer was then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate). The desired fractions were combined and concentrated. The residue was triturated with 20 mL of acetonitrile to provide the title compound (2.82 g, 82 % yield). 1H NMR (300 MHz, 6) δ 1.23 (t, J = 7.3 Hz, 3H), 3.11 (q, J = 7.3 Hz, 2H), 3.53 (s, 3H), 6.27 - 6.22 (m, 1H), 6.91 (d, J = 8.7 Hz, 1H), 7.13 - 6.93 (m, 2H), 7.19 (dd, J = 8.8, 2.7 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.42 - 7.31 (m, 2H), 9.77 (s, 1H), 12.04 (bs, 1H). MS (ESI+) m/z 460.1 (M+H)+.
Example 37 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetamide Example 27b (50 mg, 0.136 mmol) and triethylamine (56.9 µL, 0.408 mmol) were combined in CH2Cl2 (10 mL). Acetyl chloride (11.6 µL, 0.163 mmol) was added dropwise and the solution stirred for 1 hour at ambient ature. Water (25 mL) and saturated aqueous sodium bicarbonate (25 mL) were added, and the mixture was extracted with CH2Cl2 (3x25 mL). The combined organics were washed with brine, dried (MgSO 4), filtered, and trated. cation of the residue by reverse phase HPLC (C18, % acetonitrile/water, 0.1% TFA) afforded 15 mg (28 %) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.04 (s, 3H), 3.52 (s, 3H), 6.29 6.23 (m, 1H), 7.08-6.85 (m, 3H), 7.39- 7.25 (m, 3H), 7.53 (dd, J = 8.8, 2.6 Hz, 1H), 7.77 (d, J = 2.6 Hz, 1H), 10.00 (s, 1H), 12.07- 11.96 (m, 1H). MS (ESI+) m/z 410.3 (M+H)+.
Example 38 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-3,3,3-trifluoropropanamide Example 38 was prepared according to the procedure used for the preparation of Example 37, substituting 3,3,3-trifluoropropanoyl chloride for acetyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 3.54-3.46 (m, 2H), 3.53 (s, 3H), 6.27 (t, J = 2.3 Hz, 1H), 7.14-6.87 (m, 3H), 7.28 (t, J = 2.7 Hz, 1H), 7.31 (s, 1H), 7.37 (ddd, J = 11.3, 8.7, 2.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.6 Hz, 1H), 7.76 (d, J = 2.6 Hz, 1H), 10.38 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z 478.2 (M+H)+.
Example 39 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-2,2-dimethylpropanamide Example 39 was prepared according to the procedure used for the preparation of Example 37, substituting pivaloyl de for acetyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 1.22 (s, 9H), 3.53 (s, 3H), .25 (m, 1H), 6.88 (d, J = 8.8 Hz, 1H), 7.08-6.92 (m, 2H), 7.31-7.24 (m, 2H), 7.40-7.29 (m, 1H), 7.62 (dd, J = 8.8, 2.6 Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 9.28 (s, 1H), 12.00 (bs, 1H). MS (ESI+) m/z 452.3 (M+H)+.
Example 40 ethyl 4-(cyclopentylamino)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzoate A e of Example 9a (0.094 g, 0.2 mmol), cyclopentanamine (0.034 g, 0.4 mmol), and triethylamine (0.081 g, 0.8 mmol) in DMSO (2 mL) was heated at 120 °C overnight. The reaction mixture was purified by ative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water to afford 0.019 g of the title product. 1H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J=7.02 Hz, 3H), 1.32-1.36 (m, 2H), 1.47-1.55 (m, 3H), .93 (m, 2H), 3.55 (s, 3H), 3.83-3.88 (m, 1H), 4.22 (q, J=7.02 Hz, 2H), 5.94 (t, J=2.29 Hz, 1H), 6.77 (d, J=8.85 Hz, 1H), 7.22 (s, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.63 (d, J=1.83 Hz, 1H), 7.82 (dd, J=8.54, 2.14, 1H), 12.01 (s, 1H). MS (ESI+) m/z 380.2 (M+H)+.
Example 41 (1,1-dioxido-1,2-thiazolidinyl)methyl]phenoxyphenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 41a 4-(5-(hydroxymethyl)phenoxyphenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 41a was isolated as a by-product from the preparation of Example 20b.
Example 41b 3-(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzyl methanesulfonate A mixture of Example 41a (0.15 g, 0.3 mmol), methanesulfonyl chloride (0.069 g, 0.6 mmol), and triethylamine (0.121 g, 1.2 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The solvent was removed, and the residue was purified by flash tography on silica gel eluting with 20-40% ethyl acetate in hexanes to afford 0.105 g of the title product.
Example 41c 4-{5-[(1,1-dioxido-1,2-thiazolidinyl)methyl]phenoxyphenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone iazolidine 1,1-dioxide (0.031 g, 0.259 mmol) in dimethylformamide (1 mL) was d with 60% sodium hydride (0.012g, 0.518 mmol, 0.021 g of a 60% in oil sion).
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. 2 N NaOH (1 mL) was added and the reaction mixture was heated at 65 °C for 2 hours. After cooling to room ature, the reaction mixture was partitioned between water and ethyl e. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA water) to afford 0.025 g (64%) of the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 2.21-2.25 (m, 2H), 3.15 (t, J=6.97 Hz, 2H), 3.23-3.27 (m, 2H), 3.50 (s, 3H), 4.13 (s, 2H), 6.25-6.26 (m, 1H), 6.88 (d, J=7.63 Hz, 2H), 7.00 (d, J=8.54 Hz, 1H), 7.03-7.05 (m, 1H), 7.25-7.30 (m, 4H), 7.34 (dd, J=8.39, 2.29, 1H), 7.48 (d, J=2.44 Hz, 1H), 12.00 (s, 1 H). MS (ESI+) m/z 450.2 (M+H)+.
Example 42 4-{[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzyl]amino}oxobutanoic acid e 42 was prepared according to the procedure used for the preparation of Example 41c, substituting pyrrolidine-2,5-dione for iazolidine 1,1-dioxide, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 2.37-2.40 (m, 2H), 2.44-2.48 (m, 2H), 3.50 (s, 3H), 4.31 (d, J=5.8 Hz, 2H), 6.23-6.24 (m, 1H), 6.84 (d, J=7.63 Hz, 2H), 6.96 (d, J=8.24 Hz, 1H), 7.00 (t, J=7.32 Hz, 1H), 7.22-7.29 (m, 5H), 7.40 (d,J= 2.14, 1H), 8.40 (t, J=5.95 Hz, 1H), 11.98 (s, 1H). MS (ESI+) m/z 446.1 (M+H)+.
Example 43 4-[2-(2,4-difluorophenoxy)(1,1-dioxido-1,2-thiazolidinyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone e 43a 3-chloro-N-(3-chloropropylsulfonyl)-N-(4-(2,4-difluorophenoxy)(6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl)propanesulfonamide A mixture of Example 27b (0.1 g, 0.272 mmol), 3-chloropropanesulfonyl chloride (0.145 g, 0.817 mmol), and triethylamine (0.165 g, 1.633 mmol) in dichloromethane (3 mL) was stirred for 2 hours. The solvent was removed, and the residue was used directly for the next reaction.
Example 43b 4-[2-(2,4-difluorophenoxy)(1,1-dioxido-1,2-thiazolidinyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone 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 on mixture was heated at 75 °C for 2 hours. After cooling, the solvent was d under reduced pressure, and the residue was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water) to afford 0.055 g of the title compound. 1H NMR (500 MHz, DMSO-d 6) δ .44 (m, 2H), 3.49-3.53 (m, 2H), 3.54 (s, 3H), 3.76 (t, J=6.56 Hz, 2H), 6.27-6.28 (m, 1H), 6.95 (d, J=8.85 Hz, 1H), 7.00-7.12 (m, 2H), 7.20 (dd, J=8.85, 2.75 Hz, 1H), 7.28 (t, J=2.75 Hz, 1H), 7.32 (s, 1H), 7.35-7.41 (m, 2H), 12.05 (s, 1H). MS (ESI+) m/z 472.2 (M+H)+.
Example 44 4-[2-(benzyloxy)(2-hydroxyethyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one Example 35d (0.039 g, 0.1 mmol) in tetrahydrofuran (2 mL) was treated dropwise with borane-tetrahydrofuran complex (1M, 0.200 mL, 0.200 mmol), and the mixture was stirred at 40 °C for 1 hour, diluted with 5 mL of methanol, heated at 50 °C for 30 minutes and concentrated. cation by chromatography (silica gel, 0.5-4 % methanol in dichloromethane) ed the title compound (0.03 g, 79%). 1H NMR (300 MHz, DMSO- d6) δ 2.70 (t, J=6.94 Hz, 2 H) 3.52 (s, 3 H) 3.57 - 3.64 (m, 2 H) 4.59 - 4.63 (m, 1 H) 5.06 (s, 2 H) 6.14 - 6.18 (m, 1 H) 7.08 - 7.18 (m, 2 H) 7.20 - 7.32 (m, 8 H) 11.95 (s, 1 H). MS (ESI+) m/z 375.0 (M+H)+.
Example 45 methyl nzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetate Example 45a benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl)acetyl chloride Example 35d (0.18 g, 0.463 mmol) in tetrahydrofuran (4.63 mL) was treated with one drop of dimethylformamide followed by drop-wise addition of oxalyl chloride (0.122 mL, 1.390 mmol), stirred for twenty minutes and concentrated.
Example 45b methyl [4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetate Example 45a (0.058 g, 0.143 mmol) in tetrahydrofuran (4 mL) was treated with methanol (5 mL, 124 mmol), stirred for 1 hour at room temperature and concentrated. cation by chromatography (silica gel, 0.5-3 % methanol in dichloromethane) afforded the title compound (0.048 g, 79%). 1H NMR (300 MHz, DMSO-d 6) δ 3.52 (s, 3 H) 3.62 (s, 3 H) 3.66 (s, 2 H) 5.09 (s, 2 H) 6.15 - 6.20 (m, 1 H) 7.10 - 7.37 (m, 10 H) 11.97 (s, 1 H). MS (ESI+) m/z 403.0 .
Example 46 2-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl]-N- ethylacetamide Example 46 was prepared according to the procedure used for the preparation of e 45b, substituting ethylamine for methanol, to provide the title compound (0.039 g, 64%). 1H NMR (300 MHz, DMSO-d 6) δ 1.01 (t, J=7.29 Hz, 3 H) 2.99 - 3.11 (m, 2 H) 3.35 (s, 2 H) 3.52 (s, 3 H) 5.07 (s, 2 H) 6.14 - 6.21 (m, 1 H) 7.08 - 7.35 (m, 10 H) 7.98 (t, J=5.43 Hz, 1 H) 11.96 (s, 1 H). MS (ESI+) m/z 416.0 (M+H)+. e 47 2-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl]- N,N-dimethylacetamide Example 47 was prepared ing to the procedure used for the preparation of Example 45b, substituting dimethylamine for methanol, to provide the title compound (0.058 g, 98%). 1H NMR (300 MHz, DMSO-d 6) δ 2.83 (s, 3 H) 3.02 (s, 3 H) 3.52 (s, 3 H) 3.66 (s, 2 H) 5.08 (s, 2 H) 6.12 - 6.24 (m, 1 H) 7.06 - 7.36 (m, 10 H) 11.96 (s, 1 H). MS (ESI+) m/z 416.0 (M+H)+.
Example 48 N-[4-(3,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 48a 4-(2-(3,4-difluorophenoxy)nitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 48a was prepared according to the ure used for the preparation of Example 2b, substituting 3,4-difluorophenol for phenol, to provide the title compound.
Example 48b 4-(5-amino(3,4-difluorophenoxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 48b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 48a for the product of e 2b, to provide the title compound.
Example 48c N-[4-(3,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 48c was prepared according to the procedure used in method A of e 4, substituting the product of Example 48b for the product of Example 3, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 3.04 (s, 3H), 3.50 (s, 3H), 6.28-6.23 (m, 1H), 6.72-6.62 (m, 1H), 6.97 (ddd, J = 11.9, 6.7, 3.0 Hz, 1H), 6.97 (ddd, J = 11.9, 6.7, 3.0 Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H), 7.41-7.19 (m, 5H), 9.78 (s, 1H), 12.03 (bs, 1H). MS (ESI+) m/z 446.1 (M+H)+.
Example 49 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- orophenoxy)phenyl]methanesulfonamide Example 49a 6-methyl(5-nitro(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(2,4,6-trifluorophenoxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 49b was prepared according to the procedure used for the ation of Example 3, substituting the product of Example 49a for the product of Example 2b, to provide the title compound. e 49c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]methanesulfonamide e 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. 1H1H NMR NMR (300 MHz, DMSO-d6) δ 2.99 (s, 3H), 3.57 (s, 3H), 6.23 (t, J = 2.3 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.15 (dd, J = 8.8, 2.7 Hz, 1H), .27 (m, 3H), 7.45- 7.34 (m, 2H), 9.66 (s, 1H), 12.07 (bs, 1H). MS (ESI+) m/z 464.1 (M+H)+.
Example 50 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzamide Example 50a ethyl 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzoate Example 50a was prepared according to the procedure used for the preparation of Example 9b, substituting 2,4-difluorophenol for phenol, to provide the title compound.
Example 50b 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin zoic acid Example 50b was prepared according to the procedure used for the ation of Example 10, substituting Example 50a for Example 9b, to provide the title compound.
Example 50c 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzamide Example 50c was prepared according to the procedure used for the preparation of Example 13a, substituting Example 50b for Example 10, to provide the title compound.
Example 50d 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin zamide Example 50d was ed according to the procedure used for the preparation of e 13b, substituting Example 50c for Example 13a, and aqueous ammonium hydroxide for ethylamine, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d δ 3.57 (s, 3H), 6.24-6.25 (m, 1H), 6.83 (d, J=8.24 Hz, 1H), 7.07-7.13 (m, 1H), 7.27-7.34 (m, 4H), 7.42-7.48 (m, 1H), 7.85 (dd, J=8.54, 2.44, 1H), 7.96 (s, 1H), 8.00 (d, J=2.44 Hz, 1H), 12.04 (s, 1H). MS (ESI+) m/z 396.3 (M+H)+.
Example 51 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- hydrofuranyl)benzamide Example 51 was prepared according to the procedure used for the preparation of Example 13b, substituting Example 50c for Example 13a, and tetrahydrofuranamine for ethylamine, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.87-1.94 (m, 1H), 2.10-2.19 (m, 1H), 3.57 (s, 3H), 3.67-3.73 (m, 2H), 3.81-3.87 (m, 2H), 4.42-4.49 (m, 1H), 6.22-6.23 (m, 1H), 6.85 (d, J=8.54 Hz, 1H), 7.07-7.13 (m, 1H), 7.25-7.34 (m, 3H), 7.42-7.47 (m, 1H), 7.85 (dd, J=8.85, 2.14, 1H), 7.96 (s, 1H), 8.00 (d, J=2.14 Hz, 1H), 8.50 (d, J=6.41 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 466.3 (M+H)+.
Example 52 4-{2-(2,4-difluorophenoxy)[(1,1-dioxidothiomorpholinyl)carbonyl]phenyl}methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 52 was prepared according to the procedure used for the preparation of Example 13b, substituting 1,1-dioxothiomorpholine for ethylamine and Example 50c for Example 13a, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 3.25-3.28 (m, 4H), 3.56 (s, 3H), 3.78 (m, 4H), 4.45-4.61 (m, 1H), 3.81-3.87 (m, 2H), 6.26- 6.27 (m, 1H), 6.86 (d, J=8.24 Hz, 1H), 7.07-7.12 (m, 1H), 7.27-7.33 (m, 3H), .48 (m, 2H), 7.63 (d, J= 2.14, 1H), 12.04 (s, 1H). MS (ESI+) m/z 514.2 (M+H)+.
Example 53 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- (1-methyloxopyrrolidinyl)benzamide Example 53 was prepared according to the ure used for the preparation of Example 13b, substituting Example 50c for Example 13a, and 3-aminomethylpyrrolidin one for mine, tively, to provide the title compound. 1H NMR (500 MHz, DMSO- d6) δ 1.87-1.97 (m, 1H), .38 (m, 1H), 2.76 (s, 3H), .34 (m, 2H), 3.57 (s, 3H), 4.45-4.61 (m, 1H), 3.81-3.87 (m, 2H), 4.42-4.49 (m, 1H), 6.23-6.24 (m, 1H), 6.87 (d, J=8.54 Hz, 1H), 7.08-7.13 (m, 1H), 7.25-7.34 (m, 3H), 7.43-7.48 (m, 1H), 7.85 (dd, J=8.54, 2.44 Hz, 1H), 7.96 (s, 1H), 7.99 (d, J=2.14 Hz, 1H), 8.73 (d, J=8.85 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 493.2 (M+H)+.
Example 54 utyl {1-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzoyl]pyrrolidinyl}carbamate Example 54 was prepared according to the procedure used for the preparation of Example 13b, substituting Example 50c for Example 13a, and tert-butyl pyrrolidin ylcarbamate for ethylamine, respectively, to provide the title nd. 1H NMR (500 MHz, DMSO-d6) δ 1.33-1.40 (m, 9H), 1.74-1.83 (m, 1H), .0.3 (m, 1H), 3.27-3.31 (m, 1H), 3.56 (s, 3H), 3.62-3.56 (m, 1H), 3.93-4.07 (m, 1H), 6.24 (d, J=2.29 Hz, 1H), 6.83 (d, J=8.54 Hz, 1H), 7.0-7.13 (m, 1H), 7.20-7.33 (m, 3H), 7.41-7.52 (m, 2H), 7.60 (d, J=16.2 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 565.2 (M+H)+.
Example 55 4-[2-(2,4-difluorophenoxy)(pyrrolidinylcarbonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 55 was prepared according to the ure used for the preparation of Example 13b, substituting e 50c for Example 13a, and pyrrolidine for ethylamine, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.82-1.86 (m, 4H), 3.45-3.48 (m, 4H), 3.56 (s, 3H), 6.24-6.26 (m, 1H), 6.82 (d, J=8.24 Hz, 1H), 7.06-7.12 (m, 1H), 7.26-7.33 (m, 3H), 7.41-7.46 (m, 1H), 7.52 (dd, J=8.54, 2.14 Hz, 1H), 7.61 (d, J=2.14 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 450.3 (M+H)+.
Example 56 4-[2-(2,4-difluorophenoxy)(morpholinylcarbonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 56 was prepared according to the procedure used for the preparation of Example 13b, substituting Example 50c for Example 13a, and morpholine for ethylamine, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 3.56 (s, 3H), 3.60-3.68 (m, 8H), 6.24-6.25 (m, 1H), 6.84 (d, J=8.54 Hz, 1H), 7.06-7.12 (m, 1H), 7.26-7.33 (m, 3H), 7.40 dd, J=8.54, 2.14 Hz, 1H), 7.44-7.46 (m, 1H), 7.50 (dd, J=2.14 Hz, 1H), 12.03 (s, 1H). MS (ESI+) m/z 466.3 (M+H)+.
Example 57 N-[4-(cyclohexyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin nyl]methanesulfonamide Example 57a 4-(2-(cyclohexyloxy)nitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 57a was prepared according to the procedure used for the preparation of e 29a, substituting exanol for tetrahydro-2H-pyranol, to provide the title compound.
Example 57b 4-(5-amino(cyclohexyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 57b was prepared according to the procedure used for the preparation of Example 3, substituting the product of e 57a for the product of Example 2b, to provide the title compound. e 57c N-[4-(cyclohexyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 57c was prepared according to the procedure used in method A of Example 4, tuting the product of Example 57b for the product of Example 3, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 1.47-1.10 (m, 6H), 1.61-1.47 (m, 2H), 1.84- 1.69 (m, 2H), 2.94 (s, 3H), 3.55 (s, 3H), 4.31-4.22 (m, 1H), 6.21 (t, J = 2.3 Hz, 1H), 7.18-7.06 (m, 2H), 7.31-7.25 (m, 3H), 9.39 (s, 1H), 11.98 (bs, 1H). MS (ESI+) m/z 416.2 (M+H)+.
Example 58 N-[4-(cyclopentyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 58a 4-(2-(cyclopentyloxy)nitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 58a was prepared according to the procedure used for the preparation of Example 29a, substituting cyclopentanol for tetrahydro-2H-pyranol, to provide the title compound.
Example 58b 4-(5-amino(cyclopentyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 58b was prepared according to the procedure used for the ation of e 3, substituting the product of Example 58a for the product of Example 2b, to provide the title compound.
Example 58c cyclopentyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide 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. 1H NMR (300 MHz, DMSO-d 6) δ 1.70-1.43 (m, 6H), 1.88-1.70 (m, 2H), 2.94 (s, 3H), 3.55 (s, 3H), 4.78-4.70 (m, 1H), 6.16 (t, J = 2.3 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.16 (dd, J = 8.7, 2.7 Hz, 1H), 7.22 (s, 1H), 7.30-7.23 (m, 2H), 9.39 (s, 1H), 11.97 (bs, 1H).MS (ESI+) m/z 402.1 (M+H)+.
Example 59 N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}methanesulfonamide Example 59a 4-(2-(4,4-difluorocyclohexyloxy)nitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- one Example 59a was prepared ing to the procedure used for the preparation of Example 29a, substituting 4,4-difluorocyclohexanol for tetrahydro-2H-pyranol, to provide the title compound.
Example 59b 4-(5-amino(4,4-difluorocyclohexyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 59b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 59a for the product of Example 2b, to provide the title compound.
Example 59c N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}methanesulfonamide Example 59c was prepared ing to the procedure used in method A of Example 4, substituting the product of e 59b for the product of Example 3, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ .61 (m, 8H), 2.95 (s, 3H), 3.55 (s, 3H), 4.55-4.46 (m, 1H), 6.22-6.17 (m, 1H), 7.20-7.15 (m, 2H), 7.31-7.25 (m, 3H), 9.47 (s, 1H), 12.01 (bs, 1H).MS (ESI+) m/z 452.2 (M+H)+.
Example 60 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran phenyl]methanesulfonamide Example 60a yl(5-nitro(tetrahydro-2H-pyranyloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 60a was prepared according to the procedure used for the preparation of Example 29a, substituting tetrahydro-2H-pyranol for tetrahydro-2H-pyranol, to provide the title compound.
Example 60b 4-(5-amino(tetrahydro-2H-pyranyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 60b was prepared according to the procedure used for the preparation of Example 29b, substituting the product of Example 60a for the product of Example 29a, to e the title compound.
Example 60c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran yloxy)phenyl]methanesulfonamide Example 60c was prepared according to the procedure used in method A of Example 4, substituting the product of e 60b for the t of Example 3, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.39-1.45 (m, 1H), 1.55-1.70 (m, 2H), 1.89- 1.96 (m, 1H), 2.95 (s, 3H), 3.41-3.57 (m, 7H), 3.65-3.69 (m, 1H), 6.24-6.26 (m, 1H), 6.84 (d, J=8.54 Hz, 1H), 7.14 (m, 2H), 7.29-7.31 (m, 2H), 7.38 (s, 1H), 9.45 (s, 1H), 12.03 (s, 1H).
MS (ESI+) m/z 418.2 (M+H)+.
Example 61 6-methyl[2-(morpholinylcarbonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 61 was prepared according to the procedure used for the preparation of Example 1f, substituting morpholino(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenyl)methanone for 2-phenoxyphenylboronic acid, followed by purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in , to e the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 2.80-2.83 (m, 2H), 2.91-2.99 (m, 2H), 3.20- 3.25 (m, 2H), 3.54-3.57 (m, 5H), 6.17-6.18 (m, 1H), 7.06 (s, 1H), 7.32 (t, J=2.9 Hz, 1H), 7.40 (d, J=7.32 Hz, 1H), .53 (m, 3H), 1H), 12.15 (s, 1H). MS (ESI+) m/z 338.1 (M+H)+.
Example 62 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]ethanesulfonamide Example 62 was prepared according to the ure used in method A of Example 4, substituting Example 33b for Example 3 and substituting ethanesulfonyl chloride for methanesulfonyl chloride respectively to provide the title compound. 1H NMR (300 MHz, 6) δ 1.22 (t, J = 7.3 Hz, 3H), 3.09 (q, J = 7.3 Hz, 2H), 3.56 (s, 3H), 6.22 (t, J = 2.3 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 7.15 (dd, J = 8.8, 2.7 Hz, 1H), 7.44-7.27 (m, 5H), 9.72 (s, 1H), 12.06 (bs, 1H).MS (ESI+) m/z 478.1 (M+H)+.
Example 63 N-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 63a 4-(2-(benzyloxy)nitrophenyl)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-pyranol, to provide the title compound.
Example 63b 4-(5-amino(benzyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 63b was prepared according to the procedure used for the preparation of Example 3, substituting the product of e 63a for the product of Example 2b, to provide the title nd.
Example 63c N-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide Example 63c was ed according to the procedure used in method A of Example 4, substituting the product of Example 63b for the product of Example 3, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ 2.94 (s, 3H), 3.51 (s, 3H), 5.07 (s, 2H), 6.24- 6.18 (m, 1H), 7.22-7.16 (m, 2H), 7.37-7.24 (m, 8H), 9.45 (s, 1H), 12.00 (bs, 1H).MS (ESI+) m/z 424.2 (M+H)+.
Example 64 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]fluoroethanesulfonamide Example 64 was prepared according to the procedure used for the preparation of Example 27c, substituting 2-fluoroethanesulfonyl chloride for methanesulfonyl de, and bypassing the sodium hydroxide hydrolysis step, to provide the title compound. 1H NMR (300 MHz, 6) δ 3.52 (s, 3H), 3.63 (t, J = 6.0 Hz, 2H), 4.12 (q, J = 6.0 Hz, 2H), 6.25- 6.19 (m, 1H), 7.08-6.62 (m, 5H), 7.27-7.20 (m, 3H), 11.99-11.92 (m, 1H).MS (ESI+) m/z 478.2 (M+H)+.
Example 65 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin nyl]-N'-methylsulfuric e Example 65 was prepared according to the procedure used for the ation of Example 27c, substituting methylsulfamoyl chloride for methanesulfonyl chloride, to provide the title nd. 1H NMR (300 MHz, DMSO-d 6) δ 2.50 (m, 3H solvent obscured), 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 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)phenyl]ethanesulfonamide Example 66 was ed ing 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. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (t, J = 7.3 Hz, 3H), 1.93-1.80 (m, 1H), 2.20-2.04 (m, 1H), 3.02 (q, J = 7.3 Hz, 2H), 3.55 (s, 3H), 3.65 (m, 3H), 3.82 (dd, J = 10.0, 4.5 Hz, 1H), 5.00-4.91 (m, 1H), 6.16 (t, J = 2.3 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.16 (dd, J = 8.7, 2.7 Hz, 1H), 7.24 (s, 1H), 7.31-7.25 (m, 3H), 9.53 (s, 1H), 12.01 (bs, 1H), MS (ESI+) m/z 418.1 (M+H)+.
Example 67 methyl 6-methyloxo(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine carboxylate Example 67a ethyl 4-bromomethyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylate Diisopropylamine (0.111 g, 1.102 mmol) in tetrahydrofuran (3 mL) was treated with BuLi (2.5 M, 0.44 mL, 1.102 mmol) at -78 °C. The solution was stirred for 20 minutes at -78 °C, and warmed up to room ature for 5 minutes, and cooled down to -78 °C again. To this solution was added N1,N1,N2,N2-tetramethylethane-1,2-diamine (0.128 g, 1.102 mmol).
Then Example 1e (0.30 g, 0.787 mmol) in ydrofuran (3 mL) was added to the reaction mixture via cannula under nitrogen. The reaction mixture was d at -78 °C for 1 hour, warmed to 0 °C briefly, and cooled down to -78 °C. To this suspension was added ethyl carbonochloridate (0.205 g, 1.889 mmol) via a syringe. The reaction mixture was allowed to warm to room temperature gradually overnight. The mixture was then ioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and trated. The residue was purified by flash chromatography on silica gel eluting with 30- 50% ethyl acetate in hexanes to afford 0.074 g of the title compound.
Example 67b methyl 6-methyloxo(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine carboxylate Example 67b was prepared according to the procedure used for the preparation of Example 1f, substituting Example 67a for Example 1e, and ing the use of potassium carbonate, followed by purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 3.50 (s, 3H), 3.80 (s, 3H), 6.80-6.82 (m, 3H), 7.00 (t, J=7.32 Hz, 1H), 7.06 (d, J=7.02 Hz, 1H), 7.23- 7.32 (m, 4H), 7.40-7.42 (m, 1H), 7.52 (dd, J=7.48, 1.68 Hz, 1H), 12.85 (s, 1 H). MS (ESI+) m/z 375 (M+H)+.
Example 68 methyl 1,6-dimethyloxo(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine carboxylate The title compound was obtained as a by-product from the preparation of Example 67b. 1H NMR (500 MHz, DMSO-d 6) δ 3.48 (s, 3H), 3.81 (s, 3H), 4.38 (s, 3H), 6.81-6.84 (m, 3H), .07 (m, 2H), 7.25-7.31 (m, 3H), 7.34 (s, 1H), 7.41-7.47 (m, 1H), 7.48 (dd, J=7.48, 1.68 Hz, 1H). MS (ESI+) m/z 389 (M+H)+.
Example 69 ethyl 4-(5-aminophenoxyphenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- oxylate Example 69a ethyl 1-benzylbromooxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylate Example 69a was prepared according to the ure used for the preparation of Example 2a (Method B), substituting Example 67a for Example 1e, to provide the title compound.
Example 69b ethyl 6-methyl(5-nitrophenoxyphenyl)oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine carboxylate Example 69b was ed according to the procedure used for the preparation of Example 2b, substituting Example 69a for e 2a, to provide the title compound.
Example 69c ethyl 4-(5-aminophenoxyphenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 2-carboxylate Example 69c was prepared according to the ure used for the preparation of Example 29b, substituting Example 69b for Example 29a, and purified by preparative HPLC (C18, 10-100% itrile in 0.1 % TFA/water) to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.30 (t, J = 7.02 Hz, 3H), 3.49 (s, 3H), 4.27 (q, J=7.12 Hz, 2H), 6.77 (d, J = 7.93 Hz, 2H), 6.86 (d, J = 2.14 Hz, 1H), 6.93-7.03 (m, 3H), 7.11 (s, 1H), 7.20-7.24 (m, 2H), 7.31 (s, 1H), 12.86 (s, 1H). MS (ESI+) m/z 404.1 (M+H)+.
Example 70 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylic acid Example 70a (Z)-ethyl 3-(5-bromomethoxynitropyridinyl)hydroxyacrylate To a solution of ethanol (15 mL) and ether (150 mL) were added 5-bromo ymethylnitropyridine (14.82 g, 60 mmol), diethyl oxalate (13.15 g, 90 mmol), and potassium ethoxide (6.06 g, 72 mmol). The reaction e was heated at 45 ºC 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 with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10-20% ethyl acetate in hexanes to 9.5 g of the title compound (yield 46%).
Example 70b ethyl 4-bromomethoxy-1H-pyrrolo[2,3-c]pyridinecarboxylate A mixture 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 ºC for 1 hour. The solution turned from red to gray. The solid was filtered off, and then washed with additional ethyl acetate. The solvents were removed under reduced pressure to 20% of original volume, and it was ioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate several times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-40% ethyl acetate in hexanes to afford 6.05g of the title compound.
Example 70c ethyl 1-benzylbromomethoxy-1H-pyrrolo[2,3-c]pyridinecarboxylate Example 70b (0.88 g, 2.94 mmol) in dimethylformamide (15 mL) was treated with 60% sodium hydride (0.106 g, 4.41 mmol, 0.117 g of a 60% in oil dispersion). The solution was d at room temperature for 10 s. To this solution was added benzyl bromide (0.59 g, 3.45 mmol). The reaction mixture was stirred for another 2 hours. It was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined c layers were washed with brine, dried over MgSO4, ed, and concentrated. The residue was purified by flash chromatography on silica gel g with 20-40% ethyl acetate in hexanes to afford 1.07 g of the title nd.
Example 70d ethyl 1-benzylbromooxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylate Example 70d was prepared according to the procedure used for the preparation of Example 1d, substituting Example 70c for Example 1c, to provide the title compound.
Example 70e ethyl 1-benzylbromomethyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylat Example 70e was prepared according to the ure used for the ation of Example 1e, substituting Example 70d for Example 1d, to provide the title compound. e 70f ethyl 1-benzyl(2-fluoronitrophenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinecarboxylate 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 ethyl 1-benzylmethyl(5-nitrophenoxyphenyl)oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinecarboxylate e 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 ethyl minophenoxyphenyl)benzylmethyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinecarboxylate Example 70h was ed according to the procedure used for the preparation of Example 29b, substituting Example 70g for Example 29a, to provide the title compound.
Example 70i ethyl 1-benzylmethyl(5-(N-(methylsulfonyl)methylsulfonamido)phenoxyphenyl) oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylate Example 70i was prepared according to the procedure used in method A of Example 4, substituting Example 70h for Example 3, except the use of 1 M NaOH, to provide the title compound.
Example 70j ethyl 6-methyl(5-(N-(methylsulfonyl)methylsulfonamido)phenoxyphenyl)oxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylate A mixture of Example 70i (0.53 g, 0.816 mmol), anisole (0.176 g, 1.631 mmol), and concentrated H2SO4 (0.5 mL) in TFA (10 mL) was heated at 90 °C 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 with additional ethyl acetate several times. The combined c layers were washed with saturated aqueous sodium bicarbonate, followed by brine, dried over MgSO4, filtered, and concentrated to afford 0.48 g of the title compound. The crude material was used ly for the next reaction.
Example 70k 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylic acid Example 70j (0.4 g, 0.858 mmol) in e (5 mL) was d with 2.0 N NaOH (1.72 mL, 3.43 mmol). The reaction mixture was heated at 65 °C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). After addition of concentrated HCl (1 mL), the mixture was extracted with ethyl acetate three times (3 x 30 mL). The combined c layers were washed with brine, dried over MgSO4, filtered, and concentrated to afford 0.36 g (93%) of the title compound. A small amount of sample was purified by preparative HPLC (C18, 10-70% acetonitrile in 0.1% TFA/water) to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 3.03 (s, 3H), 3.49 (s, 3H), 6.81 (d, J = 7.63 Hz, 2H), 6.84 (d, J = 2.14 Hz, 1H), 6.96-7.00 (m, 1H), 7.08 (d, J = 8.85 Hz, 1H), 7.22-7.27 (m, 3H), 7.34 (s, 1H), 7.37 (d, J = 2.75 Hz, 1H), 9.77 (s, 1H), 12.62 (d, J = 1.53 Hz, 1H), 13.00 (s, br, 1H). MS (ESI+) m/z 454.1 (M+H)+. e 71 ethyl yl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylate Example 70k (0.2 g, 0.441 mmol) in ethanol (10 mL) was treated with concentrated H2SO4 (0.5 mL). The reaction mixture was heated under reflux overnight. The solvent was removed, and the remaining was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate several times. The combined organic layers were washed with sat. NaHCO3, brine, dried over MgSO4, filtered, and trated to afford 0.19 g of the title compound. A small amount of crude product was purified by preparative HPLC to provide clean product for biological testing. 1H NMR (500 MHz, DMSO-d 6) δ 1.30 (t, J = 7.17 Hz, 3H), 3.04 (s, 3H), 3.50 (s, 3H), 4.26 (q, J=7.22 Hz, 2H), 6.80 (d, J = 7.63 Hz, 2H), 6.86 (d, J = 2.14 Hz, 1H), 6.96-7.00 (m, 1H), 7.09 (d, J = 8.85 Hz, 1H), 7.21-7.28 (m, 3H), 7.35 (s, 1H), 7.36 (d, J = 2.75 Hz, 1H), 9.78 (s, 1H), 12.86 (s, 1H). (ESI+) m/z 482.1 .
Example 72 N-ethylmethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide Example 72a 6-methyl(5-(methylsulfonamido)phenoxyphenyl)oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinecarbonyl chloride Example 72a was prepared ing to the procedure used for the ation of Example 13a, tuting Example 70k for Example 10, to provide the title compound.
Example 72b N-ethylmethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide Example 72b was prepared according to the procedure used for the ation of Example 13b, substituting Example 72a for Example 13a, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.12 (t, J = 7.17 Hz, 3H), 3.03 (s, 3H), 3.23-3.30 (M, 2H), 3.49 (s, 3H), 6.81 (d, J = 7.63 Hz, 2H), 6.86 (d, J = 2.44 Hz, 1H), 6.96-7.00 (m, 1H), 7.07 (d, J = 8.54 Hz, 1H), 7.22-7.28 (m, 3H), 7.30 (s, 1H), 7.34 (d, J = 2.75 Hz, 1H), 8.34 (t, J = 5.34 Hz, 1H), 9.79 (s, 1H), 12.22 (s, 1H). (ESI+) m/z 481.1 (M+H)+.
Example 73 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide 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 ethyl amine, respectively, to e the title compound. 1H NMR (500 MHz, DMSO-d δ 3.03 (s, 3H), 3.50 (s, 3H), 6.82 (d, J = 7.63 Hz, 2H), 6.88 (d, J = 2.44 Hz, 1H), 6.97-7.01 (m, 1H), 7.06 (d, J = 8.54 Hz, 1H), 7.22-7.28 (m, 3H), 7.31 (s, 1H), 7.35 (d, J = 2.75 Hz, 1H), 7.46 (s, 1H), 7.81 (s, 1H), 9.78 (s, 1H), 12.22 (s, 1H). MS (ESI+) m/z 453.1 (M+H)+.
Example 74 ethyl 4-(5-aminophenoxyphenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3- d]pyridazinecarboxylate Example 74a 4-aminochloromethylpyridazin-3(2H)-one A mixture of chloromethylpyridazin-3(2H)-one (5.0 g, 27.9 mmol) and ammonium ide (55 mL, 1412 mmol) was heated at 150 °C for 2 hours 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 with onal ethyl acetate three times. The combined organic layers were washed with brine, dried and concentrated.
The residue was purified by flash chromatography (silica gel, eluted with 40% ethyl acetate in s to afford 3.85 g (87%) of the title compound.
Example 74b 4-aminochloroiodomethylpyridazin-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 (30 mL) was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The ed 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 in hexanes to afford 3.27 g (86%) of the title nd.
Example 74c 4-chloromethyloxo-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazinecarboxylic 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 ed and back-filled with nitrogen three times. The reaction mixture was then heated at 105 ºC overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The s layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over ous magnesium sulfate, filtered, and concentrated. The residue was ated in 30% ethyl acetate in hexanes to afford 0.25 g (53%) of the title compound.
Example 74d ethyl 4-chloromethyloxo-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazinecarboxylate Example 74c (0.45 g, 2.0 mmol) in ethanol (15 mL) was treated concentrated sulfuric acid (1 mL). The reaction mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The s layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over ous magnesium sulfate, filtered, and concentrated to afford 0.45 g (89%) of the title compound.
Example 74e ethyl 4-chloromethyloxo((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H- pyrrolo[3,2-d]pyridazinecarboxylate A solution of Example 74d (0.41 g, 1.6 mmol) in ylformamide (15 mL) was treated with 60% sodium e (0.096 g, 2.4 mmol) at room temperature. The reaction mixture was stirred for 30 min, and then was treated with (2- (chloromethoxy)ethyl)trimethylsilane (0.40 g, 2.4 mmol). The reaction e was then stirred for 2 hours. It was partitioned between ethyl acetate and water. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 20% ethyl acetate to afford 0.50 g (81%) of the title compound.
Example 74f ethyl 4-(2-fluoronitrophenyl)methyloxo((2-(trimethylsilyl)ethoxy)methyl)-6,7- dihydro-1H-pyrrolo[3,2-d]pyridazinecarboxylate 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 ethyl 6-methyl(5-nitrophenoxyphenyl)oxo-6,7-dihydro-1H-pyrrolo[3,2-d]pyridazine- 2-carboxylate A mixture of Example 74f (0.26 g, 0.53 mmol), phenol (0.060 g, 0.64 mmol) and cesium ate (0.21 g, 0.63 mmol) in dimethylsulfoxide (5 mL) was heated at 110 °C for 6 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous ium sulfate, filtered, and concentrated. The residue was then treated with 15 mL of ethanol and 1 mL of concentrated H2SO4. The mixture was heated under reflux overnight.
The reaction mixture was cooled to room temperature and ioned between ethyl acetate and water. The organic layer was washed with brine, dried over ous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40-80% ethyl acetate to afford 0.14 g (61 %) of the title compound.
Example 74h ethyl 4-(5-aminophenoxyphenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3- d]pyridazinecarboxylate Example 74h was prepared according to the procedure used for the preparation of Example 29b, tuting Example 74g for e 29a, and ethanol for ethyl acetate, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.29 (t, J=7.02 Hz, 3H), 3.61 (s, 3H), 4.28 (q, J=7.22 Hz, 2H), 5.22 (s, 2H), 6.65 (d, J=7.33 Hz, 2H), 6.74 (dd, J=8.85, 2.75 Hz, 1H), 6.79 (t, J=2.75 Hz, 1H), 6.87 (d, J=7.32 Hz, 1H), 6.91-6.93 (m, 2H), 7.13-7.17 (m, 2H), 13.37 (br s, 1H). MS (ESI+) m/z 405.1 (M+H)+.
Example 75 ethyl 4-[5-(ethylamino)phenoxyphenyl]methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dazinecarboxylate Example 75 was obtained as a by-product from the preparation of e 74h.1H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J=7.17 Hz, 3H), 1.30 (t, J=7.02 Hz, 3H), 3.03-3.08 (m, 2H), 3.62 (s, 3H), 4.29 (q, J=7.02 Hz, 2H), 5.71 (t, J=5.19 Hz, 1H), 6.65 (d, J=7.63 Hz, 2H), .74 (m, 2H), 6.87 (t, J=7.32 Hz, 1H), 6.91 (s, 1H), 6.99 (d, J=9.16 Hz, 1H), 7.13-7.17 (m, 2H), 13.47 (br s, 1H). MS (ESI+) m/z 433.1 (M+H)+.
Example 76 ethyl 4-{5-[ethyl(methylsulfonyl)amino]phenoxyphenyl}methyloxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxylate Example 76 was prepared according to the procedure used in method A of Example 4, substituting Example 75 for Example 3, except the use of NaOH, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.07 (t, J=7.02 Hz, 3H), 1.30 (t, J= 7.17 Hz, 3H), 3.02 (s, 3H), 3.67-3.72 (m, 5H),4.23 (q, J=7.22 Hz, 2H), 6.93 (d, J=7.93 Hz, 2H), 6.99 (d, J= 2.14 Hz, 1H), 7.07-7.12 (m, 2H), 7.30-7.34 (m, 2H), 7.52-7.55 (m, 1H), 7.85 (d, J=2.75 Hz, 1H). MS (ESI+) m/z 511.1 (M+H)+.
Example 77 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxylic acid Example 77 was prepared according to the procedure used in method A of Example 4, tuting e 74h for Example 3, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.04 (s, 3H), 3.66 (s, 3H),6.39-6.40 (m, 1H), 6.81-6.83 (m, 2H), 6.93 (d, J = 1.53 Hz, 1H), 6.98-7.01 (m, 1H), 7.14 (d, J= 8.85 Hz, 1H), 7.23-7.27 (m, 2H), 7.37-7.42 (m, 1H), 7.43 (d, J=2.75 Hz, 1H), 9.82 (s, 1H), 13.35 (s, 1H). MS (ESI+) m/z 455.1 (M+H)+. e 78 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxamide Example 78a 6-methyl(5-(methylsulfonamido)phenoxyphenyl)oxo-6,7-dihydro-1H-pyrrolo[2,3- d]pyridazinecarbonyl chloride Example 78a was prepared according to the ure used for the preparation of Example 13a, substituting Example 77 for Example 10, to provide the title compound.
Example 78b 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxamide Example 78b was prepared according to the procedure used for the ation of Example 13b, substituting Example 78a for Example 13a, and aqueous ammonium hydroxide for ethylamine, tively, to provide the title compound. 1H NMR (500 MHz, DMSO-d δ 3.03 (s, 3H), 3.67 (s, 3H), 6.85 (d, J=7.63 Hz, 2H), 6.99-7.04 (m, 2H), 7.10 (d, J = 8.54 Hz, 1H), 7.23-7.28 (m, 2H), 7.37-7.40 (m, 2H), 7.57 (s, 1H), 7.91 (s, 1H), 9.82 (s, 1H), 12.95 (s, 1H). MS (ESI+) m/z 454.1 .
Example 79 6-methyl-N-[2-(4-methylpiperazinyl)ethyl]{5-[(methylsulfonyl)amino] phenoxyphenyl}oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazinecarboxamide 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 yl)ethanamine for ethylamine, tively, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6) δ .80 (m, 6H), 3.04 (s, 3H), 3.49 (br, 8 H), 3.67 (s, 3H), 6.82 (d, J=7.63 Hz, 2H), 6.99-7.03 (m, 2H), 7.13 (d, J = 8.85 Hz, 1H), 7.24-7.28 (m, 2H), 7.37-7.40 (m, 2H), 8.50-8.52 (m, 1H), 9.85 (s, 1H), 13.03 (s, 1H). MS (ESI+) m/z 580.2 (M+H)+.
Example 80 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazinyl) phenoxyphenyl]methanesulfonamide Example 80a (E)aminochloro(2-ethoxyvinyl)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- ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for ronitrophenylboronic acid, respectively, to provide the title compound. e 80b 4-chloromethyl-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one Example 80a (0.1 g, 0.435 mmol) in acetic acid (5 mL) was heated at 90 ºC overnight.
The solvent was evaporated under reduced pressure to afford 0.071 g of the title compound.
Example 80c 4-chloromethyl((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-d]pyridazin-7(6H)- e 80c was prepared according to the procedure used for the preparation of Example 74e, substituting Example 80b for Example 74c, to provide the title compound.
Example 80d 4-(2-fluoronitrophenyl)methyl((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 e the title compound.
Example 80e 6-methyl(5-nitrophenoxyphenyl)-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one e 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-aminophenoxyphenyl)methyl-1H-pyrrolo[3,2-d]pyridazin-7(6H)-one Example 80f was prepared according to the procedure used for the preparation of Example 29b, tuting Example 80e for e 29a, to provide the title compound.
Example 80g N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazinyl) phenoxyphenyl]methanesulfonamide Example 80g was prepared according to the procedure used in method A of Example 4, substituting Example 80f for Example 3, to e the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.03 (s, 3H), 3.67 (s, 3H),6.39-6.40 (m, 1H), 6.87 (d, J=7.63 Hz, 2H), 7.01 (t, J = 7.48 Hz, 1H), 7.08 (d, J=8.54 Hz, 1H), 7.24-7.28 (m, 2H), 7.35 (dd, J=8.85, 2.75 Hz, 1H), 7.42-7.43 (m, 2H), 9.80 (s, 1H), 12.67 (s, 1H). MS (ESI+) m/z 411.1 (M+H)+.
Example 81 N-ethylmethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxamide Example 81 was prepared ing to the procedure used for the preparation of Example 13b, substituting e 78a for Example 13a, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.12 (t, J=7.17 Hz, 3H), 3.03 (s, 3H), 3.27-3.30 m, 2H), 3.66 (s, 3H), 6.82-6.84 (m, 2H), 6.98-7.02 (m, 2H), 6.97-7.01 (m, 1H), 7.12 (d, J = 9.16 Hz, 1H), 7.23-7.28 (m, 2H), 7.37-7.40 (m, 2H), 8.44 (t, J=5.34 Hz, 1H), 9.83 (s, 1H), 12.97 (s, 1H).
MS (ESI+) m/z 482.1 (M+H)+.
Example 82 6-methyl(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazinone Example 82 was prepared according to the procedure used for the preparation of Example 1f, substituting Example 80b for Example 1e, except for the use of ium carbonate, followed by purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in , to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 3.70 (s, 3H), 6.36-6.37 (m, 1H), 6.91-6.93 (m, 2H), 7.02-7.07 (m, 2H), .31 (m, 3H), 7.41 (t, J=2.75 Hz, 1H), 7.47-7.52 (m, 1H), 7.56 (dd, J=7.63, 1.83 Hz, 1H), 12.65 (s, 1H). MS (ESI+) m/z 318.1 (M+H)+.
Example 83 N-ethyl-N,6-dimethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro- 1H-pyrrolo[2,3-d]pyridazinecarboxamide Example 83 was prepared according to the procedure used for the ation of Example 13b, substituting Example 78a for Example 13a, and N-methylethanamine for ethylamine, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.07 (br, 3H), 2.94 (s, 3H), 3.03 (s, 3H), 3.45 (br, 2H), 3.68 (s, 3H), 6.88 (d, J=7.93 Hz, 2H), 7.01 (t, J= 7.32 Hz, 1H), 7. 12 (d, J=8.85 Hz, 1H), 7.24-7.28 (m, 2H), 7.36 (dd, J=8.85, 2.75 Hz, 1H), 7.43 (d, J=2.75 Hz, 1H), 9.81 (s, 1H), 13.01 (s, 1H). MS (ESI+) m/z 496.1 (M+H)+.
Example 84 4-{4-[(ethylsulfonyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin noxy}benzamide To a mixture of Example 33b (50 mg, 0.14 mmol) 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 stirred at ambient temperature for 1 hour. The on mixture was concentrated under d pressure, dioxane (4 mL) and sodium ide (10% w/v, 3 mL, 0.14 mmol) were added, and the reaction mixture was heated at 70 ºC for 1 hour. The mixture was cooled to t temperature and then neutralized with saturated aqueous ammonium chloride (50 mL) to a pH of 7. The organic layer was separated and the aqueous phase was extracted with ethyl e (3 x 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-100% acetonitrile/water, 0.1% TFA) to afford the title compound (22 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.01 (s, 1 H) 9.86 (s, 1 H) 7.77 (s, 1 H) 7.74 (d, J = 8.82 Hz, 2 H) 7.42 (d, J = 2.37 Hz, 1 H) 7.22 - 7.30 (m, 3 H) 7.18 (s, 1 H) 7.11 - 7.16 (m, 1 H) 6.83 (d, J = 8.82 Hz, 2 H) 6.23 - 6.28 (m, 1 H) 3.47 (s, 3 H) 3.15 (q, J = 7.35 Hz, 2 H) 1.21 - 1.29 (m, 3 H). MS (ESI+) m/z 467.2 (M+H)+.
Example 85 6-methyl[5-(methylsulfonyl)phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin Example 85a 4-(methylsulfonyl)nitrophenoxybenzene Example 85a was prepared ing to the procedure used for the preparation of Example 2b, tuting ro(methylsulfonyl)nitrobenzene for Example 2a, to provide the title compound.
Example 85b -(methylsulfonyl)phenoxyaniline Example 85b was prepared according to the procedure used for the preparation of Example 29b, substituting 85a for Example 29a, to e the title compound.
Example 85c 2-iodo(methylsulfonyl)phenoxybenzene Example 85b (0.27 g, 1.025 mmol) in dioxane (1 mL) was treated with concentrated HCl (6 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes. To this solution was added sodium nitrite (0.085 g, 1.23 mmol) in water (1 mL). The reaction was stirred at 0 °C 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 for 1 hour at room ature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted with additional ethyl acetate twice. The combined organic layer were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10-30% ethyl acetate in s to afford 0.28 g of the title product.
Example 85d 6-methyl[5-(methylsulfonyl)phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin one Example 85d was prepared ing to the procedure used for the preparation of Example 1f, substituting 85c for Example 1e, and Example 6a for 2-phenoxyphenylboronic acid, followed by purification by preparative HPLC (C18, 10-100% acetonitril/0.1% TFA in , to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 3.26 (s, 3H), 3.57 (s, 3H), 6.29-6.30 (m, 1H), 7.03 (d, J=8.54 Hz, 1H), 7.11 (d, J=7.63 Hz, 2H), 7.20 (t, J=7.32 Hz, 1H), 7.30 (t, J=2.75 Hz, 1H), 7.40-7.44 (m, 3H), 7.88 (dd, J=8.54, 2.44 Hz, 1H), 8.00 (d, J=2.44 Hz, 1H), 12.07 (s, 1H). MS (ESI+) m/z 395.2 (M+H)+. e 86 -(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)pyridinesulfonamide Example 86a -bromochloropyridinesulfonamide -Bromochloropyridinesulfonyl chloride (8.2 g) in methanol (20 mL) was cooled to 0 ºC. To this solution was added 7N NH3 in methanol (80 mL). The reaction mixture was stirred over night at room temperature. The solvent was d at low temperature, and the residue was partitioned between ethyl acetate and water. The aqueous layer was ted with ethyl acetate three times. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The solid was purified by flash column chromatography on silica gel to afford 4.2 g of the clean product.
Example 86b -bromo(tetrahydrofuranyloxy)pyridinesulfonamide Example 86b was prepared according to the procedure used for the preparation of Example 29a, tuting 86a for Example 2a, and tetrahydrofuranol for tetrahydro-2H- pyranol, to e the title compound.
Example 86c -(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)pyridinesulfonamide Example 86c was prepared according to the procedure used for the preparation of Example 1f, substituting 86b for Example 1e, and Example 6a for 2-phenoxyphenylboronic acid, ed by purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ 1.91-1.97 (m, 1H), 2.18-2.25 (m, 1H), 3.59 (s, 3H), 3.66-3.76 (m, 3H), 3.92-3.95 (m, 1H), 5.63-5.66 (m, 1H), .21 (m, 1H), 7.34 (t, J=2.75 Hz, 1H), 7.41 (s, 1H), 7.47 (s, 2H), 8.14 (d, J=2.44 Hz, 1H), 8.54 (d, J=2.44 Hz, 1H), 12.11 (s, 1H). MS (ESI+) m/z 391.1 (M+H)+.
Example 87 N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran- 3-yloxy)pyridinesulfonamide Example 87 was obtained as a by-product from the preparation of Example 86c. 1H NMR (500 MHz, DMSO-d6) δ 1.93-1.98 (m, 1H), 2.17-2.24 (m, 1H), 2.48 (d, J= 5.19 Hz, 3H), 3.57 (s, 3H), 3.67-3.78 (m, 3H), 3.91-3.94 (m, 1H), 5.65-5.67 (m, 1H), 6.19 (t, J=2.29 Hz, 1H), 7.33 (t, J=2.75 Hz, 1H), 7.43 (s, 1H), 7.55 (q, J=4.88 Hz, 1H), 8.06 (d, J=2.44 Hz, 1H), 8.51 (d, J=2.44 Hz, 1H), 12.13 (s, 1H). MS (ESI+) m/z 405.1 (M+H)+.
Example 88 6-methyl(2-phenoxyphenyl)phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone 4-bromoiodomethyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 88a To a cold (-78 °C, dry ice/acetone bath) on of Example 1e (0.2 g, 0.525 mmol) in tetrahydrofuran (6 mL) was added a freshly prepared solution of lithium di-isopropyl amide (1.2 equivalents). The reaction mixture was stirred at -78 °C for 45 minutes. A solution of iodine (0.054 ml, 1.049 mmol) in tetrahydrofuran (0.5 mL) was added at -78 °C.
The cooling bath was d, and the reaction mixture was allowed to warm to room ature and stirred for 1 hour. The reaction was ed by the addition of saturated aqueous sodium thiosulfate (20 mL). The reaction mixture was partitioned between water and ethyl e. The layers were ted, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were washed with brine, dried with anhydrous MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 1-100% ethyl acetate/hexane). The recovered material was further purified by e phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to afford the title compound (55 mg, 21%).
Example 88b 4-bromomethylphenyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one A mixture of Example 88a (0.1g, 0.197 mmol), phenylboronic acid (0.024 g, 0.197 mmol), Pd(PPh3)4 (0.011g, 0.0096 mmol), and sodium hydrogencarbonate (0.041 g, 0.493 mmol) in dimethylformamide (2 mL) and water (0.6 mL) was heated at 85 °C for 4 hours.
After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was ed by flash chromatography on silica gel eluting with 30% ethyl acetate to afford 0.084 g of the title compound.
Example 88c 6-methyl(2-phenoxyphenyl)phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 88c was prepared according to the procedure used for the preparation of e 1f, substituting 88b for Example 1e, followed by purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.53 (s, 3H), 6.67 (d, J=1.22 Hz, 1H), 6.93 (d, J=7.63 Hz, 2H), 7.01- 7.04 (m, 2H), 7.26-7.31 (m, 5H), 7.36-7.43 (m, 3H), 7.56 (dd, J=7.48, 1.68 Hz, 1H), 7.89 (d, J=7.32 Hz, 1H), 12.31 (s, 1H). MS (ESI+) m/z 393.3 (M+H)+.
Example 89 N-{3-[2-(hydroxymethyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl] phenoxyphenyl}methanesulfonamide Example 89 was prepared according to the procedure used for the preparation of Example 20b, substituting e 71 for e 20a, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.02 (s, 3H), 3.47 (s, 3H), 4.50 (s, 2H), 6.19 (d, J=1.83 Hz, 1H), 6.82 (d, J=7.63 Hz, 2H), 6.99 (t, J=7.32 Hz, 1H), 7.05 (d, J=8.85 Hz, 1H), 7.21-7.27 (m, 4H), 7.38 (d, J=2.75 Hz, 1H), 9.75 (s, 1H), 11.60 (s, 1H). MS (ESI+) m/z 440.1 (M+H)+.
Example 90 N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide Example 90a 4-(2-bromonitrophenoxy)benzonitrile Example 90a was prepared according to the procedure used for the ation of e 7a, substituting oxybenzonitrile for phenol, to provide the title compound.
Example 90b 4-(4-aminobromophenoxy)benzonitrile To a 250 mL stainless steel pressure bottle were added Example 90a (3.21 g, 10.1 mmol), platinum (IV) oxide (0.642 g, 2.83 mmol) and ydrofuran (70 mL) under a stream of nitrogen. The reaction flask was charged with hydrogen to 30 psi and d 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% .
Example 90c 4-(4-amino(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy)benzonitrile A mixture of example 90b (1.75 g, 6.05 mmol), ,4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (3.07 g, 12.1 mmol), 1,3,5,7-tetramethylphenyl-2,4,8-trioxa phosphaadamante (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 (30 mL) was ed and backfilled with nitrogen. The reaction mixture was heated at 80 °C 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 ted and washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and trated. The residue was purified by flash chromatography (silica gel, /ethyl acetate) to provide the title compound (2.0 g, 98% yield).
Example 90d 4-(4-amino(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy)benzonitrile Example 90d was prepared according to the procedure used for the preparation of Example 1f, substituting Example 90c for 2-phenoxyphenylboronic acid, with purification by preparative HPLC (C18, 10-100% acetonitrile in 0.1% TFA in water), to provide the title compound.
Example 90e N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide Example 90e was prepared ing to the procedure used for the preparation of Example 4, Method A, substituting ethanesulfonyl chloride for methanesulfonyl chloride, and Example 90d for Example 3, tively, to provide the title nd. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.01 - 12.05 (m, 1 H) 9.94 (s, 1 H) 7.62 - 7.69 (m, 2 H) 7.43 (d, J = 2.75 Hz, 1 H) 7.21 - 7.33 (m, 4 H) 6.86 - 6.93 (m, 2 H) 6.22 (dd, J = 2.75, 2.14 Hz, 1 H) 3.46 (s, 3 H) 3.16 (q, J = 7.32 Hz, 2 H) 1.25 (t, J = 7.32 Hz, 3 H). MS (ESI+) m/z 449.1 (M+H)+. e 91 2-fluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)phenyl]ethanesulfonamide Example 91a 6-methyl(5-nitro(tetrahydrofuranyloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 91a was prepared according to the procedure used for the preparation of Example 29a, substituting tetrahydrofuranol for tetrahydro-2H-pyranol, to provide the title compound.
Example 91b 4-(5-amino(tetrahydrofuranyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 91b was prepared according to the procedure used for the preparation of Example 29b, substituting Example 91a for Example 29a, to provide the title compound. e 91c 2-fluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)phenyl]ethanesulfonamide 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 dropwise 2-fluoroethanesulfonyl chloride (144 mg, 0.984 mmol), and the reaction mixture was stirred at about ambient temperature for about 1 hour. The reaction mixture was neutralized with saturated aqueous um de solution (50 mL) and the mixture was extracted with ethyl acetate (3 x 50 mL). The ed organic layers were washed with saturated aqueous sodium chloride on, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% ter) to provide the title compound (7.0 mg, 6.5% yield). 1H NMR (300 MHz, CDCl 3) δ ppm 11.54 (bs, 1H), 7.45 (t, J = 2.8 Hz, 1H), 7.19 (s, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H) 6.67 (dd, J = 3.1, 8.8 Hz, 1H), 6.40 (dd, J = 2.0, 2.7 Hz, 1H), 4.76 (m, 1H), 3.82 (s, 3H), 3.85-3.62 (m, 8H), 2.97 (bs, 1H), 2.24-1.85 (m, 2H). MS (ESI+) m/z 436.2 (M+H)+. e 92 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)phenyl]propanesulfonamide Example 92 was prepared according to the procedure used for the preparation of Example 4, (Method A), substituting Example 91b for Example 3 and substituting propane sulfonyl chloride for methanesulfonyl chloride, to provide the title nd. 1H NMR (300 MHz, CDCl3) δ ppm 10.63 (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)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]propanesulfonamide Example 93 was prepared according to the procedure used for the preparation of Example 4, (Method A), substituting Example 33b for Example 3 and substituting propane sulfonyl chloride for methanesulfonyl chloride, to provide the title compound. 1H NMR (300 MHz, 6) δppm 12.03 (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), .65 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). MS (ESI+) m/z 463.2 (M+H)+.
Example 94 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]propanesulfonamide Example 94a yl(5-nitro(2,4,6-trifluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 94a was prepared ing to the procedure used for the preparation of Example 2b, substituting 2,4,6-trifluorophenol for phenol, to provide the title compound.
Example 94b 4-(5-amino(2,4,6-trifluorophenoxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 94b was prepared according to the procedure used for the preparation of Example 3, substituting Example 94a for Example 2b, to provide the title compound.
Example 94c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- orophenoxy)phenyl]propanesulfonamide Example 94c was prepared according to the procedure used for the preparation of Example 4, (Method A), substituting Example 94b for e 3 and substituting propane sulfonyl chloride for methanesulfonyl de, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.07 (bs, 1H), 9.72 (s, 1H), 7.44 7.33 (m, 2H), 7.33 7.28 (m, 3H), 7.14 (dd, J = 8.8, 2.7 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.24 6.19 (m, 1H), 3.56 (s, 3H), 3.11 3.02 (m, 2H), 1.78 1.62 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI+) m/z 492.1 .
Example 95 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzenesulfonamide Example 95a ophenoxybenzenesulfonamide Phenol (1.282 g, 13.63 mmol) in dimethylformamide (20 mL) was treated with 60% sodium hydride (0.545 g, 13.63 mmol). The reaction mixture was stirred for 10 minutes. To this on was added 4-fluoronitrobenzenesulfonamide (0.75 g, 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 with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous ium sulfate, filtered, and concentrated. The e was purified by flash chromatography (1:1 ethyl acetate/hexanes) on silica gel to give 0.96 g of the title product.
Example 95b ophenoxybenzenesulfonamide Example 95b was prepared according to the procedure used for the preparation of Example 29b, substituting 95a for Example 29a, to provide the title nd.
Example 95c 3-iodophenoxybenzenesulfonamide Example 95c was prepared according to the procedure used for the preparation of Example 85c, substituting 95b for Example 85b, to provide the title compound.
Example 95d ethyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzenesulfonamide A mixture of Example 6a (0.086 g, 0.20 mmol), Example 95c (0.083 g, 0.22 mmol), Pd(PPh3)4 (0.012 g, 5 mol%) and cesium fluoride (0.091 g, 0.6 mmol) in dimethoxyethane (2 mL) and methanol (1 mL) was heated under microwave conditions (110 ºC, 30 minutes). The reaction mixture was cooled to ambient ature and portioned between ethyl e 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 in 0.1% TFA/water) to provide the title compound (48 mg, 61% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.08 (s, 1H), 7.95 (d, J = 2.14 Hz, 1H), 7.79 (dd, J = 8.54, 2.44 Hz, 1H), 7.36-7.39 (m, 5H), 7.16 (t, J = 7.48 Hz, 1H), 7.03-7.05 (m, 3H), 6.28 (t, J = 2.29 Hz, 1H), 3.55 (s, 3H). MS (ESI+) m/z 396.2 (M+H)+.
Example 96 lohexylamino)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)pyridine- 3-sulfonamide Example 96a -bromo(cyclohexylamino)pyridinesulfonamide A mixture of Example 86a (0.136 g, 0.5 mmol) and cyclohexanamine (0.198 g, 2.0 mmol) in e (2 mL) was heated under microwave conditions (140 ºC, 1 hour). The solvent was removed, and the residue was purified by flash chromatography (3:2 ethyl acetate/hexanes) on silica gel to give 0.164 g of the title product.
Example 96b 6-(cyclohexylamino)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)pyridine- 3-sulfonamide Example 96b was prepared according to the procedure used for the preparation of Example 95d, substituting e 96a for Example 95c, to e the title compound. 1H NMR (500 MHz, DMSO- d6) δ ppm 12.17 (s, 1H), 8.38 (d, J = 2.44 Hz, 1H), 7.69 (d, J = 2.44 Hz, 1H), 7.32 (t, J = 2.75 Hz, 1H), 7.29 (s, 1H), 7.18 (br s, 2H), 6.04 (t, J = 2.29 Hz, 1H), 5.97 (d, J = 7.63 Hz, 1H), 3.56 (s, 3H), 1.81-1.82 (m, 2H), 1.54-1.65 (m, 3H), 1.01-1.33 (m, 5H) MS (ESI+) m/z 402.1 (M+H)+.
Example 97 6-(cyclohexylamino)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide Example 97 was isolated as a minor product during the preparation of Example 96b. 1H NMR (500 MHz, DMSO- d 6) δ ppm 12.16 (s, 1H), 8.35 (d, J = 2.44 Hz, 1H), 7.69 (d, J = 2.44 Hz, 1H), 7.32 (t, J = 2.75 Hz, 1H), 7.29 (s, 1H), 7.18 (q, J = 4.88 Hz, 1H), 6.02 (t, J = 2.29 Hz, 1H), 5.96 (d, J = 7.24 Hz, 1H), 3.99-4.05 (m, 1H), 3.55 (s, 3H), 2.42 (d, J = 4.88 Hz, 3H), 1.80-1.82 (m, 2H), 1.54-1.65 (m, 3H), 1.01-1.33 (m, 6H) MS (ESI+) m/z 416.1 (M+H)+.
Example 98 N-methyl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]sulfuric diamide 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 hour.
The reaction mixture was concentrated under reduced pressure, and the residue was mixed with dioxane (5 mL) and 1M aqueous sodium hydroxide (3 mL, 0.2 mmol) and heated at 70 °C for 1 hour. The on mixture cooled to ambient temperate and then neutralized with saturated aqueous ammonium chloride (50 mL) and the aqueous extracted with ethyl acetate (3x50 mL). The combined c layers were washed with ted aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-80% acetonitrile in 0.1% TFA/water) to provide the title compound (11 mg, 11% yield). 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.04 (bs, 1H), 9.58 (s, 1H), 7.43-7.32 (m, 6H), 7.32-7.16 (m, 1H), 7.10 (dd, J = 8.8, 2.7 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.23 (t, J = 2.3 Hz, 1H), 3.57 (bs, 3H), 2.35 (d, J = 4.9 Hz, 3H). ). MS (ESI+) m/z 479.1 (M+H)+.
Example 99 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran yloxy)phenyl]propanesulfonamide e 99a 6-methyl(5-nitro(tetrahydro-2H-pyranyloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one To a solution of tetrahydro-2H-pyranol (231 mg, 2.265 mmol) in tetrahydrofuran (10 mL) was added sodium e (181 mg, 4.53 mmol) portion wise. After stirring for 10 minutes, Example 2a (500 mg, 1.133 mmol) was added. The mixture was heated at 50 °C for 2 hours. Upon g, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL), diluted with 50% aqueous sodium chloride (80 mL) and extracted with ethyl acetate (75 mL, 2 X 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 in dichloromethane) to provide the title compound (220 mg, 52.6% yield).
Example 99b 4-(5-amino(tetrahydro-2H-pyranyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 99b was prepared according to the procedure used for the preparation of Example 29b, tuting e 99a for e 29a, to provide the title compound.
Example 99c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran phenyl]propanesulfonamide Example 99c was prepared according to the procedure used for the preparation of Example 4 (Method A), substituting Example 99b for Example 3 and propanesulfonyl chloride for methanesulfonyl chloride with the ion that the reaction mixture was initially stirred for 18 hours at ambient temperature and then heated at 50 °C for 1 hour in the presence of sodium hydroxide, to provide the title nd. 1H NMR (300 MHz, DMSO- d6) δ ppm 12.00 (s, 1H), 9.50 (s, 1H), 7.24-7.33 (m, 3H), 7.14 (s, 2H), 6.19 (t, J = 2.37 Hz, 1H), 4.39-4.53 (m, 1H), 3.53-3.68 (m, 5H), .45 (m, 2H), 2.96-3.06 (m, 2H), 1.78-1.92 (m, 2H), 1.63-1.78 (m, 2H), 1.39-1.54 (m, 2H), 0.95 (t, J = 7.46 Hz, 3H). MS (ESI+) m/z 446.1 .
Example 100 2,2,2-trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydro-2H-pyranyloxy)phenyl]ethanesulfonamide To a solution of Example 99b (43.2 mg, 0.127 mmol) in dichloromethane (2 mL) 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 for 18 hours at ambient temperature. The on mixture was concentrated and the residue was purified by flash column chromatography (silica gel, 0.5-5% methanol in dichloromethane) to provide the title compound (20.8 mg, 33.7% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), .16 (s, 1H), 7.25-7.32 (m, 3H), .20 (m, 2H), 6.18-6.24 (m, 1H), 4.36-4.55 (m, 3H), 3.52-3.68 (m, 5H), 3.33-3.45 (m, 2H), 1.79-1.94 (m, 2H), 1.39-1.57 (m, 2H). MS (ESI+) m/z 486.1 (M+H)+. e 101 N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}ethanesulfonamide Example 101a 4-(2-(4,4-difluorocyclohexyloxy)nitrophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- one Example 101a was prepared according to the procedure used for the preparation of Example 99a, substituting 4,4-difluorocyclohexanol for tetrahydro-2H-pyranol, to provide the title compound.
Example 101b 4-(5-amino(4,4-difluorocyclohexyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 101b was prepared according to the procedure used for the preparation of Example 29b, substituting Example 101a for Example 29a, to provide the title compound.
Example 101c N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}ethanesulfonamide Example 101c was prepared according to the ure used for the preparation of Example 4 (Method A), substituting Example 101b for Example 3 and ethanesulfonyl chloride for methanesulfonyl chloride with the exception that the reaction mixture was initially d for 18 hours at t temperature and then heated at 50 °C for 1 hour in the presence of sodium hydroxide to provide the title compound. 1H NMR (300 MHz, DMSO- d6) δ ppm 12.02 (s, 1H), 9.56 (s, 1H), 7.24-7.34 (m, J = 4.36 Hz, 3H), 7.17 (s, 2H), 6.15-6.23 (m, 1H), 4.48 (s, 1H), 3.49-3.61 (m, 3H), 3.05 (q, J = 7.27 Hz, 2H), 1.62-1.88 (m, 8H), 1.22 (t, J = 7.34 Hz, 3H). MS (ESI+) m/z 466.1 (M+H)+.
Example 102 N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)phenyl}propanesulfonamide Example 102 was prepared according to the procedure used for the preparation of Example 4 (Method A), substituting Example 101b for Example 3 and propanesulfonyl de for methanesulfonyl chloride with the ion that the reaction e was initially stirred for18 hours at ambient temperature and then heated at 50 °C for for 1 hour in the presence of sodium hydroxide, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.02 (s, 1H), 9.54 (s, 1H), .31 (m, 3H), 7.17 (s, 2H), .22 (m, 1H), 4.44-4.56 (m, J = 2.78 Hz, 1H), 3.51-3.57 (m, 3H), 2.96-3.08 (m, 2H), 1.61-1.89 (m, 10H), 0.95 (t, J = 7.54 Hz, 3H). MS (ESI+) m/z 480.2 (M+H)+.
Example 103 N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}-2,2,2-trifluoroethanesulfonamide Example 103 was prepared according to the procedure used for the preparation of Example 100, substituting Example 101b for Example 99b, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.00 (s, 1H), 10.19 (s, 1H), 7.25-7.32 (m, 3H), 7.19 (s, 2H), 6.17-6.24 (m, 1H), .60 (m, 3H), 3.55 (s, 3H), 1.60-1.88 (m, J = 4.07 Hz, 8H).
MS (ESI+) m/z 520.1 (M+H)+.
Example 104 N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}-N'-methylsulfuric diamide Example 104 was prepared according to the procedure used for the preparation of Example 100, substituting e 101b for Example 99b and methylsulfamoyl chloride for trifluoroethanesulfonyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.98 (s, 1H), 9.41 (s, 1H), 7.21-7.30 (m, 3H), 7.06-7.17 (m, 3H), 6.15- 6.24 (m, 1H), 4.44 (s, 1H), 3.55 (s, 3H), 2.51 (s, 3H), 1.59-1.86 (m, 8H). MS (ESI+) m/z 467.1 .
Example 105 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran yloxy)phenyl]ethanesulfonamide Example 105a 6-methyl(5-nitro(tetrahydro-2H-pyranyloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 105a was prepared according to the procedure used for the preparation of Example 99a, substituting tetrahydro-2H-pyranol for tetrahydro-2H-pyranol, to provide the title nd.
Example 105b 4-(5-amino(tetrahydro-2H-pyranyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 105b was prepared according to the procedure used for the preparation of Example 29b, substituting Example 105a for Example 29a, to provide the title compound.
Example 105c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran yloxy)phenyl]ethanesulfonamide Example 105c was prepared according to the procedure used for the preparation of e 4 (Method A), substituting Example 105b for e 3 and ethanesulfonyl chloride for methanesulfonyl chloride with the exception that the reaction mixture was initially stirred for18 hours at ambient temperature and then heated at 50 °C for for 1 hour in the presence of sodium hydroxide, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.02 (s, 1H), 9.53 (s, 1H), 7.37 (s, 1H), 7.27-7.33 (m, 2H), 7.09-7.17 (m, 2H), 6.23 (t, J = 2.18 Hz, 1H), 4.23-4.34 (m, 1H), 3.67 (dd, J = 11.70, 2.58 Hz, 1H), 3.37- 3.59 (m, 6H), 3.04 (q, J = 7.54 Hz, 2H), 1.85-2.00 (m, 1H), 1.51-1.73 (m, 2H), 1.33-1.49 (m, 1H), 1.21 (t, J = 7.34 Hz, 3H). MS (ESI+) m/z 432.2 (M+H)+.
Example 106 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran yloxy)phenyl]propanesulfonamide Example 106 was prepared according to the procedure used for the preparation of Example 4 (Method A), substituting Example 105b for Example 3 and propanesulfonyl chloride for esulfonyl chloride with the exception that the reaction mixture was initially stirred for18 hours at ambient temperature and then heated at 50 °C for for 1 hour in the ce of sodium hydroxide, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.02 (s, 1H), 9.52 (s, 1H), 7.37 (s, 1H), 7.30 (s, 2H), 7.12 (s, 2H), 6.23 (t, J = 2.18 Hz, 1H), 4.22-4.34 (m, 1H), 3.67 (dd, J = 11.50, 2.78 Hz, 1H), 3.36-3.59 (m, 6H), 2.96-3.07 (m, 2H), 1.85-1.99 (m, 1H), 1.52-1.79 (m, 4H), 1.32-1.50 (m, 1H), 0.95 (t, J = 7.54 Hz, 3H). MS (ESI+) m/z 446.2 (M+H)+.
Example 107 2,2,2-trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydro-2H-pyranyloxy)phenyl]ethanesulfonamide Example 107 was prepared according to the procedure used for the preparation of Example 100, substituting Example 105b for Example 99b, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.02 (s, 1H), 10.17 (s, 1H), 7.38 (s, 1H), 7.26-7.33 (m, 2H), .18 (m, J = 1.59 Hz, 2H), 6.26 (t, J = 2.38 Hz, 1H), 4.43 (q, J = 9.92 Hz, 2H), .36 (m, 1H), 3.68 (dd, J = 11.50, 2.38 Hz, 1H), 3.39-3.59 (m, 6H), 1.86-2.01 (m, 1H), 1.53-1.73 (m, 2H), 1.36-1.49 (m, 1H). MS (ESI+) m/z 486.1 (M+H)+.
Example 108 N-methyl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro- 2H-pyranyloxy)phenyl]sulfuric diamide Example 108 was prepared according to the ure used for the preparation of e 100, substituting the Example 105b for e 99b and sulfamoyl chloride for 2,2,2-trifluoroethanesulfonyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.99 (s, 1H), 9.38 (s, 1H), 7.33 (s, 1H), .30 (m, J = 2.54, 2.54 Hz, 2H), 7.05-7.13 (m, 3H), 6.22-6.27 (m, 1H), 4.16-4.27 (m, 1H), 3.65 (dd, J = 11.53, 2.37 Hz, 1H), 3.37-3.59 (m, 6H), 2.50-2.53 (m, J = 1.70 Hz, 3H), 1.84-1.96 (m, 1H), 1.50-1.71 (m, 2H), 1.35-1.47 (m, 1H). MS (ESI+) m/z 433.1 (M+H)+.
Example 109 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H-pyran yloxy)phenyl]ethanesulfonamide Example 109 was prepared ing to the procedure used for the preparation of Example 4 (Method A), tuting Example 99b for Example 3 and ethanesulfonyl chloride for methanesulfonyl chloride with the exception that the reaction mixture was initially stirred for18 hours at ambient temperature and then heated at 50 °C for 1 hour in the presence of sodium hydroxide, to e the title compound. 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.00 (s, 1H), 9.50 (s, 1H), .33 (m, 3H), 7.14 (s, 2H), 6.19 (t, J = 2.37 Hz, 1H), 4.39- 4.53 (m, 1H), 3.53-3.68 (m, 5H), 3.33-3.45 (m, 2H), 2.96-3.06 (m, 2H), 1.78-1.92 (m, 2H), 1.63-1.78 (m, 2H), 1.39-1.54 (m, 2H), 0.95 (t, J = 7.46 Hz, 3H). MS (ESI+) m/z 432.1 (M+H)+.
Example 110 methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)pyridinesulfonamide Example 110a -bromochloro-N,N-dimethylpyridinesulfonamide 5-Bromochloropyridinesulfonyl chloride (1.455 g, 5 mmol) in methanol (20 mL) was treated with 2.0 N dimethylamine (6.25 mL, 12.50 mmol). The reaction mixture was stirred at t temperature for 16 hours. The solvent was removed, and the solid was washed with water l times. The solid was then purified by chromatography on silica gel eluting with 15% ethyl acetate in hexanes to give 0.8 g of the title compound.
Example 110b -bromo-N,N-dimethyl(tetrahydrofuranyloxy)pyridinesulfonamide e 110b was prepared according to the procedure used for the preparation of Example 29a, substituting 110a for Example 2a, and tetrahydrofuranol for tetrahydro-2H- pyranol, respectively, to provide the title compound.
Example 110c N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)pyridinesulfonamide Example 110c was prepared according to the ure used for the preparation of Example 95d, substituting e 110b for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.11 (s, 1H), 8.53 (d, J = 2.44 Hz, 1H), 8.00 (d, J = 2.44 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J = 2.75 Hz, 1H), 6.17 (t, J = 2.29 Hz, 1H), 5.67 (d, J = 1.53 Hz, 1H), 3.93 (dd, J = 10.38, 4.58 Hz, 1H), 3.78 (d, J = 10.07 Hz, 1H), 3.68-3.72 (m, 2H), 3.57 (s, 3H), 2.69 (s, 6H), 2.54-2.56 (m, 5H), 2.17-2.24 (m, 1H), 1.94-1.98 (m, 1H). MS (ESI+) m/z 419.2 .
Example 111 -(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(phenylamino)pyridine sulfonamide Example 111a -bromo(phenylamino)pyridinesulfonamide 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 (2 mL) was stirred and heated at 60 °C for 16 hours. After cooling, the reaction mixture was partitioned between water and ethyl e. The s layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium de, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (2:3 ethyl acetate/hexanes) to give 0.095 g of the title product.
Example 111b -(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(phenylamino)pyridine sulfonamide e 111b was prepared ing to the procedure used for the preparation of Example 95d, substituting Example 111a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.17 (s, 1H), 8.49 (d, J = 2.44 Hz, 1H), 8.25 (s, 1H), 7.87 (d, J = 2.44 Hz, 1H), 7.55 (d, J = 7.63 Hz, 2H), 7.42 (s, 1H), 7.24-7.31 (m, 5H), 6.99 (t, J = 7.32 Hz, 1H), 6.04 (m, 1H), 3.58 (s, 3H). MS (ESI+) m/z 396.2 (M+H)+.
Example 112 N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (phenylamino)pyridinesulfonamide Example 112 was isolated as a minor product during the preparation of Example 111b. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.17 (s, 1H), 8.44 (d, J = 2.44 Hz, 1H), 8.31 (s, 1H), 7.78 (d, J = 2.44 Hz, 1H), 7.56 (d, J = 7.63 Hz, 2H), 7.45 (s, 1H), 7.34-7.37 (m, 1H), 7.25-7.30 (m, 3H), 7.00 (t, J = 7.32 Hz, 1H), 6.04 (m, 1H), 3.58 (s, 3H), 2.46 (d, J = 4.88 Hz, 3H). MS (ESI+) m/z 410.2 (M+H)+.
Example 113 N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]fluoroethanesulfonamide Example 33b (50 mg, 0.140 mmol) and triethylamine (42.6 mg, 0.421 mmol) were ed in dichloromethane (4 mL). 2-Fluoroethanesulfonyl chloride (82 mg, 0.561 mmol) was added dropwise and reaction e was stirred for 1 hour at ambient temperature. The reaction mixture was then extracted with saturated s sodium chloride, separated, dried over anhydrous magnesium sulfate, filtered, and concentrated. . The residue was purified by preparative HPLC (C18, % acetonitrile/water, 0.1% TFA) to afford the title compound (1.4 mg, 2% yield). 1H NMR (300 MHz, DMSO-d 6) δppm 11.98-11.92 (m, 1H), 7.62-7.56 (m, 2H), 7.25 (t, J = 2.7 Hz, 1H), 7.17 (s, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.82-6.70 (m, 4H), 6.24-6.13 (m, 1H), .09 (m, 2H), 3.70-3.62 (m, 2H) 3.45 (s, 3H). MS (ESI+) m/z 467.1 (M+H)+.
Example 114 ro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]ethanesulfonamide Example 114 was prepared according to the procedure used for the preparation of Example 91c, substituting Example 94b for Example 91b, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.00-11.94 (m, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.27 (m, 2H), 7.25 (s, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.63-6.47 (m, 2H), 6.22 (dd, J = 2.8, 2.0 Hz, 1H), 4.08 (q, J = 6.3, 5.7, 6.0 Hz, 2H), 3.60 (t, J = 6.3, 6.0 Hz, 2H), 3.55 (bs, 3H). MS (ESI+) m/z 496.2 (M+H)+.
Example 115 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]propanesulfonamide e 115 was prepared ing to the procedure used for the preparation of Example 27c, substituting propanesulfonyl chloride for methanesulfonyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.04 (bs, 1H), 9.76 (s, 1H), 7.42-7.26 (m, 4H), 7.18 (dd, J = 8.8, 2.7 Hz, 1H), 7.13-6.94 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 6.24 (t, J = 2.3 Hz, 1H), 3.53 (s, 3H), 3.13-3.04 (m, 2H), 1.79-1.64 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). MS (ESI+) m/z 474.1 (M+H)+.
Example 116 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- (pyrimidinyl)benzamide A solution of Example 50b (24 mg, 0.06 mmol) in a 4 mL vial was dissolved in anhydrous tetrahydrofuran (1.0 mL), followed by the addition of 1-chloro-N,N,2-trimethyl propenylamine (65 µL, 0.48 mmol). This was capped and placed to shake for 2 hours at ambient temperature. Then, a solution of pyrimidinamine (9 mg, 0.09 mmol) in anhydrous tetrahydrofuran (0.3 mL) was added, followed by a solution of 4-(dimethylamino)pyridine (37 mg, 0.3 mmol) in anhydrous tetrahydrofuran (0.5 mL). The e was stirred at 60 ºC for 16 hours, cooled, and concentrated to s. The residues were dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (10-80% acetonitrile in 0.1% TFA . 1H NMR (500 MHz, DMSO-d 6/D2O ,Temp=25 °C) δ ppm 8.73 (d, J = 4.88 Hz, 2 H) 8.09 (d, J = 2.44 Hz, 1 H) 7.95 (dd, J = 8.70, 2.29 Hz, 1 H) 7.42 - 7.48 (m, 1 H) 7.41 (s, 1 H) 7.32 - 7.38 (m, 2 H) 7.27 (t, J = 4.88 Hz, 1 H) 7.11 - 7.17 (m, 1 H) 6.90 (d, J = 8.85 Hz, 1 H) 6.32 (d, J = 2.75 Hz, 1 H) 3.60 (s, 3 H); (ESI) m/z 474 (M+H)+.
Example 117 4-(2,4-difluorophenoxy)-N-(2,6-dimethoxypyridinyl)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide Example 117 was prepared according to the procedure used for the ation of Example 116, substituting 2,6-dimethoxypyridinamine hloride for pyrimidin amine, to e the TFA salt of the title nd. 1H NMR (500 MHz, DMSO-d6/D2O ,Temp=25 °C)δ ppm 8.08 (d, J = 1.53 Hz, 1 H) 7.94 (dd, J = 8.85, 2.14 Hz, 1 H) 7.74 - 7.78 (m, 1 H) 7.40 - 7.47 (m, 1 H) 7.38 (s, 1 H) 7.28 - 7.35 (m, 2 H) 7.09 - 7.15 (m, 1 H) 6.91 (d, J = 8.54 Hz, 1 H) 6.43 (d, J = 8.24 Hz, 1 H) 6.29 (d, J = 2.75 Hz, 1 H) 3.88 (d, J = 9.46 Hz, 6 H) 3.60 (s, 3 H); (ESI) m/z 533 (M+H)+.
Example 118 4-(2,4-difluorophenoxy)-N-(1H-indazolyl)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide Example 118 was prepared according to the procedure used for the preparation of Example 116, substituting 1H-indazolamine for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O ,Temp=25 °C)δ ppm 8.22 (s, 1 H) 8.12 (d, J = 2.44 Hz, 1 H) 8.02 (s, 1 H) 7.97 (dd, J = 8.54, 2.44 Hz, 1 H) 7.73 (d, J = 8.54 Hz, 1 H) 7.42 - 7.48 (m, 1 H) 7.41 (s, 1 H) 7.30 - 7.38 (m, 3 H) 7.11 - 7.16 (m, 1 H) 6.93 (d, J = 8.54 Hz, 1 H) 6.31 (d, J = 2.75 Hz, 1 H) 3.61 (s, 3 H); (ESI) m/z 512 (M+H)+.
Example 119 4-[2-(2,4-difluorophenoxy){[4-(pyrrolidinylcarbonyl)piperazinyl]carbonyl}phenyl]- 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 119 was ed according to the procedure used for the preparation of Example 116, substituting piperazinyl(pyrrolidinyl)methanone for dinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O ,Temp=25 °C ) δ ppm 7.51 (d, J = 2.14 Hz, 1 H) 7.39 - 7.46 (m, 2 H) 7.35 (s, 1 H) 7.32 - 7.34 (m, J = 2.90, 2.90 Hz, 1 H) 7.25 - 7.31 (m, 1 H) 7.07 - 7.13 (m, 1 H) 6.87 (d, J = 8.54 Hz, 1 H) 6.28 (d, J = 2.75 Hz, 1 H) 3.59 - 3.71 (m, 1 H) 3.56 - 3.58 (m, 4 H) 3.40 - 3.55 (m, 2 H) 3.18 - 3.33 (m, J = 6.41, 6.41 Hz, 8 H) 1.75 (t, J = 6.26 Hz, 4 H); (ESI) m/z 562 (M+H)+.
Example 120 4-(2,4-difluorophenoxy)-N-[4-(dimethylamino)phenyl](6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide Example 120 was prepared according to the procedure used for the preparation of Example 116, substituting N1,N1-dimethylbenzene-1,4-diamine for pyrimidinamine, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O ,Temp=25 °C) δ ppm 8.09 (d, J = 2.44 Hz, 1 H) 7.94 (dd, J = 8.70, 2.29 Hz, 1 H) 7.76 (d, J = 9.16 Hz, 2 H) 7.41 - 7.47 (m, 1 H) 7.39 (s, 1 H) 7.29 - 7.36 (m, 2 H) 7.26 (d, J = 8.85 Hz, 2 H) 7.10 - 7.16 (m, 1 H) 6.92 (d, J = 8.54 Hz, 1 H) 6.29 (d, J = 3.05 Hz, 1 H) 3.60 (s, 3 H) 3.06 (s, 6 H); (ESI) m/z 515 (M+H)+.
Example 121 -difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- (pyridinylmethyl)benzamide Example 121 was prepared according to the procedure used for the ation of Example 116, substituting pyridinylmethanamine for pyrimidinamine, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O ,Temp=25 °C) δ ppm 8.79 (d, J = 6.41 Hz, 2 H) 8.05 (d, J = 2.14 Hz, 1 H) 7.87 - 7.96 (m, 3 H) 7.41 - 7.47 (m, 1 H) 7.28 - 7.38 (m, 3 H) 7.09 - 7.16 (m, 1 H) 6.91 (d, J = 8.54 Hz, 1 H) 6.28 (d, J = 2.75 Hz, 1 H) 4.73 (s, 2 H) 3.59 (s, 3 H); (ESI) m/z 487 (M+H)+.
Example 122 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- [2-(2-oxopyrrolidinyl)ethyl]benzamide Example 122 was prepared according to the procedure used for the preparation of e 116, substituting 1-(2-aminoethyl)pyrrolidinone for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O,Temp=25 °C) δ ppm 7.91 (d, J = 2.44 Hz, 1 H) 7.77 (dd, J = 8.70, 2.29 Hz, 1 H) 7.38 - 7.47 (m, 1 H) 7.32 - 7.36 (m, 2 H) 7.26 - 7.31 (m, 1 H) 7.07 - 7.13 (m, 1 H) 6.86 (d, J = 8.54 Hz, 1 H) 6.27 (d, J = 2.75 Hz, 1 H) 3.59 (s, 3 H) 3.33 - 3.46 (m, 6 H) 2.19 (t, J = 8.09 Hz, 2 H) 1.86 - 1.95 (m, 2 H); (ESI) m/z 507 (M+H)+.
Example 123 4-(2,4-difluorophenoxy)-N-(2-hydroxymethylpropyl)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide Example 123 was prepared according to the procedure used for the preparation of e 116, tuting 1-aminomethylpropanol for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O ,Temp=25 °C)δ ppm 7.98 (d, J = 2.14 Hz, 1 H) 7.85 (dd, J = 8.70, 2.29 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.35 (s, 1 H) 7.32 (d, J = 3.05 Hz, 1 H) 7.25 - 7.31 (m, 1 H) 7.07 - 7.13 (m, 1 H) 6.86 (d, J = 8.54 Hz, 1 H) 6.26 (d, J = 2.75 Hz, 1 H) 3.58 - 3.60 (m, 3 H) 3.27 (s, 2 H) 1.11 (s, 6 H); (ESI) m/z 468 (M+H)+.
Example 124 4-(2,4-difluorophenoxy)-N-[2-(5-methoxy-1H-indolyl)ethyl](6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzamide Example 124 was prepared according to the procedure used for the preparation of Example 116, tuting 2-(5-methoxy-1H-indolyl)ethanamine for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 7.93 (d, J = 2.14 Hz, 1 H) 7.83 (dd, J = 8.54, 2.14 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.30 - 7.33 (m, 2 H) 7.26 - 7.30 (m, 1 H) 7.24 (d, J = 8.85 Hz, 1 H) 7.14 (s, 1 H) 7.07 - 7.13 (m, 1 H) 7.03 (d, J = 2.44 Hz, 1 H) 6.86 (d, J = 8.54 Hz, 1 H) 6.72 (dd, J = 8.85, 2.44 Hz, 1 H) 6.24 (d, J = 2.75 Hz, 1 H) 3.67 (s, 3 H) 3.59 (s, 3 H) 3.53 (t, J = 7.32 Hz, 2 H) 2.92 (t, J = 7.32 Hz, 2 H); (ESI) m/z 569 . e 125 N-(3,4-difluorobenzyl)(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide Example 125 was prepared according to the procedure used for the preparation of Example 116, substituting (3,4-difluorophenyl)methanamine for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C)δ ppm 8.00 (d, J = 2.14 Hz, 1 H) 7.87 (dd, J = 8.54, 2.14 Hz, 1 H) 7.26 - 7.46 (m, 6 H) 7.15 - 7.20 (m, 1 H) 7.08 - 7.13 (m, 1 H) 6.88 (d, J = 8.54 Hz, 1 H) 6.26 (d, J = 2.75 Hz, 1 H) 4.45 (s, 2 H) 3.58 (s, 3 H); (ESI) m/z 522 .
Example 126 -difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- [4-(trifluoromethoxy)benzyl]benzamide Example 126 was prepared according to the ure used for the preparation of Example 116, substituting ifluoromethoxy)phenyl)methanamine for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 8.01 (d, J = 2.44 Hz, 1 H) 7.88 (dd, J = 8.54, 2.14 Hz, 1 H) 7.39 - 7.47 (m, 3 H) 7.35 (s, 1 H) 7.26 - 7.34 (m, 4 H) 7.08 - 7.14 (m, 1 H) 6.88 (d, J = 8.54 Hz, 1 H) 6.26 (d, J = 2.75 Hz, 1 H) 4.50 (s, 2 H) 3.58 (s, 3 H); (ESI) m/z 570 (M+H)+.
Example 127 2-{4-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzoyl]piperazinyl}-N,N-dimethylacetamide Example 127 was prepared according to the procedure used for the preparation of Example 116, substituting N,N-dimethyl(piperazinyl)acetamide for pyrimidinamine, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 7.56 (d, J = 2.14 Hz, 1 H) 7.40 - 7.48 (m, 2 H) 7.35 (s, 1 H) 7.33 (d, J = 2.75 Hz, 1 H) 7.26 - 7.32 (m, 1 H) 7.08 - 7.13 (m, 1 H) 6.88 (d, J = 8.24 Hz, 1 H) 6.28 (d, J = 2.75 Hz, 1 H) 4.26 (s, 2 H) 2.99 - 3.71 (m, 11 H) 2.92 (d, J = 5.49 Hz, 6 H); (ESI) m/z 550 (M+H)+.
Example 128 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- (pyridinylmethyl)benzamide Example 128 was prepared according to the procedure used for the preparation of Example 116, substituting nylmethanamine for pyrimidinamine, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 8.78 (s, 1 H) 8.72 (d, J = 5.19 Hz, 1 H) 8.36 (d, J = 7.93 Hz, 1 H) 8.01 (d, J = 2.14 Hz, 1 H) 7.85 - 7.92 (m, 2 H) 7.40 - 7.46 (m, 1 H) 7.35 (s, 1 H) 7.33 (t, J = 3.36 Hz, 1 H) 7.27 - 7.31 (m, 1 H) 7.09 - 7.14 (m, 1 H) 6.89 (d, J = 8.54 Hz, 1 H) 6.26 (d, 1 H) 4.63 (s, 2 H) 3.59 (s, 3 H); (ESI) m/z 487 (M+H)+.
Example 129 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- (pyridinylmethyl)benzamide Example 129 was prepared according to the procedure used for the preparation of Example 116, substituting pyridinylmethanamine for pyrimidinamine, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 8.68 (d, J = 5.49 Hz, 1 H) 8.23 - 8.29 (m, 1 H) 8.04 (d, J = 2.44 Hz, 1 H) 7.90 (dd, J = 8.70, 2.29 Hz, 1 H) 7.75 (d, J = 7.93 Hz, 1 H) 7.69 - 7.73 (m, 1 H) 7.39 - 7.47 (m, 1 H) 7.36 (s, 1 H) 7.33 (d, J = 2.75 Hz, 1 H) 7.26 - 7.32 (m, 1 H) 7.09 - 7.15 (m, 1 H) 6.90 (d, J = 8.85 Hz, 1 H) 6.27 (d, J = 2.75 Hz, 1 H) 4.73 (s, 2 H) 3.59 (s, 3 H); (ESI) m/z 487 (M+H)+.
Example 130 -difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- -trimethoxybenzyl)benzamide e 130 was prepared ing to the procedure used for the preparation of Example 116, substituting (3,4,5-trimethoxyphenyl)methanamine for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 8.00 (d, J = 2.14 Hz, 1 H) 7.87 (dd, J = 8.70, 2.29 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.35 (s, 1 H) 7.32 (d, J = 2.75 Hz, 1 H) 7.26 - 7.31 (m, 1 H) 7.11 (m, 1 H) 6.87 (d, J = 8.54 Hz, 1 H) 6.66 (s, 2 H) 6.26 (d, J = 2.75 Hz, 1 H) 4.41 (s, 2 H) 3.75 (s, 6 H) 3.63 (s, 3 H) 3.58 (s, 3 H); (ESI) m/z 576 (M+H)+.
Example 131 4-(2,4-difluorophenoxy)-N-[2-(dimethylamino)ethyl](6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide Example 131 was prepared according to the procedure used for the preparation of Example 116, substituting N1,N1-dimethylethane-1,2-diamine for pyrimidinamine, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, 5 °C) δ ppm 7.97 (d, J = 2.14 Hz, 1 H) 7.85 (dd, J = 8.70, 2.29 Hz, 1 H) 7.39 - 7.46 (m, 1 H) 7.31 - 7.35 (m, 2 H) 7.25 - 7.31 (m, 1 H) 7.09 - 7.15 (m, 1 H) 6.90 (d, J = 8.55 Hz, 1 H) 6.25 (d, J = 2.75 Hz, 1 H) 3.62 (t, J = 5.95 Hz, 2 H) 3.59 (s, 3 H) 3.26 (t, J = 5.95 Hz, 2 H) 2.84 (s, 6 H); (ESI) m/z 467 (M+H)+.
Example 132 N-[2-(1,3-benzodioxolyl)ethyl](2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinyl)benzamide e 132 was prepared ing to the procedure used for the preparation of Example 116, substituting 2-(benzo[d][1,3]dioxolyl)ethanamine for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 7.92 (d, J = 2.14 Hz, 1 H) 7.79 (dd, J = 8.70, 2.29 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.31 - 7.34 (m, 2 H) 7.25 - 7.31 (m, 1 H) 7.06 - 7.14 (m, 1 H) 6.80 - 6.87 (m, 3 H) 6.70 (d, J = 7.02 Hz, 1 H) 6.25 (d, J = 3.05 Hz, 1 H) 5.94 (s, 2 H) 3.59 (s, 3 H) 3.44 (t, J = 7.32 Hz, 2 H) 2.76 (t, J = 7.32 Hz, 2 H); (ESI) m/z 544 (M+H)+.
Example 133 4-(2,4-difluorophenoxy)-N-[2-(1H-indolyl)ethyl](6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide Example 133 was prepared according to the ure used for the preparation of Example 116, substituting 2-(1H-indolyl)ethanamine for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 8.65 (t, J = .49 Hz, 1 H) 7.94 (d, J = 2.14 Hz, 1 H) 7.83 (dd, J = 8.70, 2.29 Hz, 1 H) 7.58 (d, J = 7.93 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.36 (d, J = 7.93 Hz, 1 H) 7.32 - 7.34 (m, 2 H) 7.25 - 7.31 (m, 1 H) 7.18 (s, 1 H) 7.05 - 7.13 (m, 2 H) 6.98 (t, J = 7.32 Hz, 1 H) 6.86 (d, J = 8.54 Hz, 1 H) 6.25 (d, J = 2.75 Hz, 1 H) 3.59 (s, 3 H) 3.48 - 3.58 (m, 2 H) 2.96 (t, J = 7.48 Hz, 2 H); (ESI) m/z 539 (M+H)+.
Example 134 4-[2-(2,4-difluorophenoxy){[4-(furanylcarbonyl)piperazinyl]carbonyl}phenyl] methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 134 was prepared according to the procedure used for the preparation of Example 116, substituting furanyl(piperazinyl)methanone for pyrimidinamine, to provide the title nd. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 7.82 (s, 1 H) 7.55 (d, J = 2.14 Hz, 1 H) 7.39 - 7.48 (m, 2 H) 7.25 - 7.37 (m, 3 H) 7.07 - 7.13 (m, 1 H) 7.05 (d, J = 3.36 Hz, 1 H) 6.88 (d, J = 8.24 Hz, 1 H) 6.64 (dd, J = 3.36, 1.83 Hz, 1 H) 6.29 (d, J = 2.75 Hz, 1 H) 3.74 - 3.89 (m, 4 H) 3.41 - 3.70 (m, 7 H); (ESI) m/z 559 (M+H)+. e 135 tert-butyl {1-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzoyl]piperidinyl}carbamate Example 135 was prepared according to the ure used for the preparation of Example 116, substituting tert-butyl piperidinylcarbamate for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 7.45 (d, J = 1.83 Hz, 1 H) 7.36 - 7.44 (m, 2 H) 7.34 (s, 1 H) 7.32 (d, J = 2.75 Hz, 1 H) 7.25 - 7.31 (m, 1 H) 7.06 - 7.13 (m, 1 H) 6.86 (d, J = 8.54 Hz, 1 H) 6.27 (d, J = 2.75 Hz, 1 H) 4.31 (s, 1 H) 3.42 - 3.69 (m, 5 H) 2.85 - 3.24 (m, 2 H) 1.77 (s, 2 H) 1.21 - 1.47 (m, 11 H); (ESI) m/z 579 (M+H)+.
Example 136 utyl 4-{[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzoyl]amino}piperidinecarboxylate Example 136 was prepared according to the procedure used for the preparation of Example 116, substituting tert-butyl 4-aminopiperidinecarboxylate for pyrimidinamine, to e the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 7.95 (d, J = 2.14 Hz, 1 H) 7.83 (dd, J = 8.54, 2.14 Hz, 1 H) 7.43 (d, J = 8.54 Hz, 1 H) 7.31 - 7.35 (m, 2 H) 7.24 - 7.51 (m, 1 H) 7.10 (d, J = 1.83 Hz, 1 H) 6.86 (d, J = 8.54 Hz, 1 H) 6.24 (d, J = 2.75 Hz, 1 H) 3.87 - 4.08 (m, 3 H) 3.58 (s, 3 H) 2.91 (d, J = 85.75 Hz, 2 H) 1.78 (d, 2 H) 1.34 - 1.45 (m, 11 H); (ESI) m/z 579 (M+H)+.
Example 137 4-[2-(2,4-difluorophenoxy){[4-(ethylsulfonyl)piperazinyl]carbonyl}phenyl]methyl- hydro-7H-pyrrolo[2,3-c]pyridinone Example 137 was prepared according to the ure used for the preparation of Example 116, substituting 1-(ethylsulfonyl)piperazine for pyrimidinamine, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6/D2O, Temp=25 °C) δ ppm 7.53 (d, J = 2.14 Hz, 1 H) 7.38 - 7.47 (m, 2 H) 7.35 (s, 1 H) 7.33 (d, J = 3.05 Hz, 1 H) 7.26 - 7.32 (m, 1 H) 7.07 - 7.13 (m, 1 H) 6.87 (d, J = 8.54 Hz, 1 H) 6.28 (d, J = 2.75 Hz, 1 H) 3.43 - 3.70 (m, 7 H) 3.25 (s, 4 H) 3.07 (q, J = 7.43 Hz, 2 H) 1.22 (t, J = 7.32 Hz, 3 H); (ESI) m/z 557 (M+H)+.
Example 138 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 138a 4-(2-fluoro(methylsulfonyl)phenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one A mixture of Example 6a (0.642 g, 1.5 mmol), 2-bromofluoro lsulfonyl)benzene (0.380 g, 1.500 mmol), 1,3,5,7-tetramethylphenyl-2,4,8-trioxa phosphaadamantane (0.051 g, 0.176 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.041 g, 0.045 mmol), and potassium phosphate (0.796 g, 3.75 mmol) in dioxane (10 mL) and water (2.500 mL) was degassed and back-filled with nitrogen several times. The reaction was heated at 60 ºC for 16 hours. The reaction e was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined c layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 30% ethyl acetate in hexanes to give the title compound (0.63 g, 1.328 mmol, 89% yield).
Example 138b 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone 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 (1 mL) was heated at 120 °C for 16 hours. The on mixture was partitioned between water and ethyl e. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and trated. The residue was purified by reverse phase Preparative HPLC (10-80% acetonitrile in 0.1% TFA/water) to give the title compound (0.036 g, 0.084 mmol, 79% . 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.10 (s, 1H), 7.99 (d, J = 2.44 Hz, 1H), 7.86 (dd, J = 8.54, 2.44 Hz, 1H), 7.40-7.56 (m, 3H), 7.31 (t, J = 2.9 Hz, 1H), 7.14-7.20 (m, 1H), 6.98 (d, J = 8.54 Hz, 1H), 6.28-6.30 (m, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 431.1 (M+H)+.
Example 139 4-[2-(4-chlorobenzoyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 139 was prepared according to the procedure used for the preparation of Example 95d, substituting substituting (2-bromophenyl)(4-chlorophenyl)methanone for e 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 11.96 (s, 1H), 7.86-7.73 (m, 1H), 7.55-7.62 (m, 3H), .43 (m, 2H), 7.25-7.29 (m, 2H), 7.21 (t, J = 2.75 Hz, 1H), 6.88 (s, 1H), 6.05-6.06 (m, 1H), 3.39 (s, 3H). MS (DCI+) m/z 363.0 (M+H)+.
Example 140 4-{2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone A mixture of Example 139 (0.05 g, 0.138 mmol) and sodium tetrahydroborate (2) (5.21 mg, 0.138 mmol) in tetrahydrofuran (2 mL) was heated at 60 °C for 3 hours. The solvent was d, and the residue was purified by reverse phase Preparative HPLC (10- 80% acetonitrile in 0.1% TFA/water) to give the title compound (0.042 g, 0.115 mmol, 84% yield) . 1H NMR (500 MHz, DMSO-d 6) δ ppm 11.70 (s, 1H), 7.56 (d, J = 7.63 Hz, 1H), 7.35- 7.39 (m, 1H), 7.27-7.31 (m, 1H), 7.21-7.23 (m, 4H), 7.00 (d, J = 8.54 Hz, 2H), 6.79 (s, 1H), .94 (t, J = 2.29 Hz, 1H), 5.75 (s, 1H), 3.47 (s, 3H). MS (DCI+) m/z 365.0 (M+H)+.
Example 141 N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(pyrimidin yloxy)phenyl]ethanesulfonamide Example 141a 6-methyl(5-nitro(pyrimidinyloxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one e 141a was prepared according to the ure used for the preparation of Example 2b, substituting pyrimidinol for phenol, to provide the title compound.
Example 141b 4-(5-amino(pyrimidinyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 141b was prepared according to the procedure used for the preparation of Example 3, tuting Example 141a for Example 2b, to provide the title compound.
Example 141c N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(pyrimidin yloxy)phenyl]ethanesulfonamide Example 141c was ed according to the procedure used for the preparation of Example 4 (Method A), substituting Example 141b for Example 3 and substituting ethanesulfonyl chloride for methanesulfonyl chloride, to e the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.03 (bs, 1H), 9.90 (s, 1H), 8.35 (s, 2H), 7.40 (d, J = 2.3 Hz, 1H), 7.31-7.22 (m, 4H), 6.25-6.20 (m, 1H), 3.49 (s, 3H), 3.17 (q, J = 7.3 Hz, 2H), 1.24 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 462.2 (M+H)+.
Example 142 N-{3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)[(1-methyl-1H-pyrazol- -yl)methoxy]phenyl}ethanesulfonamide Example 142a 6-methyl(2-((1-methyl-1H-pyrazolyl)methoxy)nitrophenyl)-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 142a was prepared according to the procedure used for the preparation of e 29a, substituting (1-methyl-1H-pyrazolyl)methanol for tetrahydro-2H-pyran ol, to provide the title compound.
Example 142b 4-(5-amino((1-methyl-1H-pyrazolyl)methoxy)phenyl)methyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 142b was prepared according to the procedure used for the preparation of Example 3, tuting Example 142a for Example 2b, to e the title compound.
Example 142c N-{3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)[(1-methyl-1H-pyrazol- -yl)methoxy]phenyl}ethanesulfonamide Example 142c was ed according to the procedure used for the preparation of Example 4 (Method A), substituting Example 142b for Example 3 and substituting ethanesulfonyl chloride for methanesulfonyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.01 (bs, 1H), 9.58 (s, 1H), .14 (m, 6H), 6.20 (d, J = 1.8 Hz, 1H), 6.10 (dd, J = 2.8, 1.9 Hz, 1H), 5.10 (s, 2H), 3.63 (s, 3H), 3.50 (s, 3H), 3.04 (q, J = 7.4 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H). MS (ESI+) m/z 442.1 (M+H)+.
Example 143 N-{4-[(1,3-dimethyl-1H-pyrazolyl)methoxy](6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenyl}ethanesulfonamide Example 143a 4-(2-((1,3-dimethyl-1H-pyrazolyl)methoxy)nitrophenyl)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-pyrazolyl)methanol for tetrahydro-2H-pyran- 4-ol, to provide the title compound.
Example 143b 4-(5-amino((1,3-dimethyl-1H-pyrazolyl)methoxy)phenyl)methyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 143b was prepared according to the procedure used for the preparation of e 3, substituting Example 143a for Example 2b, to provide the title compound.
Example 143c N-{4-[(1,3-dimethyl-1H-pyrazolyl)methoxy](6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenyl}ethanesulfonamide Example 143c was ed according to the procedure used for the preparation of Example 4 (Method A), substituting Example 143b for e 3 and substituting ethanesulfonyl de for methanesulfonyl chloride, to provide the title nd. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.04-11.99 (m, 1H), 9.57 (s, 1H), 7.29-7.13 (m, 5H), 6.12-6.07 (m, 1H), 5.98 (s, 1H), 5.03 (s, 2H), 3.54 (s, 3H), 3.50 (s, 3H), 3.04 (q, J = 7.3 Hz, 2H), 2.05 (s, 3H), 1.21 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 456.2 (M+H)+. e 144 N-[4-(2,2-dimethylpropoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide Example 144a 6-methyl(2-(neopentyloxy)nitrophenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one e 144a was prepared according to the procedure used for the preparation of Example 29a, substituting 2,2-dimethylpropanol for tetrahydro-2H-pyranol, to provide the title compound.
Example 144b 4-(5-amino(neopentyloxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 144b was ed ing to the procedure used for the preparation of 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 e 144b for Example 3 and substituting ethanesulfonyl chloride for methanesulfonyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.00 (s, 1 H) 9.50 (s, 1 H) 7.26-7.33 (m, 3 H) 7.15 (dd, J = 2.71, 8.82 Hz, 1 H) 7.06 (d, J = 9.16 Hz, 1 H) 6.17-6.22 (m, 1 H) 3.59 (s, 2 H) 3.54 (s, 3 H) 3.03 (q, J = 7.23 Hz, 2 H) 1.21 (t, J = 7.29 Hz, 3 H) 0.84 (s, 9 H). MS (ESI+) m/z 416.5 (M-H)+. e 145 N-[4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide Example 145a 4-(2-(cyclopropylmethoxy)nitrophenyl)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-pyranol, to provide the title compound.
Example 145b 4-(5-amino(cyclopropylmethoxy)phenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one e 145b was prepared according to the procedure used for the preparation of Example 3, substituting e 145a for Example 2b, to provide the title compound.
Example 145c N-[4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide e 145c was prepared according to the procedure used for the preparation of Example 4 (Method A), substituting Example 145b for Example 3 and substituting ethanesulfonyl chloride for methanesulfonyl chloride, to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.02-11.97 (m, 1H), 9.49 (s, 1H), .24 (m, 3H), 7.14 (dd, J = 8.7, 2.7 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.21-6.16 (m, 1H), 3.80 (d, J = 6.7 Hz, 2H), 3.56 (s, 3H), 3.02 (q, J = 7.3 Hz, 2H), 1.21 (t, J = 7.3 Hz, 3H), 1.08 (m, 1H), 0.50- 0.39 (m, 2H), 0.27 0.18 (m, 2H). MS (ESI+) m/z 402.1 .
Example 146 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide Example 146a 4-(2,4-difluorophenoxy)nitrobenzenesulfonamide A solution of 2,4-difluorophenol (5.39 g, 41.4 mmol) in N,N-dimethylformamide (34.5 mL) was cooled to 10 °C and treated portionwise with sodium hydride (1.66 g, 41.4 mmol). After stirring 15 minutes, 4-fluoronitrobenzenesulfonamide (2.28 g, 10.36 mmol) was added nwise. The reaction e was stirred at ambient temperature for 1.5 hours, diluted into ethyl acetate and quenched with 0.5 M HCl to pH 6. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium e, filtered, and concentrated to provide the title nd (3.24 g, 95%).
Example 146b 3-amino(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 °C for 3 hours. The mixture was filtered through a nylon membrane and concentrated. The residue partitioned between ethyl e and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (2.81 g, 95%).
Example 146c 4-(2,4-difluorophenoxy)iodobenzenesulfonamide To a solution of Example 146b (2.8 g, 9.32 mmol) in dioxane (20 mL) at 0 °C was added trated hydrochloric acid (40 mL, 9.32 mmol). The mixture was stirred 15 minutes and a solution of sodium nitrite (0.772 g, 11.19 mmol) in water (10 mL) was added.
The mixture was d for 1 hour at 0 °C. A solution of potassium iodide (3.10 g, 18.7 mmol) in water (10mL) was added and stirring was continued 1 hour at ambient temperature.
The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium thiosulfate, water, and saturated aqueous sodium chloride, dried over anhydrous ium sulfate, filtered, and concentrated. The residue was purified by flash column tography (silica gel, 0-60% ethyl acetate in hexane) to provide the title compound (2.24 g, 58.4% yield).
Example 146d 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide A suspension of Example 146c (111 mg, 0.270 mmol), Example 6a (150 mg, 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 under microwave conditions at 150° C for 5 minutes. The reaction mixture was partitioned between ethyl e (75 mL) and 50% aqueous sodium chloride (75 mL). The c layer was dried over ous sodium e, filtered, and concentrated.
To a solution of the residue in dioxane (4 mL) was added a solution of lithium hydroxide hydrate (113 mg, 2.7 mmol) in water (1 mL) and the mixture was heated under microwave conditions at 120° C for 30 minutes. 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 in dichloromethane) to provide the title compound (74 mg, 63.5% yield). 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.09 (s, 1H), 7.92 (d, J = 2.37 Hz, 1H), 7.76 (dd, J = 8.82, 2.37 Hz, 1H), 7.43-7.53 (m, 1H), .40 (m, 5H), 7.08-7.18 (m, 1H), 6.95 (d, J = 8.82 Hz, 1H), 6.27 (d, J = 2.71 Hz, 1H), 3.58 (s, 3H). MS (ESI+) m/z 432.2 (M+H)+.
Example 147 4-[2-(cyclohexylamino)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone e 147a o-N-cyclohexyl(methylsulfonyl)aniline A mixture of 2-bromofluoro(methylsulfonyl)benzene (0.05 g, 0.198 mmol) and cyclohexanamine (0.059 g, 0.593 mmol) in dioxane (1 mL) in a vial was capped and heated at 110 °C for three days. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl e twice. The combined organic layers were washed with saturated aqueous sodium de, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 40% ethyl acetate in hexanes to afford the title compound (0.044 g, 0.132 mmol, 67.0% yield).
Example 147b 4-[2-(cyclohexylamino)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- dinone 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. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.13 (s, 1H), 7.66 (dd, J = 8.7, 2.29 Hz, 1H), 7.51 (d, J = 2.14 Hz, 1H), 7.30 (t, J = 2.75 Hz, 1H), 7.26 (s, 1H), 6.86 (d, J = 8.85 Hz, 1H), 6.00-6.01 (m, 1H), 4.83 (br, s, 1H), 3.56 (s, 3H), 3.35-3.44 (m, 1H), 1.84-1.87 (m, 2H), 1.53-1.62 (m, 3H), 1.27-1.37 (m, 2H), 1.03-1.12 (m, 3H). MS (APCI+) m/z 400.1 (M+H)+.
Example 148 4-[5-amino(2,4-difluorophenoxy)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- d]pyridazinone Example 148a Example 148a was prepared according to the procedure used for the preparation of Example 2b, substituting 2-bromofluoronitrobenzene for e 2a, and 2,4- difluorophenol for phenol, respectively, to provide the title compound.
Example 148b 3-bromo(2,4-difluorophenoxy)aniline Example 148b was prepared according to the procedure used for the ation of Example 3, substituting e 148a for Example 2b, to provide the title compound.
Example 148c 4-(2,4-difluorophenoxy)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)aniline e 148c was ed according to the procedure used for the preparation of Example 6a, substituting Example 148b for Example 1e, to provide the title compound.
Example 148d 4-[5-amino(2,4-difluorophenoxy)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- d]pyridazinone Example 148d was prepared according to the procedure used for the preparation of Example 95d, tuting Example 80b for Example 95c and Example 148c for Example 6a, respectively, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.69 (s, 1H), 7.44 (t, J = 2.59 Hz, 1H), 7.32-7.37 (m, 2H), 7.16 (d, J = 2.75 Hz, 1H), 7.05-7.12 (m, 1H), 6.97-7.02 (m, 1H), 6.92 (d, J = 8.54 Hz, 1H), 3.37-6.39 (m, 1H), 3.70 (s, 3H). MS (ESI+) m/z 369.4 .
Example 149 4-[2-(2-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 149 was prepared according to the procedure used for the preparation of Example 138b, tuting 2-fluorophenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.99 (d, J = 2.4 Hz, 1H), 7.89 (dt, J = 7.7, 3.9 Hz, 1H), 7.50 – 7.38 (m, 2H), 7.35 – 7.24 (m, 4H), 6.98 (d, J = 8.6 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 3.60 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 413(M+H)+.
Example 150 4-[2-(3-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone e 150 was prepared according to the procedure used for the preparation of Example 138b, substituting 3-fluorophenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.01 (t, J = 3.4 Hz, 1H), 7.93 (dt, J = 7.1, 3.5 Hz, 1H), 7.47 – 7.37 (m, 2H), 7.34 (t, J = 3.3 Hz, 1H), 7.21 (t, J = 6.3 Hz, 1H), 6.96 (dddd, J = 26.2, 21.5, 8.3, 2.2 Hz, 3H), 6.30 (d, J = 2.8 Hz, 1H), 3.57 (s, 3H), 3.27 (s, 3H).
MS (ESI+) m/z 413(M+H)+.
Example 151 4-[2-(4-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 151 was prepared ing to the procedure used for the preparation of Example 138b, tuting 4-fluorophenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ ppm 7.98 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.7, 2.4 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.31 – 7.22 (m, 2H), 7.22 – 7.10 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 6.31 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.25 (s, 3H). MS (ESI+) m/z 413(M+H)+.
Example 152 2-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 152 was prepared according to the procedure used for the preparation of Example 138b, substituting 2-chlorophenol for fluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.02 (dd, J = 7.0, 1.6 Hz, 1H), 7.96 – 7.85 (m, 1H), 7.65 – 7.57 (m, 1H), 7.47 (s, 1H), 7.44 – 7.34 (m, 2H), 7.33 – 7.21 (m, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z H)+.
Example 153 4-[2-(3-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- dinone Example 153 was prepared according to the procedure used for the preparation of Example 138b, substituting 3-chlorophenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.01 (d, J = 2.4 Hz, 1H), 7.99 – 7.88 (m, 1H), 7.43 – 7.37 (m, 2H), 7.35 (t, J = 3.3 Hz, 1H), 7.27 – 7.19 (m, 2H), 7.16 (dd, J = .2, 8.1 Hz, 1H), 7.08 – 6.93 (m, 1H), 6.30 (d, J = 2.8 Hz, 1H), 3.57 (s, 3H), 3.27 (s, 3H).
MS (ESI+) m/z 429(M+H)+.
Example 154 4-[2-(4-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone 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. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.00 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.3, 2.0 Hz, 1H), 7.56 – 7.38 (m, 3H), 7.34 (t, J = 3.3 Hz, 1H), 7.19 – 7.07 (m, 3H), 6.29 (d, J = 2.8 Hz, 1H), 3.58 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 429(M+H)+.
Example 155 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) lsulfonyl)phenoxy]benzonitrile Example 155 was prepared according to the procedure used for the preparation of Example 138b, substituting 3-cyanophenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.02 (d, J = 2.4 Hz, 1H), 7.99 – 7.91 (m, 1H), 7.68 – 7.49 (m, 3H), 7.46 – 7.38 (m, 2H), 7.38 – 7.32 (m, 1H), 7.24 (d, J = 8.6 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H). MS (ESI+) m/z 420(M+H)+.
Example 156 4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]benzonitrile Example 156 was ed according to the procedure used for the preparation of Example 138b, substituting ophenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.05 (d, J = 2.4 Hz, 1H), 8.02 – 7.94 (m, 1H), 7.80 – 7.73 (m, 2H), 7.38 (t, J = 4.3 Hz, 2H), 7.33 (t, J = 3.3 Hz, 1H), 7.17 – 7.03 (m, 2H), 6.25 (d, J = 2.8 Hz, 1H), 3.54 (s, 3H), 3.29 (s, 3H). MS (ESI+) m/z 420(M+H)+.
Example 157 6-methyl{5-(methylsulfonyl)[3-(trifluoromethyl)phenoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 157 was prepared according to the procedure used for the preparation of Example 138b, substituting 3-trifluorormethylphenol for 2,4-difluorophenol, to e the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.03 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.6, 2.4 Hz, 1H), 7.62 – 7.56 (m, 1H), 7.54 – 7.48 (m, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7.37 – 7.31 (m, 3H), 7.25 (d, J = 8.6 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 3.55 (s, 3H), 3.28 (s, 3H). MS (ESI+) m/z 463(M+H)+.
Example 158 4-[2-(cyclopropylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Cyclopropylmethanol (0.014 g, 0.19 mmol) in tetrahydrofuran (2 mL) 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 ºC for 16 hours. The solvent was d, and the residue was purified by Preparative HPLC (C18, 10-80% CH3CN/water (0.1% TFA)) to give the title compound (0.012 g, 0.032 mmol, 51.0% yield). 1H NMR (400 SO- d6/D2O) δ ppm 7.88 (dd, J = 8.6, 2.5 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.37 (s, 1H), 7.34 (d, J = 2.4 Hz, 2H), 7.32 (d, J = 3.5 Hz, 2H), 6.17 (d, J = 2.8 Hz, 1H), 3.99 (d, J = 6.8 Hz, 2H), 3.20 (s, 3H), 1.17 – 1.06 (m, 1H), 0.52 – 0.41 (m, 2H), 0.34 – 0.24 (m, 2H).MS (ESI+) m/z 373 .
Example 159 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin yl)phenyl]methanesulfonamide e 159 was prepared according to the procedure used for the preparation of Example 4 (Method A), substituting Example 148d for Example 3, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.72 (s, 1H), 9.79 (s, 1H), 7.45 (t, J = 2.59 Hz, 1H), 7.40 (t, J = 2.44 Hz, 1H), 7.31-7.38 (m, 2H), 7.11-7.17 (m, 1H), 6.89-7.03 (m, 1H), 6.39-6.40 (m, 1H), 3.70 (s, 3H), 3.02 (s, 3H). MS (ESI+) m/z 447.1 (M+H)+.
Example 160 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin yl)phenyl]ethanesulfonamide Example 160 was prepared according to the procedure used for the preparation of Example 4 d A), substituting Example 148d for Example 3, and ethanesulfonyl de for methanesulfonyl chloride, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.72 (s, 1H), 9.86 (s, 1H), 7.45 (t, J = 2.75 Hz, 1H), 7.41 (d, J = 2.75 Hz, 1H), 7.31-7.40 (m, 2H), 7.10-7.16 (m, 1H), .03 (m, 1H), .39 (m, 1H), 3.70 (s, 3H), 3.11 (q, J = 7.43 Hz, 2H), 1.23 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 461.1 (M+H)+.
Example 161 4-[2-(isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 161 was prepared according to the procedure used for the preparation of Example 138b, substituting isoquinolinol for 2,4-difluorophenol, to provide the TFA salt of the title compound. 1H NMR (400 SO-d 6/D2O) δ ppm 9.68 (s, 1H), 8.58 (d, J = 6.4 Hz, 1H), 8.30 (d, J = 6.4 Hz, 1H), 8.11 (t, J = 4.9 Hz, 2H), 8.00 (dd, J = 8.6, 2.4 Hz, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.40 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 6.39 (d, J = 2.8 Hz, 1H), 3.97 (s, 1H), 3.47 (s, 3H), 3.31 (s, 3H). MS (ESI+) m/z 445 (M+H)+.
Example 162 6-methyl[5-(methylsulfonyl)(quinolinyloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 162 was prepared according to the procedure used for the preparation of Example 138b, tuting quinolinol for 2,4-difluorophenol, to provide the TFA salt of the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 9.03 (dd, J = 4.8, 1.4 Hz, 1H), 8.71 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.6, 2.4 Hz, 1H), 7.88 – 7.80 (m, 1H), 7.74 (dt, J = 3.7, 2.5 Hz, 2H), 7.45 (s, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.32 (t, J = 3.3 Hz, 1H), 6.34 (d, J = 2.8 Hz, 1H), 3.53 (d, J = 6.8 Hz, 3H), 3.30 (s, 3H). MS (ESI+) m/z 446 (M+H)+.
Example 163 2-chloro(trifluoromethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 163 was prepared according to the procedure used for the preparation of Example 138b, substituting rotrifluoromethylphenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.03 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 8.7, 2.4 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 16.2, 8.4 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.27 – 7.13 (m, 2H), 6.33 (d, J = 2.9 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H). MS (ESI+) m/z 496 (M+H)+.
Example 164 4-{2-[2-fluoro(trifluoromethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 164 was prepared according to the procedure used for the preparation of Example 138b, substituting 2-fluorotrifluoromethylphenol for 2,4-difluorophenol, to provide the title nd. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.01 (d, J = 2.4 Hz, 1H), 7.93 (dd, J = 8.6, 2.4 Hz, 1H), 7.67 – 7.55 (m, 3H), 7.43 (s, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.23 – 7.15 (m, 2H), 6.29 (d, J = 2.8 Hz, 1H), 3.57 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 480 (M+H)+.
Example 165 2-{4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]phenyl}acetamide Example 165 was prepared according to the procedure used for the preparation of Example 138b, substituting ydroxyphenyl)acetamide for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.97 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 8.6, 2.4 Hz, 1H), 7.43 (s, 1H), 7.36 – 7.30 (m, 3H), 7.09 – 7.00 (m, 3H), 6.31 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.39 (s, 2H), 3.24 (s, 3H). MS (ESI+) m/z 452(M+H)+.
Example 166 3-aminophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone e 166 was prepared according to the procedure used for the preparation of Example 138b, substituting 3-aminophenol for 2,4-difluorophenol, to provide the TFA salt of the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.00 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.6, 2.4 Hz, 1H), 7.40 (s, 1H), 7.36 – 7.24 (m, 2H), 7.15 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 8.0, 1.9 Hz, 1H), 6.70 – 6.62 (m, 2H), 6.27 (d, J = 2.8 Hz, 1H), 3.96 (s, 1H), 3.58 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 410(M+H)+.
Example 167 6-methyl[5-(methylsulfonyl)(tetrahydrofuranylamino)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 167a N-(2-bromo(methylsulfonyl)phenyl)tetrahydrofuranamine Example 167a was prepared according to the procedure used for the preparation of Example 147a, substituting ydrofuranamine for cyclohexanamine, to provide the title compound.
Example 167b 6-methyl[5-(methylsulfonyl)(tetrahydrofuranylamino)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 167b was prepared according to the ure used for the ation of Example 95d, substituting Example 167a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 7.70 (dd, J = 8.7, 2.29 Hz, 1H), 7.54 (d, J = 2.44 Hz, 1H), 7.29 (t, J = 2.75 Hz, 1H), 7.27 (s, 1H), 6.87 (d, J = 8.85 Hz, 1H), 6.00 (t, J = 2.29 Hz, 1H), 5.25 (br s, 1H), 4.17 (br s, 1H), 3.68 (q, J = 7.32, Hz, 2H), 3.56 (s, 3H), 3.49 (dd, J = 9, 3.51 Hz, 1H), 3.12 (s, 3H), 2.12-2.19 (m, 1H), 1.74-1.77 (m, 1H). MS (ESI+) m/z 388.2 .
Example 168 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 168a (3-bromofluorophenyl)(ethyl)sulfane A mixture of 3-bromofluorobenzenethiol (3.89 g, 18.79 mmol) and sodium hydroxide (3.95 mL, 19.73 mmol) in MeOH was stirred at 0 ºC for 10 minutes. To this solution was added hane (1.803 mL, 22.54 mmol). The on 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 with addition ethyl acetate three times. The combined organic layers were washed with ted aqueous sodium chloride, 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 for the next reaction.
Example 168b 2-bromo(ethylsulfonyl)fluorobenzene Example 168a (4.4 g, 18.71 mmol) in dichloromethane (250 mL) was cooled to 0 ºC.
To this solution was treated with mCPBA (10.15 g, 41.2 mmol) portionwise. The reaction was stirred at ambient temperature for 6 hours. The solid from the reaction mixture was removed by filtration. The filtrate was washed with saturated aqueous sodium bicarbonate several times. The aqueous layer was then extracted with additional dichloromethane three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate/hexanes to afford the title nd (4.4 g, 16.47 mmol, 88% yield).
Example 168c ethylsulfonyl)fluorophenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 168c was prepared according to the procedure used for the preparation of Example 138a, tuting Example 168b for 2-bromofluoro(methylsulfonyl)benzene, to e the title nd.
Example 168d 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 168d was prepared according to the procedure used for the preparation of e 138b, substituting Example 168c for Example 138a, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.31 (s, 1H), 7.93 (d, J = 2.44 Hz, 1H), 7.83 (dd, J = 8.54, 2.44 Hz, 1H), 7.52-7.54 (m, 1H), 7.42-7.46 (m, 2H), 7.32 (t, J = 2.75 Hz, 1H), 7.16-7.19 (m, 1H), 6.99 (d, J = 8.54 Hz, 1H), .28 (m, 1H), 3.59 (s, 3H), 3.38 (q, J = 7.32, Hz, 2H), 1.15 (t, J = 7.32 Hz, 1H). MS (ESI+) m/z 445.2 (M+H)+.
Example 169 4-{2-[(4,4-difluorocyclohexyl)oxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 169 was prepared according to the procedure used for the preparation of Example 158, substituting Example 168c for Example 138a, and 4,4-difluorocyclohexanol for cyclopropylmethanol, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), .85 (m, 2H), 7.45 (d, J = 8.85 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J = 2.75 Hz, 1H), .13 (m, 1H), 4.81 (s, 1H), 3.56 (s, 3H), 3.29 (q, J = 7.32, Hz, 2H), 1.70-1.87 (m, 8H), 1.14 (t, J = 7.32 Hz, 1H). MS (ESI+) m/z 451.2 (M+H)+.
Example 170 4-{5-(ethylsulfonyl)[(1-methylpiperidinyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 170 was prepared according to the procedure used for the preparation of Example 158, substituting e 168c for Example 138a, and 1-methylpiperidinol for cyclopropylmethanol, respectively, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.13 (s, 1H), 7.81-7.87 (m, 2H), 7.46 (d, J = 8.85 Hz, 1H), 7.34 (s, 1H), 7.32 (t, J = 2.75 Hz, 1H), .12 (m, 1H), 4.86 (s, 1H), 3.56 (s, 3H), 3.30 (s, 3H), 3.29 (q, J = 7.32, Hz, 2H), .29 (m, 1H), 3.04-3.10 (m,1H), .29 (m, 2H), 1.91-2.05 (m, 2H), 1.14 (t, J = 7.32 Hz, 1H). MS (ESI+) m/z 430.2 (M+H)+.
Example 171 4-[2-(2,1,3-benzothiadiazolyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 171 was prepared according to the procedure used for the preparation of Example 138b, substituting benzo[c][1,2,5]thiadiazolol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.04 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 8.6, 2.4 Hz, 1H), 7.69 (dd, J = 8.8, 7.5 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 7.1 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 2.8 Hz, 1H), 3.55 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 453(M+H)+. e 172 4-[2-(isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 172 was prepared according to the procedure used for the preparation of e 138b, substituting isoquinolinol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d6/D2O) δ ppm 8.65 (s, 1H), 8.39 (s, 1H), 8.24 (d, J = 8.9 Hz, 1H), 8.16 – 8.04 (m, 1H), 8.03 (dd, J = 8.6, 2.4 Hz, 1H), 7.95 – 7.76 (m, 2H), 7.47 (dd, J = 20.3, 11.7 Hz, 2H), 7.31 (t, J = 5.9 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 3.51 (s, 3H), 3.31 (s, 3H). MS (ESI+) m/z 446(M+H)+.
Example 173 4-[2-(2,5-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone e 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. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.08 – 7.98 (m, 1H), 7.97 – 7.83 (m, 1H), 7.50 – 7.39 (m, 2H), 7.35 (t, J = 3.3 Hz, 1H), 7.33 – 7.21 (m, 1H), 7.20 – 7.08 (m, 2H), 6.31 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.25 (d, J = 6.7 Hz, 3H) MS (ESI+) m/z 431(M+H)+.
Example 174 4-[2-(3,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 174 was prepared according to the procedure used for the preparation of Example 138b, substituting 3,4-difluorophenol for fluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.99 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.6, 2.4 Hz, 1H), 7.53 – 7.40 (m, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.29 (ddd, J = 11.4, 6.8, 2.9 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.95 (dd, J = 8.8, 5.0 Hz, 1H), 6.31 (d, J = 2.8 Hz, 1H), 3.58 (s, 3H), 3.25 (s, 3H). MS (ESI+) m/z 431(M+H)+.
Example 175 6-methyl{5-(methylsulfonyl)[(1-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}-1,6- o-7H-pyrrolo[2,3-c]pyridinone Example 175 was prepared according to the procedure used for the preparation of Example 138b, substituting oxy-2,3-dihydro-1H-indenone for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.02 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.6, 2.4 Hz, 1H), 7.50 – 7.41 (m, 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.28 (dd, J = 7.3, 1.4 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 3.62 – 3.54 (m, 2H), 3.27 (s, 1H), 2.89 – 2.82 (m, 1H), 2.65 – 2.59 (m, 1H). MS (ESI+) m/z 449(M+H)+.
Example 176 4-[2-(3,5-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 176 was ed ing to the procedure used for the preparation of Example 138b, substituting 3,5-difluorophenol for 2,4-difluorophenol, to provide the title nd. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.02 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 8.6, 2.4 Hz, 1H), 7.40 (s, 1H), 7.34 (dd, J = 5.7, 2.8 Hz, 2H), 6.98 (tt, J = 9.3, 2.3 Hz, 1H), 6.83 – 6.62 (m, 2H), 6.29 (d, J = 2.8 Hz, 1H), 3.56 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 431(M+H)+.
Example 177 6-methyl[2-(4-methylphenoxy)(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone 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. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.96 (d, J = 2.4 Hz, 1H), 7.88 – 7.79 (m, 1H), 7.42 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.00 (dd, J = 8.6, 4.3 Hz, 3H), 6.30 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.24 (s, 3H). MS (ESI+) m/z 409(M+H)+.
Example 178 4-[2-(2-methoxyphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 178 was ed according to the procedure used for the preparation of Example 138b, substituting 2-methoxyphenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.94 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.7, 2.4 Hz, 1H), 7.47 (s, 1H), 7.39 – 7.25 (m, 2H), 7.26 – 7.13 (m, 2H), 7.03 (td, J = 7.6, 1.5 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 6.43 (d, J = 2.8 Hz, 1H), 3.61 (s, 3H), 3.23 (s, 3H). MS (ESI+) m/z 425(M+H)+.
Example 179 6-methyl{2-[(2-methylpyridinyl)oxy](methylsulfonyl)phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 179 was prepared according to the procedure used for the preparation of Example 138b, tuting ylpyridinol for 2,4-difluorophenol, to e the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.38 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.5, 2.4 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 8.4, 4.9 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 3.56 (s, 3H), 3.28 (s, 3H), 2.41 (s, 3H). MS (ESI+) m/z 410(M+H)+.
Example 180 4-{2-[3-(dimethylamino)phenoxy](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone 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. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.97 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 8.6, 2.4 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 8.3, 2.4 Hz, 1H), 6.52 – 6.43 (m, 2H), 6.31 (d, J = 2.8 Hz, 1H), 3.58 (s, 3H), 3.24 (s, 3H), 2.90 (s, 6H). MS (ESI+) m/z 438(M+H)+.
Example 181 6-methyl{5-(methylsulfonyl)[(1-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone e 181 was prepared according to the procedure used for the preparation of Example 138b, substituting 5-hydroxy-2,3-dihydro-1H-indenone for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.04 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.6, 2.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.34 (dd, J = 6.9, 5.8 Hz, 2H), 7.11 (s, 1H), 7.08 – 6.97 (m, 1H), 6.28 (d, J = 2.9 Hz, 1H), 3.54 (s, 3H), 3.29 (s, 3H), 3.00 (d, J = 5.0 Hz, 2H), 2.62 – 2.58 (m, 2H). MS (ESI+) m/z 449(M+H) Example 182 6-methyl{5-(methylsulfonyl)[(3-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 182 was prepared ing to the procedure used for the preparation of Example 138b, substituting 6-hydroxy-2,3-dihydro-1H-indenone for 2,4-difluorophenol, to provide the title compound 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.01 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 14.0 Hz, 2H), 7.34 (d, J = 2.8 Hz, 1H), 7.22 – 7.10 (m, 2H), 6.30 (d, J = 2.8 Hz, 1H), 3.56 (s, 3H), 3.26 (s, 3H), 3.06 (s, 2H), 2.69 (s, 3H). MS (ESI+) m/z 449(M+H)+.
Example 183 2-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (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 e the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.06 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.5, 2.4 Hz, 1H), 7.81 (dd, J = 7.7, 1.6 Hz, 1H), 7.67 – 7.59 (m, 1H), 7.41 (s, 1H), 7.39 – 7.24 (m, 3H), 7.09 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 3.56 (s, 3H), 3.29 (s, 3H). MS (ESI+) m/z 420(M+H)+. e 184 4-[2-(3-chlorofluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 184 was prepared according to the procedure used for the preparation of Example 138b, tuting 2-fluoro-3chlorophenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.00 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.6, 2.4 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.35 (d, J = 2.8 Hz, 1H), 7.28 – 7.23 (m, 2H), 7.13 (d, J = 8.6 Hz, 1H), 6.28 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 447(M+H)+.
Example 185 6-methyl[5-(methylsulfonyl)(naphthalenyloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 185 was prepared according to the ure used for the preparation of Example 138b, substituting naphthalenol for fluorophenol, to provide the title compound. 1H NMR (400 SO-d 6/D2O) δ ppm 8.02 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.9 Hz, 2H), 7.96 – 7.87 (m, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.59 – 7.44 (m, 4H), 7.36 – 7.28 (m, 2H), 7.15 (d, J = 8.6 Hz, 1H), 6.37 (d, J = 2.8 Hz, 1H), 3.58 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 445(M+H)+. e 186 4-[2-(2-fluoromethylphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 186 was prepared according to the procedure used for the preparation of Example 138b, substituting 2-fluoro-5methylphenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.98 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.6, 2.4 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.27 (dd, J = 10.9, 8.1 Hz, 1H), 7.14 – 7.06 (m, 2H), 6.98 (d, J = 8.6 Hz, 1H), 6.31 (d, J = 2.8 Hz, 1H), 3.60 (s, 3H), 3.25 (s, 3H), 2.27 (s, 3H). MS (ESI+) m/z 427(M+H)+.
Example 187 4-[2-(5-fluoromethylphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 187 was prepared according to the procedure used for the preparation of Example 138b, substituting 5-fluoromethylphenol for 2,4-difluorophenol, to e the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.11 – 7.96 (m, 1H), 7.91 (dt, J = .1, 2.8 Hz, 1H), 7.43 (s, 1H), 7.38 – 7.28 (m, 2H), 7.07 – 6.91 (m, 2H), 6.91 – 6.81 (m, 1H), 6.31 (t, J = 3.9 Hz, 1H), 3.58 (s, 3H), 3.26 (s, 3H), 2.04 (s, 3H). MS (ESI+) m/z 427(M+H)+.
Example 188 6-methyl[5-(methylsulfonyl)(quinolinyloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 188 was prepared according to the procedure used for the ation of Example 138b, substituting quinolinol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.97 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 8.12 (dd, J = 12.8, 5.7 Hz, 2H), 8.02 (dd, J = 8.6, 2.4 Hz, 1H), 7.69 (dd, J = 8.3, 4.8 Hz, 1H), 7.55 – 7.41 (m, 4H), 7.32 (d, J = 2.8 Hz, 1H), 6.32 (s, 1H), 3.50 (d, J = 16.9 Hz, 3H), 3.30 (d, J = 9.2 Hz, 3H). MS (ESI+) m/z 446(M+H)+.
Example 189 4-[2-(4-chlorofluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 189 was prepared according to the procedure used for the preparation of Example 138b, substituting 3-fluorochlorophenol for fluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.01 (t, J = 3.5 Hz, 1H), 7.99 – 7.90 (m, 1H), 7.68 – 7.52 (m, 1H), 7.40 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.29 – 7.24 (m, 1H), 7.20 (dd, J = 10.3, 2.7 Hz, 1H), 7.00 – 6.86 (m, 1H), 6.29 (t, J = 3.4 Hz, 1H), 3.57 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 447(M+H)+.
Example 190 6-methyl[5-(methylsulfonyl)(pyridinyloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- dinone Example 190 was prepared according to the procedure used for the preparation of Example 138b, substituting pyridinol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.03 (d, J = 2.3 Hz, 1H), 8.01 – 7.90 (m, 1H), 7.72 – 7.64 (m, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.37 – 7.30 (m, 1H), 7.30 – 7.15 (m, 1H), 6.36 – 6.24 (m, 1H), 3.56 (s, 3H), 3.27 (s, 3H). MS (ESI+) m/z 395(M+H)+.
Example 191 4-[2-(2,3-dihydro-1H-indenyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 191 was ed according to the procedure used for the preparation of e 138b, substituting 2,3-dihydro-1H-indenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.96 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 8.6, 2.4 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 2.2 Hz, 1H), 6.85 (dd, J = 8.1, 2.3 Hz, 1H), 6.31 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.23 (s, 3H), 2.88 – 2.79 (m, 4H), 2.03 (p, J = 7.4 Hz, 2H). MS (ESI+) m/z 435(M+H)+.
Example 192 6-methyl{5-(methylsulfonyl)[4-(propanyl)phenoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone e 192 was ed according to the procedure used for the preparation of Example 138b, substituting 4-isopropylphenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.97 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 8.6, 2.4 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.32 – 7.26 (m, 2H), 7.06 – 6.98 (m, 3H), 6.30 (d, J = 2.8 Hz, 1H), 3.58 (s, 3H), 3.24 (s, 3H), 2.89 (p, J = 6.9 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H) MS (ESI+) m/z 437(M+H)+.
Example 193 4-[2-(isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 193 was prepared according to the procedure used for the preparation of e 138b, substituting nolinol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.34 (bs, 1H), 8.12 (d, J = 2.3 Hz, 1H), 8.05 (dd, J = 8.4, 2.4 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.17 – 7.11 (m, 1H), 6.40 (d, J = 2.6 Hz, 1H), 3.44 (s, 3H), 3.32 (s, 3H). MS (ESI+) m/z 446(M+H)+.
Example 194 6-methyl[5-(methylsulfonyl)(3,4,5-trifluorophenoxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 194 was prepared according to the procedure used for the preparation of Example 138b, substituting 3,4,5-trifluorophenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 8.00 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 8.6, 2.4 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.18 – 7.10 (m, 2H), 6.31 (d, J = 2.8 Hz, 1H), 3.57 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 449(M+H)+. e 195 4-(2-benzylphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 195 was prepared according to the procedure used for the preparation of Example 95d, substituting 1-benzylbromobenzene for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.08 (s, 1H), 7.23-7.34 (m, 5H), 7.16- 7.19 (m, 2H), 7.09-7.12 (m, 1H), 6.92-6.93 (m, 3H), 5.95 (t, J = 2.29 Hz, 1H), 3.89 (s, 2H), 3.47 (s, 3H). MS (ESI+) m/z 315.3 (M+H)+.
Example 196 4-(biphenylyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 196 was prepared ing to the ure used for the preparation of Example 95d, substituting biphenylylboronic acid for Example 6a and e 1e for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 11.88 (s, 1H), .49 (m, 4H), 7.18-7.24 (m, 4H), 7.13-7.16 (m, 1H), 7.08 (t, J = 2.75 Hz, 1H), 6.93 (s, 1H), 5.77-5.78 (m, 1H), 3.38 (s, 3H). MS (ESI+) m/z 301.2 (M+H)+.
Example 197 1,4-dioxaspiro[4.5]decyloxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 197 was prepared according to the procedure used for the preparation of Example 158, substituting Example 168c for Example 138a, and 1,4-dioxaspiro[4.5]decan ol for cyclopropylmethanol, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 7.79-7.81 (m, 2H), 7.40-7.42 (m, 1H), 7.28-7.34 (m, 2H), 6.6.12-6.13 (m, 1H), 4.70-4.73 (m, 1H), 3.79-3.34 (m, 3H), 3.65 (s, 3H), 3.26-3.31 (m, 2H), 1.99-2.21 (m, 1H), 1.67-1.99 (m, 2H), 1.48-1.52 (m, 3H), 1.14 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 473.2 (M+H)+.
Example 198 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 198 was ed according to the procedure used for the preparation of Example 158, substituting Example 168c for Example 138a to provide the title compound. 1H NMR (500 MHz, 6) δ ppm 12.04 (s, 1H), 7.79-7.82 (m, 2H), 7.37 (s, 1H), 7.29-7.33 (m, 2H), 6.13-6.14 (m, 1H), 3.99 (d, J = 6.71 Hz, 2H), 3.58 (s, 3H), 3.27 (q, J = 7.32 Hz, 2H), 1.11-1.14 (m, 4H), 0.45-.048 (m, 2H), .29 (m, 2H). MS (ESI+) m/z 387.2 (M+H)+.
Example 199 4-{5-(ethylsulfonyl)[(4-oxocyclohexyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 197 (0.192 g, 0.406 mmol) was treated with 4.0 N en chloride in dioxane (1.016 mL, 4.06 mmol), tetrahydrofuran (10 mL), and water (2 mL). The reaction mixture was heated at 60 ºC for 2 hours. The solvent was removed, and the residue was purified by reverse phase HPLC (C18, 10-80% CH3CN/water (0.1% TFA)) to give the title compound (0.154 g, 0.359 mmol, 88% . 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.05 (s, 1H), 7.82-7.86 (m, 2H), 7.51 (d, J = 8.85 Hz, 1H), 7.34 (s, 1H), 7.28 (t, J = 2.75 Hz, 1H), 6.14 (t, J = 2.29 Hz, 1H), 4.97-4.99 (m, 1H), 3.56 (s, 3H), 3.30 (q, J = 7.32 Hz, 2H), 1.96- 2.24 (m, 8H), 1.15 (t, J = 7.48 Hz, 3H). MS (ESI+) m/z 429.2 (M+H)+.
Example 200 4-{2-[(cyclopropylmethyl)amino](ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 200a 2-bromo-N-(cyclopropylmethyl)(ethylsulfonyl)aniline Example 200a was prepared according to the procedure used for the preparation of e 147a, substituting cyclopropylmethanamine for cyclohexanamine, and Example 168b for 2-bromofluoro(methylsulfonyl)benzene to provide the title compound.
Example 200b (cyclopropylmethyl)amino](ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 200b was ed according to the procedure used for the preparation of Example 95d, substituting Example 200a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.14 (s, 1H), 7.62 (dd, J = 8.7, 2.29 Hz, 1H), 7.45 (d, J = 2.14 Hz, 1H) , 7.30 (t, J = 2.75 Hz, 1H), 7.26 (s, 1H), 6.86 ( J = 8.85 Hz, 1H), 6.00-6.01 (m, 1H), 5.50 (br s, 1H), 3.56 (s, 3H), 3.16 (q, J = 7.12 Hz, 2H), 3.04 (d, J = 6.71 Hz, 2H), 1.15 (t, J = 7.48 Hz, 3H), 0.97-1.04 (m, 1H), 0.36-0.41 (m, 2H), 0.14-0.18 (m, 2H). MS (ESI+) m/z 386.2 (M+H)+.
Example 201 6-methyl{5-(methylsulfonyl)[(tetrahydrofuranylmethyl)amino]phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 201a 2-bromo(ethylsulfonyl)-N-((tetrahydrofuranyl)methyl)aniline e 200a was prepared according to the procedure used for the preparation of Example 147a, substituting (tetrahydrofuranyl)methanamine for cyclohexanamine, and Example 168b for 2-bromofluoro(methylsulfonyl)benzene to provide the title compound.
Example 201b 6-methyl{5-(methylsulfonyl)[(tetrahydrofuranylmethyl)amino]phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 201b was prepared ing to the procedure used for the preparation of Example 95d, tuting Example 201a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 7.67 (dd, J = 8.85, 2.44 Hz, 1H), 7.50 (d, J = 2.14 Hz, 1H) , 7.28 (t, J = 2.9 Hz, 1H), 7.23 (s, 1H), 6.84 ( J = 8.85 Hz, 1H), .97 (m, 1H), 5.70 (br s, 1H), 3.55-3.70 (m, 7H), 3.38 (dd, J = 8.54, 4.88 Hz, 2H), 3.10 (m, 5H), 1.84- 1.92 (m, 1H), 1.47-1.55 (m, 1H). MS (ESI+) m/z 402.2 (M+H)+.
Example 202 4-{5-(ethylsulfonyl)[(cishydroxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone 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 ºC for 2 hours. The solvent was removed, and the solid was d with MeOH and a couple of drops of TFA. The resulting solution was purified by Preparative HPLC (C18, 10-80% CH3CN/water (0.1% TFA)) to give the title compound (second eluting peak, 0.036 g, 0.084 mmol, 68.9% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 7.78-7.82 (m, 2H), .38 (m, 2H) , 7.30 (t, J = 2.75 Hz, 1H), 6.14-6.16 (m, 1H), 4.62-4.63 (m, 1H), 3.51-3.58 (m, 5H), 3.25-3.31 (m, 2H), 1.75-1.81 (m, 2H), 1.50-1.64 (m, 4H), 1.32-1.40 (m, 2H), 1.14 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 431.2 (M+H)+.
Example 203 4-{5-(ethylsulfonyl)[(transhydroxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridineone The title compound (first eluting peak) was isolated as a minor product during the preparation of Example 202. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.02 (s, 1H), 7.77-7.81 (m, 2H), 7.40 (d, J = 8.54 Hz, 1H) , 7.31 (s, 1H), 7.28 (t, J = 2.75 Hz, 1H), .11 (m, 1H), 4.53-4.55 (m, 1H), 3.56 (s, 3H), 3.27 (q, J = 7.32 Hz, 2H), 1.95-2.00 (m, 2H), 1.68-1.71 (m, 4H), 1.27-1.38 (m, 4H), 1.13 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 431.2 (M+H)+.
Example 204 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- d]pyridazinone Example 204a 2-bromo(cyclopropylmethoxy)(ethylsulfonyl)benzene Example 204a was prepared according to the procedure used for the preparation of Example 158, substituting Example 168b for Example 138a, to provide the title compound.
Example 204b 2-(2-(cyclopropylmethoxy)(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, tuting Example 204a for Example 1e, to provide the title compound.
Example 204c 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- d]pyridazinone Example 204c was prepared according to the procedure used for the preparation of e 95d, tuting e 80b for Example 95c, and Example 204b for Example 6a, tively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.67 (s, 1H), 7.92 (dd, J = 8.85, 2.44 Hz, 1H), 7.83 (d, J = 2.44 Hz, 1H), 7.43 (t, J = 2.75 Hz, 1H), 7.40 (d, J = 8.85 Hz, 1H), 6.29-6.30 (m, 1H), 4.02 (d, J = 7.02 Hz, 2H), 3.80 (s, 3H), 3.29 (q, J = 7.12 Hz, 2H), 1.12 (t, J = 7.32 Hz, 3H), 1.01-1.08 (m, 1H), 0.40-0.45 (m, 2H), 0.21-0.25 (m, 2H). MS (ESI+) m/z 388.0 (M+H)+.
Example 205 yl[5-(methylsulfonyl)(tetrahydrofuranyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 205 was prepared according to the procedure used for the preparation of Example 158, substituting tetrahydrofuranol for cyclopropylmethanol, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.03 (s, 1H), 7.85-7.89 (m, 2H), 7.31- 7.33 (m, 1H), 7.28 (t, J = 2.75 Hz, 1H), 6.11-6.12 (m, 1H), 5.17-5.20 (m, 1H), 3.89-3.91 (m, 2H), 3.63-3.70 (m, 3H), 3.57 (s, 3H), 3.22 (s, 3H), 2.17-2.26 (m, 1H), 1.85-.1.91 (m, 1H). MS (ESI+) m/z 389.1 (M+H)+.
Example 206 4-{2-[(3-fluorooxetanyl)methoxy](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 206 was prepared according to the procedure used for the preparation of Example 158, substituting (3-fluorooxetanyl)methanol for cyclopropylmethanol, to provide the title nd. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.06 (s, 1H), .93 (m, 2H), 7.42 (d, J = 8.54 Hz, 1H), 7.37 (s, 1H), 7.30 (t, J = 2.75 Hz, 1H), 6.16-6.17 (m, 1H), .64 (m, 8H), 3.56 (s, 3H), 3.23 (s, 3H). MS (ESI+) m/z 407.1 (M+H)+.
Example 207 6-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide e 207a -bromo(cyclopropylmethoxy)pyridinesulfonamide Example 207a was prepared according to the ure used for the preparation of Example 29a, substituting 86a for Example 2a, and cyclopropylmethanol for tetrahydro-2H- pyranol, to provide the title compound.
Example 207b 6-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide Example 207b was prepared ing to the procedure used for the preparation of Example 95d, substituting Example 207a for Example 95c, to provide the title compound. 1H NMR (500 MHz, 6) δ ppm 12.12 (s, 1H), 8.52 (d, J = 2.44 Hz, 1H), 8.12 (d, J = 2.44 Hz, 1H), 7.44-7.45 (m, 3H), 7.33 (t, J = 2.75 Hz, 1H), 6.22-6.24 (m, 1H), 4.23 (d, J = 7.02 Hz, 2H), 3.58 (s, 3H), 1.14-1.24 (m, 1H), 0.47-0.52 (m, 2H), 0.29-0.33 (m, 2H). MS (ESI+) m/z 374.9 (M+H)+.
Example 208 6-(cyclopropylmethoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)pyridinesulfonamide The title nd was isolated as a minor product during the ation of Example 207b. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 8.49 (s, 1H), 8.05 (d, J = 2.44 Hz, 1H), 7.53 (q, J = 4.88 Hz, 1H), 7.46 (s, 1H), 7.33 (t, J = 2.75 Hz, 1H), 6.21-6.22 (m, 1H), 4.25 (d, J = 7.32 Hz, 2H), 3.58 (s, 3H), 2.47 (d, J = 4.88 Hz, 3H), 1.14-1.24 (m, 1H), 0.47-0.52 (m, 2H), 0.29-0.33 (m, 2H). MS (ESI+) m/z 389.2 (M+H)+.
Example 209 6-[(cyclopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide Example 209a -bromo(cyclopropylmethylamino)pyridinesulfonamide e 209a was prepared according to the ure used for the preparation of Example 96a, substituting cyclopropylmethanamine for cyclohexanamine, to provide the title compound.
Example 209b 6-[(cyclopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide Example 209b was prepared according to the procedure used for the preparation of Example 95d, substituting Example 209a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.17 (s, 1H), 8.38 (d, J = 2.44 Hz, 1H), 7.69 (d, J = 2.44 Hz, 1H), 7.32 (t, J = 2.75 Hz, 1H), 7.30 (s, 1H), 7.18 (br s, 2H), 6.62 (s, 1H), 6.05-6.06 (m, 1H), 3.56 (s, 3H), 3.22 (d, J = 3.97 Hz, 2H), 1.06-1.10 (m, 1H), 0.34-0.38 (m, 2H), 0.15-0.17 (m, 2H). MS (ESI+) m/z 374.2 (M+H)+.
Example 210 6-[(cyclopropylmethyl)amino]-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide The title compound was isolated as a minor product during the preparation of Example 209b. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.17 (s, 1H), 8.35 (d, J = 2.44 Hz, 1H), 7.60 (d, J = 2.44 Hz, 1H), 7.31-7.32 (m, 2H), 7.21 (d, J = 4.58 Hz, 1H), 6.55 (s, 1H), 6.04-6.05 (m, 1H), 3.56 (s, 3H), 3.22 (d, J = 5.19 Hz, 2H), 2.43 (d, J = 2.75 Hz, 3H), 1.05- 1.12 (m, 1H), .39 (m, 2H), .19 (m, 2H). MS (ESI+) m/z 386.7 (M+H)+.
Example 211 4-{5-(ethylsulfonyl)[(cishydroxymethylcyclohexyl)oxy]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 199 (0.052 g, 0.121 mmol) in ydrofuran was treated with 3.0 M methylmagnesium bromide in tetrahydrofuran (0.485 mL, 0.485 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The t was removed, and the solid was treated with MeOH and a few drops of TFA. The resulting solution was purified by reverse phase Preparative HPLC (C18, 10-80% CH3CN/water (0.1% TFA)) to give the title compound (first eluting peak, 0.018 g, 0.040 mmol, 33.4% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.04 (s, 1H), 7.78-7.80 (m, 2H), 7.38 (d, J = 9.77 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.11-6.12 (m, 1H), 4.46-4.49 (m, 1H), 3.57 (s, 3H), 3.27 (q, J = 7.32 Hz, 2H), 1.39-1.76 (m, 8H), 1.13 (t, J = 7.32 Hz, 3H), 1.10 (s, 3H). MS (ESI+) m/z 445.1 (M+H)+.
Example 212 4-{5-(ethylsulfonyl)[(transhydroxymethylcyclohexyl)oxy]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone The title compound d eluting peak) was isolated as a minor product in the preparation of Example 211. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.04 (s, 1H), 7.79-7.81 (m, 2H), 7.37 (d, J = 9.46 Hz, 1H), 7.30 (s, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.46-4.49 (m, 1H), 3.56 (s, 3H), 3.28 (q, J = 7.32 Hz, 2H), 1.80-1.86 (m, 2H), 1.54-1.59 (m, 2H), 1.23-1.26 (m, 4H), 1.13 (t, J = 7.32 Hz, 3H), 0.91 (s, 3H). MS (ESI+) m/z 445.1 (M+H)+.
Example 213 cyclobutyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone A 4mL 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 equivalents,0.46 mmol) in tetrahydrofuran (1 mL) and neat sodium hydride (19 mg, 7 equivalents, 0.46 mmol). The reaction mixture was stirred at 60 oC for 16 hours. The crude material was filtered, concentrated, and purified by reverse phase HPLC (C18, 10-100% CH3CN/water (0.1% TFA)) to afford the title nd. 1H NMR (400 MHz,DMSO-d 6/D2O) δ ppm 7.98 – 7.75 (m, 2H), 7.33 (d, J = 1.4 Hz, 2H), 7.16 (d, J = 8.7 Hz, 1H), 6.15 (d, J = 2.8 Hz, 1H), 4.82 (p, J = 7.2 Hz, 1H), 3.59 (s, 3H), 3.19 (d, J = 8.5 Hz, 3H), 2.47 – 2.38 (m, 2H), 1.96 (p, J = 9.6 Hz, 2H), 1.81 – 1.72 (m, 1H), 1.72 – 1.57 (m, 1H). ). MS (ESI+) m/z 373 (M+H)+.
Example 214 4-[2-(cyclopentylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 214 was prepared according to the procedure used for the preparation of Example 213, substituting cyclopentylmethanol for cyclobutanol, to provide the title nd. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.93 – 7.81 (m, 2H), 7.40 – 7.29 (m, 3H), 6.14 (d, J = 2.8 Hz, 1H), 3.99 (d, J = 6.6 Hz, 2H), 3.58 (s, 3H), 3.20 (s, 3H), 2.18 (dt, J = 14.6, 7.2 Hz, 1H), 1.59 (dt, J = 17.2, 8.5 Hz, 2H), 1.44 (dd, J = 10.1, 4.8 Hz, 4H), 1.31 – 1.16 (m, 2H). MS (ESI+) m/z 401 (M+H)+.
Example 215 4-[2-(cyclohexyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone e 215 was prepared according to the procedure used for the preparation of Example 213, substituting cyclohexanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ ppm 7.85 (dt, J = 4.1, 2.4 Hz, 2H), 7.35 (dd, J = 17.3, 5.9 Hz, 3H), 6.16 (d, J = 2.8 Hz, 1H), 4.66 – 4.49 (m, 1H), 3.58 (s, 3H), 3.20 (s, 3H), 1.94 – 1.79 (m, 2H), 1.54 (d, J = 5.1 Hz, 2H), 1.50 – 1.28 (m, 5H), 1.21 (d, J = 8.9 Hz, 1H). MS (ESI+) m/z 401 (M+H)+.
Example 216 cyclopentyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 216 was prepared according to the procedure used for the preparation of Example 213, substituting cyclopentanol for cyclobutanol, to e the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ ppm 7.88 (dd, J = 8.7, 2.5 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 10.3, 7.4 Hz, 3H), 6.10 (d, J = 2.8 Hz, 1H), 4.96 (dt, J = 8.3, 2.8 Hz, 1H), 3.58 (s, 3H), 3.19 (d, J = 8.6 Hz, 3H), 2.53 (dd, J = 3.5, 1.7 Hz, 2H), 1.98 – 1.82 (m, 2H), 1.69 – 1.56 (m, 2H), 1.56 – 1.46 (m, 4H) MS (ESI+) m/z 387 (M+H)+.
Example 217 6-methyl[5-(methylsulfonyl)(tetrahydrofuranylmethoxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 217 was ed according to the procedure used for the preparation of Example 213, substituting (tetrahydrofuranyl)methanol for cyclobutanol, to e the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.90 (dd, J = 8.6, 2.5 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 2.8 Hz, 2H), 6.14 (d, J = 2.8 Hz, 1H), 4.10 (dd, J = 9.4, 6.2 Hz, 1H), 4.03 (dd, J = 9.4, 7.5 Hz, 1H), 3.58 (s, 5H), 3.62 – 3.52 (m, 6H), 3.40 (dd, J = 8.6, 5.8 Hz, 1H), 3.20 (s, 3H), 1.93 – 1.80 (m, 1H), 1.63 – 1.51 (m, 1H). MS (ESI+) m/z 403 (M+H)+.
Example 218 6-methyl{5-(methylsulfonyl)[2-(2-oxoimidazolidinyl)ethoxy]phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 218 was prepared according to the ure used for the preparation of Example 213, substituting 1-(2-hydroxyethyl)imidazolidinone for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.90 (dd, J = 8.6, 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 2.8 Hz, 2H), 6.15 (d, J = 2.8 Hz, 1H), 4.20 (t, J = 5.2 Hz, 2H), 3.58 (s, 3H), 3.35 (t, J = 5.2 Hz, 2H), 3.21 (s, 3H), 3.07 (s, 4H). MS (ESI+) m/z 431 (M+H)+.
Example 219 4-[2-(2-cyclopropylethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone 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. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.93 (dd, J = 8.6, 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.43 – 7.32 (m, 3H), 6.14 (d, J = 2.8 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.23 (s, 3H), 1.54 (q, J = 6.5 Hz, 2H), 0.72 – 0.60 (m, 1H), 0.39 – 0.29 (m, 2H) MS (ESI+) m/z 387 (M+H)+.
Example 220 4-[2-(cycloheptyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- dinone Example 220 was ed according to the procedure used for the preparation of Example 213, substituting cycloheptanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ ppm 7.91 – 7.80 (m, 2H), 7.32 (d, J = 2.8 Hz, 2H), 7.34 – 7.27 (m, 3H), 6.14 (d, J = 2.8 Hz, 1H), 4.77 – 4.67 (m, 1H), 3.20 (s, 3H), 1.98 – 1.84 (m, 2H), 1.69 – 1.57 (m, 2H), 1.57 – 1.30 (m, 8H). MS (ESI+) m/z 415 (M+H)+.
Example 221 6-methyl[2-(2-methylpropoxy)(methylsulfonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 221 was prepared ing to the procedure used for the preparation of Example 213, substituting ylpropanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.92 – 7.82 (m, 2H), 7.38 – 7.32 (m, 3H), 7.32 (d, J = 2.8 Hz, 2H), 6.13 (d, J = 2.8 Hz, 1H), 3.88 (d, J = 6.3 Hz, 2H), 3.20 (s, 3H), 0.83 (d, J = 6.7 Hz, 6H). MS (ESI+) m/z 375 (M+H)+. e 222 6-methyl[2-{[(2S)methylpyrrolidinyl]methoxy}(methylsulfonyl)phenyl]-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 222 was prepared according to the procedure used for the ation of Example 213, substituting (S)-(1-methylpyrrolidinyl)methanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.96 (dd, J = 8.6, 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.43 – 7.33 (m, 3H), 6.20 (d, J = 2.8 Hz, 1H), 4.49 (dd, J = 11.0, 3.3 Hz, 1H), 4.27 (dd, J = 10.9, 8.2 Hz, 1H), 3.59 (s, 3H), 3.44 – 3.34 (m, 1H), 3.25 – 3.16 (m, 3H), 3.07 – 2.95 (m, 1H), 2.32 – 2.09 (m, 1H), 2.01 – 1.83 (m, 1H), 1.85 – 1.62 (m, 2H). MS (ESI+) m/z 416 (M+H)+.
Example 223 6-methyl{2-[(2-methylcyclopropyl)methoxy](methylsulfonyl)phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 223 was prepared according to the ure used for the preparation of Example 213, substituting (2-methylcyclopropyl)methanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.94 – 7.79 (m, 2H), 7.41 – 7.28 (m, 3H), 6.16 (t, J = 3.0 Hz, 1H), 4.10 – 3.97 (m, 1H), 3.91 (dd, J = 10.3, 7.3 Hz, 1H), 3.59 (d, J = 2.7 Hz, 3H), 3.19 (s, 3H), 0.91 (t, J = 11.4 Hz, 3H), 0.89 – 0.75 (m, 1H), 0.77 – 0.63 (m, 1H), 0.48 – 0.36 (m, 1H), 0.29 – 0.19 (m, 1H). MS (ESI+) m/z 387 (M+H)+.
Example 224 4-[2-(cyclohexylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 224 was prepared according to the procedure used for the preparation of Example 213, substituting cyclohexylmethanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.91 – 7.82 (m, 2H), 7.38 – 7.30 (m, 3H), 6.14 (d, J = 2.8 Hz, 1H), 3.91 (d, J = 5.7 Hz, 2H), 3.58 (s, 3H), 3.20 (s, 3H), 1.65 – 1.57 (m, 5H), 1.28 – 0.85 (m, 5H). MS (ESI+) m/z 415 (M+H)+.
Example 225 6-methyl{2-[2-(1-methylpyrrolidinyl)ethoxy](methylsulfonyl)phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 225 was prepared according to the procedure used for the preparation of Example 213, substituting 2-(1-methylpyrrolidinyl)ethanol for utanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.93 (dd, J = 8.7, 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 10.4, 7.7 Hz, 3H), 6.15 (d, J = 2.8 Hz, 1H), 4.30 – 4.12 (m, 2H), 3.59 (s, 3H), 3.57 – 3.42 (m, 1H), 3.19 (d, J = 14.3 Hz, 3H), 3.04 (dt, J = 9.9, 5.0 Hz, 1H), 2.93 (dt, J = 11.5, 8.5 Hz, 1H), 2.53 (dt, J = 3.5, 1.7 Hz, 2H), 2.34 – 2.19 (m, 1H), 2.06 (dtd, J = 12.9, 8.1, 5.0 Hz, 1H), 1.96 – 1.72 (m, 3H), 1.51 (ddd, J = 16.7, 13.2, 9.3 Hz, 1H). MS (ESI+) m/z 430 (M+H)+.
Example 226 6-methyl[5-(methylsulfonyl){[(2R)oxopyrrolidinyl]methoxy}phenyl]-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 226 was prepared according to the ure used for the preparation of Example 213, substituting (R)(hydroxymethyl)pyrrolidinone for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.91 (dd, J = 8.7, 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.42 – 7.29 (m, 3H), 6.15 (d, J = 2.8 Hz, 1H), 4.08 (qd, J = 9.9, 4.2 Hz, 2H), 3.81 (dt, J = 28.2, 14.1 Hz, 1H), 3.58 (s, 3H), 3.19 (d, J = 11.5 Hz, 3H), 2.09 – 1.87 (m, 2H), 1.86 – 1.66 (m, 2H). MS (ESI+) m/z 416 .
Example 227 6-methyl{5-(methylsulfonyl)[2-(morpholinyl)ethoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 227 was prepared according to the procedure used for the preparation of e 213, substituting holinoethanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.97 (dd, J = 8.6, 2.4 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 2.8 Hz, 2H), 6.12 (d, J = 2.8 Hz, 1H), 4.48 (t, J = 4.6 Hz, 2H), 3.96 (s, 1H), 3.59 (s, 3H), 3.57 – 3.36 (m, 3H), 3.22 (s, 3H), 3.18 (s, 1H), 3.10 – 2.68 (m, 2H). MS (ESI+) m/z 432 (M+H)+.
Example 228 6-methyl[5-(methylsulfonyl){[(2S)oxopyrrolidinyl]methoxy}phenyl]-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 228 was prepared according to the procedure used for the preparation of Example 213, substituting (S)(hydroxymethyl)pyrrolidinone for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.88 (tt, J = 15.3, 7.7 Hz, 2H), 7.46 – 7.27 (m, 3H), 6.15 (d, J = 2.8 Hz, 1H), 4.08 (qd, J = 9.9, 4.2 Hz, 2H), 3.83 (dd, J = 8.1, 4.1 Hz, 1H), 3.57 (d, J = 9.0 Hz, 3H), 3.20 (s, 3H), 2.09 – 1.90 (m, 2H), 1.85 – 1.69 (m, 2H) MS (ESI+) m/z 416 (M+H)+.
Example 229 4-{2-[(1-tert-butoxypropanyl)oxy](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 229 was prepared according to the procedure used for the preparation of Example 213, substituting 1-tert-butoxypropanol for utanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.92 – 7.80 (m, 2H), 7.45 – 7.24 (m, 3H), 6.19 (d, J = 2.8 Hz, 1H), 4.74 – 4.62 (m, 1H), 3.58 (s, 3H), 3.38 (t, J = 7.6 Hz, 2H), 3.19 (d, J = 8.9 Hz, 3H), 1.20 (t, J = 8.9 Hz, 3H), 1.02 (s, 9H). MS (ESI+) m/z 433 .
Example 230 4-{2-[(1S,4R)-bicyclo[2.2.1]heptylmethoxy](methylsulfonyl)phenyl}methyl-1,6- o-7H-pyrrolo[2,3-c]pyridinone e 230 was prepared according to the procedure used for the preparation of Example 213, substituting (1S,4R)-bicyclo[2.2.1]heptanylmethanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.92 – 7.81 (m, 2H), 7.43 – 7.28 (m, 3H), 6.14 (dd, J = 8.3, 2.8 Hz, 1H), 4.15 – 4.07 (m, 1H), 4.01 – 3.78 (m, 2H), 3.20 (s, 3H), 2.18 – 2.00 (m, 2H), 1.50 – 1.34 (m, 2H), 1.32 – 1.15 (m, 3H), 1.14 – 0.95 (m, 2H). MS (ESI+) m/z 427 (M+H)+.
Example 231 6-methyl{2-[(1-methylcyclopropyl)methoxy](methylsulfonyl)phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 231 was prepared according to the procedure used for the preparation of Example 213, tuting (1-methylcyclopropyl)methanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.90 – 7.83 (m, 2H), 7.33 (d, J = 2.9 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 6.17 (d, J = 2.8 Hz, 1H), 3.90 (s, 2H), 3.19 (s, 3H), 0.97 (s, 3H), 0.48 – 0.41 (m, 2H), 0.31 – 0.25 (m, 2H). MS (ESI+) m/z 387 (M+H)+.
Example 232 6-methyl{5-(methylsulfonyl)[2-(2-oxopyrrolidinyl)ethoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 232 was prepared according to the procedure used for the ation of Example 213, substituting 1-(2-hydroxyethyl)pyrrolidinone for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.91 (dd, J = 8.6, 2.4 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.41 – 7.30 (m, 3H), 6.10 (d, J = 2.8 Hz, 1H), 4.21 (t, J = 5.2 Hz, 2H), 3.58 (s, 3H), 3.45 (t, J = 5.2 Hz, 2H), 3.23 – 3.16 (m, 3H), 3.01 (t, J = 7.0 Hz, 2H), 2.08 (t, J = 8.0 Hz, 2H), 1.67 (p, J = 7.5 Hz, 2H). MS (ESI+) m/z 430 (M+H)+.
Example 233 yl{2-[(4-methylcyclohexyl)oxy](methylsulfonyl)phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 233 was ed according to the procedure used for the preparation of Example 213, substituting 4-methylcyclohexanol for cyclobutanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.89 – 7.83 (m, 2H), 7.39 – 7.31 (m, 3H), 6.17 (d, J = 2.8 Hz, 1H), 4.78 – 4.71 (m, 1H), 3.20 (s, 3H), 1.86 – 1.75 (m, 2H), 1.57 – 1.45 (m, 2H), 1.41 – 1.22 (m, 3H), 0.96 – 0.82 (m, 2H), 0.68 (d, J = 6.2 Hz, 3H). MS (ESI+) m/z 415 (M+H)+.
Example 234 4-[2-(cyclobutylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 234 was prepared according to the procedure used for the preparation of Example 213, substituting cyclobutylmethanol for utanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.94 – 7.80 (m, 2H), 7.34 (dd, J = 13.2, 5.7 Hz, 3H), 6.14 (d, J = 2.8 Hz, 1H), 4.07 (d, J = 6.2 Hz, 2H), 3.57 (s, 3H), 3.19 (d, J = 9.2 Hz, 3H), 2.61 (d, J = 7.1 Hz, 1H), 1.99 – 1.62 (m, 6H). MS (ESI+) m/z 387 (M+H)+.
Example 235 2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]cyclopropanesulfonamide Example 235 was prepared according to the procedure used for the ation of Example 4 (Method A), substituting Example 27c for Example 3, and cyclopropanesulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 9.70 (s, 1H), 7.35-7.38 (m, 2H), .30 (m, 2H), 7.22 (dd, J = 8.7, 2.59 Hz, 1H), 7.06-7.10 (m, 1H), 6.98-7.01 (m, 1H), 6.92 (d, J = 8.54 Hz, 1H), 6.25-6.26 (m, 1H), 3.54 (s, 3H), 2.61-2.66 (m, 1H), 0.90-0.98 (m, 4H). MS (ESI+) m/z 472.1 (M+H)+.
Example 236 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methoxyethanesulfonamide Example 236 was ed according to the procedure used for the preparation of Example 4, Method A, substituting Example 27b for Example 3, and 2- methoxyethanesulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.05 (s, 1H), 9.76 (s, 1H), 7.34-7.39 (m, 2H), 7.28-7.30 (m, 2H), 7.19 (dd, J = 8.85, 2.75 Hz, 1H), 7.05-7.10 (m, 1H), 6.98-7.01 (m, 1H), 6.91 (d, J = 8.54 Hz, 1H), 6.25-6.26 (m, 1H), 3.68 (t, J = 6.1 Hz, 2H), 3.53 (s, 3H), 3.37 (t, J = 6.1 Hz, 2H), 3.20 (s, 3H). MS (ESI+) m/z 490.1 (M+H)+.
Example 237 6-methyl{5-(methylsulfonyl)[tricyclo[3.3.1.13,7]decyloxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 237 was prepared according to the procedure used for the ation of e 158, substituting 2-adamantanol for cyclopropylmethanol, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.04 (s, 1H), 7.88 (d, J = 2.44 Hz, 1H), 7.83 (dd, J = 8.85,2.44, HZ, 1H), 7.38 (s, 1H), 7.36 (d, J = 8.85 Hz, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.18-6.19 (m, 1H), 4.70 (s, 1H), 3.56 (s, 3H), 3.21 (s, 3H), 2.06 (s, 2H), 1.80 (s, 5H), 1.62-1.65 (m, 5H), 1.34 (d, J = 11.29 Hz, 2H). MS (ESI+) m/z 453.2 (M+H)+.
Example 238 4-[(cyclopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide Example 238a 3-bromo(cyclopropylmethylamino)benzenesulfonamide Example 238a was prepared according to the procedure used for the preparation of Example 96a, substituting cyclopropylmethanamine for cyclohexanamine, and 3-bromo fluorobenzenesulfonamide for Example 86a, respectively, to provide the title compound. e 238b clopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide Example 238b was prepared according to the ure used for the ation of Example 95d, substituting Example 238a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.13 (s, 1H), 7.61-7.63 (m, 1H), 7.50 (d, J = 2.14 Hz, 1H), 7.30 (t, J = 2.75 Hz, 1H), 7.20 (s, 1H), 6.97 (br s, 2H), 6.80 (d, J = 8.85 Hz, 1H), 6.01 (s, 1H), 3.56 (s, 3H), 3.02 (d, J = 6.71 Hz, 2H), .03 (m, 1H), 0.35-0.39 (m, 2H), 0.13-0.16 (m, 2H). MS (ESI+) m/z 373.2 (M+H)+.
Example 239 4-[(cyclopropylmethyl)amino]-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide The title compound was isolated as a minor product in the preparation of Example 238b. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.13 (s, 1H), 7.56 (dd, J = 8.54, 2.44 Hz, 1H), 7.42 (d, J = 2.14 Hz, 1H), 7.23 (s, 1H), 7.30 (t, J = 2.75 Hz, 1H), 7.02 (d, J = 4.88 Hz, 1H), 6.83 (d, J = 8.54 Hz, 1H), 6.00-6.01 (m, 1H), 3.56 (s, 3H), 3.02 (d, J = 6.71 Hz, 2H), 2.38 (d, J = 4.58 Hz, 3H), 0.99-1.18 (m, 1H), 0.36-0.40 (m, 2H), .17 (m, 2H). MS (ESI+) m/z 387.2 (M+H)+.
Example 240 4-{2-[(2,2-difluorocyclopropyl)methoxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone e 240a 2-bromo((2,2-difluorocyclopropyl)methoxy)(ethylsulfonyl)benzene Example 240a was prepared according to the procedure used for the preparation of Example 158, substituting Example 168b for Example 138a, and (2,2- difluorocyclopropyl)methanol for cyclopropylmethanol, to provide the title nd.
Example 240b 4-{2-[(2,2-difluorocyclopropyl)methoxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 240b was prepared according to the ure used for the ation of Example 95d, tuting Example 240a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 7.81-7.85 (m, 2H), 7.37-7.39 (m, 2H), 7.29 (t, J = 2.75 Hz, 1H), 6.14-6.15 (m, 1H), 4.25-4.29 (m, 2H), 4.16-4.20 (m, 2H), 3.57 (s, 3H), 3.29 (q, J = 7.43 Hz, 2H), 2.08-2.16 (m, 1H), 1.63-1.66 (m, 1H), 1.44-1.46 (m, 1H), 1.13 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 423.1 (M+H)+.
Example 241 4-(4-bromomethoxyphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 241a 4-(4-bromomethoxyphenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one The product from Example 6a (0.2 g, 0.467 mmol), 4-bromoiodo ybenzene (0.16 g, 0.514 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol), 1,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamante (0.014 g, 0.047 mmol) and potassium phosphate tribasic (0.347 g, 1.634 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (7.5 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon.
The mixture was stirred at ambient ature for 20 minutes and ioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), treated with 3-mercaptopropyl functionalized silica gel for twenty minutes, filtered, and concentrated. Purification by chromatography (silica gel, 10-80% ethyl e in heptanes) afforded the title compound (0.2 g, 88%) Example 241b romomethoxyphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone 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, 0.021 mmol) were combined in dioxane (8 mL) and water (4 mL) and heated at 100 ºC 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, dried (Na2SO4), filtered, and concentrated. Purification by trituration in dichloromethane afforded the title nd (0.1 g, 73 %). 1H NMR (300 MHz, DMSO-d 6) δ ppm 11.97 (s, 1 H) 7.05 - 7.42 (m, 5 H) 5.87 - 6.09 (m, 1 H) 3.75 (s, 3 H) 3.54 (s, 3 H). MS (ESI+) m/z 333/335 (M +H) +.
Example 242 -difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide Example 242a -bromo(2,4-difluorophenoxy)pyridinesulfonamide A mixture of Example 86a (0.543 g, 2 mmol), 2,4-difluorophenol (0.390 g, 3.00 mmol), and cesium carbonate (1.955 g, 6.00 mmol) in DMSO (10 mL) was heated at 110 °C for 16 hours. After cooling, the reaction e was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and ted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous ium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (3:2 ethyl acetate/hexanes) on silica gel to give the title compound (0.53 g, 1.451 mmol, 72.6% yield).
Example 242b 6-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide e 242b was prepared according to the procedure used for the preparation of Example 95d, substituting Example 242a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.19 (s, 1H), 8.46 (d, J = 2.44 Hz, 1H), 8.29 (d, J = 2.14 Hz, 1H), 7.56 (s, 2H), 7.54 (s, 1H), 7.44-7.50 (m, 2H), 7.35 (t, J = 2.75 Hz, 1H), .18 (m, 1H), 6.34 (t, J = 2.44 Hz, 1H), 3.61 (s, 3H). MS (ESI+) m/z 433.2 (M+H)+.
Example 243 4-{2-(cyclopropylmethoxy)[(trifluoromethyl)sulfonyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 243a (3-bromofluorophenyl)(trifluoromethyl)sulfane 3-Bromofluorobenzenethiol (2.071 g, 10 mmol) in dimethylformamide (10 mL) was treated with 60% sodium hydride (0.480 g, 12.00 mmol). The solution was stirred for 10 minutes at room temperature. Trifluoroiodomethane (2.74 g, 14.00 mmol) was released into a balloon with a three-way ck. The balloon was then put onto the flask and trifluoroiodomethane was released into the reaction. After 1 hour, all the content in the balloon was gone. And the balloon was filled with 2.74 g of trifluoroiodomethane again. The reaction mixture was stirred for 16 hours. The reaction mixture was poured into water, and ted with ethyl acetate several times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting oil was used directly in the next reaction.
Example 243b 2-bromofluoro(trifluoromethylsulfonyl)benzene Example 243a (2.75 g, 10.00 mmol) in acetonitrile (4 mL), carbon tetrachloride (4.00 mL), and water (16.00 mL) was treated with sodium periodate (6.42 g, 30.0 mmol) and ium(III) chloride hydrate (0.023 g, 0.100 mmol). The reaction mixture was d at ambient temperature for 16 hours. Dichloromethane (100 mL) was added to the reaction mixture, which was then filtered through a pad of ing agent. The filtrate was treated with saturated sodium bicarbonate (50 mL). And the organic layer was separated. The aqueous layer was then extracted with additional dichloromethane three times. The ed organic layers were washed with saturated aqueous sodium de, dried over anhydrous ium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 5% ethyl acetate in hexanes to give 2.14 g of the title compound (7.85 mmol, 79% yield).
Example 243c 2-bromo(cyclopropylmethoxy)(trifluoromethylsulfonyl)benzene Example 243c was prepared according to the procedure used for the preparation of Example 158, substituting e 243b for Example 138a, to provide the title compound.
Example 243d 4-{2-(cyclopropylmethoxy)[(trifluoromethyl)sulfonyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 243d was prepared according to the procedure used for the preparation of Example 95d, tuting Example 243c for Example 95c, to provide the title nd. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 8.08 (dd, J = 8.85, 2.44 Hz, 1H), 7.95 (d, J = 2.44 Hz, 1H), 7.50 (d, J = 8.85 Hz, 1H), 7.44 (s, 1H), 7.35 (t, J = 2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.09 (d, J = 7.02 Hz, 2H), 3.58 (s, 3H), 1.11-1.17 (m, 1H), 0.48-0.50 (m, 2H), 0.29- 0.33 (m, 2H). MS (ESI+) m/z 427.0 (M+H)+.
Example 244 4-{2-[(cyclopropylmethyl)amino][(trifluoromethyl)sulfonyl]phenyl}methyl-1,6- o-7H-pyrrolo[2,3-c]pyridinone Example 244a Example 244a was ed according to the procedure used for the preparation of Example 96a, substituting cyclopropylmethanamine for cyclohexanamine, and Example 243b for Example 86a, respectively, to provide the title compound.
Example 244b 4-{2-[(cyclopropylmethyl)amino][(trifluoromethyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 244b was prepared according to the procedure used for the preparation of Example 95d, tuting Example 244a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.16 (s, 1H), 7.80 (dd, J = 8.85, 2.44 Hz, 1H), 7.53 (d, J = 2.44 Hz, 1H), 7.29-7.31 (m, 2H), 7.02 (d, J = 9.16 Hz, 1H), 6.41 (t, J = 5.8 Hz, 1H), 5.96- .97 (m, 1H), 3.56 (s, 3H), 3.10 (t, J = 6.26 Hz, 2H), 1.01-1.06 (m, 1H), 0.39-0.43 (m, 2H), 0.16-0.20 (m, 2H). MS (ESI+) m/z 426.1 (M+H)+.
Example 245 6-[(cyclopropylmethyl)amino]-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)pyridinesulfonamide Example 245a -bromo(cyclopropylmethylamino)-N,N-dimethylpyridinesulfonamide Example 245a was prepared ing to the ure used for the ation of Example 96a, tuting cyclopropylmethanamine for cyclohexanamine, and e 110a for Example 86a, tively, to e the title compound.
Example 245b 6-[(cyclopropylmethyl)amino]-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)pyridinesulfonamide 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. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.16 (s, 1H), 8.35 (d, J = 2.44 Hz, 1H), 7.51 (d, J = 2.44 Hz, 1H), 7.20-7.32 (m, 2H), 6.69 (t, J = 5.34 Hz, 1H), 6.03-6.04 (m, 1H), 3.58 (s, 3H), 3.24 (t, J = 5.95 Hz, 2H), 2.62 (s, 6H), 1.05-1.12 (m, 1H), 0.34-0.39 (m, 2H), 0.15-0.19 (m, 2H).
MS (ESI+) m/z 402.1 (M+H)+. e 246 6-(2,4-difluorophenoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)pyridinesulfonamide The title compound was isolated as a minor product in the preparation of Example 242b. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.19 (s, 1H), 8.45 (d, J = 2.44 Hz, 1H), 8.22 (d, J = 2.44 Hz, 1H), 7.60 (q, J = 4.78 Hz, 1H), 7.57 (s, 1H), 7.46-7.52 (m, 3H), 7.36 (t, J = 2.75 Hz, 1H), 7.14-7.19 (m, 1H), 6.34-6.35 (m, 1H), 3.61 (s, 3H), 2.50 (d, J = 4.88 Hz, 3H).
MS (ESI+) m/z 477.1 (M+H)+.
Example 247 4-[2-(cyclopropylmethoxy)methylphenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 247a 2-bromo(cyclopropylmethoxy)methylbenzene A 250 mL flask with stirbar was charged with 2-bromomethylphenol (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 for 16 hours at ambient temperature and then heated at 50 °C for 3 hours. The mixture was cooled to ambient temperature and partitioned 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)methylphenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 247b was ed according to the procedure used for the preparation of Example 7d, substituting the product of Example 247a for the product of Example 7c and stirring at 65 °C for 2.5 hours, to provide the title compound.
Example 247c 4-(2-(cyclopropylmethoxy)methylphenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 247c was prepared according to the procedure used for the preparation of Example 4b, substituting the t of Example 247b for the product of Example 4a to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.91 (bds, 1H), 7.23 - 7.18 (m, 2H), 6.99 (s, 1H), 6.91 (d, J = 3.1 Hz, 1H), 6.89 (m, 1H), 5.79 (m, 1H), 3.74 (dd, J = 6.6, 2.3 Hz, 2H), 3.54 (s, 3H), 2.06 (s, 3H) 0.99 (m, 1H), 0.33 (m, 2H), 0.08 (m, 2H). MS (DCI+) m/z 309.1 (M+H)+.
Example 248 4-{5-(ethylsulfonyl)[(cismethoxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro-7H- o[2,3-c]pyridinone Example 248a 2-bromo(ethylsulfonyl)(4-methoxycyclohexyloxy)benzene 4-Methoxycyclohexanol (a mixture of 70% cis and 30% trans isomers) (0.521 g, 4.00 mmol) in dioxane (20 mL) was treated with sodium hydride (0.240 g, 6.00 mmol). The reaction e was stirred for 10 minutes. To this solution was added Example 168b (0.534 g, 2 mmol). The reaction was heated at 60 °C for 16 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was ted with additional ethyl acetate two more times. The combined organic layers were washed with ted aqueous sodium chloride, dried over anhydrous magnesium e, 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% .
Example 248b 4-{5-(ethylsulfonyl)[(cismethoxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone 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. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.05 (s, 1H), 7.78-7.80 (m, 2H), 7.38-7.40 (m, 1H), 7.34 (s, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.63-4.66 (m, 1H), 3.56 (s, 3H), 3.28 (t, J = 7.32 Hz, 2H), 3.19-3.23 (m, 1H), 3.15 (s, 3H), 1.65-1.72 (m, 6H), 1.42-1.48 (m, 2H), 1.13 (t, J = 7.32, 3H). MS (ESI+) m/z 445.0 (M+H)+.
Example 249 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide Example 249a 3-bromo(cyclopropylmethoxy)benzenesulfonamide Example 249a was ed according to the procedure used for the preparation of Example 29a, substituting 3-bromofluorobenzenesulfonamide for Example 2a, and cyclopropylmethanol for tetrahydro-2H-pyranol, to provide the title compound. e 249b 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide Example 249b was prepared ing to the procedure used for the preparation of Example 95d, substituting Example 249a for Example 95c, to provide the title compound. 1H NMR (500 MHz, 6) δ ppm 12.03 (s, 1H), 7.80 (d, J = 2.44 Hz, 1H), 7.76 (dd, J = 8.54, 2.44 Hz, 1H), 7.31 (s, 1H), 7.30 (t, J = 2.9 Hz, 1H), .25 (m, 3H), 6.15-6.16 (m, 1H), 3.93 (d, J = 6.71 Hz, 2H), 3.57 (s, 3H), 1.08-1.13 (m, 1H), 0.44-0.49 (m, 2H), 0.25-0.28 (m, 2H). MS (ESI+) m/z 374.1 (M+H)+.
Example 250 4-(cyclopropylmethoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)benzenesulfonamide The title compound was isolated as a minor t in the preparation of Example 249b. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.05 (s, 1H), 7.70-7.74 (m, 2H), 7.35 (s, 1H), 7.30 (t, J = 2.9 Hz, 1H), 7.26-7.32 (m, 3H), 6.14 (t, J = 2.44 Hz, 1H), 3.95 (d, J = 6.71 Hz, 2H), 3.58 (s, 3H), 2.41 (d, J = 4.88 Hz, 3H), 1.07-1.15 (m, 1H), 0.45-0.50 (m, 2H), 0.26-0.29 (m, 2H). MS (ESI+) m/z 388.1 (M+H)+.
Example 251 N-[4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide Example 251a 2-bromo(cyclopropylmethoxy)methylnitrobenzene Example 251a was prepared ing to the procedure used for the preparation of Example 247a, tuting 2-bromomethylnitrophenol for omethylphenol, to provide the title compound.
Example 251b 4-(6-(cyclopropylmethoxy)methylnitrophenyl)methyltosyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one e 251b was prepared according to the procedure used for the preparation of Example 7d, substituting the product of Example 251a for the product of Example 7c and stirring at 65 °C for 2.5 hours, to provide the title compound.
Example 251c 4-(3-amino(cyclopropylmethoxy)methylphenyl)methyltosyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 251c was prepared ing to the procedure used for the preparation of e 3, substituting the product of Example 251b for the product of Example 2b to provide the title compound.
Example 251d N-(4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl)ethanesulfonamide Example 251d was prepared according to the procedure used for the preparation of Example 4 (Method A), substituting e 251c for Example 3, and ethanesulfonyl chloride for methanesulfonyl chloride, respectively, to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (bds, 1H), 8.89 (bds, 1H), 7.23 - 7.19 (m, 2H), 6.99 (s, 1H), 6.91 (d, J = 3.1 Hz, 1H), 5.75 (m, 1H), 3.74 (dd, J = 6.6, 2.3 Hz, 2H), 3.54 (s, 3H), 3.07 (m, 2H), 2.06 (s, 3H), 1.27 (m, 3H), 0.99 (m, 1H), 0.33 (m, 2H), 0.08 (m, 2H). MS (ESI+) m/z 416.1 (M+H)+.
Example 252 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide Example 252a 1-(2,4-difluorophenoxy)(methylsulfonyl)nitrobenzene A mixture of 1-fluoro(methylsulfonyl)nitrobenzene (20 g, 91 mmol), 2,4- difluorophenol (11.87 g, 91 mmol) and potassium carbonate (12.6 g, 91 mmol) in DMSO (90 mL) was heated at 120 °C for 2 hours. The reaction mixture was quenched with water and extracted with ethyl e. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to e the title compound (28 g, 89% yield).
Example 252b 2-(2,4-difluorophenoxy)(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 bottle and the mixture was stirred for 24 hour under a 30 psi hydrogen atmosphere at 40 °C.. The mixture was filtered through a nylon membrane and concentrated. The residue was purified flash chromatography (silica gel, 70:30 ethyl acetate/hexanes) to e the title compound (8.6 g, 55% yield).
Example 252c 1-(2,4-difluorophenoxy)iodo(methylsulfonyl)benzene Example 252b (5.00 g, 16.7 mmol) in dioxane (30 mL) was treated with concentrated HCl (150 mL) at 0 °C. The reaction mixture was stirred at 0 °C 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 °C for one hour. To this solution was added potassium iodide (5.55 g, 33.4 mmol) in water (20 mL). The reaction mixture was d for two hours at 10 °C. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was extracted with onal ethyl e twice. The combined organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, and trated. The residue was purified by flash chromatography (silica gel, 2:3 ethyl e/hexanes) to provide the title compound (8.9 g, 89 % yield) Example 252d ethyl 1-benzylmethyloxo(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxylate A mixture of Example 70e (2 g, 5.14 mmol), bis(pinacolato)diboron (2.61 g, 10.3 mmol), potassium e (1.11 g, 11.3 mmol tris(dibenzylideneacetone)dipalladium(0) (0.235 g, 0.257 mmol) and 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (0.245 g, 0.514 mmol) in dioxane (50 mL) was stirred at 90 °C for 16 hour under an argon atmosphere.
The e was filtered through Celite, washed with ethyl acetate several times and concentrated. The residue was purified by flash chromatography (silica gel, 50-75% ethyl acetate /petroleum ether gradient) to afford the title compound (1.15 g, 40 % .
Example 252e ethyl 1-benzyl(2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl)methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylate Example 252d (2.3 g, 5.27 mmol), Example 252c (2.270 g, 5.54 mmol), 1,3,5,7- tetramethylphenyl-2,4,8-trioxaphosphaadamantane (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 (30 mL) and water (7.5 mL) was added and the reaction mixture was stirred at 60 °C for 16 hours. 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, dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography (silica gel, % ethyl e in eum ether) to afford the title compound (1.77 g, 33.4% yield).
Example 252f ethyl 4-(2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl)methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxylate A mixture of Example 252e, anisole (1.585 mL, 14.51 mmol) and concentrated sulfuric acid (4.3 mL, 81 mmol) in trifluoroacetic acid (20 mL, 260 mmol) was heated at 90 °C for 4 hours. Excess trifluoroacetic acid was removed under reduced re, 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 x 200 mL). The combined organic layers were washed with ted aqueous sodium bicarbonate (100 mL), followed by saturated aqueous sodium chloride (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was taken into ol (50 mL) and the resulting solid was filtered, rinsed with methanol, and dried to e the title compound (3.1 g, 63% .
Example 252g 4-(2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylic acid Example 252f (1.1 g, 2.2 mmol) in dioxane (60 mL) was treated with 2.0 M s lithium hydroxide (4.38 mL, 8.76 mmol). The reaction mixture was heated at 65 °C for two hours. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was dissolved in water (50 mL) and the pH ed 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 nd (0.85 g, 77% yield).
Example 252h 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide To a solution of Example 252g (0.10 g, 0.21 mmol) in ous dichloromethane (5 mL) was added oxalyl chloride (0.037 mL, 0.42 mmol) and dimethylformamide (0.816 µl, .5 µmol) The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated. The residue was redissolved in dichloromethane (5 mL) and treated with ammonium hydroxide (2 mL, 92 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between water (15 mL) and ethyl acetate (25mL). The aqueous layer was extracted with additional ethyl acetate (2 x 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 was filtered, washed with dichloromethane and dried under vacuo to provide the title compound (48 mg, 47% yield). 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.33 (s, 1 H), 7.98 (s, 1 H), 7.98-7.88 (m, 1H), 7.82 (s, 1 H), 7.56-7.40 (m, 4H), 7.19 (m, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.87 (s, 1H), 3.59 (s, 3 H), 3.27 (s, 3 H). MS (ESI+) m/z 474.1 (M+H)+ Example 253 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]-N-ethylmethyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 253 was prepared ing to the procedure used for the preparation of Example 252h, substituting ethanamine for ammonium hydroxide, to e the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.32 (s, 1 H), 8.35-8.32 (m, 1H), 7.98 (s, 1 H), 7.89 (dd, J = 2.4, 6.4 Hz, 1 H), .21 (m, 3H), .16 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 3.59 (s, 3 H), 3.30-3.23 (m, 5 H), 1.11 (t, J = 7.2 Hz, 3H). MS (ESI+) m/z 502.1 .
Example 254 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-N-(2,2,2- trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide Example 254 was prepared according to the ure used for the preparation of Example 252h, substituting 2,2,2-trifluoroethanamine for ammonium hydroxide, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.56 (s, 1 H), 8.94 (t, J = 6 Hz, 1H), 7.99 (s, 1 H), 7.98-7.89 (m, 1 H), 7.52-7.50 (m, 2H), .40 (m, 1H), 7.17 (m, 1 H), 7.03-7.00 (m, 2H), .08 (m, 2 H), 3.59 (s, 3 H), 3.26 (s, 3H). MS (ESI+) m/z 556.1 Example 255 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(morpholinylcarbonyl)- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone 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. 1H NMR (400 MHz, DMSO-d 6) δ ppm 7.99 (s, 1 H), 7.88 (dd, J = 2.4, 6 Hz, 1 H), 7.59-7.42 (m, 3 H), .17 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 3.59 (s, 3 H), 3.55 (m, 8H), 3.27 (s, 3H). MS (ESI+) m/z 544.2 (M+H)+.
Example 256 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(4-methylpiperazin yl)carbonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone e 256 was prepared according to the procedure used for the preparation of Example 252h, substituting 1-methylpiperazine for ammonium hydroxide, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 7.97 (d, J = 2 Hz, 1 H), 7.84 (dd, J = 2.4, 6 Hz, 1 H), 7.32 (s, 1 H), 7.13-7.10 (m, 2H), 6.94-6.91 (m, 2H), 6.51 (s, 1H), 3.68-3.65 (m, 4H), 3.60 (s, 3 H), 3.08 (s, 3 H), 2.38 (m, 4 H), 2.24 (s, 3H). MS (ESI+) m/z 557.2 (M+H)+.
Example 257 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-N-(1,3-thiazolyl)- 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide Example 257 was prepared according to the procedure used for the preparation of Example 252h, substituting lamine for ammonium ide, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.82 (s, 1 H), 12.49 (s, 1 H), 8.01 (s, 1 H), 7.92 (dd, J = 2.4, 6.4 Hz, 1 H), 7.56-7.45 (m, 4 H), 7.34-7.29 (m, 2H), 7.22-7.18 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.61 (s, 3 H), 3.28 (s, 3H). MS (ESI+) m/z 557.1 (M+H)+.
Example 258 ethyl 4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]piperidinecarboxylate Example 258 was prepared according to the procedure used for the preparation of Example 158, substituting ethyl 4-hydroxypiperidinecarboxylate for cyclopropylmethanol, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.01 (s, 1H), 7.84- 7.87 (m, 2H), 7.41 (d, J = 9.46 Hz, 1H), 7.31 (s, 1H), 7.27 (t, J = 2.59 Hz, 1H), 6.12 (s, 1H), 4.75-4.79 (m, 1H), 3.98 (q, J = 7.02 Hz, 2H), 3.56 (s, 3H), .26 (m, 2H), 3.20 (s, 3H), 2.10 (s, 1H), 1.83-1.88 (m, 2H), 1.43-1.55 (M, 2H), 1.13 (t, J = 7.02 Hz, 3H). MS (ESI+) m/z 474.1 (M+H)+.
Example 259 4-[2-ethoxy(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin The title compound was isolated as a minor product in the preparation of Example 258. 1H NMR (500 MHz, DMSO- d 6) δ ppm 12.02 (s, 1H), 7.88 (dd, J = 8.54, 2.44 Hz, 1H), 7.82 (d, J = 2.44 Hz, 1H), 7.32-7.34 (m, 2H), 7.28 (t, J = 2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.17 (q, J = 6.92 Hz, 2H), 3.57 (s, 3H), 3.21 (s, 3H), 3.20 (s, 3H), 1.22 (t, J = 7.02 Hz, 3H).
MS (ESI+) m/z 347.1 (M+H)+.
Example 260 4-{5-(ethylsulfonyl)[(transmethoxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone The title compound (first eluting peak) was isolated as a second t in the preparation of Example 248b. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.03 (s, 1H), 7.78- 7.81 (m, 2H), 7.40 (d, J = 8.54 Hz, 1H), 7.31 (s, 1H), 7.28 (t, J = 2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.57-4.61 (m, 1H), 3.56 (s, 3H), 3.28 (t, J = 7.32 Hz, 2H), 3.19 (s, 3H), 3.14-3.18 (m, 1H), .97 (m, 2H), 1.73-1.77 (m, 2H), 1.31-1.42 (m, 4H), 1.13 (t, J = 7.32, 3H). MS (ESI+) m/z 445.0 (M+H)+.
Example 261 4-{2-[(cyclopropylmethyl)amino](propanylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 261a (3-bromofluorophenyl)(isopropyl)sulfane Example 261a was ed according to the procedure used for the preparation of Example 168a, substituting 2-iodopropane for iodoethane, to provide the title compound.
Example 261b 2-bromofluoro(isopropylsulfonyl)benzene Example 261b was prepared according to the procedure used for the preparation of Example 168b, substituting Example 261a for Example 168a, to provide the title compound. e 261c 2-bromo-N-(cyclopropylmethyl)(isopropylsulfonyl)aniline e 261c was prepared according to the procedure used for the preparation of Example 147a, substituting cyclopropylmethanamine for cyclohexanamine, and Example 261b for 2-bromofluoro(methylsulfonyl)benzene to provide the title compound.
Example 261d 4-{2-[(cyclopropylmethyl)amino](propanylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone e 261d was prepared according to the procedure used for the preparation of Example 95d, substituting e 261c for Example 95c, to provide the title nd. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 7.59 (dd, J = 8.7, 2.29 Hz, 1H), 7.40 (d, J = 2.44 Hz, 1H), 7.30 (t, J = 2.9 Hz, 1H), 7.25 (s, 1H), 6.88 (d, J = 8.85 Hz, 1H), 5.98-5.99 (m, 1H), 5.61 (br s, 1H), 3.56 (s, 3H), 3.22-3.30 (m, 2H), 3.03 (d, J = 6.71 Hz, 2H), 1.16 (d, J = 7.02 Hz, 6H), 0.98-1.14 (m, 1H), .41 (m, 2H), 0.14-0.18 (m, 2H). MS (ESI+) m/z 400.1 (M+H)+.
Example 262 N-[4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide Example 262 was prepared according to the procedure used for the preparation of Example 4 (Method A), substituting Example 251c for Example 3, to provide the title compound. 1H NMR (500 MHz, CD 3OD) δ ppm 7.34 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 6.98 (s, 1H), 6.93 (d, J = 8.9 Hz, 1H), 5.93 (d, J = 2.8 Hz, 1H), 3.78 (m, 2H), 3.69 (s, 3H), 2.98 (s, 3H), 2.13 (m, 3H), 0.99 (m, 1H), 0.35 (m, 2H), 0.08 (m, 2H). MS (ESI+) m/z 402.1 (M+H)+.
Example 263 N-[4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)phenyl]methanesulfonamide Example 263a 1-bromo(cyclopropylmethoxy)methylnitrobenzene Example 263a was prepared according to the procedure used for the preparation of Example 247a, substituting 2-bromomethylnitrophenol for 2-bromomethylphenol to provide the title compound.
Example 263b 4-(2-(cyclopropylmethoxy)methylnitrophenyl)methyltosyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 263b was prepared according to the procedure used for the preparation of Example 7d, tuting the product of Example 263a for the product of Example 7c and stirring at 65 °C for 2.5 hours, to provide the title compound.
Example 263c 4-(5-amino(cyclopropylmethoxy)methylphenyl)methyltosyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 263c was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 263b for the product of e 2b to provide the title compound.
Example 263d N-(4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl)methanesulfonamide Example 263d was prepared according to the procedure used for the preparation of e 4 (Method A), substituting Example 263c for Example 3, to provide the title compound. 1H NMR (500 MHz, CD 3OD) δ ppm 7.36 (s, 1H), 7.31 (d, J = 2.8 Hz, 1H), 7.28 (s, 1H), 6.96 (s, 1H), 6.35 (d, J = 2.8 Hz, 1H), 3.84 (d, J = 6.7 Hz, 2H), 3.69 (s, 3H), 3.11 (s, 3H), 2.41 (s, 3H), 1.11 (m, 1H), 0.47 (m, 2H), 0.24 (m, 2H). MS (ESI+) m/z 402.1 (M+H)+.
Example 264 4-[5-(ethylsulfonyl)(tetrahydro-2H-thiopyranyloxy)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 264a 4-(2-bromo(ethylsulfonyl)phenoxy)tetrahydro-2H-thiopyran Example 264a was prepared according to the procedure used for the preparation of Example 158, substituting e 168b for Example 138a, and tetrahydro-2H-thiopyran ol for cyclopropylmethanol, respectively, to provide the title compound. e 264b 4-[5-(ethylsulfonyl)(tetrahydro-2H-thiopyranyloxy)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone 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 nd. 1H NMR (500 MHz, 6) δ ppm 12.05 (s, 1H), 7.79-7.82 (m, 2H), 7.40 (d, J = 9.77 Hz, 1H), 7.34 (s, 1H), 7.30 (t, J = 2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.69-4.72 (m, 1H), 3.58 (s, 3H), 3.28 (d, J = 7.32 Hz, 2H), 2.50-2.62 (m, 4H), 2.06-2.12 (m, 2H), 1.74-1.81 (m, 2H), 1.13 (d, J = 7.32 Hz, 6H). MS (ESI+) m/z 433.1 (M+H)+.
Example 265 4-{2-[(1,1-dioxidotetrahydro-2H-thiopyranyl)oxy](ethylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 265 was prepared according to the procedure used for the preparation of Example 168b, substituting 264b for e 168a, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.09 (s, 1H), 7.83-7.87 (m, 2H), 7.48 (d, J = 8.85 Hz, 1H), 7.35 (s, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.14-6.15 (m, 1H), 4.90-4.93 (m, 1H), 3.58 (s, 3H), 3.30 (q, J = 7.43 Hz, 2H), 3.01-3.04 (m, 2H), 2.76-2.82 (m, 2H), 2.12-2.18 (m, 4H), 1.14 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 465.1 (M+H)+.
Example 266 6-(2,4-difluorophenoxy)-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide Example 266a -bromo(2,4-difluorophenoxy)-N,N-dimethylpyridinesulfonamide Example 242a (0.365 g, 1 mmol) in 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 iodomethane (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 with additional ethyl e two more times.
The ed organic layers were washed with saturated s sodium de, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was ed by flash chromatography on silica gel to give the title compound (0.365 g, 0.928 mmol, 93% yield).
Example 266b -difluorophenoxy)-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide Example 266b was prepared according to the procedure used for the preparation of Example 95d, substituting Example 266a for Example 95c, to e the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.17 (s, 1H), 8.50 (d, J = 2.44 Hz, 1H), 8.18 (d, J = 2.44 Hz, 1H), 7.57 (s, 1H), 7.46-7.51 (m, 2H), 7.35 (t, J = 2.75 Hz, 1H), 7.15-7.18 (m, 1H), 6.33- 6.34 (m, 1H), 3.61 (s, 3H), 2.71 (s, 6H). MS (ESI+) m/z 461.1 (M+H)+.
Example 267 4-[2-(cyclopropylamino)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 267a 2-bromo-N-cyclopropyl(ethylsulfonyl)aniline e 267a was prepared according to the procedure used for the preparation of Example 147a, substituting cyclopropylamine for cyclohexanamine, and Example 168b for 2- 1-fluoro(methylsulfonyl)benzene to provide the title compound.
Example 267b 4-[2-(cyclopropylamino)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 267b was prepared according to the procedure used for the preparation of Example 95d, tuting Example 267a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.32 (s, 1H), 7.92 (dd, J = 8.7, 2.29 Hz, 1H), 7.68 (d, J = 2.44 Hz, 1H), 7.51 (t, J = 2.75 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J = 8.54 Hz, 1H), 6.14-6.15 (m, 1H), 6.11 (s, 1H), 3.77 (s, 3H), 3.40 (q, J = 7.32 Hz, 2H), 2.63-2.67 (m, 1H), 1.35 (t, J = 7.32 Hz, 3H), 0.95-0.97 (m, 2H), 0.62-0.68 (m 2H). MS (ESI+) m/z 372.1 (M+H)+.
Example 268 4-(5-(ethylsulfonyl)(cismethoxymethylcyclohexyloxy)phenyl)methyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one Example 268a 8-(2-bromo(ethylsulfonyl)phenoxy)-1,4-dioxaspiro[4.5]decane Example 268a was prepared according to the procedure used for the preparation of Example 158, substituting Example 168b for Example 138a, and 1,4-dioxaspiro[4.5]decan ol for cyclopropylmethanol, respectively, to provide the title compound.
Example 268b 4-(2-bromo(ethylsulfonyl)phenoxy)cyclohexanone Example 268b was prepared according to the ure used for the preparation of Example 199, substituting Example 268a for Example 197, to e the title compound.
Example 268c (cis)(2-bromo(ethylsulfonyl)phenoxy)methylcyclohexanol Example 268b (0.95 g, 2.63 mmol) in THF (15 mL) was cooled to 0 ºC. This solution was d with 3.0 M methylmagnesium e (2.63 ml, 7.89 mmol) and stirred at room temperature ght. The reaction mixture was quenched with saturated NH4Cl solution and partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The ed organic layers were washed with brine, drie over MgSO4, 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 was the first fraction to elute from the column.
Example 268d 2-bromo(ethylsulfonyl)((cis)methoxymethylcyclohexyloxy)benzene Example 268c (0.43 g, 1.140 mmol) in 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 ºC for 16 ours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate two more times. The combined organic layers were washed with saturated s sodium chloride, dried over anhydrous magnesium sulfate, ed, and concentrated. The residue was ed by flash chromatography on silica gel to give the title compound (0.356 g, 0.910 mmol, 80% yield). e 268e ethylsulfonyl)(cismethoxymethylcyclohexyloxy)phenyl)methyl-1H- o[2,3-c]pyridin-7(6H)-one Example 268e was prepared ing to the procedure used for the preparation of Example 95d, substituting Example 268d for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.04 (s, 1H), 7.77-7.81 (m, 2H), 7.39 (d, J = 8.85 Hz, 1H), 7.31 (s, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.10-6.11 (m, 1H), 4.50-4.55 (m, 1H), 3.57 (s, 3H), 3.28 (q, J = 7.32 Hz, 2H), 1.69-1.78 (m, 4H), 1.46-1.53 (m, 2H), 1.33-1.38 (m, 2H), 1.13 (t, J = 7.32 Hz, 3H), 1.05 (s, 3H). MS (ESI+) m/z 459.1 (M+H)+.
Example 269 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]-N,N,6-trimethyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide Example 269 was prepared according to the procedure used for the preparation of Example 252h, substituting dimethylamine for ammonium hydroxide, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 8.08 (s, 1 H), 7.95 (dd, J = 2.4, 6 Hz, 1 H), 7.43 (s, 1 H), 7.26-7.15 (m, 2H), 7.05-6.99 (m, 2H), 6.69 (s, 1H), 3.72 (s, 3 H), 3.25 (s, 3 H), 3.19 (s, 3 H), 3.12 (s, 1 H). MS (ESI+) m/z 502.0 (M+H)+.
Example 270 6-methyl{5-(methylsulfonyl)[4-(methylsulfonyl)phenoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone 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 nd. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.08 (s, 1H), 8.06 (d, J = 2.44 Hz, 1H), 7.97 (dd, J = 8.7, 2.29 Hz, 1H), .88 (m, 2H), 7.40 (s, 1H), 7.35 (d, J -= 8.54 Hz, 1H), 7.29 (t, J = 2.75 Hz, 1H), 7.20-7.23 (m, 2H), 6.24-6.25 (m, 1H), 3.54 (s, 3H), 3.30 (s, 3H), 3.17 (s, 3H). MS (ESI+) m/z 471.2 (M+H)+. e 271 4-[2-(2,4-difluorophenoxy)(propanylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone e 271a 2-bromo(2,4-difluorophenoxy)(isopropylsulfonyl)benzene Example 271a was prepared according to the procedure used for the preparation of Example 138b, substituting Example 261b for Example 138a, to provide the title compound.
Example 271b 4-[2-(2,4-difluorophenoxy)(propanylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 271b was prepared according to the procedure used for the ation of Example 95d, substituting Example 271a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.11 (s, 1H), 7.88 (d, J = 2.44 Hz, 1H), 7.80 (dd, J = 8.85, 2.44 Hz, 1H), 7.50-7.54 (m, 1H), 7.42-7.49 (m, 2H), 7.31 (t, J = 2.75 Hz, 1H), 7.15-7.19 (m, 1H), 7.00 (d, J = 8.54, Hz, 1H), 6.25-6.26 (m, 1H), 3.59 (s, 3H), 3..44-3.48 (m, 1H), 1.20 (d, J = 7.02 Hz, 6H). MS (ESI+) m/z 459.0 (M+H)+.
Example 272 6-(cyclopropylmethoxy)-N,N-diethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide Example 272a -bromo(cyclopropylmethoxy)-N,N-diethylpyridinesulfonamide Example 272a was prepared according to the ure used for the preparation of Example 266a, substituting Example 207a for Example 242a, and ethyl iodide for thane, respectively, to provide the title compound.
Example 272b 6-(cyclopropylmethoxy)-N,N-diethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide Example 272b was prepared according to the procedure used for the preparation of Example 95d, substituting Example 272a for Example 95c, to e the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 8.54 (d, J = 2.44 Hz, 1H), 8.01 (d, J = 2.44 Hz, 1H), 7.44 (s, 1H), 7.32 (t, J = 2.75 Hz, 1H), 6.15-6.16 (m, 1H), 4.24 (d, J = 7.02 Hz, 2H), 3.58 (s, 3H), 3.21 (q, J = 7.02 Hz, 4H), 1.17-1.20 (m, 4H), 1.08 (t, J = 7.02 Hz, 6H), 0.47- 0.51 (m, 2H), 0.29-0.32 (m, 2H). MS (ESI+) m/z 431.1 (M+H)+.
Example 273 4-(cyclopropylmethoxy)-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide Eample 273a 3-bromo(cyclopropylmethoxy)-N,N-dimethylbenzenesulfonamide Example 273a was ed according to the ure used for the preparation of Example 266a, substituting Example 249a for Example 242a, to provide the title compound.
Example 273b 4-(cyclopropylmethoxy)-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide Example 273b was prepared according to the procedure used for the preparation of Example 95d, substituting Example 273a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.05 (s, 1H), 7.70 (dd, J = 8.54, 2.44 Hz, 1H), 7.66 (d, J = 2.44 Hz, 1H), 7.37 (s, 1H), 7.29-7.32 (m, 2H), 6.12-6.13 (m, 1H), 3.98 (d, J = 6.71 Hz, 2H), 3.57 (s, 3H), 2.62 (s, 6H), 3.21 (q, J = 7.02 Hz, 4H), 1.11-1.15 (m, 1H), 0.46-0.49 (m, 2H), 0.27-0.30 (m, 2H). MS (ESI+) m/z 402.1 (M+H)+.
Example 274 cyclopropylmethoxy)fluorophenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one Example 274a o(cyclopropylmethoxy)fluorobenzene To a solution of 2-bromofluorophenol (0.50 g, 2.6 mmol) in tetrahydrofuran (13 mL) were 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 d for 16 hours at ambient temperature. The solvent was removed under d pressure. The residue was triturated with hexanes. The mixture was filtered, and the filtrate containing the product was concentrated by under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes) to e the title compound (400 mg, 62% yield).
Example 274b (2-(cyclopropylmethoxy)fluorophenyl)boronic acid To a solution of Example 274a (0.1 g, 0.408 mmol) in tetrahydrofuran (2 mL) at -20 °C was added nBuLi (0.180 mL of a 2.5 M solution in hexanes, 0.449 mmol). The reaction mixture was stirred for 2 hours, then cooled to -40 °C. 2-Isopropoxy-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (0.092 mL, 0.449 mmol) was added dropwise. The reaction mixture was stirred for 30 s. The reaction mixture was quenched with 1M citric acid at 0 °C. The e 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 e, ed, and concentrated. The crude material was purified by flash chromatography (silica gel, 10-33% ethyl e/hexanes gradient) to provide the title compound (23 mg, 20% yield).
Example 274c 4-[2-(cyclopropylmethoxy)fluorophenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one en was bubbled through a 4:1 dimethoxyethane/ethanol solution for 20 minutes.
A microwave vial was charged with Example 1e (.05 g, 0.131 mmol), Example 274b (0.046 g, 0.144 mmol), Pd(Ph3P)4 (7.58 mg, 6.56 µmol), and cesium fluoride (0.060 g, 0.393 mmol).
The vial was sealed and d with nitrogen. The 4:1 dimethoxyethane/ethanol mixture (0.5 mL) was added. The reaction mixture was heated in a ave reactor at 120 °C for 40 minutes. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated. The aqueous layer was extracted with ethyl acetate. The ed 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). 1H NMR (300 MHz, DMSO-d 6) δ ppm 11.98 (s, 1 H), 7.29 (s, 1 H), 7.26 (t, J = 2.71 Hz, 1 H), 7.05 - 7.18 (m, 3 H), 6.14 (dd, J = 2.71, 2.03 Hz, 1 H), 3.80 (d, J = 6.78 Hz, 2 H), 3.55 (s, 3 H), 0.98 - 1.09 (m, 1 H), 0.39 - 0.46 (m, 2 H), 0.17 - 0.22 (m, 2 H). MS (ESI+) m/z 313.1 (M+H)+.
Example 275 4-[2-(2,4-difluorophenoxy)(trifluoromethyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 275a 2-bromo(2,4-difluorophenoxy)(trifluoromethyl)benzene A e of 3-bromofluorobenzotrifluoride (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 °C for 16 hours. The reaction mixture was cooled to ambient ature and partitioned between ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The ed organics were washed with water and ted aqueous sodium chloride, dried over ous 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 (1.0 g, 80% yield).
Example 275b (2-(2,4-difluorophenoxy)(trifluoromethyl)phenyl)boronic acid To a suspension of magnesium (0.083 g, 3.42 mmol) in ydrofuran (1.00 mL) was added 0.5 mL of a 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 reaction commenced.
The remaining on of starting bromide was added dropwise. The on mixture was d 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 °C. The reaction mixture was stirred at ambient temperature for 1 hour, quenched with ice water and then neutralized with 2 M HCl. The mixture was extracted 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 4-[2-(2,4-difluorophenoxy)(trifluoromethyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 275c was ed according to the procedure used for the preparation of Example 274c, substituting example 275b for example 274b, to provide the title compound. 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.06 (s, 1 H), 7.78 (d, J = 2.37 Hz, 1 H), 7.70 (dd, J = 8.48, 1.70 Hz, 1 H), 7.49 (td, J = 11.36, 8.65, 3.05 Hz, 1 H), 7.40 (s, 1 H), 7.34 - 7.43 (m, 1 H), 7.28 (t, J = 2.71 Hz, 1 H), 7.10 - 7.17 (m, 1 H), 6.95 (d, J = 8.48 Hz, 1 H), 6.24 (dd, J = 2.71, 2.03 Hz, 1 H), 3.57 (s, 3 H). MS (ESI+) m/z 421.1 (M+H)+.
Example 276 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl](hydroxymethyl)methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone To a suspension of Example 252f (0.20 g, 0.40 mmol) in tetrahydrofuran (5 mL) stirring at 0 °C was added lithium aluminum hydride (1M in tetrahydrofuran, 0.398 mL, 0.398 mmol) and the mixture was stirred at 0 °C for two hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The mixture was filtered to remove the undissolved materials. The aqueous layer was extracted with ethyl acetate (2 x 30 mL). The ed organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The e was triturated with dichloromethane and the resulting solid was filtered and dried to provide the title compound (0.10 g, 55% yield). 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.91 (s, 1 H), 7.97 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 2.4, 6.4 Hz, 1 H), 7.56-7.38 (m, 3 H), 7.20-7.15 (m, 1H),6.97 (d, J = 8.4 Hz, 1H), 6.18 (s, 1H), 5.11 (t, J = 5.6 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.57 (s, 3 H), 3.16 (s, 3H). MS (ESI+) m/z 461.2 (M+H)+. e 277 4-[2-(2,3-dihydro-1H-indenyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 277 was prepared according to the procedure used for the preparation of Example 158, substituting hydro-1H-indenol for cyclopropylmethanol, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 11.97 (s, 1H), 7.91 (dd, J = 8.54, 2.44 Hz, 1H), 7.85 (d, J = 2.44 Hz, 1H), 7.47 (d, J = 8.85 Hz, 1H), 7.20-7.23 (m, 2H), 7.12- 7.17 (m, 3H), 7.07 (s, 1H), 6.00-6.01 (m, 1H), 5.41-5.44 (m, 1H), 3.36-3.42 (m, 2H), 3.56 (s, 3H), 3.23 (s, 3H), 3.20 (s, 3H), 2.97 (dd, J = 16.94, 1.98 Hz, 2H). MS (ESI+) m/z 435.1 (M+H)+.
Example 278 2,4-difluorophenoxy)(methylsulfonyl)phenyl](1-hydroxyethyl)methyl-1,6- o-7H-pyrrolo[2,3-c]pyridinone Example 278a 4-(2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarbaldehyde To the on of Example 276 (1.0 g, 2.2 mmol) in dichloromethane (50 mL) at 0 °C was added Dess-MartinPeriodinane (1.84 g, 4.34 mmol) and the on mixture was stirred at 0 °C for 30 minutes. The reaction mixture was then stirred at ambient temperature for three hours. A solution of sodium bisulfite (0.9 g, 9 mmol) in saturated aqueous sodium bicarbonate (5 mL) was added, and the reaction mixture was d 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 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl](1-hydroxyethyl)methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone To a solution of Example 278a (0.20 g, 0.44 mmol) in tetrahydrofuran (6 mL) at 0 °C was added methylmagnesium bromide (1.0 M in tetrahydrofuran, 0.873 mL, 0.873 mmol).
The on mixture was stirred at 0 °C for one hour, and then 1M aqueous HCl (2 mL) was added. The on mixture was concentrated and partitioned between saturated aqueous sodium chloride (10mL) and ethyl acetate (2 x 30 mL). The combined organic phase was washed with saturated aqueous sodium chloride (30mL), dried over anhydrous sodium e, 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). 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.83 (s, 1 H), 7.96 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 2.4, 6.4 Hz, 1 H), 7.55-7.50 (m, 1 H), .36 (m, 2H), 7.20-7.15 (m, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.15 (d, J = 2 Hz, 1H), 5.13 (d, J = 5.2 Hz, 1H), 4.80-4.77 (m, 1H), 3.57 (s, 3 H), 3.25 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H). MS (ESI+) m/z 475.1 (M+1)+. e 279 2,4-difluorophenoxy)(methylsulfonyl)phenyl][(dimethylamino)methyl]methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone To a solution of e 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 one hour, and then sodium cyanoborohydride (0.055 g, 0.873 mmol) was added and the reaction mixture was stirred at ambient temperature for three days. The resulting solid was filtered and washed with methanol (10 mL), and the eluant was concentrated. The residue was purified by ative thin layer chromatography a gel, dichloromethane/methanol,15/1) to provide the title compound (75 mg, 34% yield). 1H NMR (400 MHz, CD 3OD) δ ppm 8.07 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 2.4, 6.4 Hz, 1 H), 7.38 (s, 1H), 7.25-7.06 (m, 2H), 7.04-6.98 (m, 2H), 6.31 (s, 1H), 3.71 (s, 3 H), 3.67 (s, 2 H), 3.19 (s, 3 H), 2.28 (s, 6 H). MS (ESI+) m/z 488.1 (M+H)+.
Example 280 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(morpholinylmethyl)- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 280 was ed according to the procedure used for the preparation of Example 279, substituting line for dimethylamine hydrochloride, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.98 (s, 1 H), 7.98 (d, J = 2.4 Hz, 1 H), 7.87 (dd, J = 2.4, 6.4 Hz, 1 H), .50 (m, 1 H), 7.44-7.38 (m, 2 H), 7.19-7.16 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 3.58 (s, 3H), 3.55 (s, 2 H), .47 (m, 4 H), 3.26 (s, 3H), 2.31 (m, 4 H). MS (ESI+) m/z 530.2 (M+H)+.
Example 281 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(4-methylpiperazin yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone 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 nd. 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.94 (s, 1 H), 7.98 (d, J = 2.4 Hz, 1 H), 7.87 (dd, J = 2.4, 6.4 Hz, 1 H), 7.55-7.49 (m, 1 H), 7.43-7.37 (m, 2 H), 7.18-7.13 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 3.57 (s, 3H), 3.52 (s, 2 H), 3.26 (s, 3H), 2.32- 2.21 (m, 8 H), 2.09 (s, 3 H). MS (ESI+) m/z 543.2 (M+H)+.
Example 282 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(phenylamino)methyl]- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 282 was prepared according to the procedure used for the preparation of Example 279, substituting aniline for dimethylamine hydrochloride, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.95 (s, 1 H), 7.93 (d, J = 2.4 Hz, 1 H), 7.84 (dd, J = 2.4, 6.8 Hz, 1 H), 7.48 (m, 1 H), 7.40 (s, 1 H), .28 (m, 1 H), 7.12 (m, 1 H), 6.99-6.91 (m, 3H), 6.58 (d, J = 7.6 Hz, 2H), 6.49 (t, J = 7.2 Hz, 1H), 6.19 (d, J = 2.0 Hz, 1H), .94 (m, 1H), 4.31 (d, J = 6.4 Hz, 2H), 3.56 (s, 3H), 3.23 (s, 3H). MS (ESI+) m/z 536.2 (M+H)+.
Example 283 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(1,3-thiazol ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 283 was prepared ing to the procedure used for the preparation of Example 279, substituting thiazolamine for dimethylamine hydrochloride, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.99 (s, 1 H), 7.94 (d, J = 2.4 Hz, 1 H), 7.86-7.83 (m, 2 H), 7.51-7.45 (m, 1 H), 7.42 (s, 1 H), 7.30-7.26 (m, 1 H), 7.14-7.13 (m, 1 H), 6.99-6.92 (m, 2H), 6.62 (d, J = 3.6 Hz, 1H), 6.18 (s, 1H), 5.94 (m, 1H), 4.49 (d, J = 5.6 Hz, 2H), 3.58 (s, 3H), 3.24 (s, 3H). MS (ESI+) m/z 543.2 (M+H)+.
Example 284 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(tetrahydrofuran ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 284 was prepared according to the procedure used for the preparation of Example 279, substituting tetrahydrofuranamine for dimethylamine hydrochloride, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.86 (s, 1 H), 7.97 (d, J = 2.4 Hz, 1 H), 7.87-7.85 (m, 2 H), 7.54-7.39 (m, 3 H), .16 (m, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.17 (s, 1H), 3.72-3.66 (m, 3H), 3.57-3.53 (m, 5H), 3.25 (s, 3H), 3.14-3.13 (m, 1H), 2.27-2.26 (m, 1H), .77 (m, 1 H), 1.58-1.57 (m, 1 H). MS (ESI+) m/z 530.2 (M+H)+.
Example 285 4-[2-(cyclopropylmethoxy)(phenylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- dinone e 285a 1-(cyclopropylmethoxy)(phenylsulfonyl)benzene Example 285a was prepared according to the procedure used for the preparation of Example 158, substituting 1-fluoro(phenylsulfonyl)benzene for Example 138a, to provide the title compound. e 285b 2-bromo(cyclopropylmethoxy)(phenylsulfonyl)benzene Example 285a (0.087 g, 0.3 mmol) in acetic acid (5 mL) was cooled to 0 ºC. To this solution was added opyrrolidine-2,5-dione (2) (0.059 g, 0.330 mmol). The reaction mixture was heated at 80 ºC for 16 hours. After cooling, the reaction mixture was partitioned n water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate two more times. The combined c layers were washed with saturated aqueous sodium chloride, 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 4-[2-(cyclopropylmethoxy)(phenylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 285c was prepared according to the procedure used for the preparation of Example 95d, substituting Example 285b for Example 95c, to e the title compound. 1H NMR (500 MHz, 6) δ ppm 11.80 (s, 1H), 7.63-7.74 (m, 4H), 7.36-7.46 (m, 3H), 7.12 (s, 1H), 7.04-7.06 (m, 2H), 5.80-5.81 (m, 1H), 3.72 (d, J = 6.71 Hz, 2H), 3.34 (s, 3H), 0.82- 0.89 (m, 1H), 0.29-0.24 (m, 2H), 0.00-0.04 (m, 2H). MS (ESI+) m/z 434.9 (M-H)+.
Example 286 4-[2-(cyclopropylmethoxy)(morpholinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 286a 4-(3-bromofluorophenylsulfonyl)morpholine 3-Bromofluorobenzenesulfonyl chloride (0.44 g, 1.609 mmol) in tetrahydrofuran (10 mL) was treated with morpholine (0.294 g, 3.38 mmol). The reaction mixture was d for 16 hours at ambient temperature. The solvent was removed, and the residue was loaded onto a silica gel column and eluted with 20% ethyl acetate in hexanes to give the title nd (0.45 g, 1.388 mmol, 86% .
Example 286b romo(cyclopropylmethoxy)phenylsulfonyl)morpholine Example 286b was prepared according to the ure used for the preparation of Example 158, substituting Example 286a for Example 138a, to provide the title compound.
Example 286c 4-[2-(cyclopropylmethoxy)(morpholinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 286c was prepared according to the procedure used for the preparation of Example 95d, substituting Example 286b for Example 95c, to e the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.03 (s, 1H), 7.69 (dd, J = 8.85, 2.44 Hz, 1H), 7.64 (d, J = 2.44 Hz, 1H), 7.37 (s, 1H), 7.33 (d, J = 8.85 Hz, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.11-6.13 (m, 1H), 3.97 (d, J = 6.71 Hz, 2H), 3.62-3.65 (m, 4H), 3.57 (s, 3H), 2.86-2.88 (m, 4H), 0.45- 0.48 (m, 2H), 0.27-0.29 (m, 2H). MS (ESI+) m/z 444.1 (M+H)+.
Example 287 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 287a 3-bromo(2,4-difluorophenoxy)benzaldehyde A mixture of 3-bromofluorobenzaldehyde (4.06 g, 20 mmol), 2,4-difluorophenol (2.60 g, 20 mmol) and cesium carbonate (7.17 g, 22 mmol) in yl ide (20 mL) was heated at 100 °C for 1 hour. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and trated. The residue was purified by flash chromatography a gel, 20% ethyl e in heptanes) to provide the title compound (5.94 g, 95%).
Example 287b (3-bromo(2,4-difluorophenoxy)phenyl)methanol To a solution of Example 287a (3.76 g, 12 mmol) in the mixture of ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (0.136 g, 3.60 mmol). The reaction mixture was stirred at ambient ature for 1 hour. The solvent was evaporated and the residue was ioned with ethyl acetate and water. The organic layer was washed with ted aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated to e the title compound (3.72 g, 98%).
Example 287c o(bromomethyl)(2,4-difluorophenoxy)benzene To a solution of Example 287b (3.70 g, 11.74 mmol) in dichloromethane (20 mL) 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 the careful addition of saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (4.15 g, 93%).
Example 287d (3-bromo(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 ylformamide (8 mL) was stirred at ambient temperature for 6 hours.
The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (1.38 g, 100%).
Example 287e 2-bromo(2,4-difluorophenoxy)(methylsulfonylmethyl)benzene To a solution of Example 287d (1.38 g, 4.00 mmol) in methanol (15 mL) was added oxone (5.16 g, 8.40 mmol) in water (15 mL) at 0 °C. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash tography (silica gel, 20 to 40% ethyl acetate in heptanes) to provide the title compound (1.49 g, 98%).
Example 287f 4-(2-(2,4-difluorophenoxy)(methylsulfonylmethyl)phenyl)methyltosyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one e 287e (94 mg, 0.25 mmol), Example 6a (107 mg, 0.250 mmol), potassium phosphate (186 mg, 0.875 mmol), tris(dibenzylideneacetone)dipalladium (6.9 mg, 7.5 µmol) and 7-tetramethylphenyl-2,4,8-trioxaphosphaadamante (6.6 mg, 0.023 mmol) were combined in a ave tube and purged with nitrogen for 15 minutes. A mixture of dioxane (2 mL) and water (0.5 mL) was purged with nitrogen for 15 minutes and transferred to the microwave tube. The reaction mixture was heated at 60 °C for 1 hour. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium e, treated with 3- mercaptopropyl functionalized silica gel, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1 to 2% methanol in dichloromethane) to provide the title compound (62 mg, 41%).
Example 287g 2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 287f (59.9 mg, 0.100 mmol), ium hydroxide (84 mg, 1.5 mmol) and cetyltrimethylammonium bromide (1.8 mg, 5.0 µmol) were combined in a mixture of tetrahydrofuran (4 mL) and water (2 mL). The reaction mixture was heated at 100 °C 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 1M HCl. The mixture was ted with ethyl acetate and the c layer was washed with saturated aqueous sodium chloride twice, dried with ous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2 to 4% methanol in dichloromethane) to provide the title nd (31 mg, 70%). 1H NMR (300 MHz, DMSO-d 6) δ ppm12.04 (s, 1 H) 7.57 (d, J = 2.37 Hz, 1 H) 7.26 - 7.48 (m, 4 H) 7.16 - 7.26 (m, 1 H) 7.00 - 7.11 (m, 1 H) 6.88 (d, J = 8.48 Hz, 1 H) 6.23 - 6.33 (m, 1 H) 4.51 (s, 2 H) 3.55 (s, 3 H) 2.94 (s, 3 H). MS (ESI+) m/z 445 (M+H)+.
Example 288 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)pyridinyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone e 288a 2-fluoro(methylthio)pyridine A mixture of 5-bromofluoropyridine (2.05 g, 11.7 mmol) and N1,N1,N2,N2- tetramethylethane-1,2-diamine (2.27 mL, 15.1 mmol) was purged with nitrogen for 45 minutes. Toluene (116 mL) was added and the reaction mixture was cooled to -78 °C. N- butyllithium (2.5 M in hexanes, 5.59 mL, 14.0 mmol) was added dropwise over 6 minutes.
The reaction mixture was stirred at -78 °C for 1hour. Dimethyl disulfide (1.26 mL, 14.0 mmol) was added. The reaction mixture was stirred at -78 °C for 1hour. The on mixture was warmed to 0 °C, then immediately quenched with saturated aqueous ammonium chloride. The layers were separated, and the organic layer was washed with saturated aqueous sodium de, dried over anhydrous magnesium e, filtered, and concentrated. The residue was purified by flash tography (10% ethyl acetate/heptane) to provide the title compound (1.00g, 60%).
Example 288b 2-fluoro(methylsulfonyl)pyridine To a solution of Example 288a (2.17 g, 15.2 mmol) in romethane (50.5 mL) was added 3-chlorobenzoperoxoic acid (7.15 g, 31.1 mmol) portionwise over 10 minutes.
The reaction mixture was stirred at ambient temperature for 4 hours. Additional 3- chlorobenzoperoxoic 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, and the layers were separated. The aqueous layer was ted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium de, dried over anhydrous magnesium sulfate, filtered, and trated. The residue was ed by flash chromatography (silica gel, 0-10% methanol/dichloromethane) to provide the title compound (1.81g, 68 %).
Example 288c -(methylsulfonyl)pyridin-2(1H)-one Example 288b (0.679 g, 3.88 mmol) was treated with acetic acid (35.2 mL) and water (3.52 mL) at 110 °C for 16 hours. The reaction mixture was cooled to ambient ature and the solvent was removed to e the title compound (0.700g, 100%).
Example 288d o(methylsulfonyl)pyridin-2(1H)-one To a solution of e 288c (0.671 g, 3.87 mmol) and sodium e (0.318 g, 3.87 mmol) in acetic acid (8.50 mL) was added bromine (0.201 mL, 3.91 mmol) dropwise as a solution in acetic acid (1.7 mL). The reaction mixture was stirred at 40 °C for 3 hours.
Bromine (0.05 mL) was added, and the reaction mixture was stirred at 40 °C for 2 hours. 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 collected and dried for 16 hours to provide the title compound (0.64 g, 66%).
Example 288e 3-bromochloro(methylsulfonyl)pyridine Example 288d (0.6395 g, 2.54 mmol) was treated with phosphorus oxychloride (12.7 mL) at 110°C for 4 hours. The on mixture was cooled to ambient temperature and poured onto ice. The resulting sion was filtered and rinsed with water, and the off white solid was collected and dried in a 60 °C vacuum oven for 16 hours to provide the title compound (0.244g, 35%).
Example 288f 3-bromo(2,4-difluorophenoxy)(methylsulfonyl)pyridine Example 288f was ed 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)(methylsulfonyl)pyridinyl)methyltosyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one Example 288g was ed according to the procedure used for the preparation of Example 4a, substituting Example 288f for Example 7c to provide the title compound.
Example 288h 4-(2-(2,4-difluorophenoxy)(methylsulfonyl)pyridinyl)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 e the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.16 (s, 1H) 8.59 (d, J = 2.37 Hz, 1H) 8.37 (d, J = 2.37 Hz, 1H) 7.58 (s, 1H) 7.48 (m, 2H) 7.34 (t, J = 2.71 Hz, 1H) 7.16 (m, 1H) 6.36 (dd, J = 2.71, 2.03 Hz, 1H) 3.61 (s, 3H) 3.35 (s, 3H). MS (ESI+) m/z 432.4 (M+H)+.
Example 289 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(pyridin yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 289a oromethyl)(2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl)methyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one A e of Example 276 (0.50 g, 1.09 mmol) and thionyl chloride (5.0 mL, 69 mmol) was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was dried under vacuo for 1 hour to provide the title compound.
Example 289b 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(pyridin methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone To a solution of pyridinol (0.039 g, 0.407 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (16 mg, 0.407 mmol) at 0 °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 under reflux for 16 hours. The reaction mixture was poured into a mixture of ethyl acetate (30 mL) and saturated s sodium chloride (20 mL). The aqueous layer was extraceted with ethyl acetate (20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, water (10 mM NH4HCO3):acetonitrile, 25-50% gradient) to provide the title compound (18 mg, 16% yield). 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.52 (s, 1 H), 7.95 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 2.4, 6.4 Hz, 1 H), 7.56 - 7.38 (m, 5 H), 7.22 - 7.18 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.84 - 6.82 (m, 1H), 6.48 (s, 1H), 5.38 (s, 2H), 3.58 (s, 3 H), 3.25 (s, 3H). ). MS (ESI+) m/z 538.1 (M+1) +. e 290 4-[5-(cyclopropylsulfonyl)(2,4-difluorophenoxy)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone e 290a (3-bromofluorophenyl)(cyclopropyl)sulfane Example 290a was prepared according to the procedure used for the preparation of Example 168a, tuting bromocyclopropane for iodoethane, to provide the title compound e 290b 2-bromo(cyclopropylsulfonyl)fluorobenzene Example 290b was prepared according to the procedure used for the preparation of Example 168b, tuting Example 290a for Example 168a, to provide the title compound.
Example 290c 2-bromo(cyclopropylsulfonyl)(2,4-difluorophenoxy)benzene Example 290c was ed according to the procedure used for the preparation of Example 138b, substituting Example 290b for Example 138a, to provide the title compound.
Example 290d 4-[5-(cyclopropylsulfonyl)(2,4-difluorophenoxy)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone Example 290d was prepared according to the procedure used for the ation of Example 95d, substituting Example 290c for Example 95c, to provide the title nd. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.11 (s, 1H), 7.94 (d, J = 2.44 Hz, 1H), 7.83 (dd, J = 8.54, 2.44 Hz, 1H), 7.42-7.55 (m, 3H), 7.32 (t, J = 2.75 Hz, 1H), 7.15-7.20 (m, 1H), 6.97 (d, J = 8.54 Hz, 1H), 6.28-6.29 (m, 1H), 3.59 (s, 3H), 2.90-2.96 (m, 1H), 1.12-1.15 (m, 2H), 1.03- 1.09 (m, 2H). MS (ESI+) m/z 457.1 (M+H)+.
Example 291 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(propenyl)-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone To a on of Example 252f (0.10 g, 0.20 mmol) in tetrahydrofuran (6 mL) stirring at 0 °C was added methylmagnesium bromide (0.498 mL, 0.498 mmol). The reaction mixture was stirred at 0 °C for 1 hour, and then aqueous HCl (1 M, 2 mL) was added. The reaction mixture was concentrated and partitioned between saturated aqueous sodium chloride (10 mL) and ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The e was purified by reverse phase-HPLC (C 18 40-90% gradient acetonitrile:water (0.1%TFA)) to provide the title compound (25 mg, 25% yield). 1H NMR (400 MHz, DMSO- d6) δ ppm 12.05 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 8.7, 2.4 Hz, 1H), 7.61 – 7.36 (m, 3H), 7.18 (t, J = 8.6 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.34 (d, J = 2.2 Hz, 1H), 5.85 (s, 1H), 5.07 (s, 1H), 3.60 (s, 3H), 3.26 (s, 3H), 2.02 (s, 3H). MS (ESI+) m/z 471.1 (M+1)+.
Example 292 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(phenoxymethyl)-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 292 was prepared according to the procedure used for the preparation of Example 289b, substituting phenol for pyridinol, to provide the title compound. 1H NMR (400 MHz, 6) δ ppm 12.32 (s, 1 H), 7.96 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 2.4, 6.4 Hz, 1 H), 7.55 - 7.50 (m, 1 H), 7.49 (s, 1 H), 7.45 - 7.36 (m, 1H), 7.26 - 7.16 (m, 3H), 6.98 - 6.89 (m, 4H), 6.37 (s, 1H), 5.11 (s, 2H), 3.59 (s, 3 H), 3.23 (s, 3H). MS (ESI+) m/z 537.2 (M+1)+ e 293 4-[2-(2,4-difluorophenoxy)(morpholinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 293a 4-((3-bromo(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 4-[2-(2,4-difluorophenoxy)(morpholinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 293b was prepared according to the ure used for the preparation of Example 95d, substituting Example 293a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 7.76 (d, J = 2.44 Hz, 1H), 7.83 (dd, J = 8.7, 2.44 Hz, 1H), 7.42-7.54 (m, 3H), 7.30 (t, J = 2.75 Hz, 1H), 7.14-7.16 (m, 1H), 7.01 (d, J = 8.54 Hz, 1H), 6.25-6.27 (m, 1H), 3.64-3.66 (m, 4H), 3.59 (s, 3H), 2.88-2.92 (m, 4H). MS (ESI+) m/z 502.2 .
Example 294 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)pyridinyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 294a 3-bromochloro(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 on. The mixture was heated at 75 °C. 3-Bromochloropyridinesulfonyl chloride (2.132 g, 7.33 mmol) was added portionwise over 1 hour. The reaction mixture was stirred at 75 °C 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, 7.33 mmol) were added. The resulting mixture was heated to 75 °C for 2 hours and then cooled to ambient temperature. The e was partitioned n ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, ed, and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to provide the title nd.
Example 294b 4-(2-chloro(ethylsulfonyl)pyridinyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 294b was prepared according to the procedure used for the preparation of Example 4a, substituting e 294a for Example 7c to provide the title compound.
Example 294c 4-(2-(2,4-difluorophenoxy)(ethylsulfonyl)pyridinyl)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. 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.17 (bs, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.58 (s, 1H), 7.54–7.43 (m, 2H), 7.34 (t, J = 2.7 Hz, 1H), 7.21–7.12 (m, 1H), 6.35 (t, J = 2.1 Hz, 1H), 3.61 (s, 3H), 3.44 (q, J = 7.3 Hz, 2H), 1.18 (t, J = 7.3 Hz, 1H). MS (ESI+) m/z 446.2 (M+H)+.
Example 295 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl](morpholinyl)ethanesulfonamide Example 295a 4-(5-amino(2,4-difluorophenoxy)phenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 295a was prepared according to the procedure used for the ation of Example 138a, substituting Example 1e for ofluoro(methylsulfonyl)benzene, and Example 148c for Example 6a, respectively, to provide the title compound.
Example 295b 2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl](morpholinyl)ethanesulfonamide A mixture of Example 295a, 2-chloroethanesulfonyl de (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 hours. 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 ºC for 2 hours. To this solution was added 2.0 N sodium hydroxide (2.00 mL, 4.00 mmol). The reaction mixture was heated at 85 ºC for 2 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and 1.0 N HCl. The aqueous layer was extracted with onal ethyl acetate several times. The combined organic layers were washed with ted aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was ed by ative HPLC % acetonitrile in 0.1% TFA water) to give the TFA salt of the title compound (0.077 g, 0.117 mmol, 58.5% . 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.08 (s, 1H), 10.18 (s, 1H), 7.37-7.43 (m, 2H), 7.30-7.31 (m, 2H), 7.22 (dd, J = 8.85, 2.75 Hz, 1H), .14 (m, 1H), 7.00-7.04 (m, 1H), 6.91 (d, J = 8.54 Hz, 1H), 6.28-6.29 (m, 1H), 3.51-3.62 (m, 11H), 3.24 (br s, 4H). MS (ESI+) m/z 545.1 (M+H)+.
Example 296 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin 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 minutes. To this solution was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.113 g, 0.490 mmol). The solution was stirred for three hours at ambient temperature. The solvent was removed, and the residue was purified by preparative HPLC (10-80% acetonitrile in 0.1% TFA water) to give the title compound (0.055 g, 0.104 mmol, 31.8% yield). 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.06 (s, 1H), 7.51 (d, J = 2.44 Hz, 1H), 7.41-7.47 (m, 1H), 7.35-7.37 (m, 2H), 7.23-7.31 (m, 2H), .11 (m, 1H), 6.85 (d, J = 8.85 Hz, 1H), 3.57 (t, J = 6.71 Hz, 2H), 3.56 (s, 3H), 3.17 (q, J = 7.32 Hz, 1H), 2.25 (m, 2H), 2.13 (s, 6H), 1.25 (q, J = 7.48 Hz, 3H). MS (ESI+) m/z 531.2 (M+H)+.
Example 297 4-{2-(2,4-difluorophenoxy)[(ethylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 297a (3-bromo(2,4-difluorophenoxy)benzyl)(ethyl)sulfane Example 297a was prepared according to the procedure used for the preparation of Example 287d, substituting sodium ethanethiolate for sodium thiomethoxide, to provide the title compound (1.04 g, 99%).
Example 297b o(2,4-difluorophenoxy)(ethylsulfonylmethyl)benzene Example 297b was prepared according to the procedure used for the ation of Example 287e, substituting Example 297a for Example 287d, to provide the title compound (1.01 g, 89%).
Example 297c 4-(2-(2,4-difluorophenoxy)(ethylsulfonylmethyl)phenyl)methyltosyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one Example 297c was prepared according to the procedure used for the preparation of Example 287f, substituting Example 297b for Example 287e. Purification by flash chromatography a gel, 0 to 2% ol in dichloromethane) afforded the title compound (63 mg, 51%).
Example 297d 4-{2-(2,4-difluorophenoxy)[(ethylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 297d was prepared according to the procedure used for the preparation of Example 287g, substituting Example 297c for Example 287f, to provide the title compound (34 mg, 75%). 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.04 (s, 1 H) 7.56 (d, J = 2.37 Hz, 1 H) 7.15 - 7.48 (m, 5 H) 6.99 - 7.11 (m, 1 H) 6.87 (d, J = 8.14 Hz, 1 H) 6.25 - 6.35 (m, 1 H) 4.49 (s, 2 H) 3.55 (s, 3 H) 3.07 (q, J = 7.23 Hz, 2 H) 1.23 (t, J = 7.46 Hz, 3 H). MS (ESI+) m/z 459 (M+H)+.
Example 298 4-{2-(2,4-difluorophenoxy)[2-(ethylsulfonyl)propanyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 298a 2-bromo(2,4-difluorophenoxy)(2-(ethylsulfonyl)propanyl)benzene To a solution of Example 297b (469 mg, 1.20 mmol) in tetrahydrofuran (10 mL) was added 60% sodium hydride in mineral oil (240 mg, 6.00 mmol) at 0 °C. The reaction e was stirred at t temperature under nitrogen for 10 s. Iodomethane (0.750 mL, 12.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 20 hours.
The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20 to 40% ethyl acetate in heptanes) to provide the title compound (442 mg, 88 %).
Example 298b 4-(2-(2,4-difluorophenoxy)(2-(ethylsulfonyl)propanyl)phenyl)methyltosyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one Example 298b was prepared ing to the procedure used for the preparation of Example 287f, substituting Example 298a for Example 287e. Purification by flash chromatography (silica gel, 0 to 2% methanol in dichloromethane) ed the title compound (80 mg, 62%).
Example 298c 4-{2-(2,4-difluorophenoxy)[2-(ethylsulfonyl)propanyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 298c was prepared according to the procedure used for the ation of 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%). 1H NMR (400 MHz, DMSO-d6) δppm 12.06 (s, 1 H) 7.71 (d, J = 2.44 Hz, 1 H) 7.55 (dd, J = 8.70, 2.59 Hz, 1 H) 7.38 - 7.48 (m, 1 H) 7.33 (s, 1 H) 7.19 - 7.31 (m, 2 H) 7.02 - 7.12 (m, 1 H) 6.85 (d, J = 8.24 Hz, 1 H) 6.29 (d, J = 2.14 Hz, 1 H) 3.56 (s, 3 H) 2.90 (q, J = 7.43 Hz, 2 H) 1.77 (s, 6 H) 1.06 (t, J = 7.48 Hz, 3 H). MS (ESI+) m/z 487 (M+H)+.
Example 299 2,4-difluorophenoxy)(pyrrolidinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 299a 1-((3-bromofluorophenyl)sulfonyl)pyrrolidine To a solution of 3-bromofluorobenzenesulfonyl chloride (1.0g, 3.66 mmol) in mL dichloromethane at 0 °C was added pyrrolidine (0.635 mL , 7.68 mmol). The mixture was stirred at 0 oC for 30 minutes and then at room ature overnight. The reaction mixture was d with dichloromethane, washed with 1% HCl solution and water, dried over anhydrous magnesium sulfate, filtered, and trated to give the title compound (0.86 g, 76% yield) Example 299b 1-((3-bromo(2,4-difluorophenoxy)phenyl)sulfonyl)pyrrolidine A mixture of Example 299a (250 mg, 0.811 mmol), 2,4-difluorophenol (106 mg, 0.811 mmol) and cesium carbonate (317 mg, 0.973 mmol) in 5 mL dimethylsulfoxide was heated at 110 °C for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The c phase was washed with water (2X), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and ed. The filtrate was trated to give the title compound (278mg, 82% yield), which was used without further purification.
Example 299c 4-[2-(2,4-difluorophenoxy)(pyrrolidinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone A mixture of Example 299b (100 mg, 0.239 mmol), Example 6a (102 mg, 0.239 mmol), tetrakis(triphenylphosphine)palladium(0) (13.81 mg, 0.012 mmol) and cesium fluoride (109 mg, 0.717 mmol) in 2 mL dimethxoyethane and 1 mL methanol was heated at 120°C in a microwave oven (Biotage Initiator) for 40 minutes. The mixture was then treated with 4 N NaOH (1 mL ) and stirred at ambient temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate (2X). The c phase was washed with saturated s sodium de, dried over anhydrous magnesium sulfate, and filtered.
The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 60-100% ethyl e/heptanes gradient) to give the title compound (75 mg, 64.6% yield). 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.06 (s, 1H), 12.06 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.77 – 7.72 (m, 1H), 7.79 – 7.72 (m, 1H), 7.47 (ddd, J = 11.5, 8.8, 3.0 Hz, 1H), 7.47 (ddd, J = 17.8, 10.4, 6.0 Hz, 1H), 7.42 – 7.39 (m, 1H), 7.43 – 7.35 (m, 2H), 7.30 (t, J = 2.8 Hz, 1H), 7.30 (t, J = 2.8 Hz, 1H), 7.28 – 7.09 (m, 1H), 7.17 – 7.09 (m, 1H), 6.98 – 6.93 (m, 1H), 6.99 – 6.93 (m, 1H), 6.24 (ddd, J = 23.2, 2.6, 2.2 Hz, 1H), 6.22 (dd, J = 2.6, 2.2 Hz, 1H), 3.57 (s, 3H), 3.57 (s, 3H), 3.22 – 3.09 (m, 4H), 3.19 – 3.11 (m, 4H), 1.72 – 1.64 (m, 4H), 1.75 – 1.61 (m, 4H), 1.17 (dd, J = 18.8, 11.7 Hz, 1H), 0.87 – 0.74 (m, 1H). MS (ESI+) m/z 464.2 (M+H)+. e 300 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl](dimethylamino)ethanesulfonamide Example 300 was prepared according to the procedure used for the preparation of Example 295b, substituting N, N-dimethylamine for morpholine, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.07 (s, 1H), 10.18 (s, 1H), 9.86 (br s, 1H), 7.37-7.42 (m, 2H), 7.29-7.31 (m, 2H), 7.22 (dd, J = 8.54, 2.75 Hz, 1H), 7.09-7.14 (m, 1H), 7.01-7.07 (m, 1H), 6.91 (d, J = 8.85 Hz, 1H), 6.28 (t, J = 2.29 Hz, 1H), 3.62-3.65 (m, 2H), 3.54 (s, 3H), 3.48-3.51 (m, 2H), 2.83 (s, 6H). MS (ESI+) m/z 503.1 (M+H)+.
Example 301 ethyl 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy]piperidinecarboxylate Example 301a ethyl 4-(2-bromo(ethylsulfonyl)phenoxy)piperidinecarboxylate Example 301a was prepared according to the procedure used for the preparation of Example 158, substituting Example 138a for Example 168b, and ethyl 4-hydroxypiperidine- oxylate for cyclopropylmethanol, respectively, to provide the title nd.
Example 301b ethyl 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin noxy]piperidinecarboxylate Example 301b was prepared according to the procedure used for the preparation of Example 95d, substituting Example 301a for Example 95c, to e the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.04 (s, 1H), 7.80-7.83 (m, 2H), 7.44 (d, J = 8.54 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.76-4.81 (m, 1H), 3.99 (q, J = 7.02 Hz, 2H), 3.57 (s, 3H), .39 (m, 6H), 1.86-1.90 (m, 2H), 1.49-1.53 (m, 2H), 1.12- 1.16 (M, 6H). MS (ESI+) m/z 488.1 (M+H)+. e 302 4-[2-(cyclopropylmethoxy)(pyrrolidinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone e 302a 1-((3-bromo(cyclopropylmethoxy)phenyl)sulfonyl)pyrrolidine To a solution of cyclopropylmethanol (115 µL, 1.460 mmol) in dioxane (8 mL) at room temperature was added sodium hydride (78 mg, 1.947 mmol). After stirring at ambient temperature for 10 minutes, Example 299a (300 mg, 0.973 mmol) was added as a solid. The mixture was then heated at 65 °C overnight. Water was added. The mixture was extracted with ethyl acetate, wahsed with water (2X), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-50% ethyl acetate/heptanes gradient) to give the title compound (156mg, 44.5% yield) Example 302b 4-[2-(cyclopropylmethoxy)(pyrrolidinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone A mixture of Example 302a (84 mg, 0.233 mmol), Example 6a (100 mg, 0.233 mmol), is(triphenylphosphine)palladium(0) (13.49 mg, 0.012 mmol) and cesium fluoride (106 mg, 0.700 mmol) in 2 mL dimethoxyethane and 1 mL ol was purged with nitrogen gas and heated at 130 °C under microwave conditions (Biotage Initiator) for 40 minutes.The mixture was then treated with 4 N NaOH (1mL) and stirred at room ature for 2 hours. Water was added and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was absorbed on silica gel and ed by flash chromatography (silica gel, 0-10% methanol/dichloromethane gradient) to give the title compound (64 mg, 64.1% yield). 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.10 – 11.92 (m, 1H), 7.77 – 7.70 (m, 2H), 7.37 (s, 1H), 7.30 (dd, J = 6.9, 4.1 Hz, 2H), 6.17 – 6.03 (m, 1H), 3.97 (d, J = 6.8 Hz, 2H), 3.58 (s, 3H), 3.14 (t, J = 6.7 Hz, 4H), 1.71 – 1.64 (m, 4H), 1.15 – 1.08 (m, 1H), 0.50 – 0.44 (m, 2H), 0.30 – 0.24 (m, 2H). MS (ESI+) m/z 482.2 (M+H)+.
Example 303 4-{2-[(1-acetylpiperidinyl)oxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H- o[2,3-c]pyridinone Example 303a 1-(4-(2-bromo(ethylsulfonyl)phenoxy)piperidinyl)ethanone Example 303a was prepared according to the procedure used for the preparation of Example 158, substituting Example 168b for Example 138a, and tuting 1-(4- hydroxypiperidinyl)ethanone for cyclopropylmethanol, respectively, to provide the title compound.
Example 303b 4-{2-[(1-acetylpiperidinyl)oxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone 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 nd. 1H NMR (500 MHz, 6) δ ppm 12.04 (s, 1H), 7.80-7.84 (m, 2H), 7.45 (d, J = 8.54 Hz, 1H), 7.33 (s, 1H), 7.29 (t, J = 2.75 Hz, 1H), 6.12-6.13 (m, 1H), 4.81-4.84 (m, 1H), 3.57 (s, 3H), 3.24-3.39 (m, 6H), 2.09 (s, 3H), 1.49-1.53 (m, 2H), 1.12-1.16 (m, 3H). MS (ESI+) m/z 458.2 (M+H)+.
Example 304 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy]benzonitrile Example 304 was prepared according to the procedure used for the preparation of Example 138b, substituting Example 168c for Example 138a, and 4-cyanophenol for 2,4- difluorophenol, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.09 (s, 1H), 8.00 (d, J = 2.44 Hz, 1H), 7.92 (dd, J = 8.54, 2.54 Hz, 1H), 7.79-7.82 (m, 2H), 7.39 (s, 1H), 7.35 (d, J = 8.54 Hz, 1H), 7.29 (t, J = 2.75 Hz, 1H), 7.14-7.17 (m, 2H), .23 (m, 1H), 3.54 (s, 3H), 3.38 (q, J = 7.32 Hz, 2H), 1.17 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 434.2 (M+H)+.
Example 305 cyclopropylmethoxy)(2,3-dihydro-1H-indolylsulfonyl)phenyl]methyl-1,6- o-7H-pyrrolo[2,3-c]pyridinone Example 305a 1-(3-bromofluorophenylsulfonyl)indoline A solution of 3-bromofluorobenzenesulfonyl de (Aldrich) (2.53 g, 8.33 mmol), ne (0.99 g, 8.33 mmol), N,N-diisopropylethylamine (1.60 mL, 9.16 mmol) and tetrahydrofuran (20 mL) was stirred at ambient temperature for 16 hours.. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with additional ethyl acetate. The combined c layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and trated to afford a brown oil which solidified upon standing. The crude product was recrystallized from ether/heptane to afford the title compound (1.99g, 5.59 mmol, 67% yield).
Example 305b 1-(3-bromo(cyclopropylmethoxy)phenylsulfonyl)indoline Example 305b was prepared according to the procedure used for the preparation of e 29a, substituting cyclopropylmethanol for tetrahydro-2H-pyranol and tuting Example 305a for Example 2a to afford the title compound.
Example 305c 4-(2-(cyclopropylmethoxy)(indolinylsulfonyl)phenyl)methyltosyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one Example 305c was prepared according to the procedure used for the preparation of Example 6c, substituting Example 305b for Example 6b to afford the title compound.
Example 305d 4-(2-(cyclopropylmethoxy)(indolinylsulfonyl)phenyl)methyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 305d was prepared according to the procedure used for the preparation of Example 6d, substituting Example 305c for Example 6c to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.24 (tt, J = 13.4, 6.6 Hz, 2H) 0.35 - 0.50 (m, 2H) 1.01 - 1.18 (m, 1H) 2.90 (t, J = 8.3 Hz, 2H) 3.54 (s, 3H) 3.90 (t, J = 8.4 Hz, 2H) 3.92 (d, J = 6.8 Hz, 2H) .80-5.86 (m, 1H) 7.04 (td, J = 7.4, 1.0 Hz, 1H) 7.14-7.36 (m, 5H) 7.50 (d, J = 8.0 Hz, 1H) 7.66 (d, J = 2.4 Hz, 1H) 7.77 (dd, J = 8.7, 2.5 Hz, 1H) 12.02 (bs, 1H). MS (ESI+) m/z 476 [M+H]+. e 306 4-{2-(2,4-difluorophenoxy)[(phenylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone e 306a (3-bromo(2,4-difluorophenoxy)benzyl)(phenyl)sulfane e 306a was prepared according to the procedure used for the preparation of Example 287d, substituting sodium thiophenoxide for sodium thiomethoxide, to provide the title compound (815 mg, 100%). e 306b o(2,4-difluorophenoxy)(phenylsulfonylmethyl)benzene Example 306b was prepared according to the procedure used for the preparation of Example 287e, substituting Example 306a for Example 287d, to provide the title compound (867 mg, 99%).
Example 306c 4-(2-(2,4-difluorophenoxy)(phenylsulfonylmethyl)phenyl)methyltosyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one Example 306c was prepared according to the procedure used for the preparation of Example 287f, substituting Example 306b for Example 287e. Purification by flash tography (silica gel, 0 to 2% methanol in romethane) afforded the title compound (51 mg, 52%).
Example 306d 4-{2-(2,4-difluorophenoxy)[(phenylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 306d was prepared according to the procedure used for the preparation of Example 287g, substituting Example 306c for Example 287f, to provide the title compound (30 mg, 80%). 1H NMR (300 MHz, DMSO-d 6) δppm 12.02 (s, 1 H) 7.69 - 7.81 (m, 3 H) 7.55 - 7.67 (m, 2 H) 7.34 - 7.46 (m, 1 H) 7.20 - 7.29 (m, 2 H) 6.98 - 7.18 (m, 4 H) 6.80 (d, J = 8.48 Hz, 1 H) 6.09 (dd, J = 2.37, 1.70 Hz, 1 H) 4.71 (s, 2 H) 3.52 (s, 3 H). MS (ESI+) m/z 507 (M+H)+.
Example 307 4-{2-[(2,2-difluorocyclopropyl)methoxy](pyrrolidinylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 307a 1-((3-bromo((2,2-difluorocyclopropyl)methoxy)phenyl)sulfonyl)pyrrolidine Example 307a was prepared according to the procedure used for the preparation of Example 302a, substituting (2,2-difluorocyclopropyl)methanol for cyclopropylmethanol, to provide the title compound.
Example 307b 4-{2-[(2,2-difluorocyclopropyl)methoxy](pyrrolidinylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone e 307b was prepared according to the procedure used for the preparation of Example 302b, substituting 307a for 302a, to provide the title compound. 1H NMR (300 MHz, 6) δ ppm 12.05 (s, 1H), 12.05 (s, 1H), 7.76 (tt, J = 6.9, 3.5 Hz, 2H), 7.81 – 7.71 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.38 – 7.27 (m, 3H), 7.30 (t, J = 2.6 Hz, 1H), 6.12 (dd, J = 2.5, 1.6 Hz, 1H), 6.12 (dd, J = 2.5, 1.6 Hz, 1H), 4.21 (dt, J = 18.8, 9.6 Hz, 2H), 3.57 (s, 3H), 3.57 (s, 3H), 3.15 (t, J = 6.7 Hz, 4H), 3.15 (t, J = 6.7 Hz, 4H), 2.21 – 2.04 (m, 1H), 2.19 – 1.98 (m, 1H), 1.74 – 1.57 (m, 5H), 1.77 – 1.57 (m, 5H), 1.52 – 1.36 (m, 1H), 1.53 – 1.38 (m, 1H). MS (ESI+) m/z 464.2 (M+H)+.
Example 308 4-{2-(cyclopropylmethoxy)[(3,3-difluoroazetidinyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 308a 1-((3-bromofluorophenyl)sulfonyl)-3,3-difluoroazetidine To a suspension of 3,3-difluoroazetidine hydrochloric acid (0.947 g, 7.31 mmol) in 20 mL dichloromethane at 0 °C was added l-N-isopropylpropanamine (2.80 mL , 16.1 mmol) followed by the on of a solution of 3-bromofluorobenzenesulfonyl chloride (2.0 g, 7.3 mmol) in 4 mL dichloromethane. The mixture was stirred at room temperature overnight and then heated at 55 °C for 5 hours, diluted with dichloromethane, washed with water, dried over ous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 10-50% ethyl acetate/heptanes gradient) to give the title compound (1.5 g, 62.1% yield) Example 308b 1-((3-bromo(cyclopropylmethoxy)phenyl)sulfonyl)-3,3-difluoroazetidine e 308b was prepared according to the ure used for the preparation of Example 302a, substituting Example 308a for Example 299a to provide the title compound.
Example 308c 4-{2-(cyclopropylmethoxy)[(3,3-difluoroazetidinyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 308c was prepared according to the procedure used for the preparation of e 302b, substituting e 308b for Example 302a to provide the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.04 (s, 1H), 7.87 (dd, J = 8.7, 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.40 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.29 (t, J = 2.7 Hz, 1H), 6.12 – 6.08 (m, 1H), 4.26 (t, J = 12.7 Hz, 4H), 4.01 (d, J = 6.8 Hz, 2H), 3.58 (s, 3H), 1.14 – 1.08 (m, 1H), 0.50 – 0.43 (m, 2H), 0.30 – 0.25 (m, 2H). MS (DCI+) m/z 491.4 (M+CH3CN)+.
Example 309 2-(2-hydroxyethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 304 was prepared according to the ure used for the preparation of Example 138b, substituting 2-(2-hydroxyethyl)phenol for 2,4-difluorophenol, to provide the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.11 (s, 1H), 8.00 (d, J = 2.44 Hz, 1H), 7.85 (dd, J = 8.85, 2.44 Hz, 1H), 7.45 (s, 1H), 7.36 (dd, J = 7.63, 1.53 Hz, 1H), 7.32 (t, J = 2.9 Hz, 1H), 7.24-7.28 (m, 1H), 7.14-7.18 (m, 1H), 6.98-7.01 (m, 1H), 6.89 (d, J = 8.54 Hz,1H), 6.29-6.31 (m, 1H), 3.57 (s, 3H), 3.46 (t, J = 7.02 Hz, 2H), 3.25 (s, 3H), 2.63 (t, J = 7.02 Hz, 2H). MS (ESI+) m/z 439.1 (M+H)+.
Example 310 4-[2-(cyclopropylmethoxy){[3-(dimethylamino)pyrrolidinyl]sulfonyl}phenyl] methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone Example 310a 1-(3-bromofluorophenylsulfonyl)-N,N-dimethylpyrrolidinamine A solution of ofluorobenzenesulfonyl chloride (Combi-blocks) (250mg, 0.91 mmol), N,N-dimethylpyrrolidinamine (218mg, 1.9 mmol) in tetrahydrofuran (5.7 mL) was stirred at ambient temperature for 16 hours. The solvent was evaporated and residue was purified by flash chromatography (silica gel, dichloromethane /gradient with MeOH) to afford the title nd (220 mg, 69% yield).
Example 310b 1-(3-bromo(cyclopropylmethoxy)phenylsulfonyl-N,N-dimethylamine Example 310b was prepared according to the procedure used for the preparation of Example 29a, substituting cyclopropylmethanol for tetrahydro-2H-pyranol and substituting Example 310a for Example 2a to afford the title compound.
Example 310c 4-(2-(cyclopropylmethoxy)(3-(dimethylamino)pyrrolidinylsulfonyl)phenyl)methyl- 1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 310c was ed according to the ure used for the preparation of Example 6c, tuting Example 310b for Example 6b, to afford the title compound.
Example 310d 4-(2-(cyclopropylmethoxy)(3-(dimethylamino)pyrrolidinylsulfonyl)phenyl)methyl- 1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 310d was prepared according to the procedure used for the preparation of Example 6d, substituting Example 310c for Example 6c, to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm .31 (m, 2 H) 0.44-0.51 (m, 2 H) 1.06-1.17 (m, 1 H) .59 (m, 1 H) 1.86-1.97 (m, 1 H) 2.04 (s, 6 H) 2.52-2.57 (m, 1 H) 2.82-2.90 (m, 1 H) 3.07-3.18 (m, 1 H) 3.25-3.28 (m, 1 H) 3.34-3.42 (m, 1 H) 3.57 (s, 3 H) 3.98 (d, J = 6.78 Hz, 2 H) 6.12 (t, J = 2.71, 2.03 Hz, 1 H) 7.28-7.33 (m, 2 H) 7.35 (s, 1 H) 7.71-7.79 (m, 2 H) 12.04 (s, 1 H). MS (ESI+) m/z 471 [M+H]+.
Example 311 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]pyridinyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone e 311a -bromo(2,4-difluorophenoxy)nicotinic acid -bromochloronicotinic 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 combined in DMSO (25.4 mL), heated at 100 °C for 6 hours, cooled, diluted with 150 mL of iced water and the pH was adjusted to pH 3 with 12M HCl. The resulting solid was collected by filtration, washed with cold water and dried to constant mass to afford the title compound (2.84 g, 64%).
Example 311b (5-bromo(2,4-difluorophenoxy)pyridinyl)methanol The product from Example 311a (1.0 g, 3.03 mmol) and borane ydrofuran x (6.06 mL, 6.06 mmol) were combined in tetrahydrofuran (15.15 mL) and heated at 50 °C for 2 hours, cooled, treated with 10 mL of methanol, heated at 50 °C for 1 hour, cooled and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried 4), ed, and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate in heptanes) afforded the title compound (0.73 g, 76%).
Example 311c 3-bromo(bromomethyl)(2,4-difluorophenoxy)pyridine A solution of the product from Example 311b (0.73 g, 2.309 mmol) in dichloromethane (11.55 mL) under nitrogen was d dropwise with tribromophosphine (0.218 mL, 2.309 mmol), d for one hour at t temperature and poured into ice water and the pH was adjusted to pH 9 by addition of solid sodium bicarbonate added nwise. An emulsion formed that was partially removed by filtration. The aqueous layer was extracted with dichloromethane and the organics were combined, washed with saturated aqueous sodium chloride, dried (Na2SO4) filtered, and concentrated to afford the title nd (0.75 g, 86%).
Example 311d 3-bromo(2,4-difluorophenoxy)(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 for 4 hours at ambient temperature, and partitioned into ethyl acetate and cold water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated to afford the title compound (0.66 g, 96%).
Example 311e 3-bromo(2,4-difluorophenoxy)(methylsulfonylmethyl)pyridine A solution of the product from Example 311d (0.66 g, 1.906 mmol) at 0 °C in methanol (7.33 mL) was treated with a solution of Oxone (2.461 g, 4.00 mmol) in water (7.33 mL), stirred at ambient temperature for two hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-5% methanol in romethane) afforded the title compound (0.433 g, 60%).
Example 311f 4-(2-(2,4-difluorophenoxy)((methylsulfonyl)methyl)pyridinyl)methyltosyl-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), ), ibenzylideneacetone)dipalladium(0) (5.45 mg, 5.95 µmol), 1,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamante (5.80 mg, 0.020 mmol) and ium ate (0.126 g, 0.595 mmol) were combined and d with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (2 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 2 hours at 60 °C and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), 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 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]pyridinyl}methyl-1,6-dihydro- rolo[2,3-c]pyridinone The product from Example 311f (0.083 g, 0.138 mmol), potassium hydroxide (0.194 g, 3.46 mmol) and trimethylhexadecanaminium bromide (2.52 mg, 6.92 µmol) were combined in dioxane (1.8 mL) /water (0.9 mL) and heated at 100 °C for 4 hours, cooled, and partitioned into ethyl acetate adjusting the pH to 7 with 1 M HCl. The organic layer was washed with saturated aqueous sodium chloride, dried 4), filtered, and concentrated.
Purification by chromatography (silica gel, 0-4% ol in dichloromethane) afforded the title compound (0.035 g, 57%). 1H NMR (400 MHz, DMSO-d 6) δ ppm 12.14 (s, 1 H) 8.03 (dd, J = 22.74, 2.29 Hz, 2 H) 7.30 - 7.51 (m, 4 H) 7.03 - 7.17 (m, 1 H) 6.39 (d, J = 2.14 Hz, 1 H) 4.57 (s, 2 H) 3.60 (s, 3 H) 3.00 (s, 3 H). MS (ESI+) m/z 446 [M+H]+.
Example 312 tert-butyl 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy]piperidinecarboxylate Example 312a tert-butyl 4-(2-bromo(ethylsulfonyl)phenoxy)piperidinecarboxylate Example 312a was prepared according to the procedure used for the preparation of Example 158, substituting Example 168b for Example 138a, and tert-butyl 4- hydroxypiperidinecarboxylate for cyclopropylmethanol, respectively, to provide the title compound.
Example 312b tert-butyl 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy]piperidinecarboxylate Example 312b was prepared according to the procedure used for the ation of e 95d, substituting Example 312a for Example 95c, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.02 (s, 1H), 7.79-7.842 (m, 2H), 7.42 (d, J = 8.54 Hz, 1H), 7.31 (s, 1H), 7.27 (t, J = 2.75 Hz, 1H), 6.10-6.11 (m, 1H), .78 (m, 1H), 3.55 (s, 3H), 3.14-3.32 (m, 6H), 1.82-1.87 (m, 2H), 1.43-1.51 (m, 2H), 1.35 (s, 9H), 1.12 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 515.9 (M+H)+.
Example 313 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- phenylbenzenesulfonamide Example 313a ofluoro-N-phenylbenzenesulfonamide Example 313a was prepared ing to the procedure used for the preparation of Example 305a, tuting aniline for indoline. The crude product was purified by flash chromatography (silica gel, eluted with 10% ethyl acetate in heptane) to afford title compound Example 313b 3-bromo(cyclopropylmethoxy)-N-phenylbenzenesulfonamide Example 313b was prepared according to the procedure used for the preparation of Example 29a, substituting cyclopropylmethanol for tetrahydro-2H-pyranol and substituting Example 313a for Example 2a to afford the title compound.
Example 313c 4-(cyclopropylmethoxy)(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-phenylbenzenesulfonamide Example 313c was prepared according to the procedure used for the preparation of Example 6c, substituting e 313b for Example 6b to afford the title compound.
Example 313d 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- phenylbenzenesulfonamide Example 313d was prepared according to the procedure used for the preparation of Example 6d, substituting Example 313c for e 6c to afford the title compound. 1H NMR (300 MHz, DMSO-d6)  0.25 (tt, J = 15.6, 7.6 Hz, 2H) 0.39 - 0.50 (m, 2H) 1.01 - 1.18 (m, 1H) 3.55 (s, 3H) 3.91 (d, J = 6.8 Hz, 2H) 5.91 (dd, J = 2.8, 2.0 Hz, 1H) 7.01-7.15 (m, 3H) 7.15-7.34 (m, 5H) 7.65-7.72 (m, 2H) 10.12 (s, 1H) 12.02 (bs, 1H). MS (ESI+) m/z 450 [M+H]+. e 314 cyclopropylmethoxy)(pyrrolidinylmethyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone Example 314a 4-bromo(cyclopropylmethoxy)iodobenzene A mixture of 4-bromoiodophenol (5.00 g, 16.7 mmol), bromomethylcyclopropane (2.26 g, 16.7 mmol) and cesium carbonate (6.54 g, 20.1 mmol) in 15 mL dimethylformamide was stirred at 50 °C overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The te was concentrated to the provide title compound (5.84 g, 99% yield).
Example 314b 4-(5-bromo(cyclopropylmethoxy)phenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one A mixture of Example 6a (1.1 g, 2.57 mmol), Example 314a (0.907 g, 2.57 mmol), 1,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamantane (0.060 g, 0.21 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.094 g, 0.103 mmol), and potassium ate (1.635 g, 7.70 mmol) in 15 mL dioxane and 5 mL water was purged with nitrogen gas and then heated at 55 °C for 3 hours. Saturated aqueous sodium de was added and the mixture was extracted with ethyl acetate (2X). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated. The e was purified by flash chromatography (silica gel, 0-80% ethyl acetate/heptanes gradient) to give the title compound (1.24 g, 92% yield).
Example 314c 4-[2-(cyclopropylmethoxy)(pyrrolidinylmethyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone A mixture of Example 314b (100 mg, 0.190 mmol) , potassium trifluoro(pyrrolidin ylmethyl)borate (36.2 mg, 0.190 mmol), palladium(II) acetate (2.55 mg, 0.011 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (10.85 mg, 0.023 mmol), and cesium carbonate (185 mg, 0.569 mmol) in 4 mL dioxane/water (9:1) was purged with nitrogen gas and then heated under microwave conditions (Biotage Initiator) at 140 oC for 40 minutes. The reaction mixture was then treated with 2 mL of 4 N NaOH and heated in a ave oven (Biotage Initiator) at 100 oC for 30 minutes. Water was added. The mixture was extracted with ethyl e, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 2-14% ol/dichloromethane nt) to give the title compound (8.0 mg, , 11% yield). 1H NMR (300 MHz, DMSO-d 6) δ ppm 11.93 (s, 1H), 7.29 – 7.17 (m, 4H), 7.00 (d, J = 8.4 Hz, 1H), 6.11 (dd, J = 2.6, 2.2 Hz, 1H), 3.81 (d, J = 6.7 Hz, 2H), 3.56 (s, 3H), 3.53 (s, 2H), 2.43 (s, 4H), 1.68 (s, 4H), 1.13 – 0.98 (m, 1H), 0.48 – 0.36 (m, 2H), 0.26 – 0.16 (m, 2H). MS (ESI+) m/z 378.0 (M+H)+.
Example 315 4-[2-(cyclopropylmethoxy)(pyridinyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone A sion of Example 314b (100 mg, 0.190 mmol), pyridinylboronic 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 4 mL dioxane-water (3:1) was heated under nitrogen under microwave conditions (Biotage Initiator) at 120 oC for minutes. The reaction mixture was the treated with 1 mL aqueous 4 N NaOH and heated at 120 oC under microwave conditions again for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate (2X), washed with ted aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography a gel, 0-10% methanol/dichloromethane gradient) to give the title compound (53mg, 75% yield). 1H NMR (300 MHz, DMSO-d 6) δ ppm 11.95 (s, 1H), 8.90 (dd, J = 2.4, 0.7 Hz, 1H), 8.56 – 8.49 (m, 1H), 8.07 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.71 – 7.64 (m, 2H), 7.45 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.34 (s, 1H), 7.26 (t, J = 2.7 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.18 (dd, J = 2.6, 2.2 Hz, 1H), 3.91 (d, J = 6.7 Hz, 2H), 3.58 (s, 3H), 1.15 – 1.04 (m, 1H), 0.49 – 0.42 (m, 2H), 0.28 – 0.21 (m, 2H). MS (ESI+) m/z 372.2 .
Example 316 4-[2-(cyclopropylmethoxy)(morpholinylmethyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 316 was prepared according to the procedure used for the preparation of Example 314c, substituting potassium trifluoro(morpholinomethyl)borate for potassium trifluoro(pyrrolidinylmethyl)borate to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.01 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 4.9, 2.0 Hz, 2H), 7.18 (d, J = 8.5 Hz, 1H), 6.21 – 6.14 (m, 1H), 4.32 (s, 2H), 3.97 (d, J = 12.4 Hz, 2H), 3.89 (d, J = 6.7 Hz, 2H), 3.63 (d, J = 11.7 Hz, 2H), 3.57 (s, 3H), 3.29 (d, J = 12.8 Hz, 2H), 3.10 (d, J = 10.4 Hz, 2H), 1.17 – 1.02 (m, 1H), 0.51 – 0.42 (m, 2H), 0.28 – 0.21 (m, 2H). ). MS (ESI+) m/z 394.0 (M+H)+.
Example 317 4-{5-(ethylsulfonyl)[3-(hydroxymethyl)phenoxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 317 was prepared according to the procedure used for the preparation of Example 138b, substituting 3-(hydroxymethyl)phenol for 2,4-difluorophenol, and Example 168c for e 138a, respectively, to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.93 (d, J = 2.44 Hz, 1H), 7.83 (dd, J = 8.7, 2.29 Hz, 1H), 7.42 (s, 1H), 7.35 (t, J = 7.93 Hz, 1H), 7.30 (t, J = 2.75 Hz, 1H), 7.15 (d, J = 7.63 Hz, 1H), .05 (m, 2 H), 6.97 (dd, J = 7.93, 2.14 Hz, 1H), 6.26 (t, J = 2.44 Hz, 1H), 4.48 (s, 2H), 3.57 (s, 3H), 3.34 (q, J = 7.32 Hz, 2H), 1.15 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 439.0 (M+H)+.
Example 318 4-[2-(cyclopropylmethoxy)(1-methyl-1H-pyrazolyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 318 was prepared according to the procedure used for the preparation of Example 315, substituting yl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H- pyrazole for pyridinylboronic acid to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 8.05 (d, J = 7.4 Hz, 1H), 7.77 (dd, J = 6.3, 0.6 Hz, 1H), 7.48 (q, J = 2.2 Hz, 2H), 7.28 – 7.24 (m, 2H), 7.06 (d, J = 8.3 Hz, 1H), 6.21 – 6.05 (m, 1H), 3.83 (d, J = 4.9 Hz, 5H), 3.56 (d, J = 5.7 Hz, 3H), 1.06 – 1.02 (m, 1H), 0.46 – 0.40 (m, 2H), 0.24 – 0.19 (m, 2H). ). MS (ESI+) m/z 375.2 (M+H)+.
Example 319 4-[2-(2,4-difluorophenoxy)(2,3-dihydro-1H-indolylsulfonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 319a 1-(3-bromo(2,4-difluorophenoxy)phenylsulfonyl)indoline Example 319a was prepared according to the procedure used for the preparation of e 2b, substituting 2,4-difluorophenol for phenol and substituting Example 305a for e 2a, to provide the title compound.
Example 319b 4-(2-(2,4-difluorophenoxy)(indolinylsulfonyl)phenyl)methyltosyl-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 e 6b, to afford the title compound.
Example 319c 2,4-difluorophenoxy)(2,3-dihydro-1H-indolylsulfonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone Example 319c was prepared according to the ure used for the preparation of e 6d, and substituting Example 319b for Example 6c to afford the title compound. 1H NMR (300 MHz, DMSO-d6)  2.92 (t, J = 8.3 Hz, 2H) 3.55 (s, 3H) 3.93 (t, J = 8.3 Hz, 2H) .98 (dd, J = 2.8, 1.9 Hz, 1H) 6.91 (dd, J = 9.3, 1.0 Hz, 1H) 6.98-7.29 (m, 6H) 7.34-7.58 (m, 3H) 7.74-7.91 (m, 2H) 12.08 (bs, 1H). MS (ESI+) m/z 534 [M+H]+.
Example 320 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin yl)phenyl]ethanesulfonamide Example 320a 5-bromo-1,4-dimethylnitropyridin-2(1H)-one Example 320a was ed according to the procedure used for the preparation of Example 1e, substituting Example 1d for 5-bromomethylnitropyridinol, to provide the title compound. e 320b 3-aminobromo-1,4-dimethylpyridin-2(1H)-one e 320b was prepared according to the procedure used for the preparation of Example 7b, substituting Example 320a for Example 7a, to provide the title compound.
Example 320c 4-bromomethyl-1H-pyrazolo[3,4-c]pyridin-7(6H)-one Example 320b (1 g, 4.61 mmol), acetic anhydride (1.304 mL, 13.82 mmol), and potassium acetate (0.543 g, 5.53 mmol) were stirred in toluene (25mL) for 18 hours. Isoamyl nitrite (0.930 mL, 6.91 mmol) was added dropwise and the solution heated at 80°C for 24 hours. The solution was cooled, water added, and the aqueous extracted with ethyl acetate.
The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), ed, and concentrated. The residue was triturated with % ethyl acetate in hexanes to afford 0.415 g of the title nd.
Example 320d 4-bromomethyl((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)- Example 320c (0.228 g, 1.000 mmol) in dimethylformamide (5 mL) was treated with sodium hydride (0.060 g, 1.500 mmol). The reaction mixture was stirred at ambient temperature for 10 s. To this on 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 c phase separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and trated. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane nt) to afford the title compound (0.301 g, 0.840 mmol, 84 % yield).
Example 320e 4-(5-amino(2,4-difluorophenoxy)phenyl)methyl((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolo[3,4-c]pyridin-7(6H)-one Example 320e was prepared according to the procedure used for the ation of Example 138a, substituting Example 320d for 2-bromofluoro(methylsulfonyl)benzene, and Example 148c for Example 6a, respectively, to provide the title nd.
Example 320f N-(4-(2,4-difluorophenoxy)(6-methyloxo((2-(trimethylsilyl)ethoxy)methyl)-6,7- dihydro-1H-pyrazolo[3,4-c]pyridinyl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide A mixture of Example 320e (0.1 g, 0.201 mmol), ethanesulfonyl chloride (0.077 g, 0.602 mmol), and triethylamine (0.081 g, 0.802 mmol) in dichloromethane was d for 2 hours at room temperature. The solvent was removed, and the residue was purified by flash chromatography on silica gel (4:1 ethyl acetate/hexanes) to give the title compound (0.11 g, 0.161 mmol, 80% yield).
Example 320g N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin yl)phenyl]ethanesulfonamide Example 320f in dichloromethane (3 mL) was treated with 2,2,2-trifluoroacetic acid (1.837 g, 16.11 mmol). The reaction mixture was stirred for 16 hours at ambient temperature.
The solvent was removed, and the residue was put on high vacuum for 1 hour. It was then treated with dioxane (5 mL) and 2.0 N sodium hydroxide (1.611 mL, 3.22 mmol). The reaction mixture was heated at 85 °C for 2 hours. After cooling, the reaction mixture was partitioned between 0.1% HCl and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated s sodium chloride, dried over anhydrous magnesium e, filtered, and concentrated. The residue was then purified by reverse phase preparative HPLC (10-80% itrile in 0.1% TFA water) to afford the TFA salt of the title nd (0.055 g, 0.119 mmol, 74.1% . 1H NMR (500 MHz, DMSO-d 6) δ ppm 9.80 (s, 1H), 7.86 (s, 1H), 7.36- 7.42 (m, 3H), 7.22 (dd, J = 8.85, 2.75 Hz, 1H), 7.13-7.15 (m, 1H), 6.99-7.04 (m, 1H), 6.92 (d, J = 8.85 Hz,1H), 3.56 (s, 3H), 3.13 (t, J = 7.32 Hz, 2H), 1.23 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 461.0 .
Example 321 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrazolo[3,4-c]pyridinone Example 321a 2-(2-(2,4-difluorophenoxy)((methylsulfonyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane Example 287e (1.13 g, 3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.52 g, 6 mmol), potassium acetate (1.18 g, 12 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.126 g, 0.18 mmol) were combined 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 °C for 8 hours.
The reaction mixture was partitioned between water and ethyl e. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, treated with 3-mercaptopropyl-functionalized silica gel, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 10% ethyl acetate in dichloromethane) and then triturated with heptane to provide the title compound (0.64 g, 50%).
Example 321b 4-(2-(2,4-difluorophenoxy)((methylsulfonyl)methyl)phenyl)methyl((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one Example 320d (0.04 g, 0.112 mmol), e 321a (0.052 g, 0.123 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0031 g, 3.35 µmol), (1S,3R,5R,7S)-1,3,5,7- tetramethylphenyl-2,4,6-trioxaphosphaadamantane 3 g, 0.011 mmol) and sodium carbonate (0.051 g, 0.48 mmol) were combined in a 5-mL microwave vial and sparged with nitrogen for 30 minutes. To this mixture was added nitrogen-sparged dioxane (0.8 mL) and water (0.2 mL). The reaction mixture was d at 60 °C for 4.5 hours. The reaction mixture was cooled to ambient temperature and then partitioned between ethyl e and water. The organic layer was washed with saturated aqueous sodium chloride, 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 to 10% methanol in romethane) to provide the title compound (0.06 g, 93%).
Example 321c 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrazolo[3,4-c]pyridinone e 321b (0.06 g, 0.104 mmol) was treated with 2,2,2-trifluoroacetic acid (2 mL, 26.1 mmol), d at ambient temperature for 30 minutes and then concentrated to dryness.
The residue was purified by reverse phase HPLC (C18, CH3CN/water (0.1%TFA), ) to provide the title compound (0.03 g, 65%). 1H NMR (400 MHz, DMSO-d 6) δ ppm 7.91 (s, 1H), 7.60 (d, J = 2.14 Hz, 1H), 7.42 (m, 3H), 7.29 (m, J = 9.23, 9.23, 5.65 Hz, 1H), 7.09 (m, 1 H), 6.89 (d, J = 8.54 Hz, 1H), 4.53 (s, 2H), 3.58 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 446.1 (M+H)+.
Example 322 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrazolo[3,4- c]pyridinone e 322a ethyl(4-fluorophenyl)sulfane Triethylamine (5.44 mL, 39 mmol) was added to a solution of 4-fluorobenzenethiol (5 g, 39 mmol) 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 te was concentrated, triturated with hexane, and dried under vacuum to afford the title nd (4.8 g, 76%).
Example 322b 1-(ethylsulfonyl)fluorobenzene Example 322a (5 g, 32 mmol) in dichloromethane (200 mL) was treated with 3- peroxybenzoic 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 solution (50 mL, twice) and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 15% ethyl acetate in petroleum ether) to afford the title compound (4.6 g, 76%).
Example 322c 2-bromo(ethylsulfonyl)fluorobenzene Example 322b (1 g, 5.31 mmol) in sulfuric acid (6 mL, 113 mmol) was treated with N-bromosuccinimide (1.04 g, 5.84 mmol), stirred at ambient temperature for 6 hours and then at 50 °C for 16 hours. The on mixture was then poured into ice water and the resulting solid was collected by tion, washed with cold water three times, and dried in a vacuum oven for 16 hours. The solid was then purified by flash chromatography (silica gel, 9-20% ethyl acetate in petroleum ether) to afford the title compound (1.1 g, 78%).
Example 322d 2-(5-(ethylsulfonyl)fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(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]dichloropalladium(II) (0.041 g, 0.056 mmol) were combined in an argon-sparged mixture of dioxane (10 mL)/dimethyl sulfoxide (0.3 mL) and heated at 90 ºC under argon for 24 hours. The reaction mixture was ioned 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 minimal amount of heptane/diethyl ether (20:1) and filtered to give crude product. This 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 afford the title compound (0.3 g, 77%).
Example 322e 4-(5-(ethylsulfonyl)fluorophenyl)methyl((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[3,4-c]pyridin-7(6H)-one e 322e was ed 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%). e 322f 4-(2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl)methyl((2- thylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one e 322e (0.0635 g, 0.136 mmol), 2,4-difluorophenol (0.021 g, 0.164 mmol) and cesium carbonate (0.089 g, 0.273 mmol) were combined in a 4-mL vial with dimethyl sulfoxide (1.5 mL), stirred at 60 °C for 8 hours and then at ambient temperature for 16 hours.
The reaction mixture was partitioned between ethyl e and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous ium sulfate, filtered, and concentrated. The residue was purified by flash chromatography a gel, 0 to 8% methanol in dichloromethane) to provide the title compound (0.0574 g, 73%).
Example 322g 4-(2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl)methyl-1H-pyrazolo[3,4-c]pyridin- 7(6H)-one Example 322g was prepared according to the procedure used for the preparation of Example 321c, substituting Example 322f for e 321b, to provide the title compound (0.0299 g, 67%). 1H NMR (400 MHz, DMSO-d 6) δ ppm 7.96 (d, J = 2.14 Hz, 1H), 7.91 (s, 1H), 7.85 (dd, J = 8.70, 2.29 Hz, 1H), 7.54 (m, 3 H), 7.20 (m, 1H), 7.00 (d, J = 8.85 Hz, 1H), 3.61 (s, 3H), 3.35 (q, J = 7.32 Hz, 2H), 1.15 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 446.2 (M+H)+. e 323 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrazolo[3,4- dinone Example 323a 4-(2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl)methyl((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-7(6H)-one Cyclopropylmethanol (0.018 g, 0.25 mmol) in 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 minutes. A solution of Example 322e (0.0683 g, 0.147 mmol) in dioxane (0.75 mL) was added and the mixture was stirred at 60 °C for 8 hours and then at ambient ature 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 °C for 9 hours. The reaction e was cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, ed, and concentrated. The residue was purified by flash chromatography (silica gel, 0 to 30% ethyl acetate in dichloromethane) to provide the title compound 5 g, 90%).
Example 323b 4-(2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl)methyl-1H-pyrazolo[3,4-c]pyridin- 7(6H)-one Example 323b was prepared according to the procedure used for the preparation of Example 321c, substituting Example 323a for Example 321b, to provide the title compound (0.0302 g, 59%). 1H NMR (400 MHz, DMSO-d 6) δ ppm 14.07 (s, 1H), 7.85 (dd, J = 8.70, 2.29 Hz, 1H), 7.80 (d, J = 2.14 Hz, 1H), 7.78 (m, 1H), 7.41 (s, 1H), 7.34 (d, J = 8.54 Hz, 1H), 4.01 (d, J = 7.02 Hz, 2H), 3.60 (s, 3H), 3.29 (q, J = 7.32 Hz, 2H), 1.13 (t, J = 7.32 Hz, 3H), 1.06 (m, 1H), 0.45 (m, 2H), 0.27 (m, 2H). MS (ESI+) m/z 388.2 (M+H)+.
Example 324 N-[2-cyano(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide Example 324a 4-bromo(2,4-difluorophenoxy)nitrobenzoic acid e 324a was prepared according to the procedure used for the preparation of Example 7a, substituting 4-bromofluoronitrobenzoic acid for 2-bromofluoro nitrobenzene (Combi Blocks) and substituting 2,4-difluorophenol for phenol to afford the title compound.
Example 324b methyl 4-bromo(2,4-difluorophenoxy)nitrobenzoate Oxalyl chloride (1.4 mL, 16.6 mmol) was added dropwise to a 0° C suspension of Example 324a (5.47 g, 14.6 mmol) and dichloromethane (65 mL). 3 drops dimethylformamide was added and the on mixture was stirred at ambient temperature for 2 hours. After cooling to 0° C, methanol (12 mL, 296 mmol) was added dropwise. The solution was stirred for 15 minutes at 0° C and for 2.5 hours at ambient temperature. The solution was diluted with dichloromethane and was washed with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (5.42 g, 96% .
Example 324c methyl 2-aminobromo(2,4-difluorophenoxy)benzoate e 324c was ed according to the procedure used for the preparation of e 7b, tuting e 324b for Example 7a to afford the title compound.
Example 324d 4-bromo(2,4-difluorophenoxy)(ethylsulfonamido)benzoic acid Example 324d was prepared according to the procedure used for the preparation of Example 7c, substituting Example 324c for Example 7b to afford the title compound.
Example 324e 4-bromo(2,4-difluorophenoxy)(ethylsulfonamido)benzamide Oxalyl chloride (0.046 mL, 0.54 mmol) was added dropwise to a suspension of e 324d (214mg, 0.49 mmol) and dichloromethane (2.2 mL). 1 Drop dimethylformamide was added and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated and the e was dried (in-vacuo). The resulting acid chloride was suspended in tetrahydrofuran (1.0 mL) and was cooled to 0° C as ammonium hydroxide (0.65 mL, 4.7 mmol) was added dropwise. The reaction mixture was d at ambient temperature for 2 hours. Ethyl acetate was added and the solution was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-8 % methanol/dichloromethane gradient) to afford the title compound (176 mg, 82 % yield).
Example 324f N-(5-bromocyano(2,4-difluorophenoxy)phenyl)ethanesulfonamide To a sion 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 ted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 5-40% ethyl acetate/heptane gradient) to afford the title compound (135 mg, 61% yield).
Example 324g yano(2,4-difluorophenoxy)(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl)ethanesulfonamide Example 324g was prepared according to the procedure used for the ation of Example 6c, tuting Example 324f for Example 6b to afford the title compound.
Example 324h yano(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl)ethanesulfonamide Example 324h was prepared according to the procedure used for the preparation of Example 6d, tuting Example 324g for Example 6c to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (t, J = 7.12 Hz, 3 H) 3.20 (q, J = 7.46, 5.76 Hz, 2 H) 3.54 - 3.57 (m, 3 H) 6.32 (t, J = 2.71, 2.03 Hz, 1 H) 7.03 - 7.11 (m, 1 H) 7.24 - 7.32 (m, 1 H) 7.32 (t, J = 2.71 Hz, 1 H) 7.37 (s, 1 H) 7.38 - 7.48 (m, 1 H) 7.46 (s, 1 H) 7.59 (s, 1 H) .07 (s, 1 H) 12.13 (brs, 1 H). MS (ESI+) m/z 485 [M+H]+.
Example 325 tert-butyl 4-[4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate Example 325 was prepared ing to the procedure used for the preparation of Example 315, substituting tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6- dihydropyridine-1(2H)-carboxylate for pyridinylboronic acid to afford the title compound. 1H NMR (400 MHz, DMSO-d 6) δ ppm 11.93 (s, 1H), 7.40 – 7.34 (m, 2H), 7.27 – 7.22 (m, 2H), 7.04 (d, J = 9.0 Hz, 1H), 6.13 – 6.09 (m, 1H), 6.07 (s, 1H), 3.97 (s, 2H), 3.83 (d, J = 6.7 Hz, 2H), 3.56 (s, 3H), 3.52 (dd, J = 9.1, 3.4 Hz, 2H), 2.45 (s, 2H), 1.42 (d, J = 5.3 Hz, 9H), 1.06 – 0.97 (m, 1H), 0.46 – 0.38 (m, 2H), 0.26 – 0.17 (m, 2H). MS (ESI+) m/z 476.2 (M+H)+.
Example 326 4-[5-(6-aminopyridinyl)(cyclopropylmethoxy)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone 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-dioxaborolanyl)pyridinamine for pyridinylboronic acid to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.6, 2.5 Hz, 1H), 7.49 (dd, J = 6.3, 2.4 Hz, 2H), 7.30 (s, 1H), 7.25 (t, J = 2.7 Hz, 1H), 7.14 – 7.07 (m, 1H), 6.49 (t, J = 7.5 Hz, 1H), 6.16 (t, J = 2.4 Hz, 1H), 5.94 (s, 2H), 3.86 (d, J = 6.7 Hz, 2H), 3.57 (s, 3H), 1.14 – 1.00 (m, 1H), 0.51 – 0.38 (m, 2H), 0.27 – 0.14 (m, 2H). MS (ESI+) m/z 387.2 (M+H)+.
Example 327 4-{2-[(2,2-difluorocyclopropyl)methoxy](ethylsulfonyl)phenyl}methyloxo-N-(2,2,2- oroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide Example 327a ethyl ylmethyloxo(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxylate 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 nd.
Example 327b ethyl 1-benzyl(5-(ethylsulfonyl)fluorophenyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylate 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 fluoro(methylsulfonyl)benzene, respectively, to provide the title compound.
Example 327c ethyl 4-(5-(ethylsulfonyl)fluorophenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinecarboxylate Example 327c was prepared according to the ure used for the preparation of e 70j, substituting e 327b for Example 70i, to provide the title compound.
Example 327d (2,2-difluorocyclopropyl)methoxy)(ethylsulfonyl)phenyl)methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylic acid To the solution of Example 327c (1 g, 2.460 mmol) and (2,2-difluorocyclopropyl) methanol (0.532 g, 4.92 mmol) in dimethylsulfoxide (10 mL) was added cesium carbonate (1.203 g, 3.69 mmol). The reaction mixture was sealed in a microwave tube and heated at 110 °C for 5 days. During the 5 days, three additional batches of (2,2- rocyclopropyl)methanol (0.532 g, 4.92 mmol) were added into the reaction mixture.
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 aqueous layer was adjusted pH 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 4-{2-[(2,2-difluorocyclopropyl)methoxy](ethylsulfonyl)phenyl}methyloxo-N-(2,2,2- trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide To a solution of Example 327d (0.070g, 0.15 mmol) in anhydrous dichloromethane (5 mL) were added oxalyl chloride (0.026 mL, 0.300 mmol) and dimethylformamide (0.581 µl, 7.50 µmol). 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- oroethylamine (0.048 mL, 0.600 mmol) and the mixture was stirred at ambeint temperature overnight. The on mixture was partitioned between water (15 mL) and ethyl acetate (25mL). The aqueous layer was ted with onal ethyl acetate (15 mL) twice. The combined organic layers were dried over anhydrous sodium e, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, mobile phase A:water (10 mM NH4HCO3); B: acetonitrile, Gradient 25-60% B in A) to give the title compound (70 mg, 85%). 1H NMR (400 MHz, CD 3OD) δ ppm 7.96 – 7.90 (m, 2H), 7.66 – 7.25 (m, 2H), 6.92 (s, 1H), 4.29 (t, J = 7.5 Hz, 1H), 4.16 (t, J = 9.2 Hz, 1H), 4.05 (tt, J = 9.2, 4.5 Hz, 2H), 3.72 (s, 3H), 3.22 (q, J = 7.4 Hz, 2H), 2.00 (td, J = 12.0, 7.3 Hz, 1H), 1.58 – 1.46 (m, 1H), 1.32-1.25 (m, 4H). MS (ESI+) m/z 548.1 (M+H)+.
Example 328 4-{2-[(cyclopropylmethyl)amino][(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 328a thylsulfonyl)methyl)nitrobenzene To a solution of 4-nitrobenzyl bromide (10.02 g, 46.4 mmol) in N,N- dimethylformamide (25 mL) was added sodium methanesulfinate (7.10 g, 69.6 mmol). The reaction mixture was stirred at 65 °C for 1 hour. The on mixture was cooled to ambient temperature and diluted with water. The resulting suspension was d for 10 minutes and filtered through a medium frit to provide the title compound. e 328b 4-((methylsulfonyl)methyl)aniline Example 328a (8.2 g, 38.1 mmol) and tetrahydrofuran (200 mL) were added to 5% Pd/C, wet (1.6 g, 0.376 mmol) in a 50 mL pressure bottle and stirred for 2 hours at 30 psi and 50 °C. The e was filtered through a nylon membrane and washed with a small amount of tetrahydrofuran and ol. The solvent was evaporated to provide the title compound.
Example 328c 2-iodo((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 e was quenched with 150 mL 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 and concentrated. Water was added, and the resulting suspension was stirred at ambient temperature 10 s. The suspension was filtered, and the solids collected was rinsed with water, and dried overnight to provide the title compound.
Example 328d N-(cyclopropylmethyl)iodo((methylsulfonyl)methyl)aniline Example 328c (0.200 g, 0.643 mmol) and cyclopropanecarbaldehyde (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 °C 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. Cyclopropanecarbaldehyde (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, ghly rinsed with dichloromethane, and trated. The residue was purified by flash chromatography (silica gel, % ethyl acetate/heptane gradient) to provide the title compound.
Example 328e 4-(2-((cyclopropylmethyl)amino)((methylsulfonyl)methyl)phenyl)methyltosyl-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 e 7c to provide the title compound.
Example 328f 4-{2-[(cyclopropylmethyl)amino][(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 328f was prepared according to the procedure used for the ation of Example 4b, substituting Example 328e for Example 4a to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 (bs, 1H), 7.29 (t, J = 2.3 Hz, 1H), 7.21 (dd, J = 8.3, 2.1 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.05 (d, J = 2.7 Hz, 1H), 4.67 (t, J = 5.7 Hz, 1H), 4.30 (bs, 2H), 3.55 (s, 3H), 2.96 (t, J = 6.1 Hz, 2H), 2.86 (s, 3H), 1.05 - 0.92 (m, 1H), 0.41 - 0.29 (m, 2H), 0.19 - 0.10 (m, 2H). MS (ESI+) m/z 386.0 (M+H)+ Example 329 4-{2-[(cyclopropylmethyl)amino](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 329a o-N-(cyclopropylmethyl)(methylsulfonyl)aniline Example 329a was prepared according to the procedure used for the preparation of e 147a, substituting cyclopropylmethanamine for cyclohexanamine to provide the title compound.
Example 329b 4-(2-((cyclopropylmethyl)amino)(methylsulfonyl)phenyl)methyltosyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one Example 329b was prepared according to the procedure used for the ation of Example 7d, substituting the product of Example 329a for the product of Example 7c and stirring at 100 °C for 30 minutes, to provide the title compound. e 329c 4-{2-[(cyclopropylmethyl)amino](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 329c was prepared ing to the procedure used for the preparation of Example 4 (Method B), substituting the product of Example 329b for the product of Example 7d, and purified by Preparative HPLC (C18, 10-100 % acetonitrile in 0.1 % TFA/water) to provide the TFA salt of the title nd. 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.12 (bds, 1H), 7.67 (dd, J = 2.4, 8.8 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.29 (t, J = 3.1 Hz, 1H), 7.26 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.02 (t, J = 2.2 Hz, 1H), 5.45 (m, 1H), 3.56 (s, 3H), 3.10 (m, 2H), 3.04 (m, 2H), 1.01 (m, 1H), 0.37 (m, 2H), 0.16 (m, 2H). MS (ESI+) m/z 372.1 (M+H)+.
Example 330 4-[5-(ethylsulfonyl)(pyrrolidinyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 330a 4-(5-(ethylsulfonyl)fluorophenyl)methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one A mixture of Example 168b (0.935 g, 3.50 mmol), Example 6a (1.5 g, 3.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.202 g, 0.175 mmol) and cesium de (1.596 g, 10.51 mmol) in 12 mL dimethoxyethane and 4 mL methanol was heated at 120 °C under microwave ions for 40 minutes. The mixture was concentrated and the residue was absorbed on silica gel and purified by flash chromatography (SiO2, 0-10% methanol/dichloromethane gradient) to give the title compound (1.01 g, 86% yield).
Example 330b 4-[5-(ethylsulfonyl)(pyrrolidinyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone A mixture of Example 330a (90 mg, 0.27 mmol) and pyrrolidine (668 µL, 8.08 mmol) in 1 mL DMSO was heated at 160 oC uner microwave conditions for 30 minutes. The product was ed by preparative HPLC (C18, 10-80% CH3CN/water (0.1% TFA)) to give the title compound (37 mg, 35.7 % yield). 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.07 (s, 1H), 7.61 (dd, J = 8.8, 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.26 (t, J = 2.8 Hz, 1H), 7.20 (s, 1H), 6.95 (d, J = 8.9 Hz, 1H), 5.99 – 5.94 (m, 1H), 3.56 (s, 3H), 3.16 (q, J = 7.3 Hz, 2H), 3.06 (s, 4H), 1.69 (t, J = 6.3 Hz, 4H), 1.10 (t, J = 7.4 Hz, 3H). MS (ESI+) m/z 386.1 (M+H)+.
Example 331 4-[5-(ethylsulfonyl)(4-methylpiperazinyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 331 was prepared ing to the procedure used for the ation of Example 330b, substituting N-methylpiperazine for pyrrolidine, to afford the TFA salt of the title compound. 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.12 (s, 1H), 9.57 (s, 1H), 7.80 (dd, J = 8.5, 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.45 (s, 1H), 7.32 (dd, J = 8.6, 5.7 Hz, 2H), 6.17 (t, J = 2.3 Hz, 1H), 3.60 (s, 3H), 3.49 (t, J = 6.7 Hz, 2H), 3.28 (q, J = 7.4 Hz, 4H), 2.94 (t, J = 11.8 Hz, 2H), 2.71 (s, 3H), 2.68 – 2.53 (m, 2H), 1.13 (t, J = 7.3 Hz, 3H). MS (ESI+) m/z 415.2 (M+H)+.
Example 332 4-{2-[(4-fluorophenyl)amino](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 332a 4-(2-amino(methylsulfonyl)phenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 6a (1.71 g, 4.00 mmol), o(methylsulfonyl)aniline (1.00 g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium (0.110 g, 0.120 mmol), 1,3,5,7-tetramethyl phenyl-2,4,8-trioxaphosphaadamante (0.117 g, 0.400 mmol) and sodium carbonate (1.48 g, 14.0 mmol) were combined and purged with argon for 15 minutes. A mixture of dioxane (21.3 mL) and water (5.3 mL) was purged with nitrogen for 15 s and transferred to the reaction vessel. The reaction mixture was heated at 60 °C for 3 hours, cooled to ambient temperature and diluted with water. The resulting solid was ed, washed with water and dried to afford the title compound (2.06 g, quantitative yield).
Example 332b 4-(2-((4-fluorophenyl)amino)(methylsulfonyl)phenyl)methyltosyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 332a (47.2 mg, 0.100 mmol), 1-bromofluorobenzene (17.5 mg, 0.100 mmol), diacetoxypalladium (0.9 mg, 4 µmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'- biphenyl]yl)phosphine (3.8 mg, 8.0 µmol) and cesium carbonate (45.6 mg, 0.140 mmol) were combined in a mixture of e (1.6 mL) and tert-butanol (0.4 mL). The reaction mixture was heated in a microwave reactor at 150 °C for 15 minutes. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium de, dried with anhydrous sodium sulfate, treated with 3- mercaptopropyl functionalized silica gel, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2 to 4% methanol in romethane) to provide the title compound (30 mg, 53%).
Example 332c (4-fluorophenyl)amino](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 332b (28 mg, 0.050 mmol), potassium hydroxide (41.7 mg, 0.743 mmol) and cetyltrimethylammonium bromide (0.90 mg, 2.5 µmol) were ed in a mixture of tetrahydrofuran (2 mL) and water (1 mL). The reaction mixture was heated at 100 °C for 20 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 1M HCl. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 2 to 4% methanol in dichloromethane) to provide the title compound (13 mg, 64%). 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.04 (s, 1 H) 7.57 - 7.71 (m, 3 H) 7.34 (s, 1 H) 7.08 - 7.27 (m, 6 H) 6.06 (t, J = 2.20 Hz, 1 H) 3.57 (s, 3 H) 3.15 (s, 3 H). MS (ESI+) m/z 412 (M+H)+. e 333 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- inylmethyl)benzenesulfonamide Example 333a 3-bromofluoro-N-(pyridinylmethyl)benzenesulfonamide Example 333a was prepared according to the procedure used for the preparation of Example 305a, substituting pyridinylmethanamine for indoline. The crude product was purified by crystallization from ethyl acetate/ethyl ether to afford title compound Example 333b 3-bromo(cyclopropylmethoxy)-N-(pyridinylmethyl)benzenesulfonamide Example 333b was prepared ing to the procedure used for the preparation of Example 29a, substituting cyclopropylmethanol for ydro-2H-pyranol and tuting Example 333a for e 2a to afford the title compound.
Example 333c 4-(cyclopropylmethoxy)(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)-N-(pyridinylmethyl)benzenesulfonamide Example 333c was prepared according to the procedure used for the preparation of Example 6c, substituting Example 333b for Example 6b to afford the title compound.
Example 333d 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)-N- (pyridinylmethyl)benzenesulfonamide Example 333d was ed according to the procedure used for the preparation of Example 6d, substituting Example 333c for Example 6c, and and purified by ative HPLC (C18, 10-100 % acetonitrile in 0.1 % TFA/water) to provide the TFA salt of the title nd. 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.03 (s, 1 H) 8.55 (s, 2 H) 8.17 (t, J = 6.44 Hz, 1 H) 7.88 (d, J = 7.80 Hz, 1 H) 7.70 - 7.76 (m, 2 H) 7.50 (dd, J = 7.12, 4.75 Hz, 1 H) 7.27 - 7.32 (m, 2 H) 7.20 - 7.26 (m, 1 H) 6.10 - 6.16 (m, 1 H) 4.11 (d, J = 6.44 Hz, 2 H) 3.95 (d, J = 6.78 Hz, 2 H) 3.58 (s, 3 H) 1.03 - 1.19 (m, 1 H) 0.44 - 0.52 (m, 2 H) 0.24 - 0.31 (m, 2 H). MS (ESI+) m/z 465.0 [M+H]+.
Example 334 4-[4-(cyclopropylmethoxy)-3'-fluorobiphenylyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone Example 334a romo(cyclopropylmethoxy)phenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 334a was prepared according to the procedure used for the preparation of Example 6c, substituting Example 314a for Example 6b to afford the title compound.
Example 334b 4-(4-(cyclopropylmethoxy)-3'-fluorobiphenylyl)methyltosyl-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 tuting (3- fluorophenyl)boronic acid for Example 6a to afford the title compound.
Example 334c 4-(4-(cyclopropylmethoxy)-3'-fluorobiphenylyl)methyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 334c was prepared ing to the procedure used for the preparation of Example 6d, substituting Example 334b for Example 6c to afford the title compound. 1H NMR (300 MHz, 6) δ ppm 0.22 - 0.28 (m, 2 H) 0.42 - 0.49 (m, 2 H) 1.03 - 1.14 (m, 1 H) 3.58 (s, 3 H) 3.90 (d, J = 6.78 Hz, 2 H) 6.17 (t, J = 2.71, 2.03 Hz, 1 H) 7.09 - 7.20 (m, 2 H) 7.27 (t, J = 3.05 Hz, 1 H) 7.34 (s, 1 H) 7.42 - 7.55 (m, 3 H) 7.62 - 7.69 (m, 2 H) 11.98 (brs, 1 H). MS (ESI+) m/z 389 .
Example 335 4-{2-[(4-fluorophenyl)amino][(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 335a 4-(2-amino((methylsulfonyl)methyl)phenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin- 7(6H)-one Example 335a was prepared according to the ure used for the preparation of Example 4a, substituting Example 328c for Example 7c to provide the title compound.
Example 335b 4-(2-((4-fluorophenyl)amino)((methylsulfonyl)methyl)phenyl)methyltosyl-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 µmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'- biphenyl]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 t-butanol (0.69 mL). The reaction mixture was heated at 150 ºC for 30 minutes under microwave conditions. The reaction mixture was filtered through a 2.5g Celite column and rinsed thoroughly with ethyl acetate. The filtrate was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and mercaptopropyl silica gel, ed, and trated. The residue was purified by flash chromatography (silica gel, 0-4% methanol/dichloromethane gradient) to provide the title compound. e 335c 4-{2-[(4-fluorophenyl)amino][(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 335c was prepared according to the procedure used for the preparation of Example 4b, tuting Example 335b for Example 4a to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.99 (bs, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.25 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 - 7.23 (m, 4H), 6.97 - 7.07 (m, 4H), 6.06 (t, J = 2.0 Hz, 1H), 4.40 (bs, 2H), 3.53 (s, 3H), 2.91 (s, 3H). MS (ESI+) m/z 426.2 (M+H)+ Example 336 [4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetonitrile A mixture of Example 314b (100 mg, 0.190 mmol), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)isoxazole (44.4 mg, 0.228 mmol), bis(diphenylphosphino)ferrocene]- ropalladium (II), complex with dichloromethane (1:1) (15.5 mg, 0.019 mmol), and potassium fluoride (44.1 mg, 0.758 mmol) in ylsulfoxide (1.9 mL) and water (0.75 mL) was purged with nitrogen gas and heated under microwave conditions at 130 °C at for 1.5 hours. The mixture was then treated with 1 mL 4N NaOH and stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layers was extracted with ethyl acetate. The combined organic phases were washed with water (2X), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The te was concentrated and the residue was purified by flash tography (silica gel, 0-8% methanol/dichloromethane nt) to give the title compound (30 mg, 48% yield). 1H NMR (300 MHz, DMSO-d 6) δ ppm 12.00 (s, 1H), 12.00 (s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.34 – 7.25 (m, 4H), 7.30 – 7.25 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.14 (dd, J = 2.6, 2.2 Hz, 1H), 6.14 (dd, J = 2.6, 2.2 Hz, 1H), 3.99 (s, 2H), 3.99 (s, 2H), 3.84 (d, J = 6.7 Hz, 2H), 3.84 (d, J = 6.7 Hz, 2H), 3.56 (s, 3H), 3.56 (s, 3H), 1.11 – 1.02 (m, 1H), 1.12 – 1.02 (m, 1H), 0.48 – 0.39 (m, 2H), 0.49 – 0.35 (m, 2H), 0.31 – 0.18 (m, 2H), 0.26 – 0.19 (m, 2H). MS (ESI+) m/z 334.1 (M+H)+.
Example 337 N-{4-(2,4-difluorophenoxy)[2-(hydroxymethyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl]phenyl}ethanesulfonamide Example 337a ethyl 4-(5-amino(2,4-difluorophenoxy)phenyl)benzylmethyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylate Example 337a was prepared according to the procedure used for the ation of Example 138a, substituting Example 70e for 2-bromofluoro(methylsulfonyl)benzene, and Example 148c for Example 6a, respectively, to provide the title compound.
Example 337b ethyl 1-benzyl(2-(2,4-difluorophenoxy)(N-(ethylsulfonyl)ethylsulfonamido)phenyl) methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylate Example 337b was prepared according to the procedure used for the preparation of Example 320f, substituting Example 337a for e 320e, to provide the title compound.
Example 337c ethyl 4-(2-(2,4-difluorophenoxy)(N-(ethylsulfonyl)ethylsulfonamido)phenyl)methyl oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxylate Example 337c was prepared ing to the procedure used for the preparation of Example 70j, substituting Example 337b for Example 70i, to provide the title compound.
Example 337d 4-(2-(2,4-difluorophenoxy)(ethylsulfonamido)phenyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylic acid e 337d was prepared according to the procedure used for the preparation of Example 70k, substituting e 337c for Example 70j, to provide the title compound.
Example 337e N-{4-(2,4-difluorophenoxy)[2-(hydroxymethyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl]phenyl}ethanesulfonamide Example 337d (0.060 g, 0.12 mmol) in tetrahydrofuran (5 mL) was d with 1.0 N borane (0.119 mL, 0.119 mmol). The reaction mixture was heated at 60 °C for 2 hours. The on mixture was partitioned between water and ethyl acetate. The organic layer was extracted with additional ethyl acetate twice. The combined organic layer were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to give the title product. (0.035 g, 60% yield). 1H NMR (500 MHz, DMSO- d6) δ ppm 11.81 (s, 1H), 9.78 (s, 1H), 7.33-7.39 (m, 2H), 7.28 (s, 1H), 7.20 (dd, J = 8.7, 2.59 Hz, 1H), 6.97-7.08 (m, 2H), 6.91 (d, J = 8.85 Hz, 1H), 6.15 (d, J = 2.14 Hz, 1H), 4.50 (s, 2H), 3.52 (s, 3H), 3.10 (q, J = 7.32 Hz, 2H), 1.23 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 490.2 (M+H)+.
Example 338 N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)carbonyl]oxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide Example 338a 4-(2-(2,4-difluorophenoxy)(ethylsulfonamido)phenyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarbonyl de e 338a was prepared according to the procedure used for the preparation of Example 13a, substituting Example 337d for Example 10, to provide the title compound.
Example 338b N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)carbonyl]oxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide Example 338b was ed according to the procedure used for the preparation of Example 13b, substituting Example 338a for Example 13a, and 1-methylpiperazine for ethylamine, tively, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO- d6) δ ppm 12.53 (s, 1H), 10.14 (br s, 1H), 9.81 (s, 1H), 7.34-7.40 (m, 3H), 7.20 (dd, J = 8.85, 2.75 Hz, 1H), 7.06-7.12 (m, 1H), 6.98-7.04 (m, 1H), 6.93 (d, J = 8.54 Hz, 1H), 6.53 (d, J = 2.14 Hz, 1H), 3.55 (s, 3H), 3.02-3.43 (m, 6H), 2.84 (s, 3H), 1.24 (t, J = 7.32 Hz, 3H).
MS (ESI+) m/z 586.2 (M+H)+.
Example 339 N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)methyl]oxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide Example 339 was prepared according to the procedure used for the preparation of Example 337e, substituting Example 338b for Example 337d, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO- d 6) δ ppm 12.01 (s, 1H), 9.80 (s, 1H), 7.34-7.39 (m, 2H), 7.31 (s, 1H), 7.19 (dd, J = 8.85, 2.75 Hz, 1H), 7.05-7.11 (m, 1H), 6.98-7.04 (m, 1H), 6.91 (d, J = 8.85 Hz, 1H), 6.19 (d, J = 2.14 Hz, 1H), 3.75 (s, 2H), 3.11 (q, J = 7.32 Hz, 2H), 2.95 (br s, 2H), 2.76 (s, 3H), 2.35 (br s, 2H), 1.24 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 572.0 Example 340 4-[2-(cyclopropylmethoxy)(1,2,3,6-tetrahydropyridinyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone Example 325 (100 mg, 0.210 mmol) in 2 mL dichloromethane was treated with 1 mL trifluoroacetic acid. The e 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 e (4X). The organic phase was dried over anhydrous magnesium sulfate, filtered, and trated to give the title compound (26 mg, 32.9% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.94 (s, 1H), 7.37 – 7.31 (m, 1H), 7.25 (dd, J = 5.3, 3.0 Hz, 2H), 7.18 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 8.4, 2.3 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.12 (m, 2H), 3.80 (d, J = 6.7 Hz, 2H), 3.56 (s, 3H), 3.09 (d, J = 12.1 Hz, 2H), 2.73 – 2.53 (m, 2H), 1.76 (d, J = 11.0 Hz, 1H), 1.55 (qd, J = 12.4, 3.8 Hz, 2H), 1.12 – 1.01 (m, 1H), 0.49 – 0.38 (m, 2H), 0.25 – 0.17 (m, 2H). MS ((DCI+) m/z 376.5 (M+H)+.
Example 341 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide To a 4 mL vial was added (azidocarbonyl) dipiperidine (ADDP) (25.9 mg, 0.102 mmol) in anhydrous toluene. The vial was introduced into a dry box and tributylphosphine (41.5 mg, 3 eq, 0.205 mmol) was added to the vial. This mixture was shaken until the solution turned clear. To this solution was added a solution of 2-methoxyethanol in anhydrous tetrahydrofuran (1.2 equivalents, 0.082 mmol, 6.24 mg). This mixture was stirred for 10 minutes at ambient temperature. To this 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 on mixture was stirred at room temperature overnight in the dry box. The reaction mixture was concentrated to dryness and the residue purified by reverse phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to provide the title compound (4.24%, 1.5 mg). 1H NMR (400 MHz, DMSO d6/D2O) δ ppm 7.49 (d, J=2.75 Hz, 1 H), 7.38 - 7.43 (m, 1 H), 7.37 (d, J=2.75 Hz, 1 H), 7.35 - 7.36 (m, 1 H), 7.34 (d, J=2.75 Hz, 1 H), 7.22 - 7.27 (m, 1 H), 7.05 - 7.11 (m, 1 H), 6.87 (d, J=8.54 Hz, 1 H), 6.30 (d, J=2.75 Hz, 1 H), 3.78 - 3.81 (m, 2 H), 3.57 (s, 3 H), 3.37 (t, J=5.65 Hz, 2 H), 3.20 (s, 3 H), 3.16 (t, J=7.32 Hz, 2 H), 1.26 (t, J=7.48 Hz, 3 H). ESI+ m/z= 518.0 (M+H)+.
Example 342 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-(pyridinylmethyl)ethanesulfonamide Example 342 was prepared according to the procedure used for the ation of Example 341, substituting pyridinylmethanol for 2-methoxyethanol, to provide the TFA salt of the title compound. 1H NMR (400 MHz, DMSO d 6/D2O) δ ppm 8.60 (d, J=4.58 Hz, 1 H), 8.07 (t, J=7.78 Hz, 1 H), 7.70 (d, J=7.93 Hz, 1 H), 7.56 (d, J=2.44 Hz, 1 H), 7.53 (dd, , 5.80 Hz, 1 H), 7.45 (dd, J=8.85, 2.75 Hz, 1 H), 7.35 - 7.41 (m, 1 H), 7.33 (d, J=2.75 Hz, 1 H), 7.29 (s, 1 H), 7.17 - 7.23 (m, 1 H), 7.03 - 7.09 (m, 1 H), 6.81 (d, J=8.85 Hz, 1 H), 6.17 (d, J=2.75 Hz, 1 H), 5.10 (s, 2 H), 3.56 (s, 3 H), 3.33 (q, J=7.43 Hz, 2 H), 1.31 (t, J=7.32 Hz, 3 H). ESI+ m/z= 551.0 (M+H)+. e 343 N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenyl]ethanesulfonamide Example 343 was prepared according to the procedure used for the ation of Example 341, tuting ropylmethanol for 2-methoxyethanol, to provide the title compound. 1H NMR (400 MHz, DMSO d 6/D2O) δ ppm 7.51 (d, J=2.44 Hz, 1 H), 7.36 - 7.42 (m, 2 H), 7.35 (s, 1 H), 7.34 (d, J=2.75 Hz, 1 H), 7.20 - 7.27 (m, 1 H), 7.04 - 7.10 (m, 1 H), 6.88 (d, J=8.85 Hz, 1 H), 6.29 (d, J=2.75 Hz, 1 H), 3.57 (s, 3 H), 3.52 (d, J=7.02 Hz, 2 H), 3.12 - 3.18 (m, 2 H), 1.26 (t, J=7.32 Hz, 3 H), 0.83 - 0.93 (m, 1 H), 0.40 - 0.45 (m, 2 H), 0.08 - 0.13 (m, 2 H). ESI+ m/z= 514.0 (M+H)+.
Example 344 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-[2-(2-oxopyrrolidinyl)ethyl]ethanesulfonamide Example 344 was prepared according to the procedure used for the preparation of Example 341, tuting 1-(2-hydroxyethyl)pyrrolidinone for oxyethanol, to provide the title compound. 1H NMR (400 MHz, DMSO d 6/D2O) δ ppm 7.50 (d, J=2.44 Hz, 1 H), 7.38 - 7.43 (m, 2 H), 7.37 (s, 1 H), 7.33 (d, J=2.75 Hz, 1 H), 7.22 - 7.28 (m, 1 H), 7.05 - 7.11 (m, 1 H), 6.84 (d, J=8.54 Hz, 1 H), 6.34 (d, J=2.75 Hz, 1 H), 3.83 (t, J=5.65 Hz, 2 H), 3.58 (s, 3 H), 3.27 - 3.32 (m, 4 H), 3.14 (q, J=7.32 Hz, 2 H), 2.11 (t, J=8.09 Hz, 2 H), 1.74 - 1.82 (m, 2 H), 1.25 (t, J=7.32 Hz, 3 H). ESI+ m/z= 571.1 (M+H)+.
Example 345 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-(tetrahydrofuranylmethyl)ethanesulfonamide Example 345 was prepared according to the ure used for the preparation of Example 341, substituting (tetrahydrofuranyl)methanol for 2-methoxyethanol, to provide the title compound. 1H NMR (400 MHz, DMSO d 6/D2O) δ ppm 7.51 (d, J=2.75 Hz, 1 H), 7.37 - 7.43 (m, 2 H), 7.36 (s, 1 H), 7.34 (d, J=2.75 Hz, 1 H), 7.21 - 7.27 (m, 1 H), 7.04 - 7.11 (m, 1 H), 6.86 (d, J=8.85 Hz, 1 H), 6.31 (d, J=2.75 Hz, 1 H), 3.78 - 3.84 (m, 1 H), 3.58 - 3.70 (m, 4 H), 3.57 (s, 3 H), 3.13 - 3.19 (m, 2 H), 1.73 - 1.93 (m, 3 H), 1.51 - 1.59 (m, 1 H), 1.25 (t, J=7.32 Hz, 3 H). ESI+ m/z= 544.0 (M+H)+.
Example 346 N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-(3,3,3-trifluoropropyl)ethanesulfonamide Example 346 was prepared according to the procedure used for the preparation of Example 341, substituting 3,3,3-trifluoropropanol for oxyethanol, to provide the title compound. 1H NMR (400 MHz, DMSO-d 6/D2O) δ ppm 7.54 (d, J=2.75 Hz, 1 H), 7.31 - 7.44 (m, 4 H), 7.23 - 7.30 (m, 1 H), 7.05 - 7.11 (m, 1 H), 6.89 (d, J=8.54 Hz, 1 H), 6.31 (d, J=2.75 Hz, 1 H), 3.93 - 3.98 (m, 2 H), 3.57 (s, 3 H), 3.18 (q, J=7.32 Hz, 2 H), 2.41 - 2.51 (m, 2 H), 1.25 (t, J=7.32 Hz, 3 H). ESI+ m/z= 556.0(M+H)+.
Example 347 4-(cyclopropylmethoxy)-N-(4-fluorophenyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide Example 347a 3-bromofluoro-N-(4-fluorophenyl)benzenesulfonamide Example 347a was prepared according to the procedure used for the preparation of Example 305a, tuting 4-fluoroaniline for indoline. The crude product was ed by flash chromatography a gel, 10% ethyl acetate in heptane) to afford title compound Example 347b 3-bromo(cyclopropylmethoxy)-N-(4-fluorophenyl)benzenesulfonamide Example 347b was prepared according to the procedure used for the preparation of Example 29a, substituting cyclopropylmethanol for tetrahydro-2H-pyranol and substituting Example 347a for Example 2a to afford the title compound.
Example 347c 4-(cyclopropylmethoxy)-N-(4-fluorophenyl)(6-methyloxotosyl-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzenesulfonamide Example 347c was prepared according to the procedure used for the preparation of Example 6c, substituting Example 347b for Example 6b to afford the title compound.
Example 347d lopropylmethoxy)-N-(4-fluorophenyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide Example 347d was prepared according to the procedure used for the preparation of Example 6d, substituting Example 347c for e 6c to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.04 (s, 1 H) 10.07 (s, 1 H) 7.60 - 7.68 (m, 2 H) 7.23 - 7.31 (m, 2 H) 7.20 (d, J = 9.16 Hz, 1 H) 7.12 (d, J = 6.78 Hz, 4 H) 5.88 - 5.95 (m, 1 H) 3.92 (d, J = 6.78 Hz, 2 H) 3.55 (s, 3 H) 1.02 - 1.17 (m, 1 H) 0.43 - 0.50 (m, 2 H) 0.22 - 0.30 (m, 2 H). MS (ESI+) m/z 468.1 [M+H]+. e 348 4-[2-(cyclopropylmethoxy)(6-fluoropyridinyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone Example 348a 4-(2-(cyclopropylmethoxy)(6-fluoropyridinyl)phenyl)methyltosyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one Example 348a was prepared according to the procedure used for the preparation of Example 6c, substituting Example 334a for Example 6b and substituting oropyridin yl)boronic acid for e 6a to afford the title compound.
Example 348b 4-(2-(cyclopropylmethoxy)(6-fluoropyridinyl)phenyl)methyl-1H-pyrrolo[2,3- c]pyridin-7(6H)-one Example 348b was prepared according to the procedure used for the ation of Example 6d, substituting Example 348a for Example 6c to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.21 - 0.28 (m, 2 H) 0.41 - 0.49 (m, 2 H) 1.03 - 1.15 (m, 1 H) 3.57 (s, 3 H) 3.91 (d, J = 6.78 Hz, 2 H) 6.17 (t, J = 2.71, 2.03 Hz, 1 H) 7.17 - 7.28 (m, 3 H) 733 (s, 1 H) 7.63 - 7.69 (m, 2 H) 8.23 - 8.32 (m, 1 H) 8.54 (d, J = 2.37 Hz, 1 H) 11.95 (brs, 1 H). MS (ESI+) m/z 390 [M+H]+.
Example 349 N-[4-(2,4-difluorophenoxy)(3-formylmethyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide Example 349a 4-bromomethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one A mixture of e 1e (7 g, 18.36 mmol) and lithium hydroxide monohydrate (3.08 g, 73.4 mmol) in tetrahydrofuran (50 mL) and water (20 mL) was heated at 80 °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-bromomethyl((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 349a (3.92 g, 17.26 mmol) in ydrofuran (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 te was concentrated. The e was purified by flash chromatography (silica gel, 20% ethyl acetate in helptanes) to give the title compound (5.84 g, 95% yield).
Example 349c omethyloxo((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinecarbaldehyde e 349b (3.92 g, 17.3 mmol) in dimethylformamide (15 mL) was treated with phosphorus oride (9.66 mL, 104 mmol) dropwise at 0 ºC. After the addition was complete, the solution was heated at 80 ºC for 6 hours. After cooling to ambient temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 50-100% ethyl acetate/heptanes) to give the title compound (1.35 g, 20.3% yield).
Example 349d 4-(5-amino(2,4-difluorophenoxy)phenyl)methyloxo((2- (trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarbaldehyde Example 349d was ed according to the ure used for the preparation of Example 138a, tuting Example 349c for 2-bromofluoro(methylsulfonyl)benzene, and Example 148c for Example 6a, respectively, to provide the title compound. After aqueous workup, the crude product was used for the next reaction without purification.
Example 349e 2,4-difluorophenoxy)(3-formylmethyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide A mixture of e 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 (10 mL) was stirred at ambient temperature for 2 hours. The solvent was evaporated under reduced re, and the residue was treated with dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The reaction mixture was d at ambient temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was d with dixoane (10 mL) and 2.0 N NaOH (5 mL). The reaction mixture was heated at 90 °C for 2 hours. After cooling to ambient temperature, the reaction mixture was partitioned between water and ethyl acetate.
The organic layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium de, dried over ous 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). 1H NMR (500 MHz, DMSO-d 6) δ ppm 13.07 (s, 1H), 9.78 (s, 1H), 9.40, (s, 1H), 7.99 (d, J = 3.36 Hz, 1H), 7.38 (s, 1H), 7.23-7.31 (m, 3H), 6.89-6.97 (m, 3H), 3.55 (s, 3H), 3.10 (q, J = 7.32 Hz, 2H),1.21 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 488.0 (M+H)+. e 350 N-{4-(2,4-difluorophenoxy)[6-methyl(morpholinylmethyl)oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl]phenyl}ethanesulfonamide A mixture of Example 349e (0.04 g, 0.082 mmol), morpholine (0.014 g, 0.164 mmol), and sodium toxyhydroborate (0.035 g, 0.164 mmol) in 1,2-dichloroethane (2 mL) was stirred at ambient temperature overnight. The solvent was evaporated under reduced pressre, and the e was purified by reverse phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to give the TFA salt of the title compound (0.035 g, 0.052 mmol, 63.4% yield). 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.59 (s, 1H), 9.86 (s, 1H), 9.58, (s, 1H), 7.56 (s, 1H), 7.26-7.38 (m, 4H), .09 (m, 2H), 6.93 (d, J = 8.85 Hz, 1H), 4.23-4.29 (m, 1H), .81 (m, 3H), 3.52 (s, 3H), 3.16 (q, J = 7.32 Hz, 2H), 2.37-2.71 (m 4H), 1.24 (t, J = 7.32 Hz, 3H).
MS (ESI+) m/z 558.9 (M+H)+.
Example 351 N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)methyl]oxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide Example 351 was prepared according to the procedure used for the preparation of Example 350, substituting 1-methylpiperazine for morpholine, to provide the TFA salt of the title compound. 1H NMR (500 MHz, DMSO-d 6) δ ppm 12.11 (s, 1H), 9.86 (s, 1H), 9.58, (s, 1H), 7.29-7.35 (m, 2H), .22 (m, 2H), 7.11 (s, 1H), 6.97-7.06 (m, 2H), 6.91 (d, J = 9.46 Hz, 1H), 3.85 (br s, 4H), 3.48 (s, 3H), 3.12-3.40 (m, 4H), 2.69 (s, 3H), 1.25 (t, J = 7.32 Hz, 3H). MS (ESI+) m/z 571.9 (M+H)+.
Example 352 4-{2-[(cyclopropylmethyl)amino]phenyl}methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin Example 352a 2-bromo-N-(cyclopropylmethyl)aniline A solution of 2-bromoaniline (1.720 g, 10.00 mmol), cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), and acetic acid (2.86 mL, 50.0 mmol) in dichloromethane (50 mL) was heated at 50 °C for 1 hour. The solution was cooled in an ice bath and sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added. This e was stirred for 2 hours while warming to ambient temperature and then partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The c layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate in heptane) to provide the title compound (1.05 g, 93% yield).
Example 352b (cyclopropylmethyl)amino)phenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)- Example 352b was prepared according to the procedure used for the preparation of Example 4a, substituting Example 352a for Example 7c with the ion that the reaction mixture was heated at 90 °C for 2.5 hours and the material was purified by flash column chromatography (silica gel, 0-5% methanol in dichloromethane) to provide the title compound.
Example 352c 4-{2-[(cyclopropylmethyl)amino]phenyl}methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin Example 352c was prepared according to the procedure used for the preparation of Example 4b, substituting Example 352b for Example 4a with the exception that the reaction was heated at 90 °C for 2.5 hours and the material was purified by flash column chromatography a gel, 0-5% methanol in dichloromethane) to provide the title compound. 1H NMR (400 MHz, CDCl 3) δ ppm 10.99 (s, 1H) 7.24-7.31 (m, 2H) 7.15 (dd, J = 7.32, 1.53 Hz, 1H) 6.97 (s, 1H) 6.70-6.78 (m, 2H) 6.20-6.25 (m, 1H) 3.99 (s, 1H) 3.73 (s, 3H) 2.97 (d, J = 6.41 Hz, 2H) 0.90-1.02 (m, 1H) .45 (m, 2H) 0.09-0.15 (m, 2H). MS (ESI+) m/z 294.0 (M+H)+. e 353 4'-(cyclopropylmethoxy)-3'-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)biphenylcarbonitrile Example 353a 4'-(cyclopropylmethoxy)-3'-(6-methyloxotosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)biphenylcarbonitrile Example 353a was prepared according to the procedure used for the preparation of Example 6c, substituting Example 334a for Example 6b and substituting (3- cyanophenyl)boronic acid for Example 6a to afford the title nd.
Example 353b clopropylmethoxy)-3'-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)biphenylcarbonitrile Example 353b was prepared according to the procedure used for the preparation of Example 6d, substituting e 353a for e 6c to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.21 - 0.28 (m, 2 H) 0.41 - 0.49 (m, 2 H) 1.00 - 1.15 (m, 1 H) 3.58 (s, 3 H) 3.91 (d, J = 6.78 Hz, 2 H) 6.17 (t, J = 2.03 Hz, 1 H) 7.20 (d, J = 8.48 Hz, 1 H) 7.26 (t, J = 2.71 Hz, 1 H) 7.33 (s, 1 H) 7.63 (t, J = 7.80 Hz, 1 H) 7.67 - 7.79 (m, 3 H) 8.03 (d, J = 8.14 Hz, 1 H) 8.16 (t, J = 1.70 Hz, 1 H) 11.94 (brs, 1 H). MS (ESI+) m/z 396 [M+H]+.
Example 354 4-{2-(cyclopropylmethoxy)[(4-hydroxypiperidinyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone e 354a 1-(3-bromofluorophenylsulfonyl)piperidinol e 354a was prepared according to the procedure described for the preparation of Example 310a, substituting piperidinol for N,N-dimethylpyrrolidinamine to afford the title compound.
Example 354b 1-(3-bromofluorophenylsulfonyl)(tetrahydro-2H-pyranyloxy)piperidine 3,4-Dihydro-2H-pyran (0.28 mL, 3.1 mmol) was added dropwise to a 0 °C solution of Example 354a (0.51 g, 1.5 mmol), 4-methylbenzenesulfonic 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, ted aqueous sodium chloride, dried over anhydrous sodium e, filtered and concentrated. The residue was purified by flash tography (silica gel, dichloromethane / gradient with methanol) to afford the title compound (420 mg, 65.9 % .
Example 354c 1-(3-bromo(cyclopropylmethoxy)phenylsulfonyl)(tetrahydro-2H-pyran yloxy)piperidine Example 354c was prepared according to the procedure used for the preparation of Example 29a, tuting cyclopropylmethanol for tetrahydro-2H-pyranol and substituting Example 354b for Example 2a to afford the title compound.
Example 354d 4-(2-(cyclopropylmethoxy)(4-(tetrahydro-2H-pyranyloxy)piperidin ylsulfonyl)phenyl)methyltosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one Example 354d was prepared according the to the procedure used for the preparation of Example 6c, tuting e 354c for Example 6b to afford the title compound.
Example 354e 4-(2-(cyclopropylmethoxy)(4-(tetrahydro-2H-pyranyloxy)piperidin ylsulfonyl)phenyl)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 afford the title compound.
Example 354f 4-(2-(cyclopropylmethoxy)(4-hydroxypiperidinylsulfonyl)phenyl)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 (1 mL) was stirred at 45 °C for 2.5 hours. The reaction mixture was concentrated to dryness and the residue was dried overnight (in-vacuo). The crude product was triturated with diethyl ether, filtered and dried cuo) to afford the title compound (30 mg, 66 % yield). 1H NMR (300 MHz, DMSO-d 6) δ ppm 0.25 - 0.31 (m, 2 H) 0.44 - 0.51 (m, 2 H) 1.08 - 1.17 (m, 1 H) 1.38 - 1.51 (m, 2 H) 1.70 - 1.80 (m, 2 H) 2.70 - 2.80 (m, 2 H) 3.10 - 3.18 (m, 2 H) 3.51 - 3.56 (m, 1 H) 3.57 (s, 3 H) 3.97 (d, J = 6.78 Hz, 2 H) 4.66 (d, J = 4.07 Hz, 1 H) 6.12 (t, J = 2.71, 2.03 Hz, 1 H) 7.27 - 7.32 (m, 2 H) 7.36 (s, 1 H) 7.64 - 7.70 (m, 2 H) 12.04 (brs, 1 H). MS (ESI+) m/z 458 [M+H]+.
Biological Examples Bromodomain domain g assay A time-resolved fluorescence resonance energy transfer (TR-FRET) assay was used to determine the affinities of compounds of the Examples listed in Table 1 for each bromodomain of human BRD4. His-tagged first (BD1: amino acids 68) and second (BD2: amino acids E352- E168) bromodomains of human BRD4 were expressed and purified. An Alexa647-labeled BET-inhibitor was used as the fluorescent probe in the assay. sis of Alexa647-labeled bromodomain inhibitor compound 2-((6S,Z)(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepinyl)acetic acid. Methyl ,Z)(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetate (see e.g., WO 2006129623)(100.95 mg, 0.243 mmol was suspended in 1 mL methanol to which was added a freshly prepared solution of lithium ide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken at ambient temperature for 3 hours. The methanol was evaporated and the pH adjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) and ted four times with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and concentrated to afford 2-((6S,Z)(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetic acid (85.3 mg, 87.0%); ESI-MS m/z = 401.1 [(M+H)+] which was used directly in the next reaction.
N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)((6S,Z)(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetamide bis(2,2,2-trifluoroacetate). 2-((6S,Z)(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepinyl)acetic acid (85.3 mg, 0.213 mmol) was combined with 2,2'-(ethane-1,2- s(oxy))diethanamine (Sigma-Aldrich, 0.315 mg, 2.13 mmol) were combined in 5 mL anhydrous dimethylformamide. (1H-benzo[d][1,2,3]triazolyloxy)tripyrrolidin ylphosphonium hexafluorophosphate(V) (PyBOB, CSBio, Menlo Park CA; 332 mg, 0.638 mmol) was added and the reaction shaken at ambient temperature for 16 hours. The reaction mixture was diluted to 6 mL with ylsulfoxide:water (9:1, v:v) and purified in two injections with time collection Waters ak C18 200 x 25 mm column eluted with a gradient of 0.1% trifluoroacetic acid (v/v) in water and acetonitrile. The fractions containing the two purified products were lyophilized to afford N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)- 2-((6S,Z)(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepinyl)acetamide bis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS m/z = 531.1 +]; 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-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetamide) bis(2,2,2-trifluoroacetate) (3.0 mg, 1.5%); ESI-MS m/z = 913.2 [(M+H)+]; 911.0 [(M-H)-]. 2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)((6S,Z)(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetamide(2,2,2- trifluoroacetate). N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)((6S,Z)(4-chlorophenyl)- 2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetamide bis(2,2,2- trifluoroacetate) (5.4 mg, 0.0071 mmol) was combined with Alexa Fluor® 647 carboxylic Acid, imidyl ester (Life Technologies, Grand Island, NY; 3 mg, 0.0024 mmol) were combined in 1 mL ous dimethylsulfoxide containing diisopropylethylamine (1% v/v) and shaken at ambient temperature for 16 hours. The reaction was diluted to 3 mL with ylsulfoxide:water (9:1, v:v) and purified in one injection with time collection Waters Deltapak C18 200 x 25 mm column eluted with a gradient of 0.1% trifluoroacetic acid (v/v) in water and acetonitrile. The fractions containing the purified product were lyophilized to afford N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)((6S,Z)(4-chlorophenyl)- 2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepinyl)acetamide(2,2,2- trifluoroacetate) (1.8 mg); MALDI-MS m/z = 1371.1, 1373.1 [(M+H)+] as a dark blue powder.
Assay Compound dilution series were prepared in DMSO via a 3-fold serial dilution from 2.5 mM to 42 nM. Compounds were then diluted 6:100 in assay buffer (20 mM Sodium Phosphate, pH 6.0, 50 mM NaCl, 1 mM Ethylenediaminetetraacetic acid disodium salt dihydrate, 0.01% Triton X-100, 1 mM DL-Dithiothreitol) to yield 3X working solutions. Six microliters (µL) of the working solution was then transferred to white, lume assay plates (Costar #3673). A 1.5X assay mixture containing gged bromodomain, Europium-conjugated anti-His antibody (Invitrogen PV5596) and the Alexaconjugated probe molecule was also prepared. Twelve µ L of this solution were added to the assay plate to reach a final volume of 18 µL. The final concentration of 1X assay buffer contains 2% DMSO, 50 µM - 0.85 nM compound, 8 nM gged bromodomain, 1 nM Europiumconjugated is-tag antibody and 100 nM or 30 nM probe (for BDI or BDII, respectively). After a one-hour incubation at room temperature, TR-FRET ratios were determined using an on abel plate reader (Ex 340, Em 495/520).
TR-FRET data were ized to the means of 24 no-compound controls (“high”) and 8 ls containing 1 µM un-labeled probe (“low”). t inhibition was plotted as a function of compound concentration and the data were fit with the 4 parameter logistic equation to obtain IC50s. tion constants (Ki) were ated from the IC50s, probe Kd and probe concentration. Typical Z’ values were between 0.65 and 0.75. The minimum significant ratio was determined to evaluate assay reproducibility (Eastwood et al., (2006) J Biomol Screen, 11: 253-261). The MSR was determined to be 2.03 for BDI and 1.93 for BDII, and a moving MSR (last six run MSR overtime) for both BDI and BDII was typically < 3. The Ki values are reported in Table 1.
MX-1 cell line eration assay The impact of compounds of the Examples on cancer cell proliferation was determined using the breast cancer cell line MX-1 (ATCC) in a 3-day proliferation assay. MX-1 cells were maintained in RPMI 1640 medium (Sigma) supplemented with 10% FBS (Fetal Bovine Serum) at 37 Co and an atmosphere of 5% CO2. For compound testing, MX-1 cells were plated in 96-well black bottom plates at a density of 5000 cells/well in 90 µL of culture media and incubated at 37° overnight to allow cell adhesion and spreading. Compound dilution series were prepared in DMSO via a 3-fold serial dilution from 3 mM to 0.1 µM. The DMSO dilution series were then diluted 1:100 in phosphate buffered saline, and 10 µL of the resulted solution were added to the appropriate wells of the MX-1 cell plate. The final compound concentrations in the wells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003 and 0.0001 µ M. After the on of compounds, the cells were incubated for 72 more hours and the amounts of viable cells were determined using the Cell Titer Glo assay kit (Promega) according to manufacturer suggested protocol.
Luminescence readings from the Cell Titer Glo assay were normalized to the DMSO treated cells and analyzed using the GraphPad Prism software with sigmoidal curve fitting to obtain EC50s. The m significant ratio (MSR) was determined to evaluate assay reproducibility (Eastwood et al., (2006) J Biomol Screen, 11: 253-261). The l MSR was determined to be 2.1 and a moving MSR (last six run MSR overtime) has been <2.
Proliferation panel assay The compounds of Examples 4 and 78 were tested for their impact on proliferation of a panel of cancer cell lines types (with specific cell line tested) as set out in (Table 2). Cells were plated in 96-well plates at 1500 cells/well in the appropriate culture media without test compound and incubated overnight at 37oC and an atmosphere of 5 % CO2. Series dilution of compounds were prepared and added to the wells as in the MX-1 proliferation assay. After the addition of compounds, cells were incubated for another 3 days at 37oC and an atmosphere of 5 % CO2. The amounts of viable cells were ined using the Cell Titer Glo assay kit (Promega) according to manufacturer suggested ol. Cell proliferation data were analyzed as described above in the MX-1 proliferation assay to obtain the EC50 for the compounds of Examples 4 and 78 and reported in Table 2.
Table 1 TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 1 0.136* 0.0410* 0.137 2 0.529* 0.178* 0.860 3 0.0646 0.0736 0.185 4 0.0014* 0.0020* 0.0164 0.0150 0.0064 0.0310 6 0.0053 0.0058 0.0460 7 0.119 0.0773 > 3.0 8 0.0026 0.0039 0.0244* 9 0.0180 0.0101 0.113* 0.0154 0.0086 > 3.0 11 0.0018 0.0024 0.0342 12 1.8 4.33 > 3.0 13 0.0037 0.0034 0.128 14 0.0055 0.0123 0.170 0.0042 0.0075 0.140 16 0.0043 0.0053 0.0946 17 0.0171* 0.0322* 0.283 18 * 0.0103* 0.209 19 0.0074 0.0042 0.123 0.0109 8 0.190 21 0.00039 0.00025 0.0139* 22 0.0022 0.0010 0.0652 23 0.0012 0.00075 0.0459 24 0.0025 0.0021 0.0126 0.0030 0.0036 0.0562 26 0.0021 0.0033 0.0171 27 0.0025* 0.0022* 0.0317 TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 28 0.0017 0.0020 0.0239 29 0.0011 0.0067 0.0718 0.0177 0.0104 0.562 31 0.0018 0.0134 0.0398 32 0.0160 0.0075 0.0833 33 0.0026 0.0048 0.0417 34 0.0035 0.0021 0.0268 0.661 1.14 NA 36 0.0035* 0.0014* 0.0174* 37 0.0113 0.0108 0.0593 38 0.148 0.257 NA 39 0.112 0.124 NA 40 0.0145 0.0439 0.167 41 0.0028 0.00051 0.0298 42 0.0546 0.0934 > 3.0 43 0.0017 0.0012 0.0169 44 0.286 0.236 0.828 45 0.0128 0.0190 0.233 46 0.0516 0.0169 0.588 47 0.235 0.205 1.1 48 0.0023 0.0033 0.0235 49 * 0.0015* 0.0196* 50 0.0215 0.0081 0.206* 51 0.0097 0.0161 0.101 52 0.0241 0.0260 0.309 53 0.0622 0.0054 0.0765 54 0.0951 0.0375 0.266 55 0.0555 0.0336 0.200 TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 56 0.0122 0.0024 0.251 57 0.00088 0.0020 0.0138* 58 0.0021 0.0081 0.0451 59 0.00084 0.0016 0.0187* 60 0.00075 0.0066 0.0142* 61 > 13.0 > 22.2 NA 62 0.0030* 0.0019* 0.0079* 63 0.0180 0.0427 0.105 64 0.0531* 0.0633* 0.773 65 0.0116* 0.0049* 0.0255 66 4 0.0034 0.0332 67 0.0561* 0.0938* 0.341 68 1.7 2.55 5.9 69 0.0390 0.0123 0.140 70 0.0118 0.0468 > 3.0 71 1* 0.0012* 0.0175* 72 0.0015* 0.0011* 0.0457* 73 0.00098 0.00050 0.0207 74 0.0961 0.101 0.275 75 0.137 0.0594 0.478 76 0.0658 0.0297 0.290 77 0.0124 0.0157 > 3.0 78 0.0025 0.0018 0.400 79 0.0062 0.0018 0.887 80 0.0091 0.0061 0.0620 81 0.0095 0.00099 0.103 82 0.519 0.183 0.767 83 0.0209 0.0422 0.424 TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 84 0.00167 0,00065 0.231 85 0.0064 0.0017 0.0520 86 0.0043 0.0024 0.182 87 0.0056 0.0067 0.0534 88 0.635 0.236 > 3.0 89 0.0016 0.0021 0.0252* 90 0.0040 0.0068 0.0168 91 0.0122 0.0874 0.240 92 0.0025 0.0253 0.0840 93 0.0076 0.0322 0.120 94 0.0162 0.0100 0.110 95 0.0087 0.0011 0.0560 96 3 0.0011 0.0160 97 0.0023 0.0028 0.0140 98 0.0065 0.0027 0.0529 99 0.0035 0.0247 0.0977 100 0.0014 0.0027 0.107 101 0.0012 0.0043 0.0112 102 0.0034 0.0242 0.0615 103 0.0019 0.0038 0.0338 104 0.0044 0.0179 0.0653 105 0.00052 0.0015 0.0160 106 0.0013 0.0109 0.0468 107 0.00050 0.00087 0.0310 108 0.0014 0.0053 0.0380 109 0.00072 0.0034 0.0320 110 0.0031 0.0051 0.0324 111 0.0087 0.0103 0.199 TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. 57-E168) (BDII_E352-M457) (µM) (µM) (µM) 112 0.0169 0.0206 0.240 113 0.0474 0.381 > 3.0 114 0.136 0.121 > 3.0 115 0.0671 0.0269 0.0550 116 0.105 0.0891 NA 117 2.3 0.486 NA 118 NA NA NA 119 0.0444 0.0225 NA 120 0.190 0.304 NA 121 0.0155 0.0334 0.251 122 NA NA NA 123 0.0271 0.0361 0.118 124 0.320 0.169 NA 125 0.215 0.274 NA 126 2.0 0.768 NA 127 NA NA NA 128 0.0725 0.112 NA 129 0.0379 0.0456 0.118 130 0.183 0.174 NA 131 0.0986 0.0600 NA 132 0.238 0.344 NA 133 NA NA NA 134 0.0435 0.0073 0.137* 135 0.274 0.0774 NA 136 0.234 0.295 NA 137 0.0687 0.0089 0.303* 138 0.0167 0.0095 0.0851 139 7.1 3.89 NA TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. 57-E168) (BDII_E352-M457) (µM) (µM) (µM) 140 3.6 1.58 NA 141 0.0054 0.0152 0.125 142 0.0065 0.0794 0.138 143 0.0223 0.107 0.370 144 0.0136 0.0178 0.0769 145 0.0027 0.0056 0.0264 146 0.0075 0.0019 0.0609 147 0.0021 0.0011 0.0148 148 0.205 0.152 0.740 149 0.0115 0.0030 0.0297 150 0.0097 0.0042 0.0665 151 0.0107 0.0081 0.0549 152 0.0246 0.0048 0.105 153 0.0228 0.0082 0.0933 154 0.0208 0.0131 0.0655 155 0.0193 0.0148 0.117 156 0.0113 0.0209 0.114 157 0.0308 0.0218 0.150 158 0.0041* 0.0097* 0.0243* 159 0.0370 0.0207 0.0624 160 0.0416 0.0065 0.119 161 0.0204 0.0055 0.104 162 0.0111 0.0046 0.127 163 0.0857 0.0235 0.295 164 NA NA NA 165 0.0050 0.0022 0.104 166 0.0109 0.0036 0.0482 167 0.0065 0.0122 0.0430 TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 168 0.0054 0.0013 0.0277 169 8* 0.00086* 0.0053 170 0.0228 0.0940 0.332 171 0.0138 0.0103 NA 172 0.0133 0.0059 NA 173 0.0157 0.0066 NA 174 0.0192 0.0143 NA 175 0.0258 0.0178 NA 176 0.0213 0.0060 NA 177 0.0113 0.0044 0.0535 178 0.0105 0.0032 0.0362 179 0.0225 0.0165 NA 180 0.0179 0.0071 0.115 181 0.0305 0.0224 NA 182 0.0190 0.0097 NA 183 0.0412 0.0198 NA 184 0.0166 0.0045 0.0788 185 0.0345 0.0122 NA 186 0.0101 0.0033 0.0484 187 0.0248 0.0082 NA 188 0.0294 0.0180 NA 189 0.0304 0.0230 NA 190 0.0346 0.0181 NA 191 0.0178 0.0088 NA 192 0.0513 0.0096 NA 193 0.0704 0.0136 NA 194 0.0289 0.0191 NA 195 5.5 1.02 NA TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 196 9.5 0.479 NA 197 0.0015 0.00079 0.0117 198 0.0013 0.0016 0.0093* 199 0.0019 0.0035 NA 200 0.00086 0.0011 0.0113 201 0.0102 0.0407 0.135 202 0.0017 0.0014 0.0228* 203 0.00069 5 0.0047 204 0.0205 0.0102 0.0829 205 0.0062 0.0102 0.0391* 206 0.0116 0.0228 0.0777 207 0.0031 0.0018 0.0251* 208 0.0056 0.0060 0.0235 209 0.0046 0.0036 0.0368 210 0.0045 0.0053 0.0367 211 0.0014 0.0021 0.0119 212 0.0018 0.0013 0.0073 213 0.0032 0.0048 0.0287 214 0.0024 0.0017 0.0105 215 0.00083 0.00046 0.0019 216 0.0018 0.0018 0.0066 217 0.0033 0.0081 0.0342 218 0.0693 0.0689 NA 219 0.0036 0.0029 0.0177 220 0.0028 0.0012 0.0213 221 0.0066 0.0050 0.0061 222 0.225 0.969 NA 223 0.0024 0.0050 0.0133 TR-FRET Binding TR-FRET Binding Cellular nd Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 224 0.0069 0.0070 0.0076 225 0.264 0.845 NA 226 0.141 0.438 > 3.0 227 0.0739 0.211 0.658 228 0.0390 0.108 > 3.0 229 0.0343 0.0613 0.288 230 0.0026 0.0015 0.0236 231 0.0037 0.0067 0.0063 232 0.213 0.443 NA 233 0.0022* 0.0015* 0.0069* 234 0.0030 0.0034 0.0159 235 0.0174 0.0070 0.0665 236 0.0145 0.0051 0.0250 237 0.0030 0.0035 0.0350 238 0.0011 0.00078 0.0033 239 0.0028 0.0024 0.0101 240 0.0020 0.0028 0.0115 241 0.332 0.603 NA 242 0.0365 0.0058 0.289 243 0.0115 0.0382 0.249 244 0.0232 0.0737 0.254 245 0.0025 0.0037 0.0269 246 0.0180 0.0046 0.0975 247 1.1 3.00 NA 248 0.0019 0.0013 0.0264* 249 0.0015 0.00083 0.0144* 250 0.0015* 0.0015* 0.0180* 251 0.0631 0.171 0.573 TR-FRET Binding TR-FRET Binding Cellular nd Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 252 0.0101 0.0017 0.246 253 0.0204 0.0012 0.145 254 0.0796 0.0087 0.0751 255 0.0105 0.154 0.265 256 0.0061 0.0840 0.405 257 0.0588 0.0030 0.360 258 0.0059 0.0124 0.0765 259 0.0242 0.0203 0.123 260 0.0010 0.0012 0.0063 261 0.0015 0.0016 0.0072 262 0.125 0.489 NA 263 0.0088 0.0163 0.0769 264 0.0012 0.0012 0.0178 265 0.0090 0.0356 > 3.0 266 0.0215 0.0078 0.0564 267 0.0044 0.0042 0.0436 268 0.00076 0.00057 0.0062 269 0.0124 0.0569 0.329 270 0.0487 0.0226 0.421 271 0.0029 0.0019 0.0213 272 0.0102 0.0116 0.112 273 0.0012 0.0013 0.0090 274 0.0933 0.310 NA 275 0.526 1.13 NA 276 0.0114 0.0171 0.149 277 0.0063 0.0143 0.0211 278 0.0121 0.0112 0.135 279 0.0314 0.131 0.364 TR-FRET Binding T Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 280 0.0192 0.0920 0.292 281 0.0018 0.108 0.191 282 0.0173 0.0723 0.204 283 0.0189 0.0346 0.138 284 0.0183 0.130 0.131 285 0.0108 0.0075 0.111 286 0.0121 0.0054 0.0746 287 0.0089 0.0095 0.0195* 288 0.0719 0.0539 0.173 289 0.0124 0.310 > 3.0 290 0.0050 0.0019 0.0362 291 0.0329 0.0237 NA 292 0.0532 0.0558 0.366 293 0.180 0.0193 0.381 294 0.0479 0.0217 0.332 295 0.0279 0.0307 0.223 296 0.705 0.101 0.535 297 0.0142 0.0052 0.0186 298 0.0029 0.0031 0.0061 299 0.0801 0.0050 0.0360 300 0.389 0.190 0.176 301 0.0179 0.0155 0.0421 302 0.0058 0.0035 0.0169 303 0.0039 0.0071 0.335* 304 0.0090 0.0218 0.0323 305 0.327 0.0257 0.110 306 0.0822 0.0639 0.0516 307 0.0024 0.0029 0.122 TR-FRET Binding T Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 308 0.0499 0.0065 0.0293 309 0.0306 0.0169 0.0859 310 0.0409 0.0711 0.103 311 0.0148 0.0045 0.0224 312 0.0141 0.0190 0.0675 313 0.0158 0.0061 0.0509 314 1.6 1.29 NA 315 0.0376 0.231 0.160 316 > 2.4 3.07 NA 317 0.0067 0.0036 0.0168 318 0.346 0.625 > 3.0 319 0.372 0.0099 0.435 320 0.0030 0.0037 0.0187 321 0.0334 0.0321 0.0344 322 0.181 0.0456 0.0668 323 0.0231 0.0255 0.0377 324 0.0032 0.0012 NA 325 0.155 0.199 0.703 326 0.145 0.272 0.286 327 0.0085 0.0042 0.0354 328 0.0245 0.0797 0.0426 329 0.0089 0.0126 0.0171 330 0.0509 0.0046 0.0306 331 0.561 0.311 0.481 332 0.0304 0.0306 0.0531 333 0.0369 0.0327 0.0740 334 0.661 1.17 0.515 335 0.0111 0.0536 0.0224 TR-FRET Binding TR-FRET Binding Cellular Compound Ki: BRD4 Ki: BRD4 proliferation: EC50 of Ex. No. (BDI_K57-E168) (BDII_E352-M457) (µM) (µM) (µM) 336 0.0762 0.152 0.115 337 0.0043 0.0042 0.0158 338 0.00086 0.0127 0.0779 339 0.00080 0.0316 0.0774 340 0.942 1.25 NA 341 0.295 0.0817 0.622 342 0.0719 0.0115 0.510 343 0.0427 0.0048 0.224 344 0.430 0.136 0.636 345 0.129 0.0326 0.479 346 0.0962 0.0160 0.213 347 0.0156 0.0040 0.0839 348 0.157 0.422 1.0 349 0.0066 0.0031 0.0321 350 1.4 0.505 NA 351 0.223 0.153 1.1 352 0.404 0.625 NA 353 0.158 0.256 0.786 354 0.066 0.0129 0.0954 * indicates average value of multiple experiments NA means not determined Table 2 Compound of Example of Example 4 Cellular ar Cell line Type Cell Line Proliferation Proliferation EC50 (µM) EC50 (µM) AML SKM1 0.005 0.058 AML Raji 0.006 0.084 Bladder EJ-1 0.202 2.090 Breast MDAMB231 0.22 1.22 Breast MDAMB453 0.02 0.24 Colon GEO 0.08 1.29 Colon DLD-1 0.20 4.97 Glioblastoma D54MG 0.038 2.299 Head & Neck FaDu 0.02 0.39 Hepatocellular HepG2 0.074565 0.8851 Melanoma A-375 0.020 3.606 Multiple OPM2 0.001 0.039 Myeloma Multiple RPMI-8226 0.011 1.402 Myeloma Multiple NCI-H929 0.003 0.154 Myeloma NHL Ramos 0.02 0.32 NHL Ly18 0.02 0.42 NSCLC H1299 0.06 2.57 NSCLC H1975 0.02 1.37 NSCLC H460 3.77 >10 Pancreas HPAC 0.05 1.19 Pancreas BxPC3FP5 0.01 0.74 Prostate PC3M 0.07 8.11 RCC 786-0 0.011 0.884 Sarcoma -1 0.025 0.934 Human, rat, and mouse microsome stability assay Microsome stability assays were carried out on nds of the Examples listed in Table 3 (“test compounds”). Human, rat, and mouse liver microsomal incubations were carried out at 37 °C with a final tion volume of 135 µL. Human liver microsomes (mixed gender, Catalog No. H2610) were obtained from XenoTech. Rat liver microsomes (male Sprague-Dawley, Catalog No. 42501) were obtained from BD Gentest. Mouse liver microsomes (male CD1, Catalog No. 452701) were ed from BD Gentest. Incubations were conducted using a test compound (initially dissolved in DMSO at 5 µM concentration) concentration of 0.5 µM and 0.25 mg/mL microsomal protein in 50 mM phosphate buffer at pH 7.4. Time zero samples were prepared by transferring 13.5 µL of nd-microsomal mix to the quench plates containing 45 µL of quench solution made of 10 nM Buspirone ) or 50nM Carbutamide (Princeton Bio) as internal standard in 1:1 methanol:acetonitrile. An aliquot of 1.5 µL Nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt (NADPH) was also added to the time zero plates. The reaction was then initiated by the addition of 13.5 µL NADPH to the compound-microsomal mix. At each of the remaining time points (5, 10, 15, 20 and 30 min) 15 µL of incubation mixture was added to 45 µL of quench solution. Samples were centrifuged for 15-30 minutes at 3800 rpm. Samples were then pooled for 6 per group. An aliquot of 60 µL of supernatant was transferred to 384-well plate, and a 5 µL aliquot was injected and analyzed by LCMS /MS ed tems API 5500 . The intrinsic clearance of a compound was calculated by converting the peak area ratios (analyte peak area/IS peak area) to % parent remaining using the area ratio at time 0 as 100%. The slope (k) was determined from the plot of the % parent remaining versus incubation time, from which the half life (t1/2; minutes), intrinsic clearance (CLint; µL/min/mg protein for liver microsomes and µL/min/million cells for hepatocytes) and scaled intrinsic clearance (scaled CLint; L/h/kg) were then derived. The t1/2 values are reported in Table 3. The term “N/A” means not determined.
Table 3 ity in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in minutes) (t1/2 in minutes) 1 9 1 1 4 59 4 57 100 6 24 6 30 7 3 7 12 2 4 8 19 1 9 9 NA 1 1 Stability in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in s) (t1/2 in minutes) (t1/2 in minutes) 78 >120 >120 11 48 19 27 12 51 10 33 13 66 2 22 14 37 6 8 10 4 7 16 >120 4 22 17 31 18 16 18 31 11 15 19 92 13 33 18 1 7 21 >120 3 22 22 32 3 10.7 23 64 11 >120 24 29 5 55 27 32 >120 59 28 21 9 NA 29 >120 26 >120 31 56 >120 19 32 24 82 32 33 >120 >120 46 34 37 42 35 37 >120 42 36 >120 >120 41 37 88.9 54 3 38 16.8 25 NA 39 09.7 8 NA 40 13.1 1 6 41 13.6 1 10 Stability in human Stability in rat liver Stability in mouse Compound liver microsomes omes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in minutes) (t1/2 in minutes) 42 >120 >120 >120 43 34.9 2 5 44 33.7 6 27 45 NA 2 3 46 10 4 13 47 8 3 5 48 37 32 35 49 71 51 46 50 35 88 46 51 6 63 >120 54 3 30 2 55 25 9 13 56 39 30 36 57 13 6 5 58 >120 1 4 59 >120 40 23 60 68 64 34 61 >120 >120 >120 62 64 45 25 63 39 13 18 64 NA 3 4 65 88 >120 11 66 >120 >120 NA 67 6 5 6 69 6 2 3 70 41 9 68 71 2 1 6 72 34 1 70 73 36 2 31 ity in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in minutes) (t1/2 in minutes) 74 17 3 5 75 9 3 4 80 62 2 31 82 19 2 2 83 NA 3 43 84 112 92 >120 85 43 6 34 86 >120 >120 43 87 >120 23 NA 88 23 12 NA 91 17 7 7 92 97 20 11 93 54 102 25 94 47 28 25 95 >120 7 36 96 24 13 33 97 26 9 28 98 26 33 10 99 >120 22 35 100 77 71 60 101 92 12 20 102 36 3 8 103 47 16 37 104 27 8 7 105 >120 13 7 106 39 8 4 107 71 16 8 108 37 33 13 109 71 61 >120 ity in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in minutes) (t1/2 in minutes) 111 >120 42 63 112 49 28 51 114 13 5 8 115 41 38 55 117 34 36 1 118 81 34 18 119 14 24 2 >120 19 12 10 121 21 25 24 122 8 16 2 123 >120 >120 45 124 2 4 NA 125 45 23 12 126 100 21 25 127 44 71 20 128 11 21 4 129 54 38 12 131 >120 71 83 133 4 5 3 134 15 21 2 135 8 24 5 137 38 31 10 138 52 51 45 139 13 8 7 140 19 13 18 141 >120 110 49 142 112 35 32 144 18 19 17 145 >120 12 16 Stability in human ity in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in minutes) (t1/2 in minutes) 146 >120 52 55 147 11 8 32 148 58 2 6 152 51 10 22 153 33 8 11 154 42 66 18 155 >120 >120 25 156 >120 >120 33 157 27 53 12 158 >120 >120 >120 159 89 107 59 160 67 119 21 161 5 10 4 162 96 41 11 165 >120 111 27 166 85 23 22 168 66 82 25 169 86 34 38 170 >120 113 27 171 15 13 9 172 9 15 7 173 38 5 16 174 40 46 14 176 48 8 29 177 16 6 18 178 27 7 10 179 80 55 34 180 12 7 5 186 9 3 8 Stability in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in s) (t1/2 in minutes) (t1/2 in minutes) 187 9 4 5 188 26 22 6 189 34 55 NA 190 27 66 8 191 7 6 2 192 9 5 3 193 11 7 2 194 41 38 49 195 13 1 1 196 59 5 3 197 16 15 10 198 NA NA 55 199 94 1 3 200 >120 31 >120 201 56 117 >120 202 NA >120 NA 203 NA >120 NA 204 >120 81 68 205 >120 81 118 206 >120 118 95 207 102 78 100 208 88 23 37 209 >120 105 116 210 104 >120 >120 211 65 48 63 212 69 67 53 213 79 38 89 214 27 9 8 215 12 6 11 Stability in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in s) (t1/2 in minutes) 217 70 101 68 218 >120 >120 >120 220 5 5 4 221 63 24 43 222 65 80 98 223 54 24 48 224 6 8 5 225 52 59 >120 226 105 >120 >120 227 50 70 >120 228 >120 107 >120 229 25 33 9 230 6 8 7 231 33 >120 72 232 57 >120 >120 235 81 49 22 236 33 32 15 237 3 7 2 238 103 >120 63 240 >120 >120 47 241 39 9 4 242 >120 86 >120 243 >120 20 109 244 53 6 87 245 32 24 12 246 52 53 56 248 13 16 5 249 >120 >120 >120 250 56 36 37 Stability in human ity in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in minutes) (t1/2 in minutes) 251 118 23 44 252 68 >120 >120 253 72 110 90 254 74 >120 91 255 70 >120 >120 256 58 58 71 257 18 56 20.3 258 42 91 69.8 259 117 87 NA 260 34 58 29 261 25 5 16 262 >120 25 NA 263 70 72 NA 264 14 6 NA 265 >120 >120 NA 266 8 20 NA 267 95 18 >120 268 10 26 NA 269 79 83 58 270 >120 >120 >120 271 23 12 11 272 2 4 1 273 9 12 8 276 >120 82 71 277 4 5 1 278 >120 >120 >120 279 NA 41 91 280 17 84 36 281 25 119 116 Stability in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in s) (t1/2 in minutes) (t1/2 in minutes) 282 9 21 7 283 7 22 12 284 12 108 >120 285 19 10 12 286 10 19 11 287 >120 116 29 288 85 >120 >120 290 73 48 52 291 16 8 16 292 8 22 12 293 4 9 3 294 >120 >120 >120 295 7 15 3 296 7 13 6 297 83 43 NA 298 9 47 3 299 1 2 1 300 30 21 17 301 20 82 13 302 5 4 3 303 42 69 >120 304 >120 65 72 305 1 2 2 306 11 9 3 307 3 3 2 308 20 10 16 309 >120 >120 >120 310 8 5 9 311 >120 83 >120 ity in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in minutes) (t1/2 in minutes) 312 56 32 9 313 5 4 3 314 81 4 6 315 34 4 11 316 47 3 12 317 88 115 83 318 35 24 13 319 2 2 2 320 >120 57 116 321 >120 103 >120 322 >120 57 >120 323 >120 >120 >120 324 >120 >120 >120 325 21 10 8 326 112 5 27 327 >120 >120 >120 328 >120 36 >120 329 >120 >120 >120 330 29.9 12 28 331 >120 >120 >120 332 65 70 >120 333 0.8 3 1 334 34 NA 21 335 35 34 54 336 44 5 17 337 >120 >120 >120 338 39 29 20 339 100 76 67 340 >120 4 9 Stability in human Stability in rat liver Stability in mouse Compound liver microsomes microsomes liver microsomes of Ex. No. (t1/2 in minutes) (t1/2 in minutes) (t1/2 in minutes) 342 2 5 1 343 2 7 1 344 NA NA 1 345 2 4 2 346 4 5 2 347 4 6 NA 348 >120 2 25 349 >120 39 36 350 59 32 23 351 76 66 30 353 40 8 10 354 23 41 24 LPS (lipopolysaccharide) induced IL-6 production mouse assay Compounds of the es listed in Table 4 were assayed for their ability to inhibit LPS (lipopolysaccharide) induced IL-6 tion in mice. Fox Chase SCID® female mice es Rivers Labs, 8 per group) received an intraperitoneal nge of lipopolysaccharide (2.5 mg/kg, L2630 E.coli 0111:B4) one hour after oral administration of compounds. Mice were euthanized 2 hours after lipopolysaccharide injection, blood was removed by cardiac puncture, and then the serum ted from the blood samples was frozen at -80 °C. On the day of the assay the serum samples were brought to room temperature and then diluted 1:20 in phosphate-buffered saline containing 2 % bovine serum albumin. Interleukin-6 measurements were performed using a cytokine assay from Meso Scale ery (Gaithersburg, Maryland) for mouse serum is according to the manufacturer’s protocol and read on a SECTOR Imager 6000 (Meso Scale Discovery, Gaithersburg, Maryland) instrument. Statistical analysis was performed using Prism software (version 5.0) incorporating Dunnett’s one way ANOVA. The IL-6 mean and standard deviation of the group of vehicle treated animals were compared with the IL-6 mean and standard deviation of the group treated with test compound. A p value < 0.05 means that there is less than a 5% ility that the mean values in the two groups are equal. The % inhibition values in Table 4 all exhibited a p value less than 0.05.
Table 4 Inhibition of LPS induced IL-6 production in Mice Example # % inhibition at 3 mg/kg 4 69* 74% at 50 mg/kg 11 34 24 58 26 60 27 89 28 52 32 69 34 78 36 78* 48 62 49 57 56 28 59 54 62 67 65 63 80 69% at 30 mg/kg 84 69 85 80 86 55 87 57 138 72 144 48 146 80 147 61 149 69 150 54 e # % inhibition at 3 mg/kg 151 66 154 73 159 58 160 51 162 41 166 44 167 64 168 70 169 67 197 59 198 66 200 75 202 68 203 78 204 35 205 48 207 62 210 78 212 47 231 51 238 69 240 62 242 46 245 71 246 71 248 82 249 59 260 66 267 74 273 47 276 25 Example # % inhibition at 3 mg/kg 278 51 286 57 287 73 288 60 290 64 294 79 304 67 308 48 311 74 321 63 328 40 329 63 330 45 * indicates average value of multiple experiments Xenograft tumor growth inhibition assay The effect of the compound of Example 36 to inhibit the growth of OPM-2 and MX-1 xenograft tumors implanted in mice was evaluated. Briefly, 5 x106 human cancer cells (OPM-2) or 1:10 tumor brie (MX-1) (in S-MEM (MEM, Suspension, no Calcium, no Glutamine))(Life Technologies Corporation) was inoculated subcutaneously into the right hind flank of female SCID-beige or female Fox Chase SCID® (Charles River Labs) mice respectively on study day 0. stration of compound (in (2% EtOH, 5% Tween-80, % PEG-400, 73% (PO, QDx14) was ted at the time of size match on day 17 (OPM-2) or day 12 (MX-1). The tumors were measured by a pair of calipers twice a week starting at the time of size match and tumor volumes were calculated according to the formula V = L×W2/2 (V: volume, mm3; L: length, mm. W: width, mm). Tumor volume was ed for the duration of the ment until the mean tumor volume in each group reached an endpoint of >1000 mm3 for OPM-2 or until day 27 post inoculation for MX-1.
Results are shown in Tables 5 and 6.
Table 5. OPM-2 human multiple myeloma cancer xenograft model.
Group ent Dose route, regimen % TGI a % TGD b 1 Vehicle 0 mg/kg/day IP, QDx14 --- --- Compound of 2 3 mg/kg/day PO, QDx14 90*** 78*** Example 36 a. Tumor growth inhibition, %TGI = 100 - mean tumor volume of ent group / mean tumor volume of control group x 100. Number of mice per treatment group = 10.
The p values (as indicated by asterisks) are derived from Student's T test ison of treatment group vs. control group. Based on day 31. 5, ** p<0.01, *** p<0.001. b. Tumor growth delay, %TGD = (T – C) / C x 100, where T = median time to endpoint of ent group and C = median time to endpoint of control group. The p values (as indicated by asterisks) derived from Kaplan Meier log-rank comparison of treatment group vs. treatment control group. Based on an endpoint of 1000 mm3. *p<0.05, ** p<0.01, *** p<0.001.
Table 6. Efficacy of BET inhibitor in the MX-1 human breast cancer xenograft model.
Group Treatment Dose route, regimen %TGIa 1 Vehicle 0 mg/kg/day PO, QDx14 --- Compound of 2 0.3 mg/kg/day PO, QDx14 43** Example 36 nd of 3 1 mg/kg/day PO, QDx14 60*** e 36 Compound of 4 3 mg/kg/day PO, QDx14 76*** Example 36 a. Tumor growth inhibition, %TGI = 100 - mean tumor volume of treatment group/ tumor volume of control group x 100. p values (as indicated by asterisks) are derived from Student's T test comparison of treatment group vs. control group. Based on day 27. *p<0.05, ** p<0.01, *** p<0.001.
Xenograft efficacy studies were conducted with onal example compounds using OPM-2, MX-1, HT1080, MV4-11, SKM1 and Ramos human cancer cells. Cancer cells were prepared from culture or from tumor brie (MX-1) as described above and inoculated subcutaneously into the right hind flank of female SCID-beige mice (OPM-2, HT1080, MV4- 11) or female Fox Chase SCID® (Charles River Labs) mice (MX-1, SKM1, Ramos).
Administration of compound was initiated at the time of size match. Tumors were measured by a pair of calipers twice a week starting at the time of size match and tumor volumes were calculated according to the formula V = L×W2/2 (V: volume, mm3; L: length, mm. W: width, mm). T umor volume was measured for the duration of the experiment until the mean tumor volume in each group reached a model-dependent endpoint of 500-2000 mm3. Results are shown in Table 7.
Table 7. Efficacy of BET inhibitors in human xenograft models. dose route, nd vehicl %TG %TG remove model mg/kg/d regime of Ex. No. ea Ib Dc d from ay n study PO,BI D (5 73** 4 MX-1 12.5 F 70*** 10 on, 3 * off)x2 BID (5 77** 4 MX-1 25 F 81*** 30 on, 3 * off)x2 4 Ramos 3.125 (5d F 19 27* 0 on,3d off)x2 4 Ramos 6.25 (5d F 24* 28* 0 on,3d off)x2 27 MX-1 0.3 PO, QD F 38** 35 0 57** 27 MX-1 1 PO, QD F 13 0 dose route, Compound vehicl %TG %TG remove model d regime of Ex. No. ea Ib Dc d from ay n study PO, QD (5 on, 3 69** 27 MX-1 3 F ND 0 off, 5 * 27 OPM-2 1 A 59 -2 0 QDx14 PO, QD (5 on, 3 27 OPM-2 3 A 67 7* 0 off, 5 HT108 PO, 36 0.3 H 26 -1 30 0 QDx14 HT108 PO, 36 1 H 41* 3 10 0 QDx14 HT108 PO, 36 3 H 47** 46*** 10 0 QDx14 MV4- PO, 36 0.2 D 22* 16*** 0 11 QDx21 MV4- PO, 57** 36 0.67 D 59*** 0 11 QDx21 * MV4- PO, 81** 36 2 D 94* 0 11 QDx21 * MV4- IP, BID 47** cytarabine 250 C 37*** 0 11 Q7Dx3 * PO/IP, 36/ MV4- QDx21/ 64** 0.67/250 E 53*** 0 cytarabine 11 BID * Q7Dx3 dose route, Compound vehicl %TG %TG remove model d regime of Ex. No. ea Ib Dc d from ay n study PO/IP, 36/ MV4- QDx21/ 90** 102** 2/250 E 0 cytarabine 11 BID * * Q7Dx3 36 MX-1 0.3 PO, QD F 43** 40 0 60** 36 MX-1 1 PO, QD F ND 0 76** 36 MX-1 3 PO, QD F ND 0 36 OPM-2 0.25 A 19 29 0 QDx21 36 OPM-2 0.25 F 45 55* 0 QDx21 PO, 75** 101** 36 OPM-2 0.5 A 0 QDx21 * * 36 OPM-2 0.5 F 49* 52** 0 QDx21 PO, 75** 107** 36 OPM-2 1 A 10 QDx21 * * 36 OPM-2 1 A 72** 64* 10 QDx21 PO, 79** 140** 36 OPM-2 1 A 0 QDx21 * * PO, 74** 140** 36 OPM-2 1 A 10 BIDx21 * * 36 OPM-2 1 A 70** 85** 0 QDx21 36 OPM-2 1 C 69** 66** 0 Q4Dx3 dose route, nd vehicl %TG %TG remove model mg/kg/d regime of Ex. No. ea Ib Dc d from ay n study 36 OPM-2 1 F 61* 80*** 0 Q4DX3 IV, 112** 36 OPM-2 1 C 80** 0 Q4Dx3 * 36 OPM-2 2 A 60 QDx21 PO, 90** 36 OPM-2 3 A 21*** 10 QDx14 * PO, 88** 131** 36 OPM-2 3 A 30 QDx21 * * 36 OPM-2 3 BIDx21 A 70 36 OPM-2 3 F 40 QDx21 36 OPM-2 3 F 70 QDx21 QD(5 36 OPM-2 4.2 A 50 on 2 off)x3 QD(4 36 OPM-2 5.25 A 40 on 3 off)x3 36 OPM-2 6 Q2D A 82* 84** 20 x21d dose route, Compound vehicl %TG %TG remove model mg/kg/d regime of Ex. No. ea Ib Dc d from ay n study 36 OPM-2 6 F 100 QDx21 QD(3 81** 36 OPM-2 7 A 97*** 0 on 4 * off)x3 BID (3 36 OPM-2 7 A 90 on 4 off)x3 QD(2 75** 36 OPM-2 10.5 A 94*** 0 on 5 * off)x3 Bortezomib OPM-2 1 B 80** 93*** 10 Q4Dx3 IP/IV, 36/ 195** OPM-2 0.25/1 QDx21/ B 94** 20 omib * Q4Dx3 IP/IV, OPM-2 0.5/1 QDx21/ B 40 Bortezomib Q4Dx3 PO/IV, OPM-2 1/1 QDx21/ B 100 Bortezomib Q4Dx3 IP/IV, OPM-2 1/1 QDx21/ G 40 Bortezomib Q4Dx3 dose route, Compound vehicl %TG %TG remove model mg/kg/d regime of Ex. No. ea Ib Dc d from ay n study 36 SKM1 0.2 A 41* 93 0 QDx21 PO, 444** 36 SKM1 0.67 A 58* 0 QDx21 * PO, 721** 36 SKM1 2 A 86** 0 QDx21 * azacitidine SKM1 6 C 54** 98* 0 Q7Dx3 PO/IV, 36/ 649** SKM1 0.67/6 QDx21/ B 86** 10 azacitidine * Q7Dx3 PO/IV, 36/ 958** SKM1 2/6 QDx21/ B 91** 10 azacitidine * Q7Dx3 IP, BID cytarabine SKM1 250 C 20 30 0 Q7Dx3 PO/IP, 36/ QDx21/ 514** SKM1 0.67/250 B 69** 0 bine BID * Q7Dx3 PO/IP, 36/ QDx21/ 739** SKM1 2/250 B 87** 0 cytarabine BID * Q7Dx3 146 OPM-2 1 A 39 35 10 QDx21 146 OPM-2 3 A 76* 78** 0 QDx21 dose route, Compound vehicl %TG %TG remove model mg/kg/d regime of Ex. No. ea Ib Dc d from ay n study 158 OPM-2 6 A 53 34 10 QDx21 158 OPM-2 20 A 78* 72** 30 QDx21 169 OPM-2 3 A 69* 77* 10 QDx21 169 OPM-2 10 A 100 QDx21 200 OPM-2 1 A 50 44 10 QDx21 200 OPM-2 3 A 80** 82** 20 QDx21 250 OPM-2 3 A 42** 29 0 QDx21 250 OPM-2 10 A 40 QDx21 287 OPM-2 10 A 50 QDx21 287 OPM-2 20 A 70 QDx21 311 OPM-2 1.25 A 60* 90* 0 QDx21 311 OPM-2 2.5 A 56 QDx21 a. Compounds were formulated in the ing vehicles: A: 10% EtOH, 30% PEG 400, 60% Phosol 53 MCT (Lipoid AG) B: 10% EtOH, 30% PEG 400, 60% Phosol 53 MCT (Lipoid AG)/ 0.9% Saline C: 0.9% Saline D: 10% EtOH, 27.5% PEG 400, 60% Phosol 53 MCT (Lipoid AG) E: 10% EtOH, 27.5% PEG 400, 60% Phosol 53 MCT (Lipoid AG)/ 0.9% Saline F: 2% EtOH, 5% Tween-80, 20% PEG400, 73% 0.2% HPMC G: 2% 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 treatment group / mean tumor volume of control group x 100. Number of mice per treatment group = 8 (MX-1, MV4-11, SKM1) or 10 (OPM-2). The p values (as indicated by sks) are derived from Student's T test comparison of treatment group vs. control group. Based on day 31. *p<0.05, ** p<0.01, *** p<0.001. %TGI values are not presented if ity ≥40%. c. Tumor growth delay, %TGD = (T – C) / C x 100, where T = median time to endpoint of treatment group and C = median time to endpoint of control group. The p values (as indicated by asterisks) derived from Kaplan Meier log-rank comparison of treatment group vs. treatment control group. *p<0.05, ** p<0.01, *** p<0.001. %TGD values are not presented if mortality ≥40%.
ND = Not ined In vivo rat collagen induced arthritis model Compound of e 36 inhibits paw swelling in a rat en induced arthritis (rCIA) model of inflammation. On day 0 of the rCIA model female Lewis rats (n=9/group) were immunized intradermally (id) with 600 µg of bovine type II collagen in an emulsion with incomplete ’s adjuvant (IFA). Immunization was given over three sites ing a 100 µL intradermal injection at each site. On day 6 rats were boosted with 600 µg of bovine type II collagen in a manner identical to the initial immunization protocol. A control group of rats received the same volume of IFA alone, also on day 0 and day 6. Using a plethysmograph water displacement system paw volume was measured on day 7 (baseline measurement) and on days 10, 12, 14 and 17. Dose groups included IFA immunized nonarthritic rats, PBS e treated, prednisolone treated (3 mg/kg positive control), compound vehicle d (10% EtOH/ 30% PEG400/ 60% Phosal 53) and Example 36 dosed orally at 1.0, 0.3, 0.1, and 0.03 mg/kg. Dosing began on day 10 and animals were treated once daily through day 17 via oral dosing with a 1.0 mL volume. Paw swelling is reported as change in paw volume from baseline and area under the curve (AUC) was calculated for the paw swelling in each dose group. Example 36 inhibited inflammation in the arthritic paw in a dose dependent manner with an ED50 of 0.21 mg/kg and an ED80 of 0.69 mg/kg ponding to maximum plasma trations of 6.8 ng/mL and 22.3 ng/mL at the ED50 and ED80, respectively.
Table 8 AUC of Paw Swelling (mlday Treatment group MEAN SEM IFA immunized (non- 0.13** 0.06 arthritic) PBS Vehicle 4.33 0.49 Compound vehicle 4.90 0.32 Example 36 dosed at 1.0 0.70** 0.16 mg/kg Example 36 dosed at 0.3 1.84** 0.23 mg/kg Example 36 dosed at 3.66* 0.21 0.1mg/kg Example 36 dosed at 4.19 0.34 0.03 mg/kg Prednisolone dosed at 0.67** 0.20 3mg/kg One way Anova (vs. compound vehicle) *p<0.05 **p<0.001 It is understood that the foregoing ed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their lents. Various changes and modifications to the disclosed embodiments will be apparent to those d in the art. Such changes and modifications, including t limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
Cross-reference to Related ations This ation is a divisional of New Zealand Patent Application No. 626090 (national phase of ), claiming priority to , the entire contents of each of which are hereby incorporated by reference in their entirety for all purposes.
WE

Claims (70)

CLAIM :
1. A nd of formula (I) or a pharmaceutically acceptable salt thereof Ry N G1 A1 A4 A2 wherein Rx is hydrogen or C1-C3 alkyl; Ry is C1-C3 alkyl, -(C2-C3 alkylenyl)-OH, or C1-C3 haloalkyl; X1 is N or CRx1 wherein Rx1 is hydrogen, C2-C6 alkenyl, C2-C6 l, -C(O)ORax1, Rbx1Rcx1, -C(O)Rdx1, S(O)2Rdx1, -S(O)2NRbx1Rcx1, Gx1, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax1, SRax1, S(O)Rdx1, S(O)2Rdx1, NRbx1Rcx1, -C(O)Rax1, -C(O)ORax1, -C(O)NRbx1Rcx1, -S(O)2NRbx1Rcx1, and Gx1; Rax1, Rbx1, and Rcx1, at each occurrence, are each ndently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga; Rdx1, at each occurrence, are each independently C1-C6 alkyl, C1-C6 haloalkyl, Ga, or -(C1-C6 alkylenyl)-Ga; X2 is N or CRx2; wherein Rx2 is en, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)ORax2, -C(O)NRbx2Rcx2, -C(O)Rdx2, -C(O)H, S(O)2Rdx2, -S(O)2NRbx2Rcx2, Gx2, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of ORax2, SRax2, S(O)Rdx2, S(O)2Rdx2, cx2, -C(O)Rax2, -C(O)ORax2, -C(O)NRbx2Rcx2, -S(O)2NRbx2Rcx2, and Gx2; Rax2, Rbx2, and Rcx2, at each ence, are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb; AH26(14386215_1):RTK Rdx2, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb; Y1 is N or CRu; wherein Ru is hydrogen, C1-C6 alkyl, halogen, or C1-C6 haloalkyl; A1 is N or CR1, A2 is N or CR2, A3 is N or CR3; and A4 is N or CR4; with the o that zero, one, two, or three of A1, A2, A3, and A4 are N; R1, R3, and R4 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, or NO2; R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, NO2, G2a, -OR2a, -OC(O)R2d, NR2bR2c, -SR2a, -S(O)2R2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)C(O)O(R2d), -N(R2e)C(O)NR2bR2c, -N(R2e)S(O)2NR2bR2c, –(C1-C6 alkylenyl)-G2a, –(C1-C6 alkylenyl)-OR2a, -(C1-C6 alkylenyl)-OC(O)R2d, –(C1-C6 alkylenyl)-OC(O)NR2bR2c, -(C1-C6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, 6 nyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, -(C1-C6 alkylenyl)-N(R2e)S(O)2R2d, 6 alkylenyl)-N(R2e)C(O)O(R2a), –(C1-C6 alkylenyl)-N(R2e)C(O)NR2bR2c, –(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c, and –(C1-C6 alkylenyl)-CN; R2a, R2b, R2c, and R2e, at each occurrence, are each independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally tuted with one substituent selected from the group consisting of –ORz1, NRz1Rz2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b; R2d, at each occurrence, is independently C2-C6 alkenyl, C2-C6 l, C1-C6 haloalkyl, G2b, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of -ORz1, 2, -C(O)ORz1, -C(O)NRz1Rz2, -S(O)2Rz1, -S(O)2NRz1Rz2, and G2b; Rz1 and Rz2, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Gx1, Gx2, Ga, Gb, G2a, and G2b, at each occurrence, are each ndently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each of which is independently tituted or substituted with 1, 2, 3, 4, or 5 of Rv; AH26(14386215_1):RTK L1 is absent, CH2, C(O), H), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or (CH2)mN(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or unsubstituted cyclopropyl; m is 0 or 1; G1 is C1-C6 alkyl, alkyl, G1a or -(C1-C6 alkylenyl)-G1a; wherein each G1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rw; Rv and Rw, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri, -OC(O)NRjRk, -SRh, -S(O)2Rh, -S(O)2NRjRk, -C(O)Rh, -C(O)-monocyclic heterocycle, -C(O)- monocyclic heteroaryl,-C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, -N(Rh)S(O)2Ri, -N(Rh)C(O)O(Ri), -N(Rh)C(O)NRjRk, –(C1-C6 nyl)-ORh, – (C1-C6 alkylenyl)-OC(O)Ri, 6 alkylenyl)-OC(O)NRjRk, –(C1-C6 alkylenyl)-S(O)2Rh, –(C1-C6 alkylenyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)-C(O)Rh, 6 alkylenyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, –(C1-C6 alkylenyl)-NRjRk, –(C1-C6 nyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, –(C1-C6 alkylenyl)-N(Rh)C(O)O(Ri), –(C1-C6 alkylenyl)-N(Rh)C(O)NRjRk, or –(C1-C6 alkylenyl)-CN; Rh, Rj, Rk, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and Ri, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl.
2. The nd of claim 1 or a pharmaceutically acceptable salt thereof wherein X2 is N or CRx2; wherein Rx2 is hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, Rax2, -C(O)NRbx2Rcx2, -C(O)Rdx2, S(O)2Rdx2, -S(O)2NRbx2Rcx2, Gx2, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally tuted with one substituent selected from the group consisting of ORax2, SRax2, S(O)Rdx2, S(O)2Rdx2, NRbx2Rcx2, -C(O)Rax2, -C(O)ORax2, -C(O)NRbx2Rcx2, -S(O)2NRbx2Rcx2, and Gx2; Rax2, Rbx2, and Rcx2, at each occurrence, are each independently en, C1-C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb; AH26(14386215_1):RTK Rdx2, at each occurrence, is independently C1-C6 alkyl, C1-C6 haloalkyl, Gb, or -(C1-C6 alkylenyl)-Gb; L1 is , CH2, C(O), (CH2)mO, (CH2)mS(O)n wherein n is 0, 1, or 2; or N(Rz) wherein Rz is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, (C2-C3 alkylenyl)-OH, or tituted cyclopropyl; m is 0 or 1; G1 is G1a or -(C1-C6 nyl)-G1a; wherein each G1a is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, and each G1a is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 of Rw; Rv and Rw, at each occurrence, are each ndently C1-C6 alkyl, C2-C6 l, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, -ORh, -OC(O)Ri, -OC(O)NRjRk, -SRh, -S(O)2Rh, -S(O)2NRjRk, -C(O)Rh, -C(O)ORh, -C(O)NRjRk, -NRjRk, -N(Rh)C(O)Ri, -N(Rh)S(O)2Ri, -N(Rh)C(O)O(Ri), -N(Rh)C(O)NRjRk, –(C1-C6 alkylenyl)-ORh, –(C1-C6 alkylenyl)-OC(O)Ri, -(C1-C6 alkylenyl)-OC(O)NRjRk, – (C1-C6 alkylenyl)-S(O)2Rh, –(C1-C6 nyl)-S(O)2NRjRk, -(C1-C6 alkylenyl)-C(O)Rh, –(C1-C6 alkylenyl)-C(O)ORh, -(C1-C6 alkylenyl)-C(O)NRjRk, –(C1-C6 alkylenyl)-NRjRk, –(C1-C6 alkylenyl)-N(Rh)C(O)Ri, -(C1-C6 alkylenyl)-N(Rh)S(O)2Ri, –(C1-C6 alkylenyl)-N(Rh)C(O)O(Ri), 6 alkylenyl)-N(Rh)C(O)NRjRk, or –(C1-C6 alkylenyl)-CN; Rh, Rj, Rk, at each occurrence, are each independently en, C1-C6 alkyl, or C1-C6 haloalkyl; and Ri, at each occurrence, is independently C1-C6 alkyl or C1-C6 kyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ry is C1- C3 alkyl.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ry is methyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X1 is CRx1; and X2 is CRx2.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y1 is N. AH26(14386215_1):RTK
7. The compound of claim 1 or a pharmaceutically able salt thereof, wherein Y1 is CRu.
8. The compound of claim 76 or a pharmaceutically acceptable salt thereof, wherein Ru is hydrogen or C1-C3 alkyl.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L1 is CH2, C(O), (CH2)mO, or (CH2)mN(Rz).
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L1 is (CH2)mO and G1 is G1a.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is CR1; A2 is CR2; A3 is CR3; and A4 is CR4.
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, n one of A1, A2, A3, and A4 is N.
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, n R2 is hydrogen, C1-C6 alkyl, NO2, G2a, -S(O)2R2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, -N(R2e)C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)S(O)2NR2bR2c, –(C1- C6 alkylenyl)-G2a, –(C1-C6 alkylenyl)-OR2a, -(C1-C6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, –(C1-C6 nyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, 6 alkylenyl)-N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c.
14. The compound of claim 1 or a pharmaceutically able salt thereof, wherein R2 is -S(O)2R2d, -S(O)2NR2bR2c, -C(O)R2d, -C(O)NR2bR2c, )C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)S(O)2NR2bR2c, -(C1-C6 alkylenyl)-S(O)2R2d, 6 alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, -(C1-C6 nyl)-C(O)NR2bR2c, AH26(14386215_1):RTK -(C1-C6 nyl)-N(R2e)C(O)R2d, -(C1-C6 alkylenyl)-N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c.
15. The compound of claim 1 or a pharmaceutically acceptable salt f, wherein R2 is -S(O)2R2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or -N(R2e)S(O)2NR2bR2c.
16. The compound of claim 1 or a pharmaceutically acceptable salt f, wherein Y1 is N; X1 is CRx1; and X2 is CRx2.
17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, n the compound is selected from the group consisting of: ethyl 4-(5-aminophenoxyphenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3- d]pyridazinecarboxylate; ethyl 4-[5-(ethylamino)phenoxyphenyl]methyloxo-6,7-dihydro-1H-pyrrolo[2,3- d]pyridazinecarboxylate; ethyl 4-{5-[ethyl(methylsulfonyl)amino]phenoxyphenyl}methyloxo-6,7- dihydro-1H-pyrrolo[2,3-d]pyridazinecarboxylate; 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxylic acid; yl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-d]pyridazinecarboxamide; 6-methyl-N-[2-(4-methylpiperazinyl)ethyl]{5-[(methylsulfonyl)amino] phenoxyphenyl}oxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazinecarboxamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazinyl) phenoxyphenyl]methanesulfonamide; N-ethylmethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro- 1H-pyrrolo[2,3-d]pyridazinecarboxamide; 6-methyl(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazinone; N-ethyl-N,6-dimethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7- dihydro-1H-pyrrolo[2,3-d]pyridazinecarboxamide; 4-[5-amino(2,4-difluorophenoxy)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- d]pyridazinone; AH26(14386215_1):RTK N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin- 4-yl)phenyl]methanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin- 4-yl)phenyl]ethanesulfonamide; and 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-d]pyridazinone.
18. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein Ry is methyl.
19. The nd of claim 18 or a pharmaceutically acceptable salt thereof, wherein L1 is CH2, C(O), O, or (CH2)mN(Rz).
20. The compound of claim 18, or a pharmaceutically able salt thereof, wherein L1 is (CH2)mO.
21. The compound of claim 20 or a pharmaceutically able salt thereof, wherein G1 is G1a.
22. The compound of claim 21 or a pharmaceutically acceptable salt f, wherein G1a is optionally tuted aryl.
23. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein G1a is optionally substituted phenyl.
24. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein G1a is optionally substituted cycloalkyl.
25. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein G1a is optionally substituted clic cycloalkyl.
26. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein G1a is optionally substituted heterocycle.
27. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein AH26(14386215_1):RTK G1a is optionally substituted monocyclic cycle.
28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y1 is CRu; X1 is CRx1; and X2 is CRx2.
29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 6-methyl(2-phenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl(5-nitrophenoxyphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(5-aminophenoxyphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]ethanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]acetamide; N-methyl-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; ethyl 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzoate; 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzoic acid; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(pyridin yloxy)phenyl]methanesulfonamide; 6-methyl[2-(morpholinylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin one; N-ethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzamide; ethyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxy-N- (tetrahydrofuranylmethyl)benzamide; N-cyclopentyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzamide; N-(2,2-difluoroethyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzamide; AH26(14386215_1):RTK 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxy-N-(1,3- thiazolyl)benzamide; N-(1,1-dioxidotetrahydrothiophenyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenoxybenzamide; 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxybenzamide; 4-[5-(hydroxymethyl)phenoxyphenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]ethanesulfonamide; N,N-dimethyl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]sulfuric diamide; N-[5-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenoxypyridin yl]methanesulfonamide; N-[3-fluoro(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; N-[4-(2-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[4-(4-fluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[3-chloro(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxyphenyl]methanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]methanesulfonamide; 6-methyl[2-phenoxy(1H-pyrazolylmethyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran phenyl]methanesulfonamide; N-{3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)[2- (trifluoromethyl)phenoxy]phenyl}methanesulfonamide; N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; AH26(14386215_1):RTK 2-chlorofluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide; [4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetic acid; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-3,3,3-trifluoropropanamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-2,2-dimethylpropanamide; ethyl 4-(cyclopentylamino)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzoate; 4-{5-[(1,1-dioxido-1,2-thiazolidinyl)methyl]phenoxyphenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzyl]amino}oxobutanoic acid; 4-[2-(2,4-difluorophenoxy)(1,1-dioxido-1,2-thiazolidinyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; benzyloxy)(2-hydroxyethyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; methyl [4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetate; 2-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl]- lacetamide; 2-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl]- N,N-dimethylacetamide; N-[4-(3,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]methanesulfonamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzamide; AH26(14386215_1):RTK 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-(tetrahydrofuranyl)benzamide; 4-{2-(2,4-difluorophenoxy)[(1,1-dioxidothiomorpholinyl)carbonyl]phenyl} methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-(1-methyloxopyrrolidinyl)benzamide; tert-butyl {1-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzoyl]pyrrolidinyl}carbamate; 4-[2-(2,4-difluorophenoxy)(pyrrolidinylcarbonyl)phenyl]methyl-1,6-dihydro- rolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(morpholinylcarbonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; N-[4-(cyclohexyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[4-(cyclopentyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}methanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]methanesulfonamide; 6-methyl[2-(morpholinylcarbonyl)phenyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin one; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]ethanesulfonamide; N-[4-(benzyloxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]fluoroethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N'-methylsulfuric e; 6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)phenyl]ethanesulfonamide; methyl 6-methyloxo(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine carboxylate; AH26(14386215_1):RTK methyl 1,6-dimethyloxo(2-phenoxyphenyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine- 2-carboxylate; ethyl 4-(5-aminophenoxyphenyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinecarboxylate; 6-methyl(5-(methylsulfonamido)phenoxyphenyl)oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylic acid; ethyl 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxylate; N-ethylmethyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinecarboxamide; 6-methyl{5-[(methylsulfonyl)amino]phenoxyphenyl}oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide; 4-{4-[(ethylsulfonyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy}benzamide; 6-methyl[5-(methylsulfonyl)phenoxyphenyl]-1,6-dihydro-7H-pyrrolo[2,3- dinone; 5-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)pyridinesulfonamide; N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)pyridinesulfonamide; 6-methyl(2-phenoxyphenyl)phenyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; N-{3-[2-(hydroxymethyl)methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl] phenoxyphenyl}methanesulfonamide; 4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide; 2-fluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)phenyl]ethanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydrofuran yloxy)phenyl]propanesulfonamide; N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]propanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]propanesulfonamide; AH26(14386215_1):RTK 3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) phenoxybenzenesulfonamide; 6-(cyclohexylamino)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide; 6-(cyclohexylamino)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; N-methyl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]sulfuric diamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]propanesulfonamide; 2,2,2-trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydro-2H-pyranyloxy)phenyl]ethanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)phenyl}ethanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- dinyl)phenyl}propanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}-2,2,2-trifluoroethanesulfonamide; N-{4-[(4,4-difluorocyclohexyl)oxy](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl}-N'-methylsulfuric diamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]ethanesulfonamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- 3-yloxy)phenyl]propanesulfonamide; 2,2,2-trifluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydro-2H-pyranyloxy)phenyl]ethanesulfonamide; N-methyl-N'-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydro-2H-pyranyloxy)phenyl]sulfuric diamide; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(tetrahydro-2H- pyranyloxy)phenyl]ethanesulfonamide; N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (tetrahydrofuranyloxy)pyridinesulfonamide; 5-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(phenylamino)pyridine- 3-sulfonamide; AH26(14386215_1):RTK N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (phenylamino)pyridinesulfonamide; N-[4-(4-cyanophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]fluoroethanesulfonamide; 2-fluoro-N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(2,4,6- trifluorophenoxy)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]propanesulfonamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-(pyrimidinyl)benzamide; 4-(2,4-difluorophenoxy)-N-(2,6-dimethoxypyridinyl)(6-methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)-N-(1H-indazolyl)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide; 4-[2-(2,4-difluorophenoxy){[4-(pyrrolidinylcarbonyl)piperazin yl]carbonyl}phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(2,4-difluorophenoxy)-N-[4-(dimethylamino)phenyl](6-methyloxo-6,7-dihydro- rolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-(pyridinylmethyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- 2-oxopyrrolidinyl)ethyl]benzamide; 4-(2,4-difluorophenoxy)-N-(2-hydroxymethylpropyl)(6-methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)-N-[2-(5-methoxy-1H-indolyl)ethyl](6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzamide; N-(3,4-difluorobenzyl)(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-[4-(trifluoromethoxy)benzyl]benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)benzoyl]piperazinyl}-N,N-dimethylacetamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-(pyridinylmethyl)benzamide; AH26(14386215_1):RTK 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-(pyridinylmethyl)benzamide; 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-(3,4,5-trimethoxybenzyl)benzamide; 4-(2,4-difluorophenoxy)-N-[2-(dimethylamino)ethyl](6-methyloxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinyl)benzamide; N-[2-(1,3-benzodioxolyl)ethyl](2,4-difluorophenoxy)(6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzamide; 4-(2,4-difluorophenoxy)-N-[2-(1H-indolyl)ethyl](6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)benzamide; 4-[2-(2,4-difluorophenoxy){[4-(furanylcarbonyl)piperazinyl]carbonyl}phenyl]- yl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; tert-butyl {1-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzoyl]piperidinyl}carbamate; tert-butyl 4-{[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzoyl]amino}piperidinecarboxylate; 4-[2-(2,4-difluorophenoxy){[4-(ethylsulfonyl)piperazinyl]carbonyl}phenyl] methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; 4-[2-(4-chlorobenzoyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)(pyrimidin yloxy)phenyl]ethanesulfonamide; N-{3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)[(1-methyl-1H- pyrazolyl)methoxy]phenyl}ethanesulfonamide; N-{4-[(1,3-dimethyl-1H-pyrazolyl)methoxy](6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenyl}ethanesulfonamide; N-[4-(2,2-dimethylpropoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide; N-[4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]ethanesulfonamide; AH26(14386215_1):RTK 4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide; 4-[2-(cyclohexylamino)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(3-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(4-fluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(3-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(4-chlorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; 3-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]benzonitrile; 4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]benzonitrile; 6-methyl{5-(methylsulfonyl)[3-(trifluoromethyl)phenoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(quinolinyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[2-chloro(trifluoromethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 2-fluoro(trifluoromethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 2-{4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]phenyl}acetamide; AH26(14386215_1):RTK 4-[2-(3-aminophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(tetrahydrofuranylamino)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(4,4-difluorocyclohexyl)oxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(1-methylpiperidinyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 2,1,3-benzothiadiazolyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2,5-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 3,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[(1-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(3,5-difluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; yl[2-(4-methylphenoxy)(methylsulfonyl)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2-methoxyphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl{2-[(2-methylpyridinyl)oxy](methylsulfonyl)phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[3-(dimethylamino)phenoxy](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[(1-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[(3-oxo-2,3-dihydro-1H-indenyl)oxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; AH26(14386215_1):RTK 2-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]benzonitrile; 4-[2-(3-chlorofluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(naphthalenyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2-fluoromethylphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(5-fluoromethylphenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(quinolinyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(4-chlorofluorophenoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(pyridinyloxy)phenyl]-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-[2-(2,3-dihydro-1H-indenyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[4-(propanyl)phenoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; isoquinolinyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- o[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(3,4,5-trifluorophenoxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; enzylphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(biphenylyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(1,4-dioxaspiro[4.5]decyloxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(4-oxocyclohexyl)oxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino](ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; AH26(14386215_1):RTK yl{5-(methylsulfonyl)[(tetrahydrofuranylmethyl)amino]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(cishydroxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(transhydroxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl)(tetrahydrofuranyloxy)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(3-fluorooxetanyl)methoxy](methylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide; lopropylmethoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; 6-[(cyclopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)pyridinesulfonamide; 6-[(cyclopropylmethyl)amino]-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; 4-{5-(ethylsulfonyl)[(cishydroxymethylcyclohexyl)oxy]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{5-(ethylsulfonyl)[(transhydroxymethylcyclohexyl)oxy]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclobutyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-[2-(cyclopentylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclohexyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; cyclopentyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 6-methyl[5-(methylsulfonyl)(tetrahydrofuranylmethoxy)phenyl]-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[2-(2-oxoimidazolidinyl)ethoxy]phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; AH26(14386215_1):RTK 4-[2-(2-cyclopropylethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cycloheptyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 6-methyl[2-(2-methylpropoxy)(methylsulfonyl)phenyl]-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[2-{[(2S)methylpyrrolidinyl]methoxy}(methylsulfonyl)phenyl]-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{2-[(2-methylcyclopropyl)methoxy](methylsulfonyl)phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclohexylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl{2-[2-(1-methylpyrrolidinyl)ethoxy](methylsulfonyl)phenyl}-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl){[(2R)oxopyrrolidinyl]methoxy}phenyl]-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[2-(morpholinyl)ethoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-methyl[5-(methylsulfonyl){[(2S)oxopyrrolidinyl]methoxy}phenyl]-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(1-tert-butoxypropanyl)oxy](methylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(1S,4R)-bicyclo[2.2.1]heptylmethoxy](methylsulfonyl)phenyl}methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-methyl{2-[(1-methylcyclopropyl)methoxy](methylsulfonyl)phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 6-methyl{5-(methylsulfonyl)[2-(2-oxopyrrolidinyl)ethoxy]phenyl}-1,6-dihydro- rolo[2,3-c]pyridinone; 6-methyl{2-[(4-methylcyclohexyl)oxy](methylsulfonyl)phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclobutylmethoxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]cyclopropanesulfonamide; AH26(14386215_1):RTK N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]methoxyethanesulfonamide; yl{5-(methylsulfonyl)[tricyclo[3.3.1.13,7]decyloxy]phenyl}-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[(cyclopropylmethyl)amino](6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)benzenesulfonamide; 4-[(cyclopropylmethyl)amino]-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide; (2,2-difluorocyclopropyl)methoxy](ethylsulfonyl)phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-(4-bromomethoxyphenyl)methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)pyridinesulfonamide; 4-{2-(cyclopropylmethoxy)[(trifluoromethyl)sulfonyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino][(trifluoromethyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-[(cyclopropylmethyl)amino]-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)pyridinesulfonamide; 6-(2,4-difluorophenoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; 4-[2-(cyclopropylmethoxy)methylphenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-{5-(ethylsulfonyl)[(cismethoxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)benzenesulfonamide; 4-(cyclopropylmethoxy)-N-methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide; cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinecarboxamide; AH26(14386215_1):RTK 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]-N-ethylmethyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; 2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-N-(2,2,2- trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(morpholin ylcarbonyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(4-methylpiperazin- 1-yl)carbonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyloxo-N-(1,3-thiazol yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; ethyl 4-[2-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl) (methylsulfonyl)phenoxy]piperidinecarboxylate; 4-[2-ethoxy(methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one; 4-{5-(ethylsulfonyl)[(transmethoxycyclohexyl)oxy]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino](propanylsulfonyl)phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; N-[4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide; N-[4-(cyclopropylmethoxy)methyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]methanesulfonamide; ethylsulfonyl)(tetrahydro-2H-thiopyranyloxy)phenyl]methyl-1,6-dihydro- rolo[2,3-c]pyridinone; 4-{2-[(1,1-dioxidotetrahydro-2H-thiopyranyl)oxy](ethylsulfonyl)phenyl}methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 6-(2,4-difluorophenoxy)-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; 4-[2-(cyclopropylamino)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-(5-(ethylsulfonyl)(cismethoxymethylcyclohexyloxy)phenyl)methyl-1H- pyrrolo[2,3-c]pyridin-7(6H)-one; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]-N,N,6-trimethyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; AH26(14386215_1):RTK 6-methyl{5-(methylsulfonyl)[4-(methylsulfonyl)phenoxy]phenyl}-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(propanylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 6-(cyclopropylmethoxy)-N,N-diethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)pyridinesulfonamide; 4-(cyclopropylmethoxy)-N,N-dimethyl(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)benzenesulfonamide; 4-[2-(cyclopropylmethoxy)fluorophenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-[2-(2,4-difluorophenoxy)(trifluoromethyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl](hydroxymethyl)methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,3-dihydro-1H-indenyloxy)(methylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl](1-hydroxyethyl)methyl-1,6- o-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl][(dimethylamino)methyl] methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(morpholin yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(4-methylpiperazin- 1-yl)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(1,3-thiazol ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(tetrahydrofuran ylamino)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(phenylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(morpholinylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; AH26(14386215_1):RTK 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)pyridinyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl[(pyridin yloxy)methyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[5-(cyclopropylsulfonyl)(2,4-difluorophenoxy)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(propenyl)-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(methylsulfonyl)phenyl]methyl(phenoxymethyl)-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(morpholinylsulfonyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)pyridinyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl](morpholinyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin nyl]-N-[2-(dimethylamino)ethyl]ethanesulfonamide; 4-{2-(2,4-difluorophenoxy)[(ethylsulfonyl)methyl]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-(2,4-difluorophenoxy)[2-(ethylsulfonyl)propanyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(pyrrolidinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl](dimethylamino)ethanesulfonamide; ethyl 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin noxy]piperidinecarboxylate; 4-[2-(cyclopropylmethoxy)(pyrrolidinylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; (1-acetylpiperidinyl)oxy](ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; AH26(14386215_1):RTK 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenoxy]benzonitrile; 4-[2-(cyclopropylmethoxy)(2,3-dihydro-1H-indolylsulfonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-(2,4-difluorophenoxy)[(phenylsulfonyl)methyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(2,2-difluorocyclopropyl)methoxy](pyrrolidinylsulfonyl)phenyl}methyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-(cyclopropylmethoxy)[(3,3-difluoroazetidinyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[2-(2-hydroxyethyl)phenoxy](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy){[3-(dimethylamino)pyrrolidinyl]sulfonyl}phenyl] -1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]pyridinyl}methyl-1,6- o-7H-pyrrolo[2,3-c]pyridinone; tert-butyl 4-[4-(ethylsulfonyl)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin- 4-yl)phenoxy]piperidinecarboxylate; 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-phenylbenzenesulfonamide; 4-[2-(cyclopropylmethoxy)(pyrrolidinylmethyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(pyridinyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(morpholinylmethyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; ethylsulfonyl)[3-(hydroxymethyl)phenoxy]phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[2-(cyclopropylmethoxy)(1-methyl-1H-pyrazolyl)phenyl]methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; 4-[2-(2,4-difluorophenoxy)(2,3-dihydro-1H-indolylsulfonyl)phenyl]methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; N-[2-cyano(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; AH26(14386215_1):RTK tert-butyl 4-[4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate; 4-[5-(6-aminopyridinyl)(cyclopropylmethoxy)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(2,2-difluorocyclopropyl)methoxy](ethylsulfonyl)phenyl}methyloxo-N- (2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinecarboxamide; 4-{2-[(cyclopropylmethyl)amino][(methylsulfonyl)methyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone; 4-{2-[(cyclopropylmethyl)amino](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-[5-(ethylsulfonyl)(pyrrolidinyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4-[5-(ethylsulfonyl)(4-methylpiperazinyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(4-fluorophenyl)amino](methylsulfonyl)phenyl}methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-(cyclopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl)- N-(pyridinylmethyl)benzenesulfonamide; 4-[4-(cyclopropylmethoxy)-3'-fluorobiphenylyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; 4-{2-[(4-fluorophenyl)amino][(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro- 7H-pyrrolo[2,3-c]pyridinone; clopropylmethoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]acetonitrile; 2,4-difluorophenoxy)[2-(hydroxymethyl)methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl]phenyl}ethanesulfonamide; N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)carbonyl]oxo- 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)methyl]oxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide; 4-[2-(cyclopropylmethoxy)(1,2,3,6-tetrahydropyridinyl)phenyl]methyl-1,6- o-7H-pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide; AH26(14386215_1):RTK 2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-(pyridinylmethyl)ethanesulfonamide; N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-[2-(2-oxopyrrolidinyl)ethyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)phenyl]-N-(tetrahydrofuranylmethyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin nyl]-N-(3,3,3-trifluoropropyl)ethanesulfonamide; 4-(cyclopropylmethoxy)-N-(4-fluorophenyl)(6-methyloxo-6,7-dihydro-1H- o[2,3-c]pyridinyl)benzenesulfonamide; 4-[2-(cyclopropylmethoxy)(6-fluoropyridinyl)phenyl]methyl-1,6-dihydro-7H- pyrrolo[2,3-c]pyridinone; N-[4-(2,4-difluorophenoxy)(3-formylmethyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenyl]ethanesulfonamide; N-{4-(2,4-difluorophenoxy)[6-methyl(morpholinylmethyl)oxo-6,7-dihydro- 1H-pyrrolo[2,3-c]pyridinyl]phenyl}ethanesulfonamide; N-[4-(2,4-difluorophenoxy){6-methyl[(4-methylpiperazinyl)methyl]oxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl}phenyl]ethanesulfonamide; 4-{2-[(cyclopropylmethyl)amino]phenyl}methyl-1,6-dihydro-7H-pyrrolo[2,3- c]pyridinone; 4'-(cyclopropylmethoxy)-3'-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin yl)biphenylcarbonitrile; and 4-{2-(cyclopropylmethoxy)[(4-hydroxypiperidinyl)sulfonyl]phenyl}methyl-1,6- dihydro-7H-pyrrolo[2,3-c]pyridinone.
30. The compound of claim 28 or a pharmaceutically acceptable salt thereof, n Ry is methyl.
31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein L1 is CH2, C(O), (CH2)mO, or (CH2)mN(Rz).
32. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein AH26(14386215_1):RTK L1 is (CH2)mO.
33. The nd of claim 32 or a pharmaceutically acceptable salt thereof, wherein G1 is G1a.
34. The compound of claim 33 or a pharmaceutically acceptable salt f, wherein G1a is optionally tuted aryl.
35. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein G1a is optionally substituted phenyl.
36. The compound of claim 33 or a ceutically acceptable salt thereof, wherein G1a is optionally substituted cycloalkyl.
37. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein G1a is optionally substituted clic cycloalkyl.
38. The compound of claim 33 or a pharmaceutically able salt thereof, wherein G1a is optionally substituted heterocycle.
39. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein G1a is optionally substituted monocyclic heterocycle.
40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y1 is CRu; X1 is N; X2 is CRx2; and Ry is .
41. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin- 4-yl)phenyl]ethanesulfonamide; 4-{2-(2,4-difluorophenoxy)[(methylsulfonyl)methyl]phenyl}methyl-1,6-dihydro- 7H-pyrazolo[3,4-c]pyridinone; AH26(14386215_1):RTK 4-[2-(2,4-difluorophenoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrazolo[3,4-c]pyridinone; and 4-[2-(cyclopropylmethoxy)(ethylsulfonyl)phenyl]methyl-1,6-dihydro-7H- pyrazolo[3,4-c]pyridinone; 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, n A1 is CR1, A2 is CR2, A3 is CR3, and A4 is CR4; or one of A1, A2, A3, and A4 is N.
43. The nd of claim 42 or a pharmaceutically acceptable salt f, wherein R2 is hydrogen, C1-C6 alkyl, NO2, G2a, -S(O)2R2d, NR2bR2c, -C(O)R2d, -C(O)OR2a, -C(O)NR2bR2c, -NR2bR2c, )C(O)R2d, -N(R2e)S(O)2R2d, -N(R2e)S(O)2NR2bR2c, –(C1- C6 alkylenyl)-G2a, –(C1-C6 alkylenyl)-OR2a, -(C1-C6 alkylenyl)-S(O)2R2d, -(C1-C6 alkylenyl)-S(O)2NR2bR2c, -(C1-C6 alkylenyl)-C(O)R2d, –(C1-C6 alkylenyl)-C(O)OR2a, -(C1-C6 alkylenyl)-C(O)NR2bR2c, -(C1-C6 alkylenyl)-NR2bR2c, -(C1-C6 alkylenyl)-N(R2e)C(O)R2d, -(C1-C6 alkylenyl)-N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)-N(R2e)S(O)2NR2bR2c.
44. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein R2 is -S(O)2R2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or -N(R2e)S(O)2NR2bR2c.
45. The compound of claim 44 or a ceutically acceptable salt thereof, wherein Rx is hydrogen or methyl.
46. The compound of claim 44 or a ceutically acceptable salt thereof, wherein Rx is en.
47. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein Rx1 is hydrogen, -C(O)ORax1, -C(O)NRbx1Rcx1, Gx1, or C1-C6 alkyl wherein the C1-C6 alkyl is optionally substituted with ORax1.
48. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein Rx1 is hydrogen, Rax1, or -C(O)NRbx1Rcx1. AH26(14386215_1):RTK
49. The compound of claim 48 or a pharmaceutically acceptable salt f, wherein Rx2 is hydrogen.
50. The compound of claim 1 or a ceutically acceptable salt thereof, wherein Rx is hydrogen; Ry is methyl; Y1 is CRu wherein Ru is hydrogen; X1 is CRx1 wherein Rx1 is hydrogen or –C(O)NRbx1Rcx1; X2 is CRx2 wherein Rx2 is hydrogen; L1 is (CH2)mO wherein m is 0; G1 is G1a or –(C1-C6 alkylenyl)-G1a, wherein G1a is optionally substituted phenyl or ally tuted cycloalkyl; and R2 is -S(O)2R2d, -S(O)2NR2bR2c, )S(O)2R2d, or –(C1-C6 alkylenyl)-S(O)2R2d.
51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein A1 is CR1, A2 is CR2, A3 is CR3, and A4 is CR4.
52. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein A1 is CR1, A2 is CR2, A3 is CR3, and A4 is N.
53. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Rx is hydrogen; Ry is methyl; Y1 is CRu wherein Ru is hydrogen; X1 is CRx1 wherein Rx1 is en; X2 is CRx2 wherein Rx2 is hydrogen; L1 is (CH2)mN(Rz) wherein m is 0 and Rz is en; G1 is –(C1-C6 alkylenyl)-G1a, wherein G1a is optionally substituted cycloalkyl; and R2 is -S(O)2R2d, -S(O)2NR2bR2c, -N(R2e)S(O)2R2d, or –(C1-C6 alkylenyl)-S(O)2R2d.
54. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein A1 is CR1, A2 is CR2, A3 is CR3, and A4 is CR4. AH26(14386215_1):RTK
55. A pharmaceutical ition comprising a therapeutically ive amount of a compound of formula (I) according to any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
56. Use of a compound of formula (I) ing to any one of claims 1 to 54 or a pharmaceutically able salt thereof in the manufacture of a medicament for treatment of cancer in the cture of a medicament for treatment of cancer.
57. The use of claim 56 wherein the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic ia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) ia, chronic enous leukemia, colon cancer, colorectal cancer, pharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, trial cancer, endotheliosarcoma, moma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, rcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, ma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT e carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary arcinomas, papillary oma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, a, sebaceous gland carcinoma, seminoma, skin , small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat AH26(14386215_1):RTK gland carcinoma, thyroid cancer, Waldenström’s macroglobulinemia, testicular tumors, uterine cancer and Wilms’ tumor.
58. Use of a compound of formula (I) according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a disease or condition selected from the group consisting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin es, chronic obstructive pulmonary disease (COPD), s disease,dermatitis, ,giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease,), Kawasaki disease, lupus nephritis, multiple sclerosis, ditis,myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, sis, 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.
59. Use of a compound of formula (I) ing to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a disease or ion selected from the group consisting of: diabetic nephropathy, ensive nephropathy, sociated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney e and tubular interstitial nephritis.
60. Use of a compound of a (I) according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of an acute kidney e, wherein said acute kidney disease or condition is selected from the group ting of: ischemia-reperfusion induced, cardiac and major surgery induced, percutaneous coronary intervention induced, contrast agent d, sepsis induced, pneumonia induced, and drug toxicity induced.
61. Use of a compound of formula (I) according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for ent of acquired immunodeficiency syndrome (AIDS).
62. Use of a compound of formula (I) according to any one of claims 1 to 54 or a ceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a AH26(14386215_1):RTK disease or condition selected from the group consisting of: obesity, dyslipidemia, hypercholesterolemia, mer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic pathy and diabetic neuropathy.
63. Use of a compound of formula (I) according to any one of claims 1 to 54 or a pharmaceutically able salt thereof in the manufacture of a medicament for male contraception.
64. The compound of claim 1, which is N-[3-(6-methyloxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridinyl)phenoxyphenyl]methanesulfonamide, or a pharmaceutically able salt thereof.
65. The compound of claim 1, which is N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.
66. The compound of claim 1, which is N-[4-(2,4-difluorophenoxy)(6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)phenyl]ethanesulfonamide, or a pharmaceutically acceptable salt f.
67. The compound of claim 1, which is -difluorophenoxy)(6-methyloxo-6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof.
68. The compound of claim 1, which is 4-[2-(cyclopropylmethoxy) (methylsulfonyl)phenyl]methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone, or a pharmaceutically acceptable salt thereof.
69. The compound of claim 1, which is 4-{2-[(cyclopropylmethyl)amino] (ethylsulfonyl)phenyl}methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridinone, or a pharmaceutically acceptable salt thereof. AH26(14386215_1):RTK
70. A ceutical composition comprising a therapeutically effective amount of a compound according to claim 66, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. AbbVie Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(14386215_1):RTK
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CNPCT/CN2011/002224 2011-12-30
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NZ62609012 2012-12-11

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