WO2010000633A1 - Novel phenylpyrazinones as kinase inhibitors - Google Patents

Novel phenylpyrazinones as kinase inhibitors Download PDF

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Publication number
WO2010000633A1
WO2010000633A1 PCT/EP2009/057707 EP2009057707W WO2010000633A1 WO 2010000633 A1 WO2010000633 A1 WO 2010000633A1 EP 2009057707 W EP2009057707 W EP 2009057707W WO 2010000633 A1 WO2010000633 A1 WO 2010000633A1
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Prior art keywords
alkyl
halogen
lower alkyl
optionally substituted
hydroxy
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PCT/EP2009/057707
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French (fr)
Inventor
Nolan James Dewdney
Yan Lou
Eric Brian Sjogren
Michael Soth
Zachary Kevin Sweeney
Original Assignee
F. Hoffmann-La Roche Ag
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Priority to BRPI0913879A priority Critical patent/BRPI0913879A2/en
Priority to PL09772333T priority patent/PL2300459T3/en
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to DK09772333.2T priority patent/DK2300459T3/en
Priority to KR1020137016860A priority patent/KR101523451B1/en
Priority to RU2011103234/04A priority patent/RU2507202C2/en
Priority to SI200930631T priority patent/SI2300459T1/en
Priority to KR1020107029738A priority patent/KR101320763B1/en
Priority to ES09772333T priority patent/ES2420854T3/en
Priority to AU2009265813A priority patent/AU2009265813B2/en
Priority to JP2011515329A priority patent/JP5490789B2/en
Priority to CN200980125623.9A priority patent/CN102083819B/en
Priority to EP09772333.2A priority patent/EP2300459B1/en
Priority to CA2728683A priority patent/CA2728683C/en
Priority to MX2010013478A priority patent/MX2010013478A/en
Publication of WO2010000633A1 publication Critical patent/WO2010000633A1/en
Priority to IL209729A priority patent/IL209729A0/en
Priority to ZA2010/08808A priority patent/ZA201008808B/en
Priority to HRP20130698AT priority patent/HRP20130698T1/en

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Definitions

  • the present invention relates to the use of novel derivatives which inhibit Btk and are useful for the treatment of auto-immune and inflammatory diseases caused by aberrant B-cell activation.
  • novel 5-phenyl-lH-pyrazin-2-one derivatives described herein are useful for the treatment of arthritis.
  • Btk is a member of the Tec family of tyrosine kinases, and has been shown to be a critical regulator of early B-cell development and mature B-cell activation and survival (Khan etal. Immunity 1995 3:283; Ellmeier et al. J. Exp. Med. 2000 192:1611). Mutation of Btk in humans leads to the condition X-linked agammaglobulinemia (XLA) (reviewed in Rosen et al. NewEng. J. Med. 1995 333:431 and Lindvall etal. Immunol. Rev. 2005 203:200). These patients are immunocompromised and show impaired maturation of B-cells, decreased immunoglobulin and peripheral B-cell levels, diminished T-cell independent immune responses as well as attenuated calcium mobilization following BCR stimulation.
  • XLA X-linked agammaglobulinemia
  • Btk-deficient mice show marked amelioration of disease progression.
  • Btk-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459).
  • a selective Btk inhibitor has been demonstrated dose-dependent efficacy in a mouse arthritis model (Pan etal., Chem. Med Chem. 2007 2:58-61).
  • Btk is also expressed by cells other than B-cells that may be involved in disease processes.
  • Btk is expressed by mast cells and Btk-deficient bone marrow derived mast cells demonstrate impaired antigen induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280:40261). This shows Btk could be useful to treat pathological mast cells responses such as allergy and asthma.
  • monocytes from XLA patients, in which Btk activity is absent show decreased TNF alpha production following stimulation (Horwood et al. J Exp Med 197:1603, 2003). Therefore TNF alpha mediated inflammation could be modulated by small molecular Btk inhibitors.
  • Btk has been reported to play a role in apoptosis (Islam and
  • Btk inhibitors would be useful for the treatment of certain B-cell lymphomas and leukemias (Feldhahn etal. J. Exp. Med. 2005 201 :1837).
  • the present invention provides 5-phenyl-lH-pyrazin-2-one derivatives of Formulae I-V
  • R is H, -R 1 , -R ! -R 2 -R 3 , -R ! -R 3 , or-R 2 -R 3 ;
  • each R 2' is independently H, lower alkyl, lower alkoxy, lower haloalkyl, or lower hydroxyalkyl; and q is 1, 2, or 3;
  • R 3 is H or R 4 ; wherein R 4 is lower alkyl, lower heteroalkyl, lower alkoxy, amino, aryl arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydro xyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
  • Q is CH 2 , CH(Y ) or NH; wherein Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy,
  • Y 2 is Y 2a or Y 2b ; wherein Y 2a is H or halogen; Y 2b is lower alkyl, optionally substituted with one or more Y 2b ; wherein Y 2b is hydroxy, lower alkoxy, or halogen; each Y 2 is independently Y 2 a or Y 2 b ; wherein Y 2 a is halogen; Y 2 b is lower alkyl, optionally substituted with one or more Y 2 b ; wherein Y 2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3;
  • Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y 4 is Y 43 , Y 413 , Y 4c , or Y 4 "; wherein
  • Y 4a is H or halogen
  • Y 4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy
  • Y 4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
  • R 3 is H or R 4 ; wherein R 4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
  • Q is CH or N;
  • Y 1 is H or lower alkyl;
  • Y 2 is Y 2a or Y 2b ; wherein Y 2a is H or halogen;
  • Y 2b is lower alkyl, optionally substituted with one or more Y 2b ; wherein Y 2b is hydroxy, lower alkoxy, or halogen;
  • each Y 2 is independently Y 2 a or Y 2 b ; wherein Y 2 a is halogen;
  • Y 2 b is lower alkyl, optionally substituted with one or more Y 2 b ; wherein Y 2 b is hydroxy, lower alkoxy, or halogen;
  • n is 0, 1, 2, or 3;
  • Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ;
  • Y 4 is Y 43 , Y 413 , Y 4c , or Y 4 "; wherein Y 4a is H or halogen;
  • Y 4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and Y 4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
  • Y 1 is methyl. In one variation of Formula I, n is 0, and m is 0.
  • Y 1 is methyl, n is 0, and m is 0.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl and Y 2 is hydroxymethyl.
  • Y 2 is hydroxymethyl, n is 0, and m is 0.
  • Y 1 is methyl
  • Y 2 is hydroxymethyl
  • n is 0, and m is 0.
  • Q is N.
  • Q is N, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, and m is 0.
  • Q is CH.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, and m is 0.
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, and m is 0.
  • R is -R ! -R 2 -R 3 ; and R 1 is heteroaryl. In one variation of Formula I, R is -R ! -R 2 ; and R 1 is heteroaryl.
  • R is -R 1 ; and R 1 is heteroaryl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is heteroaryl;
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl;
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, and m is 0.
  • R is -R ! -R 2 ;
  • R 1 is heteroaryl;
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl;
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, and m is 0.
  • R is -R 1 ; R 1 is heteroaryl; Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, and m is 0.
  • Y /4 4 ; iariess Y ⁇ , w»»uhe ⁇ «re ⁇ ;i «n ⁇ YT-5 5 a n ⁇ ndA ⁇ YT-6 b are independently
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl; Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, and m is 0.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ;
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl;
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl;
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, and m is 0.
  • the invention provides a compound of Formula I, wherein: R is H, -R 1 , -R ! -R 2 -R 3 , -R ! -R 3 , or -R 2 -R 3 ;
  • Y 2 is Y 2a or Y 2b ; wherein Y 2a is H or halogen; Y 2b is lower alkyl, optionally substituted with one or more Y 2b ; wherein Y 2b is hydroxy, lower alkoxy, or halogen; each Y 2 is independently Y 2 a or Y 2 b ; wherein Y 2 a is halogen; Y 2 b is lower alkyl, optionally substituted with one or more Y 2 b ; wherein Y 2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3.
  • Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y 4 is Y 43 , Y 413 , Y 4c , or Y 4 "; wherein
  • Y 4a is H or halogen
  • Y 4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy
  • Y 4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof (compounds of Formula I').
  • Y 1 is methyl
  • n is 0, and m is 0.
  • Q is N.
  • Y 1 is methyl and Q is N.
  • Y 1 is methyl, Q is N, n is 0, and m is 0.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl and Y 2 is hydroxymethyl.
  • Q is N, Y 1 is methyl, and Y 2 is hydroxymethyl.
  • Q is N, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0 and m is 0.
  • Q is CH.
  • Y 1 is methyl and Q is CH.
  • Y 1 is methyl, Q is CH, n is 0, and m is 0.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0 and m is O.
  • Y 2 is methyl
  • Y 2 is hydroxyethyl
  • Y 2 is halogen
  • Q is N.
  • Y 1 is methyl and Q is N.
  • Y 1 is methyl, Q is N, n is 0, and m is 0.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Y 2 is hydroxymethyl
  • Q is N, Y 1 is methyl, Y 2 is hydroxymethyl. In one embodiment of Formula I', Q is N, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0 and m is 0.
  • Q is CH.
  • Y 1 is methyl and Q is CH.
  • Y 1 is methyl, Q is CH, n is 0, and m is 0.
  • Q is CH, Y 1 is methyl, and Y 2 is hydroxymethyl.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0 and m is O.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxyethyl, n is 0 and m is 0.
  • Q is CH, Y 1 is methyl, Y 2 is halogen, n is 0, and m is 0.
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • Y 4 is lower alkyl
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • Y 4 is lower alkyl.
  • Q is N, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • Q is N, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • Q is N, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • Y 4 is group (d) independently H, lower alkyl, or lower haloalkyl.
  • Q is CH, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • Q is N, Y 1 is methyl, Y 2 is hydroxymethyl, n is 0, m is 0, and Y 4 is grou (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • the invention provides a compound of Formula II, wherein:
  • R is H, -R 1 , -R ! -R 2 -R 3 , -R ! -R 3 , or-R 2 -R 3 ;
  • R 2' is independently H, lower alkyl, lower alkoxy, lower haloalkyl, or lower hydroxyalkyl; and q is 1, 2, or 3;
  • R 3 is H or R 4 ; wherein R 4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl,
  • Y 2 is Y 2a or Y 2b ; wherein Y 2a is H or halogen; Y 2b is lower alkyl, optionally substituted with one or more Y 2b ; wherein Y 2b is hydroxy, lower alkoxy, or halogen; each Y 2 is independently Y 2 a or Y 2 b ; wherein Y 2 a is halogen; Y 2 b is lower alkyl, optionally substituted with one or more Y 2 b ; wherein Y 2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3;
  • Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; ⁇ 4 is ⁇ 4a ⁇ ⁇ 4b ⁇ ⁇ 4c ⁇ Qr ⁇ 4d. wherdn
  • Y 4a is H or halogen;
  • Y 413 is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 40 is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
  • Y 4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
  • Y 1 is methyl.
  • n is 0, and m is 0.
  • Y 1 is methyl, n is 0, and m is 0.
  • Y 2 is hydroxymethyl
  • Y 2 is hydroxymethyl and Y 1 is methyl.
  • Y 2 is hydroxymethyl, n is 0, and m is 0.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, and m is 0.
  • Q is NH
  • Q is CH 2 .
  • Q is NH
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • n is 0, and m is 0.
  • Q is CH 2 , Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, and m is 0.
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH 2 , Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, and m is 0.
  • R is R 1 ; wherein R 1 is pyrazolyl, optionally substituted with
  • R is R 1 ;
  • R 1 is pyrazolyl, optionally substituted with R 1 ;
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl;
  • Q is CH 2 , Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, and m is 0.
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl; Q is CH 2 , Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, and m is 0.
  • R is -R ! -R 2 -R 3 ; wherein R 1 is phenyl or pyridyl; R 2 is -
  • R 3 is R 4 ; and R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • R is R 1 ;
  • R 1 is pyrazolyl, optionally substituted with R 1 ;
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl;
  • Q is CH 2 , Y 2 is hydroxy- methyl, Y 1 is methyl, n is 0, and m is 0.
  • the invention provides a compound of Formula II, wherein:
  • R is H, -R 1 , -R ! -R 2 -R 3 , -R ! -R 3 , or-R 2 -R 3 ;
  • R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R 1 ; wherein R 1 is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl;
  • Q is CH 2 , CH(Y ) or NH; wherein Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; Y 1 is H or lower alkyl;
  • Y 2 is Y 2a or Y 2b ; wherein Y 2a is H or halogen; Y 2b is lower alkyl, optionally substituted with one or more Y 2b ; wherein Y 2b is hydroxy, lower alkoxy, or halogen; each Y 2 is independently Y 2 a or Y 2 b ; wherein Y 2 a is halogen; Y 2 b is lower alkyl, optionally substituted with one or more Y 2 b ; wherein Y 2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3.
  • Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y 4 is Y 4a , Y 4b , Y 4c , or Y 4d ; Y 4 " 1 is H or halogen;
  • Y 413 is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 40 is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 411 is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof (compounds of Formula IF).
  • Y 1 is methyl
  • Y 2 is hydroxymethyl. In one embodiment of Formula II', n is 0, and m is 0.
  • Y 2 is hydroxymethyl, n is 0, and m is 0.
  • Y 1 is methyl, n is 0, and m is 0.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, and m is 0.
  • Q is NH
  • Q is NH, Y 1 is methyl, n is 0, and m is 0.
  • Y 2 is hydroxymethyl
  • Q is NH
  • Y 1 is methyl
  • n is 0, and m is 0.
  • Q is CH 2 .
  • Q is CH 2 , Y 1 is methyl, n is 0, and m is 0.
  • Y 2 is hydroxymethyl
  • Q is CH 2
  • Y 1 is methyl
  • n is 0, and m is 0.
  • Y 2 is methyl
  • Y 2 is hydroxyethyl
  • Y 2 is halogen
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl
  • Q is CH 2
  • Y 1 is methyl
  • n is 0, and m is 0,
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 2 is hydroxymethyl
  • Q is NH
  • Y 1 is methyl
  • n is 0, and m is 0,
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • Y 4 is lower alkyl
  • Y 2 is hydroxymethyl
  • Q is CH 2
  • Y 1 is methyl
  • n is 0, and m is 0, and Y 4 is lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • Y 2 is hydroxymethyl
  • Q is NH
  • Y 1 is methyl
  • n is 0, and m is 0, and Y 4 is lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl
  • Q is CH 2
  • Y 1 is methyl
  • n is 0, and m is 0, and
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 2 is hydroxymethyl
  • Q is NH
  • Y 1 is methyl
  • n is 0, and m is 0,
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • Y 2 is hydroxymethyl
  • Q is CH 2
  • Y 1 is methyl
  • n is 0, and m is 0, and
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 2 is hydroxymethyl
  • Q is NH
  • Y 1 is methyl
  • n is 0, and m is 0, and
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Q is CH 2 , Y 1 is methyl, n is 0, and m is 0, and Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Q is NH, Y 1 is methyl, n is 0, and m is 0, and Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 1 is H or lower alkyl
  • Y 2 is Y 2a or Y 2b ; wherein Y 2a is H or halogen; Y 2b is lower alkyl, optionally substituted with one or more Y 2b ; wherein Y 2b is hydroxy, lower alkoxy, or halogen; each Y 2 is independently Y 2 a or Y 2 b ; wherein Y 2 a is halogen; Y 2 b is lower alkyl, optionally substituted with one or more Y 2 b ; wherein Y 2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3;
  • Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is O or l;
  • Y 4 is Y 43 , Y 413 , Y 4c , or Y 4 "; wherein Y 43 is H or halogen;
  • Y 4h is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
  • Y 1 is methyl
  • n is 0 and m is 0.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl, n is 0 and m is 0.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0 and m is 0.
  • Y 2 is methyl
  • Y 2 is hydro xyethyl.
  • Y 2 is halogen
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, m is 0, and Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • n is 0,
  • m is 0,
  • Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • the invention provides a compound of Formula IV, wherein: R is H, -R 1 , -R ! -R 2 -R 3 , -R ! -R 3 , or -R 2 -R 3 ; wherein
  • Y 2 is Y 2a or Y 2b ; wherein Y 2a is H or halogen; Y 2b is lower alkyl, optionally substituted with one or more Y 2b ; wherein Y 2b is hydroxy, lower alkoxy, or halogen; each Y 2 is independently Y 2 a or Y 2 b ; wherein Y 2 a is halogen; Y 2 b is lower alkyl, optionally substituted with one or more Y 2 b ; wherein Y 2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3.
  • Y is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y 4 is Y 43 , Y 4b , Y 4c , or Y 4 "; wherein Y 4a is H or halogen; Y 4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y 4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
  • Y 4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
  • Y 1 is methyl
  • n is 0 and m is 0.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl, n is 0 and m is 0.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0 and m is 0.
  • Y 2 is methyl
  • Y 2 is hydroxyethyl
  • Y 2 is halogen
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, m is 0, and Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is lower alkyl.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, and m is 0, and Y 4 is lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, m is 0, and Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • the invention provides a compound of Formula V, wherein: R is H, -R 1 , -R ! -R 2 -R 3 , -R ! -R 3 , or-R 2 -R 3 ; R 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R 1 ; wherein R 1 is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl;
  • R 3 is H or R 4 ; wherein R 4 is lower alkyl, lower alkoxy, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
  • Q is CH 2 , CH(Y ) or NH; wherein Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; Y 1 is H or lower alkyl;
  • Y 2 is Y 2a or Y 2b ; wherein Y 2a is H or halogen; Y 2b is lower alkyl, optionally substituted with one or more Y 2b ; wherein Y 2b is hydroxy, lower alkoxy, or halogen; each Y 2 is independently Y 2 a or Y 2 b ; Y 2 a is halogen; Y 2 b is lower alkyl, optionally substituted with one or more Y 2 b ; Y 2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3.
  • Y 3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y 4 is Y 43 , Y 4b , Y 40 ⁇ r Y 4 "; Y 4a is H or halogen;
  • Y 4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
  • Y 4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
  • Y 4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
  • Y 1 is methyl
  • Q is CH 2 .
  • Y 2 is hydroxymethyl
  • n is 0, and m is 0.
  • Y 2 is hydroxymethyl, n is 0, and m is 0.
  • Y 1 is methyl, n is 0, and m is 0.
  • Y 1 is methyl
  • Q is CH 2
  • n is 0, and m is 0.
  • Y 2 is hydroxymethyl, Y 1 is methyl, n is 0, and m is 0.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Q is CH 2
  • n is 0, and m is O.
  • Y 2 is methyl
  • Y 2 is hydroxyethyl
  • Y 2 is halogen
  • Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl, Y 1 is methyl, Q is CH 2 , n is 0, and m is 0, and Y 4 is group (a) wherein Y 5 is H, halogen, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is lower alkyl.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Q is CH 2
  • n is 0, and m is 0, and Y 4 is lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Q is CH 2
  • n is 0, and m is 0,
  • Y 4 is group (c) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • Y 2 is hydroxymethyl
  • Y 1 is methyl
  • Q is CH 2
  • n is 0, and m is 0, and
  • Y 4 is group (b) wherein Y 5 and Y 6 are independently H or lower alkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • Y 1 is methyl
  • Q is CH 2
  • n is 0, and m is 0, and Y 4 is group (d) wherein Y 5 and Y 6 are independently H, lower alkyl, or lower haloalkyl.
  • R is -R ! -R 2 -R 3 ;
  • R 1 is phenyl or pyridyl;
  • R 3 is R 4 ; and
  • R 4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
  • R is -R 2 -R 3 ;
  • R 3 is H or R 4 ; and
  • R 4 is lower alkyl.
  • R is R 1 ; and R 1 is pyrazolyl, optionally substituted with R 1 .
  • the invention provides a method for treating an inflammatory and/or autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of the Btk inhibitor compound of any one of the above Formulae I-V or variations thereof.
  • the invention provides a method for treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of any one of the above Formulae I-V or variations thereof.
  • the invention provides a method of inhibiting B-cell proliferation comprising administering to a patient in need thereof a therapeutically effective amount of any one of the above Formulae I-V or variations thereof.
  • the invention provides a method for treating an inflammatory condition comprising co- administering to a patient in need thereof a therapeutically effective amount of an antiinflammatory compound in combination with any one of the above Formulae I-V or variations thereof.
  • the invention provides a method for treating arthritis comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound in combination with any one of the above Formulae I-V or variations thereof.
  • the invention provides a method for treating a lymphoma or a BCR-ABLl + leukemia cells by administering to a patient in need thereof a therapeutically effective amount of any one of the above Formulae I-V or variations thereof.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the Btk inhibitor compound of any one of the above Formulae I-V or variations thereof, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.
  • the invention provides a method for treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of the Btk inhibitor compound any one of the above Formulae I-V or variations thereof.
  • the invention provides a method for inhibiting Btk activity comprising administering the Btk inhibitor compound of any one of the above Formulae I-V or variations thereof, wherein the Btk inhibitor compound exhibits an IC50 of 50 micromolar or less in an in vitro biochemical assay of Btk activity.
  • the Btk inhibitor compound exhibits an IC50 of 100 nanomolar or less in an in vitro biochemical assay of Btk activity.
  • the compound exhibits an IC50 of 10 nanomolar or less in an in vitro biochemical assay of Btk activity.
  • the invention provides a method for treating arthritis comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound in combination with the Btk inhibitor compound of any one of the above Formulae I-V or variations thereof.
  • the present invention provides compounds of generic Formulae I-V, which comprise the Btk inhibitor compounds of Formulae I-V, wherein variables Q, R, Y 1 , Y 2 , Y 3 , Y 4 , n, and m are as defined herein above.
  • a compound according to generic Formula I which comprises the exemplified Btk inhibitor compound of Formula 1-1.
  • a compound according to generic Formula II which comprises the exemplified Btk inhibitor compounds of Formulae II-l to 11-36.
  • a compound according to generic Formula III which comprises Btk inhibitor compounds of Formula III.
  • a compound according to generic Formula IV which comprises Btk inhibitor compounds of Formula IV.
  • a compound according to generic Formula V which comprises Btk inhibitor compounds of Formula V.
  • the compounds of generic Formulae I-V inhibit Bruton's tyrosine kinase (Btk). Activation of Btk by upstream kinases results in activation of phospholipase-C ⁇ which, in turn, stimulates release of pro-inflammatory mediators.
  • Btk Bruton's tyrosine kinase
  • the compounds of generic Formulae I-V incorporating substituted side chains of 3,4-Dihydro-2H-isoquinolin-l-one, 2,3-Dihydro-lH- quinazolin-4-one, 2H-Isoquinolin-l-one, 3H-Quinazolin-4-one, lH-Quinolin-4-one, 2H- Phthalazin-1-one, or 3,4-Dihydro-2H-benzo[e][l,2]thiazine 1,1-dioxide on the 5-phenyl-lH- pyrazin-2-one ring systems, exhibit unexpectedly enhanced inhibitory activity compared to analogues without said bicyclic side chains.
  • inhibitory activity is enhanced when Y 2 is lower alkyl optionally substituted with hydroxy.
  • Inhibitory activity is enhanced when Y 2 is hydroxymethyl.
  • Compounds of Formulae I-V are useful in the treatment of arthritis and other anti-inflammatory and auto-immune diseases.
  • Compounds according to Formulae I-V are, accordingly, useful for the treatment of arthritis.
  • Compounds of Formulae I-V are useful for inhibiting Btk in cells and for modulating B-cell development.
  • the present invention further comprises pharmaceutical compositions containing compounds of Formulae I-V admixed with pharmaceutically acceptable carrier, excipients or diluents.
  • a or “an” entity refers to one or more of that entity; e.g., a compound refers to one or more compounds or at least one compound.
  • a compound refers to one or more compounds or at least one compound.
  • the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
  • the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
  • a bond drawn into ring system indicates that the bond may be attached to any of the suitable ring atoms.
  • Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates.
  • the latter two are particularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds.
  • alkylaryl haloalkylheteroaryl
  • arylalkylheterocyclyl alkylcarbonyl
  • alkoxyalkyl alkylcarbonyl
  • phenylalkyl refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl.
  • An “alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents.
  • “Hydroxyalkyl” includes 2- hydroxyethyl, 2-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3- dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term "hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below.
  • -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group.
  • (hetero)aryl or (het)aryl refers to either an aryl or a heteroaryl group.
  • alkyl denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms.
  • lower alkyl denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms.
  • Ci-io alkyl refers to an alkyl composed of 1 to 10 carbons.
  • alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, /-propyl, «-butyl, /-butyl, ⁇ -butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
  • alkyl is used as a suffix following another term, as in "phenylalkyl,” or
  • hydroxyalkyl this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group.
  • phenylalkyl denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical.
  • arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl.
  • arylalkyl or “aralkyl” are interpreted similarly except R' is an aryl radical.
  • (het)arylalkyl” or “(het)aralkyl” are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.
  • alkylene or "alkylenyl” as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH 2 ) n )or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH 2 CH(Z-Pr)CH 2 -), unless otherwise indicated. Except in the case of methylene, the open valences of an alkylene group are not attached to the same atom.
  • alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2- ethylbutylene.
  • alkoxy as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, «-propyloxy, z-propyloxy, «-butyloxy, z-butyloxy, ⁇ -butyloxy, pentyloxy, hexyloxy, including their isomers.
  • “Lower alkoxy” as used herein denotes an alkoxy group with a "lower alkyl” group as previously defined.
  • C 1 -K) alkoxy as used herein refers to an-O-alkyl wherein alkyl is C 1-10 .
  • alkoxyalkyl refers to the radical R'R"-, wherein R' is an alkoxy radical as defined herein, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the alkoxyalkyl moiety will be on the alkylene radical.
  • C 1-6 alkoxyalkyl denotes a group wherein the alkyl portion is comprised of 1-6 carbon atoms exclusive of carbon atoms in the alkoxy portion of the group.
  • C 1-3 alkoxy-Ci_6 alkyl denotes a group wherein the alkyl portion is comprised of 1-6 carbon atoms and the alkoxy group is 1-3 carbons.
  • Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, t-butyloxybutyl, methoxypentyl, ethoxypentyl, propyloxypentyl including their isomers .
  • heteroalkoxy as used herein means an -O-(heteroalkyl) group wherein heteroalkyl is defined herein.
  • C 1 -K heteroalkoxy refers to an-O-(heteroalkyl) wherein alkyl is C 1-10 .
  • Representative examples include, but are not limited to, 2- dimethylaminoethoxy and 3-sulfonamido-l-propoxy.
  • hydroxyalkyl denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydro xyl groups.
  • Aryl means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring.
  • the aryl group can be optionally substituted as defined herein.
  • aryl moieties include, but are not limited to, optionally substituted phenyl, naph- thyl, phenanthryl, fluorenyl, indenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzodioxylyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzo- pyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphen
  • the aryl group may optionally be fused to a cycloalkyl or hetero eye Io alkyl ring, as herein defined.
  • Examples of an aryl group fused to a hetero eye Io alkyl group include 3,4-dihydro- lH-quinolin-2-one, 3,4-dihydro-2H-benzo[l,4]oxazine, and 1,2,3,4-tetrahydro-isoquinoline.
  • Preferred aryl include optionally substituted phenyl and optionally substituted naphthyl.
  • cycloalkyl refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • C3-7 cycloalkyl refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.
  • heteroaryl or “hetero aromatic” as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character.
  • heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower halo alkoxy, alkylthio, halogen, lower haloalkyl, alkylsulfmyl, alkylsulfonyl, halogen, amino, alkylamino, dialkyl- amino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbony
  • bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole.
  • Bicyclic moieties can be optionally substituted on either ring; however the point of attachment is on a ring containing a heteroatom.
  • heterocycloalkyl denotes a monovalent saturated cyclic radical, consisting of one or more fused or spirocyclic rings, preferably one to two rings, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,0 or S(0)o-2), and which can optionally be independently sub- stituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkyl- aminosulfonyl, arylaminosulfonyl, alkylsulfony
  • heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 1 ,4- dimethyl-piperazin-2-one, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.
  • arthritis means acute rheumatic arthritis, chronic rheumatoid arthritis, chlamydial arthritis, chronic absorptive arthritis, chylous arthritis, arthritis based on bowel disease, filarial arthritis, gonorrheal arthritis, gouty arthritis, hemophilic arthritis, hypertrophic arthritis, juvenile chronic arthritis, Lyme arthritis, neonatal foal arthritis, nodular arthritis, ochronotic arthritis, psoriatic arthritis or suppurative arthritis, or the related diseases which require the administration to a mammal in a therapeutic effective dose of a compound of Formulae I-V in a sufficient dose to inhibit BTK.
  • autoimmune condition and like terms means a disease, disorder or condition caused by the immune system of an animal.
  • Autoimmune disorders are those wherein the animal's own immune system mistakenly attacks itself, thereby targeting the cells, tissues, and/or organs of the animal's own body.
  • the autoimmune reaction is directed against the nervous system in multiple sclerosis and the gut in Crohn's disease.
  • systemic lupus erythematosus (lupus)
  • affected tissues and organs may vary among individuals with the same disease.
  • One person with lupus may have affected skin and joints whereas another may have affected skin, kidney, and lungs.
  • autoimmune disorders that may be ameliorated using the compounds and methods of this invention include without limitation, autoimmune disorders of the nervous system (e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barre, and autoimmune uveitis), autoimmune disorders of the blood (e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia), autoimmune disorders of the blood vessels (e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, and Behcet's disease), autoimmune disorders of the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo), autoimmune disorders of the gastrointestinal system (e.g.,
  • Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland and autoimmune disorders of multiple organs (including connective tissue and musculoskeletal system diseases) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren's syndrome) or the related diseases which require the administration to a mammal in a therapeutic effective dose of a compound of Formulae I-V in a sufficient dose to inhibit BTK.
  • connective tissue and musculoskeletal system diseases e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as
  • immune disorders are also included in the definition of immune disorders herein.
  • immune disorders are caused by inflammation, there is some overlap between disorders that are considered immune disorders and inflammatory disorders.
  • an overlapping disorder it may be considered either an immune disorder or an inflammatory disorder.
  • Treatment of an immune disorder refers to administering a compound or a composition of the invention to a subject, who has an immune disorder, a symptom of such a disease or a predisposition towards such a disease, with the purpose to cure, relieve, alter, affect, or prevent the autoimmune disorder, the symptom of it, or the predisposition towards it.
  • the term "asthma” means a pulmonary disease, disorder or condition characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness to a variety of stimuli.
  • treat refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • treating an inflammatory condition means reducing the extent or severity of the inflammation.
  • the reduction can mean but is not limited to the complete ablation of inflammation.
  • the reduction can comprise a 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction, or any point in between, compared to an untreated or control subject as determined by any suitable measurement technique or assay disclosed herein or known in the art.
  • the nomenclature used herein is based on AUTONOMTM v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. If there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, e.g., bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • ⁇ -34 4- ⁇ 6-[3-(6-Cyclopropyl-l-oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino ⁇ -N-(2- methoxy-ethyl)-benzamide ⁇ -35 4- ⁇ 6-[3-(6-Cyclopropyl-l -oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino ⁇ -N,N-bis- (2-hydroxy-ethyl)-benzamide
  • the pyrazinone derivatives described herein are kinase inhibitors, in particular Btk inhibitors. These inhibitors can be useful for treating one or more diseases responsive to kinase inhibi- tion, including diseases responsive to Btk inhibition and/or inhibition of B-cell proliferation, in mammals. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of the invention with Btk results in the inhibition of Btk activity and thus in the pharmaceutical utility of these compounds.
  • the invention in- eludes a method of treating a mammal, for instance a human, having a disease responsive to inhibition of Btk activity, and/or inhibiting B-cell proliferation, comprising administrating to the mammal having such a disease, an effective amount of at least one chemical entity provided herein.
  • An effective concentration may be ascertained experimentally, e.g. by assaying blood concentration of the compound, or theoretically, by calculating bioavailability.
  • Other kinases that may be affected in addition to Btk include, but are not limited to, other tyrosine kinases and serine/threonine kinases.
  • kinases play notable roles in signaling pathways controlling fundamental cellular processes such as proliferation, differentiation, and death (apoptosis). Abnormal kinase activity has been implicated in a wide range of diseases, including multiple cancers, autoimmune and/or inflammatory diseases, and acute inflammatory reactions. The multifaceted role of kinases in key cell signaling pathways provides a significant opportunity to identify novel drugs targeting kinases and signaling pathways.
  • An embodiment includes a method of treating a patient having an autoimmune and/or inflammatory disease, or an acute inflammatory reaction responsive to inhibition of Btk activity and/or B-cell proliferation.
  • Autoimmune and/or inflammatory diseases that can be affected using compounds and compositions according to the invention include, but are not limited to: psoriasis, allergy, Crohn's disease, irritable bowel syndrome, Sjogren's disease, tissue graft rejection, and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA- associated and other vasculitides), autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, chronic Idiopathic thrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, and myasthenia gravis, Included herein are
  • Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclo- oxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate.
  • NSAIDs non-specific and COX-2 specific cyclo- oxgenase enzyme inhibitors
  • gold compounds gold compounds
  • corticosteroids corticosteroids
  • methotrexate methotrexate
  • TNF tumor necrosis factor receptor
  • NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.
  • NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.
  • the anti-inflammatory agent is a salicylate.
  • Salicylates include by are not limited to acetyls alicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.
  • the anti-inflammatory agent may also be a corticosteroid.
  • the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.
  • the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin.
  • the invention also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydro- orotate dehydrogenase inhibitor, such as leflunomide.
  • a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydro- orotate dehydrogenase inhibitor, such as leflunomide.
  • At least one anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizu- mab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody.
  • an anti-C5 monoclonal antibody such as eculizumab or pexelizu- mab
  • TNF antagonist such as entanercept, or infliximab
  • Still other embodiments of the invention pertain to combinations in which at least one active agent is an immunosuppressant compound such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.
  • an immunosuppressant compound such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.
  • B-cells and B-cell precursors expressing BTK have been implicated in the pathology of B- cell malignancies, including, but not limited to, B-cell lymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma), hairy cell lymphoma, multiple myeloma, chronic and acute myelogenous leukemia and chronic and acute lymphocytic leukemia.
  • BTK has been shown to be an inhibitor of the Fas/APO-1 (CD-95) death inducing signaling complex (DISC) in B-lineage lymphoid cells ⁇
  • DISC Fas/APO-1
  • the fate of leukemia/lymphoma cells may reside in the balance between the opposing proapoptotic effects of caspases activated by DISC and an upstream anti-apoptotic regulatory mechanism involving BTK and/or its substrates (Vassilev et al, J. Biol. Chem. 1998, 274, 1646-1656).
  • BTK inhibitors are useful as chemosensitizing agents, and, thus, are useful in combination with other chemotherapeutic drugs, in particular, drugs that induce apoptosis.
  • chemotherapeutic drugs that can be used in combination with chemosensitizing BTK inhibitors include topoisomerase I inhibitors (camptothecin or topotecan), topoisomerase II inhibitors (e.g. daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g. taxol and vinblastine), and biological agents (e.g. antibodies such as anti CD20 antibody, IDEC 8, immunotoxins, and cytokines).
  • topoisomerase I inhibitors camptothecin or topotecan
  • topoisomerase II inhibitors e.g. daunomycin and etoposide
  • alkylating agents e.g. cyclophospham
  • Btk activity has also be associated with some leukemias expressing the bcr-abl fusion gene resulting from translocation of parts of chromosome 9 and 22. This abnormality is commonly observed in chronic myelogenous leukemia. Btk is constitutively phosphorylated by the bcr-abl kinase which initiates downstream survival signals which circumvents apoptosis in bcr-abl cells. (Feldhahn et al. J. Exp. Med. 2005 201(11):1837-1852)
  • the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers.
  • Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, syrups, or suspensions.
  • Compounds of the present invention are efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intra- venous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration.
  • the preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.
  • a compound or compounds of the present invention, as well as their pharmaceutically use- able salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal admini- stration; or in the form of sterile injectable solutions for parenteral use.
  • a typical preparation will contain from about 5% to about 95% active compound or compounds (w/w).
  • preparation or “dosage form” is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.
  • excipient refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use.
  • the compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise un- desirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • a "pharmaceutically acceptable salt” form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body.
  • pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane - sulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluene- sul
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use.
  • Emulsions may be prepared in solutions, e.g., in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, e.g. bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-f ⁇ lled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, e.g. solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • the compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, e.g., be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compounds of the present invention may be formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, e.g., by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
  • the compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the present invention may be formulated for nasal administration.
  • the solutions or suspensions are applied directly to the nasal cavity by conventional means, e.g., with a dropper, pipette or spray.
  • the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved e.g. by means of a metering atomizing spray pump.
  • the compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size e.g. of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, e.g. by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluoro- carbon (CFC), e.g., dichlorodifiuoromethane, trichlorofiuoromethane, or dichlorotetrafluoro- ethane, or carbon dioxide or other suitable gas.
  • a suitable propellant such as a chlorofluoro- carbon (CFC), e.g., dichlorodifiuoromethane, trichlorofiuoromethane, or dichlorotetrafluoro- ethane, or carbon dioxide or other suitable gas.
  • the aerosol
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, e.g. a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form e.g. in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices.
  • transdermal delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
  • Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support.
  • the com- pound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecyl- aza-cycloheptan-2-one).
  • a penetration enhancer e.g., Azone (1-dodecyl- aza-cycloheptan-2-one).
  • Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection.
  • the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polyactic acid.
  • Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the com- positions of the present invention unstable or compromising their therapeutic activity.
  • the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esteri- fication, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a par- ticular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
  • terapéuticaally effective amount means an amount required to reduce symptoms of the disease in an individual.
  • the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved.
  • a daily dosage of between about 0.01 and about 1000 mg/kg body weight per day should be appropriate in monotherapy and/or in combina- tion therapy.
  • a preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day.
  • the dosage range would be about 7 mg to 0.7 g per day.
  • the daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the com- pound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached.
  • One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures herein, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Methanesulfonic acid 31 mL, 10 equiv was added to a mixture of 5-bromo-indan-l-one (10 g, 47 mmol) in CH 2 Cl 2 (75 mL) at 0 0 C.
  • Sodium azide was added slowly in portions to this mixture. After the sodium azide addition was complete, the mixture was stirred for an additional 30 min, and an aqueous mixture of NaOH (20 wt%) was added until the mixture was slightly basic.
  • the mixture was extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure.
  • a sealable vial was charged with 6-cyclopropyl-3,4-dihydro-2H-isoquinolin-l-one (985 mg, 5 mmol), 2,6-dibromo-benzaldehyde (2.6 g, 2 equiv), Pd(dba) 2 (58 mg, 0.02 equiv), xantphos (89 mg, 0.03 equiv), and cesium carbonate (2.28 g, 1.4 equiv).
  • the vial was flushed with argon, dioxane (5 mL) was added, and the vial was capped.
  • Acetic anhydride (121 uL, 1 equiv) was added to a mixture of 2-(3-bromo-2-hydroxymethyl- phenyl)-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-l-one (475 mg, 1.27 mmol), DMAP (16 mg, 0.1 equiv), and TEA (178 uL, 1 equiv) in anhydrous CH 2 Cl 2 (6 mL). The mixture was stirred for 1 h, and the volatile materials were removed by evaporation.
  • Example 7 Acetic acid 2-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-6- (4,4,5,5-tetramethyl-[l,3 ? 2]dioxaborolan-2-yl)-benzyl ester
  • Example 8 Acetic acid 2-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-6- ⁇ 6- [4-(4-ethyl-piperazine-l-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-di- hydro-pyrazin-2-yl ⁇ -benzyl ester
  • Et3N-3HF (7.7 g, 3 equiv) was added to a mixture of 2-(4-methoxy-benzyl)-6-vinyl-3,4-di- hydro-2H-isoquinolin-l-one (4.7 g, 16 mmol) in CH 2 Cl 2 (16 mL) at 0 0 C.
  • NBS 3.5 g, 1.2 equiv was added, and the mixture was stirred at 0 0 C for 30 min.
  • the solution was warmed to RT, stirred for 1 h, and poured into ice water.
  • the mixture was made basic with concentrated NH 4 OH, and extracted with CH 2 Cl 2 .
  • Example 17 5-bromo-3-(l-ethyl-lH-pyrazol-4-ylamino)-l-methyl-lH-pyrazin-2-one
  • a solution of 1 -ethyl- lH-pyrazol-4-ylamine (0.28 g, 2.5 mmol) and 3,5-dibromo-l-methyl- lH-pyrazin-2-one (0.74 g, 1.1 equiv) were heated to 120 0 C in isopropanol for 1 h.
  • reaction mixture was cooled to RT, and 5-bromo-3-(l-ethyl-lH-pyrazol-4-ylamino)-l- methyl-lH-pyrazin-2-one was isolated by filtration (0.43 g, 57%).
  • Glacial acetic acid 100 uL was added to a suspension of 5-bromo-3-(4-hydroxymethyl- phenylamino)-l -methyl- lH-pyrazin-2 -one (0.1 g, 0.3 mmol) and 3 A molecular sieves (0.37 g) and morpholine (0.043 mL, 1.5 equiv) in DCE (10 mL). The solution was stirred for 10 min, and NaHB(OAc) 3 (0.172 g, 2.5 equiv) was added in one portion. The suspension was stirred at RT overnight. Water was added to the reaction mixture, and the precipitate was removed by filtration. The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 .
  • Example 25 Acetic acid 2-bromo-6-(6-tert-butyl-l-oxo-3,4-dihydro-lH-isoquinolin-2- yl)-benzyl ester
  • N,N'-Dimethyl-cyclo- hexane-1 ,2-diamine (1.24 mL, 0.4eq) and the resulting mixture was heated to reflux for 24 hours, after which time more copper iodide (394mg, 0.1 eq) and N,N'-Dimethyl-cyclohexane- 1,2-diamine (0.62 mL, 0.2 eq) were added. Stirred an additional 64 hours and then added more copper iodide (400 mg, 0.1 eq). Continued to stir at reflux for a total of 168 hours. Cooled to RT and then added ethylacetate (30OmL) and water (10OmL), partitioned and separated the layers.
  • the tert-butyl ester (I) ( 1 g, 5.7 mmole ) was dissolved in 40 ml methanol and to this solu- tion was added LiOH monohydrate ( 0.72 g , 17.3 mmole ) in 6 ml water. The mixture was stirred at RT for 16 hours, then concentrated in vacuo, acidified with HCl 2N and extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue (1.8 g; 97% yield ) was used in the next step without further purification.
  • amide (III) (1.3 g, 4 mmole ) was suspended in 5 ml THF and 10 ml DMF. To this mixture was added cyanuric chloride (0.370 g, 2 mmole) and after stirring at RT for 0.5 hour, the reaction mixture was partitioned between ethylacetate and brine; the organic layer was washed with 5% sodium bicarbonate, followed by brine and then dried over sodium sulfate. Purification by flash chromatograpy on silica gel column using 75% ethylacetate in hexane as eluent afforded 1.2 g ( 98% yield) of nitrile (IV).
  • 6-Dimethylamino-2H-isoquinolin-l-one 50mg, 0.27mmol
  • cuprous iodide lOmg, 0.053mmol
  • potassium carbonate 37mg, 0.27mmol
  • 3mL DMSO and 2,6-dibromotoluene 133mg, 0.532mmol were added.
  • Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150 0 C for 5 hours.
  • the resulting mixture was partitioned between ethyl acetate and water.
  • Example 36 Acetic acid 2-(6-dimethylamino-l-oxo-lH-isoquinolin-2-yl)-6-(4,4,5,5- tetramethyl-[l,3 ? 2]dioxaborolan-2-yl)-benzyl ester
  • N-Nitroso-N-methylurea (9.1g, 61.8 mmol) was added under stirring in portions to a two phase mixture of 50 ml potassium hydroxide solution (23.9g in 50 ml water) and 50 ml diethyl ether at 0 0 C.
  • the color of the organic phase changed from colorless to yellow.
  • the two phase mixture was vigorously stirred for 40 min at 0 0 C.
  • the organic layer that contains diazomethane was separated.
  • reaction mixture was refluxed overnight; filtered off the precipitate; concentrated and extracted with ethyl acetate; washed with 2 M phosphate buffer pH 5.5, then with water and brine; dried over sodium sulfate; filtered; concentrated. 4.69g of an oil was obtained.
  • 2,2,6,6-tetramethylpiperidine (2.28g, 16.17 mmol) was dissolved in 13 ml anhydrous THF under stirring; cooled by means of an ethylen glycol/ice bath mixture to -15°C.
  • Buthyllithium, 2.5 M in hexanes (6.16 ml, 15.4 mmol) was added dropwise and the temperature was kept around -15°C and stirred additionally 30 min at -15°C.
  • the assay is a capture of radioactive 33 ⁇ P phosphorylated product through filtration.
  • Biotinylated product is bound streptavidin sepharose beads. All bound, radiolabeled products are detected by scintillation counter. Plates assayed are 96-well polypropylene (Greiner) and 96-well 1.2 ⁇ m hydrophilic PVDF filter plates (Millipore).
  • IC50 determinations are calculated from 10 data points per compound utilizing data produced from a standard 96-well plate assay template.
  • One control compound and seven unknown inhibitors were tested on each plate and each plate was run twice. Typically, compounds were diluted in half-log starting at 100 ⁇ M and ending at 3 nM. The control compound was staurosporine. Background was counted in the absence of peptide substrate. Total activity was determined in the presence of peptide substrate. The following protocol was used to determine Btk inhibition.
  • test compounds were diluted at half-log increments in assay buffer (imidazole, glycerol-2 -phosphate, EGTA, MnCl 2 , MgCl 2 , BSA).
  • assay buffer imidazole, glycerol-2 -phosphate, EGTA, MnCl 2 , MgCl 2 , BSA.
  • Bead preparation a.) rinse beads by centrifuging at 500 g b.) reconstitute the beads with PBS and EDTA to produce a 20% bead slurry
  • Example 48 Inhibition of B-cell Activation - B cell FLIPR assay in Ramos cells
  • the B cell FLIPR assay is a cell based functional method of determining the effect of potential inhibitors of the intracellular calcium increase from stimulation by an anti-IgM antibody.
  • Ramos cells human Burkitt's lymphoma cell line. ATCC-No. CRL-1596
  • Growth Media described below.
  • Ramos cells were resuspended in fresh growth media (same as above) and set at a concentration of 0.5 x 10 6 /mL in tissue culture flasks.
  • cells are counted and set at a concentration of 1 x 10 6 /mLl in growth media supplemented with l ⁇ M FLUO-3AM(TefLabs Cat-No. 0116, prepared in anhydrous DMSO and 10% Pluronic acid) in a tissue culture flask, and incubated at 37°C (4% CO 2 ) for one h.
  • FLUO-3AM TefLabs Cat-No. 0116
  • Pluronic acid Pluronic acid
  • FLIPR buffer HBSS (Invitrogen, Cat-No. 141175-079), 2mM CaCl 2 (Sigma Cat-No. C-
  • HEPES Invitrogen, Cat-No. 15630-080
  • 2.5mM Probenecid Sigma, Cat-No. P-
  • test compounds are diluted in FLIPR Buffer (using Biomek 2000 robotic pipettor) resulting in the following dilution scheme: vehicle, 1.00 x 10 "4 M, 1.00 x 10 "5 , 3.16 x 10 "6 , 1.00 x 10 "6 ,
  • IC50 was determined using a non-linear curve fit (GraphPad Prism software).
  • mice are injected at the base of the tail or several spots on the back with an emul- sion of Type II Collagen (i.d.) in Complete Freund's adjuvant (CFA). Following collagen immunization, animals will develop arthritis at around 21 to 35 days. The onset of arthritis is synchronized (boosted) by systemic administration of collagen in Incomplete Freund's adjuvant (IFA; i.d.) at day 21. Animals are examined daily after day 20 for any onset of mild arthritis (score of 1 or 2; see score description below) which is the signal to boost.
  • mice are scored and dosed with candidate therapeutic agents for the prescribed time ( typically 2 — 3 weeks) and dosing frequency, daily (QD) or twice-daily (BID).
  • Example 50 Rat/ « Vivo Collagen-induced arthritis (rCIA)
  • mice are injected with an emulsion of Bovine Type II Collagen in Incomplete Freund's adjuvant (IFA) is injected intradermally (i.d.) on several locations on the back.
  • IFA Incomplete Freund's adjuvant
  • a booster injection of collagen emulsion is given around day 7, (i.d.) at the base of the tail or alternative sites on the back.
  • Arthritis is generally observed 12-14 days after the initial collagen injection. Animals may be evaluated for the development of arthritis as described below (Evaluation of arthritis) from day 14 onwards. Animals are dosed with candidate therapeutic agents in a preventive fashion starting at the time of secondary challenge and for the pre- scribed time ( typically 2 — 3 weeks) and dosing frequency, daily (QD) or twice-daily (BID).
  • QD daily
  • BID twice-daily
  • Evaluations are made on day 0 for baseline measurement and starting again at the first signs or swelling for up to three times per week until the end of the experiment.
  • the arthritic index for each mouse is obtained by adding the four scores of the individual paws, giving a maximum score of 16 per animal.
  • OA ovalbumin
  • Male Brown-Norway rats are sensitized i.p. with 100 ⁇ g of OA (ovalbumin) in 0.2 ml alum once every week for three weeks (day 0, 7, and 14).
  • the rats are dosed q.d. with either vehicle or compound formulation subcutane- ously 0.5 hour before OA aerosol challenge (1% OA for 45 minutes) and terminated 4 or 24 hours after challenge.
  • serum and plasma are collected from all animals for serology and PK, respectively.
  • a tracheal cannula is inserted and the lungs are lavaged 3X with PBS.
  • the BAL fluid is analyzed for total leukocyte number and differential leukocyte counts.
  • Total leukocyte number in an aliquot of the cells (20-100 ⁇ l) is determined by Coulter Counter. For differential leukocyte counts, 50-200 ⁇ l of the sample is centrifuged in a Cytospin and the slide stained with Diff-Quik. The proportions of monocytes, eosinophils, neutrophils and lymphocytes are counted under light microscopy using standard morphologi- cal criteria and expressed as a percentage. Representative inhibitors of Btk show decreased total leucocyte count in the BAL of OA sensitized and challenged rats as compared to control levels.
  • composition for Oral Administration (A)
  • Magnesium stearate 0.5% The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.
  • the ingredients are combined and granulated using a solvent such as methanol.
  • the formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.
  • composition for Oral Administration (C)
  • Veegum K (Vanderbilt Co.) 1.0 g
  • the ingredients are mixed to form a suspension for oral administration.
  • the active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

Abstract

The present invention provides 5 -phenyl- 1H-pyrazin-2 -one derivatives according to generic Formulae I-V: wherein, variables Q, R, Y1, Y2, Y2', Y3, Y4, n and m are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions comprising compounds of Formulae I-V and at least one carrier, diluent or excipient.

Description

NOVEL PHENYLPYRAZINONES AS KINASE INHIBITORS
The present invention relates to the use of novel derivatives which inhibit Btk and are useful for the treatment of auto-immune and inflammatory diseases caused by aberrant B-cell activation. The novel 5-phenyl-lH-pyrazin-2-one derivatives described herein are useful for the treatment of arthritis.
Btk is a member of the Tec family of tyrosine kinases, and has been shown to be a critical regulator of early B-cell development and mature B-cell activation and survival (Khan etal. Immunity 1995 3:283; Ellmeier et al. J. Exp. Med. 2000 192:1611). Mutation of Btk in humans leads to the condition X-linked agammaglobulinemia (XLA) (reviewed in Rosen et al. NewEng. J. Med. 1995 333:431 and Lindvall etal. Immunol. Rev. 2005 203:200). These patients are immunocompromised and show impaired maturation of B-cells, decreased immunoglobulin and peripheral B-cell levels, diminished T-cell independent immune responses as well as attenuated calcium mobilization following BCR stimulation.
Evidence for a role for Btk in autoimmune and inflammatory diseases has also been provided by Btk-deficient mouse models. In preclinical murine models of systemic lupus erythemato- sus (SLE), Btk-deficient mice show marked amelioration of disease progression. In addition, Btk-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459). A selective Btk inhibitor has been demonstrated dose-dependent efficacy in a mouse arthritis model (Pan etal., Chem. Med Chem. 2007 2:58-61).
Btk is also expressed by cells other than B-cells that may be involved in disease processes. For example, Btk is expressed by mast cells and Btk-deficient bone marrow derived mast cells demonstrate impaired antigen induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280:40261). This shows Btk could be useful to treat pathological mast cells responses such as allergy and asthma. Also monocytes from XLA patients, in which Btk activity is absent, show decreased TNF alpha production following stimulation (Horwood et al. J Exp Med 197:1603, 2003). Therefore TNF alpha mediated inflammation could be modulated by small molecular Btk inhibitors. Also, Btk has been reported to play a role in apoptosis (Islam and
HEI / 20.05.2009 Smith Immunol. Rev. 2000 178:49,) and thus Btk inhibitors would be useful for the treatment of certain B-cell lymphomas and leukemias (Feldhahn etal. J. Exp. Med. 2005 201 :1837).
In a first aspect, the present invention provides 5-phenyl-lH-pyrazin-2-one derivatives of Formulae I-V
Figure imgf000004_0001
IV
wherein
R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R1 ; wherein each R1 is independently lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, cycloalkyl lower alkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -(CH2)qC(=O)O, -C(=O)N(R2')2, -(CH2),, -O(CH2)q, -
CH2C(=O), -CH2C(=O)N(R2')2, or-S(=O)2; wherein each R2' is independently H, lower alkyl, lower alkoxy, lower haloalkyl, or lower hydroxyalkyl; and q is 1, 2, or 3;
R3 is H or R4; wherein R4 is lower alkyl, lower heteroalkyl, lower alkoxy, amino, aryl arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydro xyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl; Q is CH2, CH(Y ) or NH; wherein Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; Y1 is H or lower alkyl;
Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3;
Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y4 is Y43, Y413, Y4c, or Y4"; wherein
Y4a is H or halogen; Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment, the invention provides a compound of Formula I, wherein: R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3; R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R1 ; wherein each R1 is independently lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -C(=O)N(R2'), -(CH2)q, -O(CH2)q, -(CH2)qC(=O)O, -O(CH2)q
C(=O)N(R2'), -CH2C(=O)N(R2'),or -S(=O)2; wherein R2' is H or lower alkyl; and q is 1, 2, or 3;
R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
Q is CH or N; Y1 is H or lower alkyl; Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3;
Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ;
Y4 is Y43, Y413, Y4c, or Y4"; wherein Y4a is H or halogen;
Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and Y4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
In one variation of Formula I, Y1 is methyl. In one variation of Formula I, n is 0, and m is 0.
In one variation of Formula I, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula I, Y2 is hydroxymethyl.
In one variation of Formula I, Y1 is methyl and Y2 is hydroxymethyl.
In one variation of Formula I, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, Q is N.
In one variation of Formula I, Q is N, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, Q is CH.
In one variation of Formula I, Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, Y4 is group (a)
Figure imgf000007_0001
wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one variation of Formula I, Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, R is -R!-R2-R3; wherein R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one variation of Formula I, R is -R!-R2-R3; wherein R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl; Y4 is a group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, R is -R!-R2-R3; and R1 is heteroaryl. In one variation of Formula I, R is -R!-R2; and R1 is heteroaryl.
In one variation of Formula I, R is -R1; and R1 is heteroaryl.
In one variation of Formula I, R is -R!-R2-R3; R1 is heteroaryl; Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, R is -R!-R2; R1 is heteroaryl; Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, R is -R1; R1 is heteroaryl; Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
/
In one variation of Formula I, Y /44 ; i„s Y
Figure imgf000008_0001
γ , w»»uheΛ«reΛ;i«n Λ YT-55 a n∞ndA Λ YT-6b are independently
H or lower alkyl.
In one variation of Formula I, Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl; Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula I, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl; Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl; Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
In another embodiment, the invention provides a compound of Formula I, wherein: R is H, -R1, -R!-R2-R3, -R!-R3, or -R2-R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R1 ; wherein R1 is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl; R2 iiss --CC((==OO)),, --CC((==OO))OO,, --CC(=O)N(R2'), -(CH2),, or -S(=O)2; wherein R2' is H or lower alkyl; and q is 1, 2, or 3; R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl; Q is CH or N; Y1 is H or lower alkyl;
Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3.
Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y4 is Y43, Y413, Y4c, or Y4"; wherein
Y4a is H or halogen; Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof (compounds of Formula I').
In one embodiment of Formula I', Y1 is methyl.
In one embodiment of Formula I', n is 0, and m is 0.
In one embodiment of Formula I', Q is N. In one embodiment of Formula I', Y1 is methyl and Q is N.
In one embodiment of Formula I', Y1 is methyl, Q is N, n is 0, and m is 0.
In one embodiment of Formula I', Y2 is hydroxymethyl.
In one embodiment of Formula I', Y1 is methyl and Y2 is hydroxymethyl.
In one embodiment of Formula I', Q is N, Y1 is methyl, and Y2 is hydroxymethyl.
In one embodiment of Formula I', Q is N, Y1 is methyl, Y2 is hydroxymethyl, n is 0 and m is 0.
In one embodiment of Formula I', Q is CH.
In one embodiment of Formula I', Y1 is methyl and Q is CH.
In one embodiment of Formula I', Y1 is methyl, Q is CH, n is 0, and m is 0.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxymethyl.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0 and m is O.
In one embodiment of Formula I', Y2 is methyl.
In one embodiment of Formula I', Y2 is hydroxyethyl.
In one embodiment of Formula I', Y2 is halogen.
In one embodiment of Formula I', Q is N.
In one embodiment of Formula I', Y1 is methyl and Q is N.
In one embodiment of Formula I', Y1 is methyl, Q is N, n is 0, and m is 0.
In one embodiment of Formula I', Y2 is hydroxymethyl.
In one embodiment of Formula I', Y1 is methyl, Y2 is hydroxymethyl.
In one embodiment of Formula I', Q is N, Y1 is methyl, Y2 is hydroxymethyl. In one embodiment of Formula I', Q is N, Y1 is methyl, Y2 is hydroxymethyl, n is 0 and m is 0.
In one embodiment of Formula I', Q is CH.
In one embodiment of Formula I', Y1 is methyl and Q is CH.
In one embodiment of Formula I', Y1 is methyl, Q is CH, n is 0, and m is 0.
In one embodiment of Formula I', Q is CH, Y1 is methyl, and Y2 is hydroxymethyl.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0 and m is O.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxyethyl, n is 0 and m is 0.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is halogen, n is 0, and m is 0.
In one embodiment of Formula I', Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one embodiment of Formula I', Y4 is lower alkyl.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is lower alkyl.
In one variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one embodiment of Formula I', Y4 is lower alkyl. In one embodiment of Formula I', Q is N, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is lower alkyl.
In one variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula I', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In one embodiment of Formula I', Y4 is group (c)
Figure imgf000012_0001
wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one embodiment of Formula I', Q is N, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one embodiment of Formula I', Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one variation of the above embodiment of Formula I', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl. In another variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one embodiment of Formula I', Q is N, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one embodiment of Formula I', Y4 is group (d)
Figure imgf000013_0001
independently H, lower alkyl, or lower haloalkyl.
In one embodiment of Formula I', Q is CH, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one embodiment of Formula I', Q is N, Y1 is methyl, Y2 is hydroxymethyl, n is 0, m is 0, and Y4 is grou (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula I', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another embodiment, the invention provides a compound of Formula II, wherein:
R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R1 ; each R1 is independently lower alkyl, hydroxy, lower hydro xyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, cycloalkyl lower alkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -C(=O)N(R2')2, -(CH2),, -O(CH2)q, -
CH2C(=O), -CH2C(=O)N(R2')2, or-S(=O)2; wherein each R2' is independently H, lower alkyl, lower alkoxy, lower haloalkyl, or lower hydroxyalkyl; and q is 1, 2, or 3; R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl; Q is CH2, CH(Y ) orNH; Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; Y1 is H or lower alkyl;
Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3;
Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; γ4 is γ4a^ γ4b^ γ4c^ Qr γ4d. wherdn
Y4a is H or halogen; Y413 is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y40 is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof. In one variation of Formula II, Y1 is methyl.
In one variation of Formula II, n is 0, and m is 0.
In one variation of Formula II, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula II, Y2 is hydroxymethyl.
In one variation of Formula II, Y2 is hydroxymethyl and Y1 is methyl.
In one variation of Formula II, Y2 is hydroxymethyl, n is 0, and m is 0.
In one variation of Formula II, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula II, Q is NH.
In one variation of Formula II, Q is CH2.
In one variation of Formula II, Q is NH, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula II, Q is CH2, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula II, Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one variation of Formula II, Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH2, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula II, R is -R!-R2-R3; wherein R1 is phenyl or pyridyl; R2 is - C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one variation of Formula II, R is -R!-R2-R3; wherein R1 is phenyl or pyridyl; R2 is - C(=O); R3 is R4; R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl; Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH2, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0. In one variation of Formula II, R is R1; wherein R1 is pyrazolyl, optionally substituted with
R1'.
In one variation of Formula II, R is R1; R1 is pyrazolyl, optionally substituted with R1 ; Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl; Q is CH2, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula II, Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one variation of Formula II, Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl; Q is CH2, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula II, R is -R!-R2-R3; wherein R1 is phenyl or pyridyl; R2 is -
C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In one variation of Formula II, R is -R!-R2-R3; wherein R1 is phenyl or pyridyl; R2 is - C(=O); R3 is R4; R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl; Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl; Q is CH2, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one variation of Formula II, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one variation of Formula II, R is R1; R1 is pyrazolyl, optionally substituted with R1 ; Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl; Q is CH2, Y2 is hydroxy- methyl, Y1 is methyl, n is 0, and m is 0.
In another embodiment, the invention provides a compound of Formula II, wherein:
R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R1 ; wherein R1 is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl;
R2 is -C(=O), -C(=O)O, -C(=O)N(R2'), -(CH2)q, or -S(=O)2; wherein R2' is H or lower alkyl; q is 1, 2, or 3; R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
Q is CH2, CH(Y ) or NH; wherein Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; Y1 is H or lower alkyl;
Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3.
Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y4 is Y4a, Y4b, Y4c, or Y4d; Y4"1 is H or halogen;
Y413 is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y40 is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y411 is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof (compounds of Formula IF).
In one embodiment of Formula II', Y1 is methyl.
In one embodiment of Formula II', Y2 is hydroxymethyl. In one embodiment of Formula II', n is 0, and m is 0.
In one embodiment of Formula II', Y2 is hydroxymethyl, n is 0, and m is 0.
In one embodiment of Formula II', Y1 is methyl, n is 0, and m is 0.
In one embodiment of Formula II', Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one embodiment of Formula II', Q is NH.
In one embodiment of Formula II', Q is NH, Y1 is methyl, n is 0, and m is 0.
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is NH, Y1 is methyl, n is 0, and m is 0.
In one embodiment of Formula II', Q is CH2.
In one embodiment of Formula II', Q is CH2, Y1 is methyl, n is 0, and m is 0.
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is CH2, Y1 is methyl, n is 0, and m is 0.
In one embodiment of Formula II', Y2 is methyl.
In one embodiment of Formula II', Y2 is hydroxyethyl.
In one embodiment of Formula II', Y2 is halogen.
In one embodiment of Formula II', Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is CH2, Y1 is methyl, n is 0, and m is 0, and Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula II' R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl. In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH;
R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula II', R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is NH, Y1 is methyl, n is 0, and m is 0, and Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one embodiment of Formula II', Y4 is lower alkyl.
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is CH2, Y1 is methyl, n is 0, and m is 0, and Y4 is lower alkyl.
In one variation of the above embodiment of Formula II' R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is NH, Y1 is methyl, n is 0, and m is 0, and Y4 is lower alkyl.
In one variation of the above embodiment of Formula II' R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula II', R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula II', Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl. In one embodiment of Formula II', Y2 is hydroxymethyl, Q is CH2, Y1 is methyl, n is 0, and m is 0, and Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula II', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula II', R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is NH, Y1 is methyl, n is 0, and m is 0, and Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula II', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula II', R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula II', Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is CH2, Y1 is methyl, n is 0, and m is 0, and Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one variation of the above embodiment of Formula II', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl. In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH;
R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula II', R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula II', Y2 is hydroxymethyl, Q is NH, Y1 is methyl, n is 0, and m is 0, and Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one variation of the above embodiment of Formula II', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula II', R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula II', Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one embodiment of Formula II', Q is CH2, Y1 is methyl, n is 0, and m is 0, and Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula II', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula II', R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula II', Q is NH, Y1 is methyl, n is 0, and m is 0, and Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl. In one variation of the above embodiment of Formula II', R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula II', R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula II', R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In another embodiment, the invention provides a compound of Formula III, wherein: R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3; wherein R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R1 ; wherein R1 is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -C(=O)N(R2'), -(CH2)q, or -S(=O)2; wherein R2' is H or lower alkyl; q is 1, 2, or 3; R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
Y1 is H or lower alkyl;
Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3;
Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is O or l;
Y4 is Y43, Y413, Y4c, or Y4"; wherein Y43 is H or halogen;
Y4h is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula III, Y1 is methyl.
In one embodiment of Formula III, n is 0 and m is 0.
In one embodiment of Formula III, Y2 is hydroxymethyl
In one embodiment of Formula III, Y1 is methyl, n is 0 and m is 0.
In one embodiment of Formula III, Y2 is hydroxymethyl, Y1 is methyl, n is 0 and m is 0.
In one embodiment of Formula III, Y2 is methyl.
In one embodiment of Formula III, Y2 is hydro xyethyl.
In one embodiment of Formula III, Y2 is halogen.
In one embodiment of Formula III, Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one embodiment of Formula III, Y2 is hydroxymethyl, Y1 is methyl, n is 0, m is 0, and Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula III, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula III, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl. In yet another variation of the above embodiment of Formula III, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula III, Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one embodiment of Formula III, Y2 is hydroxymethyl, Y1 is methyl, n is 0, m is 0, and Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula III, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula III, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula III, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula III, Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one embodiment of Formula III, Y2 is hydroxymethyl, Y1 is methyl, n is 0, m is 0, and Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one variation of the above embodiment of Formula III, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula III, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula III, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula III, Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl. In one embodiment of Formula III, Y2 is hydroxymethyl, Y1 is methyl, n is 0, m is 0, and Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula III, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula III, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula III, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In another embodiment, the invention provides a compound of Formula IV, wherein: R is H, -R1, -R!-R2-R3, -R!-R3, or -R2-R3; wherein
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R1 ; wherein R1 is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -C(=O)N(R2'), -(CH2)q, or -S(=O)2; wherein R2' is H or lower alkyl; q is 1, 2, or 3; R3 is H or R4; R4 is lower alkyl, lower alkoxy, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl; Y1 is H or lower alkyl;
Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3. Y is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y4 is Y43, Y4b, Y4c, or Y4"; wherein Y4a is H or halogen; Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula IV, Y1 is methyl.
In one embodiment of Formula IV, n is 0 and m is 0.
In one embodiment of Formula IV, Y2 is hydroxymethyl.
In one embodiment of Formula IV, Y1 is methyl, n is 0 and m is 0.
In one embodiment of Formula IV, Y2 is hydroxymethyl, Y1 is methyl, n is 0 and m is 0.
In one embodiment of Formula IV, Y2 is methyl.
In one embodiment of Formula IV, Y2 is hydroxyethyl.
In one embodiment of Formula IV, Y2 is halogen.
In one embodiment of Formula IV, Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one embodiment of Formula IV, Y2 is hydroxymethyl, Y1 is methyl, n is 0, m is 0, and Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl. In one variation of the above embodiment of Formula IV, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula IV, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula IV, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula IV, Y4 is lower alkyl.
In one embodiment of Formula IV, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0, and Y4 is lower alkyl.
In one variation of the above embodiment of Formula IV R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula IV, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula IV, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula IV, Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one embodiment of Formula IV, Y2 is hydroxymethyl, Y1 is methyl, n is 0, m is 0, and Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula IV, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula IV, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl. In yet another variation of the above embodiment of Formula IV, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula IV, Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one embodiment of Formula IV, Y2 is hydroxymethyl, Y1 is methyl, n is 0, m is 0, and Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one variation of the above embodiment of Formula IV, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula IV, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula IV, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula IV, Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one embodiment of Formula IV, Y2 is hydroxymethyl, Y1 is methyl, n is 0, m is 0, and Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula IV, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula IV, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula IV, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In another embodiment the invention provides a compound of Formula V, wherein: R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3; R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R1 ; wherein R1 is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl;
R2 is -C(=O), -C(=O)O, -C(=O)N(R2'), -(CH2),, or -S(=O)2; wherein R2' is H or lower alkyl; q is 1, 2, or 3;
R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
Q is CH2, CH(Y ) or NH; wherein Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; Y1 is H or lower alkyl;
Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3.
Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y4 is Y43, Y4b, Y40^r Y4"; Y4a is H or halogen;
Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and Y4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of Formula V, Y1 is methyl.
In one embodiment of Formula V, Q is CH2.
In one embodiment of Formula V, Y2 is hydroxymethyl.
In one embodiment of Formula V, n is 0, and m is 0.
In one embodiment of Formula V, Y2 is hydroxymethyl, n is 0, and m is 0.
In one embodiment of Formula V, Y1 is methyl, n is 0, and m is 0.
In one embodiment of Formula V, Y1 is methyl, Q is CH2, n is 0, and m is 0.
In one embodiment of Formula V, Y2 is hydroxymethyl, Y1 is methyl, n is 0, and m is 0.
In one embodiment of Formula V, Y2 is hydroxymethyl, Y1 is methyl, Q is CH2, n is 0, and m is O.
In one embodiment of Formula V, Y2 is methyl.
In one embodiment of Formula V, Y2 is hydroxyethyl.
In one embodiment of Formula V, Y2 is halogen.
In one embodiment of Formula V, Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one embodiment of Formula V, Y2 is hydroxymethyl, Y1 is methyl, Q is CH2, n is 0, and m is 0, and Y4 is group (a) wherein Y5 is H, halogen, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula V R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula V, R is -R2-R3; R2 is -C(=O)NH;
R3 is H or R4; and R4 is lower alkyl. In yet another variation of the above embodiment of Formula V, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula V, Y4 is lower alkyl.
In one embodiment of Formula V, Y2 is hydroxymethyl, Y1 is methyl, Q is CH2, n is 0, and m is 0, and Y4 is lower alkyl.
In one variation of the above embodiment of Formula V R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula V, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula V, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula V, Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one embodiment of Formula V, Y2 is hydroxymethyl, Y1 is methyl, Q is CH2, n is 0, and m is 0, and Y4 is group (c) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula V, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula V, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula V, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula V, Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl. In one embodiment of Formula V, Y2 is hydroxymethyl, Y1 is methyl, Q is CH2, n is 0, and m is 0, and Y4 is group (b) wherein Y5 and Y6 are independently H or lower alkyl.
In one variation of the above embodiment of Formula V, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula V, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula V, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
In one embodiment of Formula V, Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one embodiment of Formula V, Y1 is methyl, Q is CH2, n is 0, and m is 0, and Y4 is group (d) wherein Y5 and Y6 are independently H, lower alkyl, or lower haloalkyl.
In one variation of the above embodiment of Formula V, R is -R!-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=O); R3 is R4; and R4 is morpholine or piperazine, optionally substituted with one or more lower alkyl.
In another variation of the above embodiment of Formula V, R is -R2-R3; R2 is -C(=O)NH; R3 is H or R4; and R4 is lower alkyl.
In yet another variation of the above embodiment of Formula V, R is R1; and R1 is pyrazolyl, optionally substituted with R1 .
The invention provides a method for treating an inflammatory and/or autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of the Btk inhibitor compound of any one of the above Formulae I-V or variations thereof.
The invention provides a method for treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of any one of the above Formulae I-V or variations thereof. The invention provides a method of inhibiting B-cell proliferation comprising administering to a patient in need thereof a therapeutically effective amount of any one of the above Formulae I-V or variations thereof.
The invention provides a method for treating an inflammatory condition comprising co- administering to a patient in need thereof a therapeutically effective amount of an antiinflammatory compound in combination with any one of the above Formulae I-V or variations thereof.
The invention provides a method for treating arthritis comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound in combination with any one of the above Formulae I-V or variations thereof.
The invention provides a method for treating a lymphoma or a BCR-ABLl+ leukemia cells by administering to a patient in need thereof a therapeutically effective amount of any one of the above Formulae I-V or variations thereof.
The invention provides a pharmaceutical composition comprising the Btk inhibitor compound of any one of the above Formulae I-V or variations thereof, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.
The invention provides a method for treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of the Btk inhibitor compound any one of the above Formulae I-V or variations thereof.
The invention provides a method for inhibiting Btk activity comprising administering the Btk inhibitor compound of any one of the above Formulae I-V or variations thereof, wherein the Btk inhibitor compound exhibits an IC50 of 50 micromolar or less in an in vitro biochemical assay of Btk activity.
In one variation of the above method, the Btk inhibitor compound exhibits an IC50 of 100 nanomolar or less in an in vitro biochemical assay of Btk activity.
In one variation of the above method, the compound exhibits an IC50 of 10 nanomolar or less in an in vitro biochemical assay of Btk activity. The invention provides a method for treating arthritis comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound in combination with the Btk inhibitor compound of any one of the above Formulae I-V or variations thereof.
The present invention provides compounds of generic Formulae I-V, which comprise the Btk inhibitor compounds of Formulae I-V, wherein variables Q, R, Y1, Y2, Y3, Y4, n, and m are as defined herein above.
In one embodiment of the present invention, there is provided a compound according to generic Formula I which comprises the exemplified Btk inhibitor compound of Formula 1-1. In another embodiment of the present invention, there is provided a compound according to generic Formula II which comprises the exemplified Btk inhibitor compounds of Formulae II-l to 11-36.
In yet another embodiment of the present invention, there is provided a compound according to generic Formula III which comprises Btk inhibitor compounds of Formula III. In yet another embodiment of the present invention, there is provided a compound according to generic Formula IV which comprises Btk inhibitor compounds of Formula IV. In yet another embodiment of the present invention, there is provided a compound according to generic Formula V which comprises Btk inhibitor compounds of Formula V.
The phrase "as defined herein above" refers to the broadest definition for each group as provided herein or the broadest claim. In all other aspects, variations and embodiments provided, substituents which can be present in each embodiment and which are not explicitly defined retain the broadest definition provided herein.
The compounds of generic Formulae I-V inhibit Bruton's tyrosine kinase (Btk). Activation of Btk by upstream kinases results in activation of phospholipase-Cγ which, in turn, stimulates release of pro-inflammatory mediators. The compounds of generic Formulae I-V, incorporating substituted side chains of 3,4-Dihydro-2H-isoquinolin-l-one, 2,3-Dihydro-lH- quinazolin-4-one, 2H-Isoquinolin-l-one, 3H-Quinazolin-4-one, lH-Quinolin-4-one, 2H- Phthalazin-1-one, or 3,4-Dihydro-2H-benzo[e][l,2]thiazine 1,1-dioxide on the 5-phenyl-lH- pyrazin-2-one ring systems, exhibit unexpectedly enhanced inhibitory activity compared to analogues without said bicyclic side chains. Furthermore, inhibitory activity is enhanced when Y2 is lower alkyl optionally substituted with hydroxy. Inhibitory activity is enhanced when Y2 is hydroxymethyl. Compounds of Formulae I-V are useful in the treatment of arthritis and other anti-inflammatory and auto-immune diseases. Compounds according to Formulae I-V are, accordingly, useful for the treatment of arthritis. Compounds of Formulae I-V are useful for inhibiting Btk in cells and for modulating B-cell development. The present invention further comprises pharmaceutical compositions containing compounds of Formulae I-V admixed with pharmaceutically acceptable carrier, excipients or diluents.
The phrase "a" or "an" entity as used herein refers to one or more of that entity; e.g., a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein.
The phrase "as defined herein above" refers to the broadest definition for each group as provided herein or the broadest claim. In all other embodiments provided below, substituents which can be present in each embodiment and which are not explicitly defined retain the broadest definition provided herein.
As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
As used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and/or" and not the "exclusive" sense of "either/or".
The term "independently" is used herein to indicate that a variable is applied in any one instance without regard to the presence or absence of a variable having that same or a different definition within the same compound. Thus, in a compound in which R" appears twice and is defined as "independently carbon or nitrogen", both R"s can be carbon, both R"s can be nitrogen, or one R" can be carbon and the other nitrogen. When any variable occurs more than one time in any moiety or formula depicting and describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.
The symbols "*" at the end of a bond or " " drawn through a bond each refer to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part. Thus, e.g.:
MeC(=O)OR4 wherein R4 = *— <] or -j-<] ]> MeC(=O)O— <]
A bond drawn into ring system (as opposed to connected at a distinct vertex) indicates that the bond may be attached to any of the suitable ring atoms.
The term "optional" or "optionally" as used herein means that a subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted" means that the optionally substituted moiety may incorporate a hydrogen or a substituent.
The phrase "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds. If a substituent is designated to be a "bond" or "absent", the atoms linked to the substituents are then directly connected.
The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%.
Certain compounds of formulae I-V may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto/enol (-C(=O)-CH- Δ -COOH)=CH-), amide/imidic acid (-C(=O)-NH- Δ -C(- OH)=N-) and amidine (-C(=NR)-NH- Δ -C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds.
Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill Companies Inc., New York (2001). Any suitable materials and/or methods known to those of skill can be utilized in carrying out the present invention. However, preferred materials and methods are described. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise noted.
The definitions described herein may be appended to form chemically-relevant combinations, such as "heteroalkylaryl," "haloalkylheteroaryl," "arylalkylheterocyclyl," "alkylcarbonyl," "alkoxyalkyl," and the like. When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl," or "hydroxyalkyl," this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically- named group. Thus, e.g., "phenylalkyl" refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. An "alkylaminoalkyl" is an alkyl group having one to two alkylamino substituents. "Hydroxyalkyl" includes 2- hydroxyethyl, 2-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3- dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups defined below. The term -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group. The term (hetero)aryl or (het)aryl refers to either an aryl or a heteroaryl group.
The term "acyl" as used herein denotes a group of formula -C(=O)R wherein R is hydrogen or lower alkyl as defined herein. The term or "alkylcarbonyl" as used herein denotes a group of formula C(=O)R wherein R is alkyl as defined herein. The term C1-6 acyl refers to a group -C(=O)R contain 6 carbon atoms. The term "arylcarbonyl" as used herein means a group of formula C(=O)R wherein R is an aryl group; the term "benzoyl" as used herein an "arylcarbonyl" group wherein R is phenyl.
The term "alkyl" as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "Ci-io alkyl" as used herein refers to an alkyl composed of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, /-propyl, «-butyl, /-butyl, ^-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl," or
"hydroxyalkyl," this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, e.g., "phenylalkyl" denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are interpreted similarly except R' is an aryl radical. The terms "(het)arylalkyl" or "(het)aralkyl" are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.
The term "alkylene" or "alkylenyl" as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH2)n)or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH(Z-Pr)CH2-), unless otherwise indicated. Except in the case of methylene, the open valences of an alkylene group are not attached to the same atom. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2- ethylbutylene. The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, «-propyloxy, z-propyloxy, «-butyloxy, z-butyloxy, ^-butyloxy, pentyloxy, hexyloxy, including their isomers. "Lower alkoxy" as used herein denotes an alkoxy group with a "lower alkyl" group as previously defined. "C1-K) alkoxy" as used herein refers to an-O-alkyl wherein alkyl is C1-10.
The term "alkoxyalkyl" as used herein refers to the radical R'R"-, wherein R' is an alkoxy radical as defined herein, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the alkoxyalkyl moiety will be on the alkylene radical. C1-6 alkoxyalkyl denotes a group wherein the alkyl portion is comprised of 1-6 carbon atoms exclusive of carbon atoms in the alkoxy portion of the group. C1-3 alkoxy-Ci_6 alkyl denotes a group wherein the alkyl portion is comprised of 1-6 carbon atoms and the alkoxy group is 1-3 carbons. Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, t-butyloxybutyl, methoxypentyl, ethoxypentyl, propyloxypentyl including their isomers .
The term "heteroalkoxy" as used herein means an -O-(heteroalkyl) group wherein heteroalkyl is defined herein. C1-K) heteroalkoxy" as used herein refers to an-O-(heteroalkyl) wherein alkyl is C1-10. Representative examples include, but are not limited to, 2- dimethylaminoethoxy and 3-sulfonamido-l-propoxy.
The term "hydroxyalkyl" as used herein denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydro xyl groups.
"Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, naph- thyl, phenanthryl, fluorenyl, indenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzodioxylyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzo- pyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like. The aryl group may optionally be fused to a cycloalkyl or hetero eye Io alkyl ring, as herein defined. Examples of an aryl group fused to a hetero eye Io alkyl group include 3,4-dihydro- lH-quinolin-2-one, 3,4-dihydro-2H-benzo[l,4]oxazine, and 1,2,3,4-tetrahydro-isoquinoline. Preferred aryl include optionally substituted phenyl and optionally substituted naphthyl.
The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C3-7 cycloalkyl" as used herein refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.
The term "heteroaryl" or "hetero aromatic" as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. As well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower halo alkoxy, alkylthio, halogen, lower haloalkyl, alkylsulfmyl, alkylsulfonyl, halogen, amino, alkylamino, dialkyl- amino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole. Bicyclic moieties can be optionally substituted on either ring; however the point of attachment is on a ring containing a heteroatom.
The term "heterocycloalkyl", "heterocyclyl", or "heterocycle" as used herein denotes a monovalent saturated cyclic radical, consisting of one or more fused or spirocyclic rings, preferably one to two rings, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,0 or S(0)o-2), and which can optionally be independently sub- stituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkyl- aminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylamino- carbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 1 ,4- dimethyl-piperazin-2-one, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.
Commonly used abbreviations include: acetyl (Ac), azo-Ms-isobutyrylnitrile (AIBN), atmospheres (Arm), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), tert-butoxycarbonyl (Boc), di-tert-buty\ pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), l,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2- dichloroethane (DCE), dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di-iso- propylazodicarboxylate (DIAD), di-ώo-butylaluminumhydride (DIBAL or DIBAL-H), di- iso-propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylamino- pyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1'-Ms- (diphenylphosphino)ethane (dppe), l,l'-Ms-(diphenylphosphino)ferrocene (dppf), l-(3-di- methylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-l-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazole-l-yl)-N, N,N'N'-tetramethyluronium hexa- fluorophosphate acetic acid (ΗATU), acetic acid (HO Ac), 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), ώo-propanol (IPA), lithium hexamethyl disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (mesyl or Ms), , methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl ^-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxyanhydride (NCA), N- chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), ώo-propyl (/-Pr), pounds per square inch (psi), pyridine (pyr), room temperature (rt or RT), tert-butyldimethylsilyl or ^-BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6,6- tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF3SO2- (Tf), trifluoroacetic acid (TFA), l,r-δw-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetra- hydrofuran (THF), trimethylsilyl or Me3Si (TMS), />toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- ortosyl (Ts), N-urethane-N-carboxyanhydride (UNCA),. Conventional nomenclature including the prefixes normal («), iso (i-), secondary (sec-), tertiary (tert-) and neo have their customary meaning when used with an alkyl moiety. (Rigaudy and Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).
The term "arthritis" as used herein means acute rheumatic arthritis, chronic rheumatoid arthritis, chlamydial arthritis, chronic absorptive arthritis, chylous arthritis, arthritis based on bowel disease, filarial arthritis, gonorrheal arthritis, gouty arthritis, hemophilic arthritis, hypertrophic arthritis, juvenile chronic arthritis, Lyme arthritis, neonatal foal arthritis, nodular arthritis, ochronotic arthritis, psoriatic arthritis or suppurative arthritis, or the related diseases which require the administration to a mammal in a therapeutic effective dose of a compound of Formulae I-V in a sufficient dose to inhibit BTK.
The compounds of this invention can be used to treat subjects with autoimmune conditions or disorders. As used herein, the term "autoimmune condition" and like terms means a disease, disorder or condition caused by the immune system of an animal. Autoimmune disorders are those wherein the animal's own immune system mistakenly attacks itself, thereby targeting the cells, tissues, and/or organs of the animal's own body. For example, the autoimmune reaction is directed against the nervous system in multiple sclerosis and the gut in Crohn's disease. In other autoimmune disorders such as systemic lupus erythematosus (lupus), affected tissues and organs may vary among individuals with the same disease. One person with lupus may have affected skin and joints whereas another may have affected skin, kidney, and lungs. Ultimately, damage to certain tissues by the immune system may be permanent, as with destruction of insulin-producing cells of the pancreas in Type 1 diabetes mellitus. Specific autoimmune disorders that may be ameliorated using the compounds and methods of this invention include without limitation, autoimmune disorders of the nervous system (e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barre, and autoimmune uveitis), autoimmune disorders of the blood (e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia), autoimmune disorders of the blood vessels (e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, and Behcet's disease), autoimmune disorders of the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo), autoimmune disorders of the gastrointestinal system (e.g., Crohn's disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis), autoimmune disorders of the endocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus, Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland); and autoimmune disorders of multiple organs (including connective tissue and musculoskeletal system diseases) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren's syndrome) or the related diseases which require the administration to a mammal in a therapeutic effective dose of a compound of Formulae I-V in a sufficient dose to inhibit BTK. In addition, other immune system mediated diseases, such as graft-versus-host disease and allergic disorders, are also included in the definition of immune disorders herein. Because a number of immune disorders are caused by inflammation, there is some overlap between disorders that are considered immune disorders and inflammatory disorders. For the purpose of this invention, in the case of such an overlapping disorder, it may be considered either an immune disorder or an inflammatory disorder. "Treatment of an immune disorder" herein refers to administering a compound or a composition of the invention to a subject, who has an immune disorder, a symptom of such a disease or a predisposition towards such a disease, with the purpose to cure, relieve, alter, affect, or prevent the autoimmune disorder, the symptom of it, or the predisposition towards it.
As used herein, the term "asthma" means a pulmonary disease, disorder or condition characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness to a variety of stimuli.
The terms "treat," "treatment," or "treating" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. For example, treating an inflammatory condition means reducing the extent or severity of the inflammation. The reduction can mean but is not limited to the complete ablation of inflammation. For example, the reduction can comprise a 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction, or any point in between, compared to an untreated or control subject as determined by any suitable measurement technique or assay disclosed herein or known in the art.
Examples of representative compounds encompassed by the present invention and within the scope of the invention are provided in the following Table. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
In general, the nomenclature used herein is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. If there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, e.g., bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
TABLE I depicts examples of pyrazinone compounds according to generic Formulae I-II:
Nomenclature
6-Cyclopropyl-2-(2-hydroxymethyl-3-{4- methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin-
2-yl}-phenyl)-2H-isoquinolin-l-one
Figure imgf000044_0001
II- 1 π-2 π-3
π-4 π-5 [4-
Figure imgf000045_0001
π-6 π-7 π-8
π-9
π- io
Figure imgf000046_0001
II- 11 6-(l-Fluoro-cyclopropyl)-2-(2- hydroxymethyl-3- {4-methyl-6-[4- (morpholine-4-carbonyl)-phenylamino]-5- oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)- 3 ,4-dihydro-2H-isoquinolin- 1 -one MP: 172.0-174.0; MS (M + Η): 624
II- 12 6-Cyclopropyl-2-(2-hydroxymethyl-3-{6- [4-(4-hydroxy-piperidine- 1 -carbonyl)- phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2 -yl} -phenyl)-3 ,4- dihydro-2H-isoquinolin- 1 -one MP: 171.0-173.0; MS (M + Η): 620
II- 13 6-Cyclopropyl-2-(2-hydroxymethyl-3-{6- [4-(4-methoxy-piperidine- 1 -carbonyl)- phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2 -yl} -phenyl)-3 ,4- dihydro-2H-isoquinolin- 1 -one MP: 146.0-148.0; MS (M + Η): 634
II- 14 6-Cyclopropyl-2-(2-hydroxymethyl-3-{4- methyl-6-[4-(4-methyl-piperazine- 1 - carbonyl)-phenylamino]-5-oxo-4,5- dihydro-pyrazin-2-yl}-phenyl)-3,4-di- hydro-2H-isoquinolin- 1 -one
Figure imgf000047_0001
MP: 172.0-175.0; MS (M + Η): 619
4-{6-[3-(6-Cyclopropyl-l -oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -N-(2- hydroxy-ethyl)-7V-methyl-benzamide MP: 115.0-117.0; MS (M + Η): 594
6-Cyclopropyl-2-[3-(6-{4-[4-(2-hydroxy- ethyl)-piperazine- 1 -carbonyl]-phenyl- amino}-4-methyl-5-oxo-4,5-dihydro-pyr- azin-2-yl)-2-hydroxymethyl-phenyl]-3,4- dihydro-2H-isoquinolin- 1 -one MP: 175.0-180.1; MS (M + Η): 649
6-Cyclopropyl-2-(3-{6-[4-(2,6-dimethyl- moφholine-4-carbonyl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-
2-hydroxymethyl-phenyl)-3,4-dihydro-
2H-isoquinolin-l-one
MP: 173.0-175.0; MS (M + Η): 634
6-Cyclopropyl-2-(3-{6-[4-(l,l-dioxo-lλ6- thiomorpholine-4-carbonyl)- phenylamino]-4-methyl-5-oxo-4,5-di- hydro-pyrazin-2-yl}-2-hydroxymethyl- phenyl)-3 ,4-dihydro-2H-isoquinolin- 1 -one MS (M + Η): 653
Figure imgf000048_0001
II- 19 π-20 π-2i π-22
Figure imgf000049_0001
π-23 2-(3-{6-[4-(4-Acetyl-piperazine-l- carbonyl)-phenylamino]-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl}-2-hydroxy- methyl-phenyl)-6-cyclopropyl-3,4- dihydro-2H-isoquinolin- 1 -one
π-24 6-Cyclopropyl-2-(2-hydroxymethyl-3-{4- methyl-5-oxo-6-[4-(3-oxo-piperazine-l- carbonyl)-phenylamino]-4,5-dihydro- pyrazin-2-yl} -phenyl)-3 ,4-dihydro-2H- isoquinolin-1-one
π-25 6-Cyclopropyl-2-(3-{6-[4-(4,4-difluoro- piperidine- 1 -carbonyl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}- 2-hydroxymethyl-phenyl)-3,4-dihydro- 2H-isoquinolin-l-one
π-26 2-(3-{6-[4-(4-Amino-piperidine-l- carbonyl)-phenylamino]-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl}-2-hydroxy- methyl-phenyl)-6-cyclopropyl-3,4- dihydro-2H-isoquinolin- 1 -one
Figure imgf000050_0001
11-27 6-Cyclopropyl-2-(2-hydroxymethyl-3-{6- [4-(4-hydroxy-4-methyl-piperidine-l- carbonyl)-phenylamino]-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4- dihydro-2H-isoquinolin- 1 -one
π-28 4-{6-[3-(6-Cyclopropyl-l-oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -N-(2- methoxy-ethyl)-N-methyl-benzamide
π-29 4-{6-[3-(6-Cyclopropyl-l-oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -N-ethyl- N-methyl-benzamide
π-30 6-Cyclopropyl-2-(2-hydroxymethyl-3-{4- methyl-6-[4-(4-methyl-piperazin-l-yl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin- 2-yl} -phenyl)-3,4-dihydro-2H- isoquinolin-1-one
Figure imgf000051_0001
π-3i - - -
Figure imgf000052_0001
π-32 6 -Dimethylamino-2 -(3 - {6- [4-(4-ethyl- piperazine- 1 -carbonyl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}- 2-hydroxymethyl-phenyl)-3,4-dihydro- 2H-isoquinolin-l-one
π-33 4-{6-[3-(6-Cyclopropyl-l-oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -N,N-bis- (2-methoxy-ethyl)-benzamide
π-34 4-{6-[3-(6-Cyclopropyl-l-oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -N-(2- methoxy-ethyl)-benzamide
Figure imgf000052_0002
π-35 4-{6-[3-(6-Cyclopropyl-l -oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -N,N-bis- (2-hydroxy-ethyl)-benzamide
π-36 6-tert-Butyl-2-(2-hydroxymethyl-3-{4- methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin- 2-yl} -phenyl)-3,4-dihydro-2H- isoquinolin-1-one
π-37 6-Cyclopropyl-2-(2-hydroxymethyl-3-{4- methyl-6-[4-(4-methyl-[l,4]diazepane-l- carbonyl)-phenylamino]-5-oxo-4,5- dihydro-pyrazin-2 -yl} -phenyl)-3 ,4- dihydro-2H-isoquinolin- 1 -one
π-38 4-{6-[3-(6-Cyclopropyl-l-oxo-3,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -N-ethyl- benzamide
Figure imgf000053_0001
π-39 6-Cyclopropyl-2-(2-hydroxymethyl-3-{6- [4-(4-isopropyl-piperazine- 1 -carbonyl)- phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2 -yl} -phenyl)-3 ,4- dihydro-2H-isoquinolin- 1 -one
π-40 6-Dimethylamino-2-(3-{6-[4-(4-ethoxy- piperidine- 1 -carbonyl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}- 2-hydroxymethyl-phenyl)-3,4-dihydro- 2H-isoquinolin-l-one
π-4i 6-Dimethylamino-2-(2-hydroxymethyl-3- {6-[4-(4-hydroxy-piperidine- 1 -carbonyl)- phenylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2 -yl} -phenyl)-3 ,4- dihydro-2H-isoquinolin- 1 -one
π-42 6-Cyclopropyl-2-(2-hydroxymethyl-3-{6- [4-(4-methoxymethyl-piperidine- 1 - carbonyl)-phenylamino]-4-methyl-5-oxo- 4,5-dihydro-pyrazin-2-yl}-phenyl)-3,4- dihydro-2H-isoquinolin- 1 -one
Figure imgf000054_0001
π-43 6-Cyclopropyl-2-(2-hydroxymethyl-3-{6- [l-(2-methoxy-ethyl)-lH-pyrazol-4-yl- amino]-4-methyl-5-oxo-4,5-dihydro-pyr- azin-2-yl} -phenyl)-3 ,4-dihydro-2H- isoquinolin-1-one
π-44 6-Cyclopropyl-2-(2-hydroxymethyl-3-{4- methyl-5-oxo-6-[l-(2,2,2-trifluoro-ethyl)- lH-pyrazol-4-ylamino]-4,5-dihydro- pyrazin-2-yl} -phenyl)-3 ,4-dihydro-2H- isoquinolin-1-one
11-45 2-(4- {ό-β-Cό-Cyclopropyl- l-oxo-3 ,4-di- hydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -pyrazol- 1 -yl)-N,N-dimethyl-acetamide
Figure imgf000055_0001
π-46 -
-
Figure imgf000055_0002
π-47 6-Dimethylamino-2-{2-hydroxymethyl-3- [4-methyl-5-oxo-6-(lH-pyrazol-3- ylamino)-4,5-dihydro-pyrazin-2-yl]- phenyl} -3,4-dihydro-2H-isoquinolin-l -
Figure imgf000055_0003
one π-48
π-49
π-50 π-51
Figure imgf000056_0001
- -
Figure imgf000057_0001
π-54 7-{6-[3-(6-Dimethylamino-l-oxo-3,4-di- hydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3,4-dihydro-pyrazin-2-ylamino}-3,4-di- hydro- lH-quinolin-2-one
π-55 6-tert-Butyl-2- {3-[6-(l -ethyl- lH-pyrazol- 4-ylamino)-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl]-2-hydroxymethyl-phenyl}- 3 ,4-dihydro-2H-isoquinolin- 1 -one
π-56 Chiral 6-Cyclopropyl-2-(3- {6-[4-((S)-3-ethoxy- pyrrolidine- 1 -carbonyl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}- 2-hydroxymethyl-phenyl)-3,4-dihydro- 2H-isoquinolin-l-one
Figure imgf000057_0002
π-57 Chiral 6-Cyclopropyl-2-(3-{6-[4-((R)-3-ethoxy- pyrrolidine- 1 -carbonyl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}- 2-hydroxymethyl-phenyl)-3,4-dihydro- 2H-isoquinolin-l-one
Figure imgf000058_0001
π-58 -
π-59 - [6 -
-
π-60 -
Figure imgf000058_0002
π-6i 2-(4- {6-[3 -(6-Dimethylamino- 1 -oxo-3 ,4- dihydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -pyrazol- 1 -yl)-N,7V-dimethyl-acetamide
π-62 6-Cyclopropyl-2-(3-{6-[3-fluoro-4-
(morpholine-4-carbonyl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-
2-hydroxymethyl-phenyl)-3,4-dihydro-
2H-isoquinolin-l-one
π-63 6-Dimethylamino-2-{3-[6-(3-fluoro-4- moφholin-4-yl-phenylamino)-4-methyl- 5-oxo-4,5-dihydro-pyrazin-2-yl]-2- hydroxymethyl-phenyl} -3 ,4-dihydro-2H- isoquinolin-1-one
π-64 2-[3-(6-{4-[Bis-(2-hydroxy-ethyl)- amino]-phenylamino}-4-methyl-5-oxo- 4 ,5 -dihydro-pyrazin-2 -yl)-2 -hydroxy- methyl-phenyl]-6-dimethylamino-3,4- dihydro-2H-isoquinolin- 1 -one
Figure imgf000059_0001
Figure imgf000060_0001
π-70 6-Cyclopropyl-2-(3- {6-[l -(2,2-difluoro- ethyl)-lH-pyrazol-4-ylamino]-4-methyl-
5-oxo-4,5-dihydro-pyrazin-2-yl}-2- hydroxymethyl-phenyl)-3,4-dihydro-2H- isoquinolin-1-one
11-71 2-(4- {ό-β-Cό-Cyclopropyl- l-oxo-3 ,4-di- hydro-lH-isoquinolin-2-yl)-2- hydroxymethyl-phenyl]-4-methyl-3-oxo- 3 ,4-dihydro-pyrazin-2-ylamino} -pyrazol- 1 -yl)-7V-methyl-acetamide
II- 6-Dimethylamino-2-{2-hydroxymethyl-3- [4-methyl-5-oxo-6-(l -propyl- lH-pyrazol- 4-ylamino)-4,5-dihydro-pyrazin-2-yl]- phenyl} -3,4-dihydro-2H-isoquinolin-l - one
π-73 2-{3-[6-(l-Cyclobutylmethyl-lH-pyrazol- 4-ylamino)-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl]-2-hydroxymethyl-phenyl}- 6 -dimethylamino-3 ,4-dihydro-2H- isoquinolin-1-one
π-74 6 -Cyclopropyl-2- {2 -hydroxymethyl-3 - [4- methyl-5-oxo-6-(l-propyl-lH-pyrazol-4- ylamino)-4,5-dihydro-pyrazin-2-yl]- phenyl} -3,4-dihydro-2H-isoquinolin-l - one
Figure imgf000061_0001
π-75
Figure imgf000062_0001
11-76 2-{3-[6-(3,4-Dihydro-2H- benzo[l,4]oxazin-6-ylamino)-4-methyl-5- oxo-4,5-dihydro-pyrazin-2-yl]-2-hydroxy- methyl-phenyl} -6-dimethylamino-3 ,4-di- hydro-2H-isoquinolin- 1 -one
π-77 6-Cyclopropyl-2-(3- {6-[l -(2-hydroxy- ethyl)-lH-pyrazol-4-ylamino]-4-methyl-
5-oxo-4,5-dihydro-pyrazin-2-yl}-2- hydroxymethyl-phenyl)-3,4-dihydro-2H- isoquinolin-1-one
Figure imgf000062_0002
π-78
π-79
Figure imgf000062_0003
π-80 2-{3-[6-(l-Ethyl-lH-pyrazol-4-ylamino)-
4-methyl-5-oxo-4,5-dihydro-pyrazin-2- yl]-2-hydroxymethyl-phenyl} -6-( 1 - hydroxy- 1 -methyl-ethyl)-3 ,4-dihydro-2H- isoquinolin-1-one π-8i 6-Dimethylamino-2-(2-hydroxymethyl-3-
{4-methyl-6-[6-(4-methyl-piperazin-l-yl)- pyridin-3-ylamino]-5-oxo-4,5-dihydro- pyrazin-2-yl} -phenyl)-3 ,4-dihydro-2H- isoquinolin-1-one
π-82 6-Dimethylamino-2-{2-hydroxymethyl-3-
[4-methyl-5-oxo-6-(l,2,3,4-tetrahydro- isoquinolin-7-ylamino)-4,5-dihydro-pyr- azin-2-yl]-phenyl}-3,4-dihydro-2H-iso- quinolin-1-one
π-83 2-(3-{6-[l-(2,2-Difluoro-ethyl)-lH-pyr- azol-4-ylamino]-4-methyl-5-oxo-4,5-di- hydro-pyrazin-2-yl}-2-hydroxymethyl- phenyl)-6-(l -hydroxy-1 -methyl-ethyl)- 3 ,4-dihydro-2H-isoquinolin- 1 -one
π-84 2-(3-{6-[l-(2,2-Difluoro-ethyl)-lH-pyr- azol-4-ylamino]-4-methyl-5-oxo-4,5-di- hydro-pyrazin-2-yl}-2-hydroxymethyl- phenyl)-6-dimethylamino-3,4-dihydro-
2H-isoquinolin-l-one
Figure imgf000063_0001
π-85 6-Dimethylamino-2-(3-{6-[4-(2-dimethyl- amino-ethoxy)-phenylamino]-4-methyl-5- oxo-4,5-dihydro-pyrazin-2-yl} -2- hydroxymethyl-phenyl)-3,4-dihydro-2H- isoquinolin-1-one
π-86 2-[2-(3-{6-[l-(2,2-Difluoro-ethyl)-lH- pyrazol-4-ylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-hydroxymethyl- phenyl)- 1 -oxo- 1 ,2 ,3 ,4-tetrahydro- isoquinolin-6-yl]-2-methyl-propionitrile
π-87 6-Dimethylamino-2-(2-hydroxymethyl-3- {6-[l-(2-hydroxy-propyl)-lH-pyrazol-4- ylamino]-4-methyl-5-oxo-4,5-dihydro- pyrazin-2-yl} -phenyl)-3 ,4-dihydro-2H- isoquinolin-1-one
π-88 6-Dimethylamino-2-(3- {6-[4-(l ,4- dimethyl-3-oxo-piperazin-2-yl)- phenylamino]-4-methyl-5-oxo-4,5-di- hydro-pyrazin-2-yl}-2-hydroxymethyl- phenyl)-3 ,4-dihydro-2H-isoquinolin- 1 -one
π-89 2-(3-{6-[l-(2,3-Dihydroxy-propyl)-lH- pyrazol-4-ylamino]-4-methyl-5-oxo-4,5- dihydro-pyrazin-2-yl}-2-hydroxymethyl- phenyl)-6-dimethylamino-3,4-dihydro-
2H-isoquinolin-l-one
Figure imgf000064_0001
1-2 6-Dimethylamino-2-(2-hydroxymethyl-3- {4-methyl-6-[4-(morpholine-4-carbonyl)- phenylamino]-5-oxo-4,5-dihydro-pyrazin- 2-yl}-phenyl)-2H-isoquinolin-l-one
1-3 6-Cyclopropyl-2-{3-[6-(l-ethyl-lH- pyrazol-4-ylamino)-4-methyl-5-oxo-4,5- dihydro-pyrazin-2 -yl] -2 -hydroxymethyl- phenyl}-2H-isoquinolin-l-one
1-4 2-(4-{6-[3-(6-Dimethylamino- 1-oxo- IH- isoquinolin-2-yl)-2-hydroxymethyl-phen- yl]-4-methyl-3 -oxo-3 ,4-dihydro-pyrazin- 2-ylamino} -phenoxy)-N-methyl- acetamide
1-5 (4-{6-[3-(6-Cyclopropyl-l-oxo-lH-iso- quinolin-2 -yl) -2 -hydroxymethyl-phenyl] - 4-methyl-3-oxo-3,4-dihydro-pyrazin-2- ylamino} -pyrazol- 1 -yl)-acetic acid
1-6 6-Cyclopropyl-2-(2-hydroxymethyl-3-{4- methyl-6-[l -(I -methyl- lH-imidazol-2-yl- methyl)-lH-pyrazol-4-ylamino]-5-oxo- 4 ,5 -dihydro-pyrazin-2 -yl} -phenyl)-2H-
Figure imgf000065_0001
isoquinolin-1-one
The pyrazinone derivatives described herein are kinase inhibitors, in particular Btk inhibitors. These inhibitors can be useful for treating one or more diseases responsive to kinase inhibi- tion, including diseases responsive to Btk inhibition and/or inhibition of B-cell proliferation, in mammals. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of the invention with Btk results in the inhibition of Btk activity and thus in the pharmaceutical utility of these compounds. Accordingly, the invention in- eludes a method of treating a mammal, for instance a human, having a disease responsive to inhibition of Btk activity, and/or inhibiting B-cell proliferation, comprising administrating to the mammal having such a disease, an effective amount of at least one chemical entity provided herein. An effective concentration may be ascertained experimentally, e.g. by assaying blood concentration of the compound, or theoretically, by calculating bioavailability. Other kinases that may be affected in addition to Btk include, but are not limited to, other tyrosine kinases and serine/threonine kinases.
Kinases play notable roles in signaling pathways controlling fundamental cellular processes such as proliferation, differentiation, and death (apoptosis). Abnormal kinase activity has been implicated in a wide range of diseases, including multiple cancers, autoimmune and/or inflammatory diseases, and acute inflammatory reactions. The multifaceted role of kinases in key cell signaling pathways provides a significant opportunity to identify novel drugs targeting kinases and signaling pathways.
An embodiment includes a method of treating a patient having an autoimmune and/or inflammatory disease, or an acute inflammatory reaction responsive to inhibition of Btk activity and/or B-cell proliferation.
Autoimmune and/or inflammatory diseases that can be affected using compounds and compositions according to the invention include, but are not limited to: psoriasis, allergy, Crohn's disease, irritable bowel syndrome, Sjogren's disease, tissue graft rejection, and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA- associated and other vasculitides), autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), atherosclerosis, rheumatoid arthritis, chronic Idiopathic thrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, and myasthenia gravis, Included herein are methods of treatment in which at least one chemical entity provided herein is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclo- oxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate.
Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.
In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include by are not limited to acetyls alicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.
The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.
In additional embodiments the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin.
The invention also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydro- orotate dehydrogenase inhibitor, such as leflunomide.
Other embodiments of the invention pertain to combinations in which at least one anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizu- mab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody.
Still other embodiments of the invention pertain to combinations in which at least one active agent is an immunosuppressant compound such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.
B-cells and B-cell precursors expressing BTK have been implicated in the pathology of B- cell malignancies, including, but not limited to, B-cell lymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma), hairy cell lymphoma, multiple myeloma, chronic and acute myelogenous leukemia and chronic and acute lymphocytic leukemia.
BTK has been shown to be an inhibitor of the Fas/APO-1 (CD-95) death inducing signaling complex (DISC) in B-lineage lymphoid cellsτ The fate of leukemia/lymphoma cells may reside in the balance between the opposing proapoptotic effects of caspases activated by DISC and an upstream anti-apoptotic regulatory mechanism involving BTK and/or its substrates (Vassilev et al, J. Biol. Chem. 1998, 274, 1646-1656).
It has also been discovered that BTK inhibitors are useful as chemosensitizing agents, and, thus, are useful in combination with other chemotherapeutic drugs, in particular, drugs that induce apoptosis. Examples of other chemotherapeutic drugs that can be used in combination with chemosensitizing BTK inhibitors include topoisomerase I inhibitors (camptothecin or topotecan), topoisomerase II inhibitors (e.g. daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g. taxol and vinblastine), and biological agents (e.g. antibodies such as anti CD20 antibody, IDEC 8, immunotoxins, and cytokines).
Btk activity has also be associated with some leukemias expressing the bcr-abl fusion gene resulting from translocation of parts of chromosome 9 and 22. This abnormality is commonly observed in chronic myelogenous leukemia. Btk is constitutively phosphorylated by the bcr-abl kinase which initiates downstream survival signals which circumvents apoptosis in bcr-abl cells. (Feldhahn et al. J. Exp. Med. 2005 201(11):1837-1852)
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, syrups, or suspensions. Compounds of the present invention are efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intra- venous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration. The preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.
A compound or compounds of the present invention, as well as their pharmaceutically use- able salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal admini- stration; or in the form of sterile injectable solutions for parenteral use. A typical preparation will contain from about 5% to about 95% active compound or compounds (w/w). The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the desired dose and pharmacokinetic parameters.
The term "excipient" as used herein refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds of this invention can be administered alone but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.
"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise un- desirable and includes that which is acceptable for veterinary as well as human pharmaceutical use. A "pharmaceutically acceptable salt" form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient which were absent in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. The phrase "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane - sulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluene- sulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, tri ethanolamine, tromethamine, N-methylgluc amine, and the like.
Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, e.g., in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, e.g. bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-fϊlled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, e.g. solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, e.g., be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, e.g., by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, e.g., with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved e.g. by means of a metering atomizing spray pump.
The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size e.g. of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, e.g. by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluoro- carbon (CFC), e.g., dichlorodifiuoromethane, trichlorofiuoromethane, or dichlorotetrafluoro- ethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, e.g. a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form e.g. in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices.
These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The com- pound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecyl- aza-cycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polyactic acid.
Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the com- positions of the present invention unstable or compromising their therapeutic activity.
The modification of the present compounds to render them more soluble in water or other vehicle, e.g., may be easily accomplished by minor modifications (salt formulation, esteri- fication, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a par- ticular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients.
The term "therapeutically effective amount" as used herein means an amount required to reduce symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.01 and about 1000 mg/kg body weight per day should be appropriate in monotherapy and/or in combina- tion therapy. A preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day. Thus, for administration to a 70 kg person, the dosage range would be about 7 mg to 0.7 g per day. The daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the com- pound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures herein, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
EXAMPLES
General Scheme 1.
Figure imgf000074_0001
Figure imgf000075_0001
Example 1: 6-Dimethylamino-2-[3-(4,4,5,5-tetramethyl-[l,3?2]dioxaborolan-2-yl)- phenyl]-3,4-dihydro-2H-isoquinolin-l-one
2-(3-Bromo-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-l-one (163 mg, 0.472 mmol), bis(pinacolato)diboron (144mg, 0.567mmol), and potassium acetate (138mg,
1.42mmol) were deposited in a sealed vessel with 2mL DMSO. Argon was bubbled through the mixture for 1 minute. [1, l '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (12mg, 0.015mmol) was added. Argon was continued to bubble through the mixture for one more minute and the lid was tightly closed. This was heated at 800C for 18 hours. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexanes) to yield 6-Dimethylamino-2- [3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-l-one (137mg, 0.349mmol). MS (ESI) 393.2 (M+H)+.
Example 2: 6-bromo-3,4-dihydro-2H-isoquinolin-l-one
Methanesulfonic acid (31 mL, 10 equiv) was added to a mixture of 5-bromo-indan-l-one (10 g, 47 mmol) in CH2Cl2 (75 mL) at 00C. Sodium azide was added slowly in portions to this mixture. After the sodium azide addition was complete, the mixture was stirred for an additional 30 min, and an aqueous mixture of NaOH (20 wt%) was added until the mixture was slightly basic. The mixture was extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure. Purification of the mixture by flash column chromatography on silica gel (0% to 50% EtOAc/Hexanes then 0% to 7% MeOH/CH2Cl2) provided 6-bromo-3,4-dihydro-2H-isoquinolin-l-one (6.5 g, 61%).
Example 3: 6-Cyclopropyl-3,4-dihydro-2H-isoquinolin-l-one
A mixture of 6-bromo-3,4-dihydro-2H-isoquinolin-l-one (2.0 g, 8.8 mmol), cyclopropyl- boronic acid (1.14 g, 1.5 equiv), tricyclohexylphosphine (250 mg, 0.1 equiv), and K3PO4 (3.8 g, 2 equiv) in toluene (30 mL) and H2O (1.2 equiv) were heated under N2 briefly to 1000C. Pd(OAc)2 (100 mg, 0.05 equiv) was added, and the combined mixture was heated for 5 h at 1000C. The reaction mixture was cooled, filtered, and purified by flash column chromatography on silica gel to provide 6-Cyclopropyl-3,4-dihydro-2H-isoquinolin-l-one (1.57 g, 95%).
Example 4: 2-Bromo-6-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-benz- aldehyde
A sealable vial was charged with 6-cyclopropyl-3,4-dihydro-2H-isoquinolin-l-one (985 mg, 5 mmol), 2,6-dibromo-benzaldehyde (2.6 g, 2 equiv), Pd(dba)2 (58 mg, 0.02 equiv), xantphos (89 mg, 0.03 equiv), and cesium carbonate (2.28 g, 1.4 equiv). The vial was flushed with argon, dioxane (5 mL) was added, and the vial was capped. The mixture was stirred at 1000C for 1 day, diluted with EtOAc, filtered through a short bed of silica gel, and concentrated under reduced pressure. Purification of the mixture by flash column chromatography on silica gel provided 2-bromo-6-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)- benzaldehyde (1.05 g, 56%).
Example 5: 2-(3-Bromo-2-hydroxymethyl-phenyl)-6-cyclopropyl-3,4-dihydro-2H-iso- quinolin-1-one
Superhydride (22.4 mL, 1.75 equiv) was added dropwise to a solution of 2-bromo-6-(6-cyclo- propyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-benzaldehyde (4.75 g, 12.8 mmol) in THF (40 mL). The mixture was stirred for 30 min, and quenched by the slow addition of IN HCl. The aqueous mixture was extracted with CH2Cl2. The organic layers were concentrated and purified by flash column chromatography on silica gel to provide 2-(3-bromo-2-hydroxy- methyl-phenyl)-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-l-one (3.2 g, 67%).
Example 6: Acetic acid 2-bromo-6-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin- 2-yl)-benzyl ester
Acetic anhydride (121 uL, 1 equiv) was added to a mixture of 2-(3-bromo-2-hydroxymethyl- phenyl)-6-cyclopropyl-3,4-dihydro-2H-isoquinolin-l-one (475 mg, 1.27 mmol), DMAP (16 mg, 0.1 equiv), and TEA (178 uL, 1 equiv) in anhydrous CH2Cl2 (6 mL). The mixture was stirred for 1 h, and the volatile materials were removed by evaporation. Purification of the mixture by flash column chromatography on silica gel provided acetic acid 2-bromo-6-(6- cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-benzyl ester (525 mg, 100%).
Example 7: Acetic acid 2-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-6- (4,4,5,5-tetramethyl-[l,3?2]dioxaborolan-2-yl)-benzyl ester
A mixture of acetic acid 2-bromo-6-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)- benzyl ester (660 mg, 1.58 mmol), bis(pinacolato)diboron (490 mg, 1.2 equiv), (dppf)PdCl2- -CH2Cl2 (58 mg, 0.05 equiv), and potassium acetate (471 mg, 3 equiv) was heated to 800C under argon in a sealed vial overnight. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was separated and evaporated under reduced pressure. Purification of the mixture by flash column chromatography on silica gel provided acetic acid 2-(6- cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-6-(4,4,5,5-tetramethyl-[l,3,2]dioxa- borolan-2-yl)-benzyl ester (0.56 g, 77%).
Example 8: Acetic acid 2-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-6-{6- [4-(4-ethyl-piperazine-l-carbonyl)-phenylamino]-4-methyl-5-oxo-4,5-di- hydro-pyrazin-2-yl}-benzyl ester
Figure imgf000077_0001
A mixture of acetic acid 2-(6-cyclopropyl-l-oxo-3,4-dihydro-lH-isoquinolin-2-yl)-6- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl ester (46 mg, 0.1 mmol), 5-bromo-3- [4-(4-ethyl-piperazine-l-carbonyl)-phenylamino]-l -methyl- lH-pyrazin-2-one (42 mg, 1 equiv), Pd(dba)2 (2 mg, 0.03 equiv), XPhos (3 mg, 0.06 equiv), and K3PO4 (42 mg, 2 equiv) was heated in a sealed vial under Ar to 1000C for 1 h. The mixture was concentrated, the residue was dissolved in EtOAc and filtered. The volatile materials were evaporated, and dissolved in THF (2 mL), MeOH (0.5 equiv) and H2O (0.5 equiv). LiOH (12.2 mg, 5 equiv) was added, and the reaction mixture was stirred at RT for 2 h. The mixture was extracted extensively with EtOAc. The combined extracts were washed with saturated aqueous sodium chloride and the solvent was evaporated under reduced pressure. Purification of the mixture by flash column chromatography on silica gel provided acetic acid 2-(6-cyclopropyl-l-oxo- 3,4-dihydro-lH-isoquinolin-2-yl)-6-{6-[4-(4-ethyl-piperazine-l-carbonyl)-phenylamino]-4- methyl-5-oxo-4,5-dihydro-pyrazin-2-yl}-benzyl ester (45 mg, 71%).
Example 9: 5-bromo-3-[4-(4-ethyl-piperazine-l-carbonyl)-phenylamino]-l-methyl- lH-pyrazin-2-one
To a solution of 4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acid (200 mg, 0.6 mmol) and N-ethylpiperazine (75 mg, 1.05 equiv) in CH2Cl2 (5 mL) were added EDC (141 mg, 1.2 equiv), HOBt (100 mg, 1.2 equiv), and Et3N (103 uL, 1.2 equiv). The mixture was stirred at RT overnight, and the solution was concentrated under reduced pressure. Purification of the residue by purification of the residue by flash column chromatography on silica gel provided 5-bromo-3-[4-(4-ethyl-piperazine-l-carbonyl)-phenylamino]-l- methyl-lH-pyrazin-2-one (220 mg, 85%).
Example 10: 6-Bromo-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l-one
NaH (1.86 g, 1.5 equiv) was added to a solution of 6-bromo-3,4-dihydro-2H-isoquinolin-l- one (7 g, 31 mmol) in DMF (100 mL) at 00C. The solution was stirred for 20 min, and PMBCl was added. The reaction mixture was warmed to RT and stirred for 1 h. Aqueous NH4Cl was added, the aqueous mixture was extracted with EtOAc, and the organic layer was separated. The volatile materials were evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to provide 6-bromo-2-(4- methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l-one (7.6 g, 73%). Example 11 : 2-(4-Methoxy-benzyl)-6-vinyl-3,4-dihydro-2H-isoquinolin-l-one
6-Bromo-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l-one (1 g, 2.9 mmol), vinyl- boronic acid 2-methyl-2,4-prentanediol ester (560 mg, 1.2 equiv), tetrakistriphenylphosphine palladium (168 mg, 0.05 equiv), and KOtBu (410 mg, 1.2 equiv) in THF (19 mL) were heated a sealed vial for 150 minutes in a microwave reactor. The mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to provide 2-(4-methoxy-benzyl)-6-vinyl-3,4-dihydro-2H-isoquinolin-l-one (469 mg, 79%).
Example 12: 6-(l-Fluoro-vinyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l- one
Et3N-3HF (7.7 g, 3 equiv) was added to a mixture of 2-(4-methoxy-benzyl)-6-vinyl-3,4-di- hydro-2H-isoquinolin-l-one (4.7 g, 16 mmol) in CH2Cl2 (16 mL) at 00C. After 1 min, NBS (3.5 g, 1.2 equiv) was added, and the mixture was stirred at 00C for 30 min. The solution was warmed to RT, stirred for 1 h, and poured into ice water. The mixture was made basic with concentrated NH4OH, and extracted with CH2Cl2. The combined organic phases were evaporated under reduced pressure, and the residue was dissolved in THF (50 mL). KOtBu (3.8 g, 2 equiv) was added and the reaction mixture was heated to 500C. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was evaporated and the residue was purified by flash column chromatography on silica gel to provide 6- (l-Fluoro-vinyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l-one (1.97 g, 39%).
Example 13 : 6-(l-Fluoro-cyclopropyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H-iso- quinolin-1-one
ZnEt2 (19 mL of a 1.0 M solution in hexanes, 4 equiv) was added to a solution OfCH2I2 (5.1 g, 4 equiv) in CH2Cl2 (45 mL), and the solution was stirred for 20 min at 00C. TFA (1.47 mL, 4 equiv) was slowly added, and the mixture was stirred for an additional 20 min. A solution of 6-(l-fluoro-vinyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l-one (1.47 g, 4.7 mmol) in CH2Cl2 (20 mL) was added slowly to this solution, and the combined mixture was warmed to RT and stirred for Id. Aqueous ammonium chloride was added, and the mixture was extracted with methylene chloride. The combined organic layers were evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to provide 6-(l-fluoro-cyclopropyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l-one (630 mg, 39%).
Example 14: 6-(l-Fluoro-cyclopropyl)-3,4-dihydro-2H-isoquinolin-l-one
A mixture of 6-(l-fluoro-cyclopropyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l- one (626 mg, 1.9 mmol) in TFA (5 mL) was heated in a sealed vial to 800C for 2 h. The mixture was concentrated under reduced pressure, the residue was taken up in CH2Cl2 and washed with aqueous sodium bicarbonate. The organic layer was evaporated, and the residue was purified by flash column chromatography on silica gel to provide 6-(l-fluoro-cycloprop- yl)-3,4-dihydro-2H-isoquinolin-l-one (400 mg, 100%).
Example 15: 2-(3-Bromo-2-ethyl-phenyl)-6-(l-fluoro-cyclopropyl)-3,4-dihydro-2H- isoquinolin-1 -one
A mixture of 6-(l-fluoro-cyclopropyl)-3,4-dihydro-2H-isoquinolin-l-one (405 mg, 1.97 mmol), l,3-dibromo-2-ethyl-benzene (1.2 g, 2 equiv), CuI (37 mg, 0.1 equiv), and K2CO3 (272 mg, 1 equiv) in DMF (9.5 mL) were heated under Ar in a microwave reactor to 2000C for 90 min. Additional CuI (37 mg, 0.1 equiv) was added, and the mixture was heated to 2000C in the microwave reactor for an additional 20 min. The mixture was cooled, poured into concentrated ammonium hydroxide, and extracted with ethyl acetate. The combined organic extracts were evaporated under reduced pressure. Purification by flash column chromatography on silica gel to provided 2-(3-bromo-2-ethyl-phenyl)-6-(l-fluoro-cyclo- propyl)-3,4-dihydro-2H-isoquinolin-l-one (260 mg, 30%).
Example 16.
Figure imgf000080_0001
The reaction was performed as described above to provide the desired product in 62% yield.
Example 17: 5-bromo-3-(l-ethyl-lH-pyrazol-4-ylamino)-l-methyl-lH-pyrazin-2-one A solution of 1 -ethyl- lH-pyrazol-4-ylamine (0.28 g, 2.5 mmol) and 3,5-dibromo-l-methyl- lH-pyrazin-2-one (0.74 g, 1.1 equiv) were heated to 1200C in isopropanol for 1 h. The reaction mixture was cooled to RT, and 5-bromo-3-(l-ethyl-lH-pyrazol-4-ylamino)-l- methyl-lH-pyrazin-2-one was isolated by filtration (0.43 g, 57%).
Example 18: 5-Bromo-3-(4-hydroxymethyl-phenylamino)-l-methyl-lH-pyrazin-2-one
DIBAL (71 mL of a 1 M solution in CH2Cl2, 5 equiv) was added to a -78°C slurry of 4-(6- bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acid ethyl ester (5 g, 14.2 mmol) in CH2Cl2 (150 mL). The solution was allowed to warm to rt gradually. After 1 hr at RT, the solution was cooled to 00C in an ice bath and ~50 mL of 1.0 N NaOH was added. The reaction was extracted with CH2Cl2, and the organic layer was washed with brine and dried over MgSO4. Evaporation of the volatile materials under reduced pressure provided a solid. Recrystallization of this material from CH2Cl2/Et20/Me0H provided 5-bromo-3-(4- hydroxymethyl-phenylamino)-l -methyl- lH-pyrazin-2-one as a yellow solid (1.35 g, 31%).
Example 19: 4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzalde- hyde
Iodine (0.82 g, 2 equiv) was added to a suspension of 5-bromo-3-(4-hydroxymethyl-phenyl- amino)-l -methyl- lH-pyrazin-2-one (0.5 g, 1.61 mmol) in CH2Cl2 (25 mL). TEMPO (38 mg, 0.15 equiv) was added, followed by a saturated NaHCO3 solution (3.2 mL). The reaction mixture was stirred at RT overnight and filtered. The solid was rinsed with CH2Cl2 and Et2O until the extractions were colorless to provide 4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro- pyrazin-2-ylamino)-benzaldehyde as a light brown solid (0.44 g, 88%).
Example 20: 5-Bromo-l-methyl-3-(4-morpholin-4-ylmethyl-phenylamino)-lH-pyrazin- 2-one
Glacial acetic acid (100 uL) was added to a suspension of 5-bromo-3-(4-hydroxymethyl- phenylamino)-l -methyl- lH-pyrazin-2 -one (0.1 g, 0.3 mmol) and 3 A molecular sieves (0.37 g) and morpholine (0.043 mL, 1.5 equiv) in DCE (10 mL). The solution was stirred for 10 min, and NaHB(OAc)3 (0.172 g, 2.5 equiv) was added in one portion. The suspension was stirred at RT overnight. Water was added to the reaction mixture, and the precipitate was removed by filtration. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, dried (MgSO4), and concentrated under reduced pressure to provide 5-bromo-l-methyl-3-(4-moφholin-4-ylmethyl-phenylamino)-lH- pyrazin-2-one as a waxy solid (0.89 mg, 72%).
Example 21: Acetic acid 2-bromo-6-(6-dimethylamino-l-oxo-3,4-dihydro-lH-iso- quinolin-2-yl)-benzyl ester
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-l-one (150mg, 0.789mmol), Acetic acid 2,6- dibromo-benzyl ester (487mg, 1.58mmol), cuprous iodide (30mg, O.lόmmol) and potassium carbonate (109mg, 0.789mmol) were deposited in a sealed vessel. 3 mL DMSO was added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 1500C for 24 hours. Cuprous iodide (30mg, O.lόmmol) was added and the mixture was heated at 1500C for an additional 24 hours. This was diluted with dichoro- methane and filtered through a pad of celite. The filtrate was partitioned between DCM and 5% aq. ammonium hydroxide. The DCM layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield Acetic acid 2-bromo-6-(6-dimethylamino- 1 -oxo-3 ,4-dihydro- lH-isoquinolin-2-yl)-benzyl ester (93mg, 0.22mmol). MS (ESI) 417.1 (M+H)+.
Example 22: l-(4-tert-Butyl-phenyl)-3-chloro-propan-l-one
To aluminum chloride (29.33g, 220mmol) in DCM (30OmL) at 00C with stirring was added dropwise a solution of t-butyl benzene (31 mL, 200 mmol) and 3-chloropropionyl chloride (19 mL, 200mmol) in DCM. After the addition was complete, the reaction mixture was stirred from 00C to RT overnight. The next morning, TLC indicated that all of the t-butyl benzene was consumed, and the reaction mixture was cooled to 00C . With stirring, water (about 120 mL) in a dropwise fashion until the effervescence ceased. Finally, the layers were separated, and the organic layer was washed with water (3X15 OmL) and then brine (lX150mL). The DCM layer was dried over magnesium sulfate, filtered, concentrated and pumped to dryness to afford the title compound as a light tan powder (45.6g).
Example 23: 5-tert-Butyl-indan-l-one
l-(4-tert-Butyl-phenyl)-3-chloro-propan-l-one (45.6g, 447 mmol) was taken up in concentrated sulfuric acid (20OmL) and the resulting mixture was heated to 1000C with stirring for 2.5 hours. TLC indicated that all of the starting material had been consumed. After cooling to RT, the reaction mixture was very carefully poured onto about IKg of crushed ice. Then some diethyl ether was added and the mixture was stirred carefully until it had cooled to about RT. Ethyl acetate (1200 mL) was added and after partitioning, the layers were sepa- rated. The acidic layer was then further extracted with ethyl acetate (2X200mL). The combined ethyl acetate layers were washed with saturated sodium bicarbonate (5X300mL). Finally the ethyl acetate layer was dried over magnesium sulfate, filtered, concentrated and pumped to dryness to afford the title compound as a colorless oil (15.764g).
Example 24: 6-tert-Butyl-3,4-dihydro-2H-isoquinolin-l-one
To 5-tert-Butyl-indan-l-one (15.7g, 83.4mmol) in DCM (150 mL) was added methanesulf- onic acid (10OmL) and the resulting mixture was cooled to 00C. Then sodium azide (10.83g, 2 eq) was added carefully portion-wise over 15 minutes. The resulting mixture was stirred at 00C for about 2.5 hours. TLC analysis confirmed that all of the 5-tert-Butyl-indan-l-one had been consumed. With stirring at 00C was added very carefully a solution of aqueous sodium hydroxide (20%) until pH = 14. Then added DCM (1000 mL) and water (500 mL) which results in a large emulsion. The layers were separated and the aqueous layer was further extracted with dicholormethane (2X200mL). Finally the combined DCM layers were washed with brine (9X200mL), dried over magnesium sulfate and filtered through a bed of celite. After concentrating and pumping to dryness there was 13.5g of crude product as a tan solid. Purification on a 400 g Analogix Column eluting with a gradient of 10% to 60% ethyl acetate in hexane provided the correct isomer as a white powder (7.22g) ((M+H)+ =204) and the undesired isomer (1.555g) as a white powder.
Example 25: Acetic acid 2-bromo-6-(6-tert-butyl-l-oxo-3,4-dihydro-lH-isoquinolin-2- yl)-benzyl ester
6-tert-Butyl-3,4-dihydro-2H-isoquinolin-l-one (4g, 19.67 mmol), Acetic acid 2,6-dibromo- benzyl ester (12. Ig, 2eq), potassium phosphate tribasic (8.35g, 2 eq) and copper iodide (787mg, 0.2 eq) were taken up in dioxane (4OmL). Finally added N,N'-Dimethyl-cyclo- hexane-1 ,2-diamine (1.24 mL, 0.4eq) and the resulting mixture was heated to reflux for 24 hours, after which time more copper iodide (394mg, 0.1 eq) and N,N'-Dimethyl-cyclohexane- 1,2-diamine (0.62 mL, 0.2 eq) were added. Stirred an additional 64 hours and then added more copper iodide (400 mg, 0.1 eq). Continued to stir at reflux for a total of 168 hours. Cooled to RT and then added ethylacetate (30OmL) and water (10OmL), partitioned and separated the layers. Washed with further water (2XlOOmL) and then finally washed with brine (IXlOOmL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to give 4.45 g of crude product. Purification on a 240 g Analogix column afforded the title compound as a white foamy solid (516mg) ((MH-H)+ = 431) and recovered 6-tert-Butyl-3 ,4-dihydro-2H-isoquinolin-l -one (2.188g).
Example 26: β-^-Methoxy-benzy^-l-oxo-l^^^-tetrahydro-isoquinolin-ό-yll-acetic acid tert-butyl ester (I)
6-Bromo-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-l-one(1.9 g, 5.5 mmole), Q- phos (0.0632 g, 0.1 lmmole ) and Pd(dba)2( 0.078 Ig, 0.11 mmole) in 10 ml THF were added to 2-tert-butoxy-2-oxoethylzinc chloride 15 ml (0.55 M) under argon. The reaction mixture was stirred at RT for 16 hours. Next a third of the initial amount of Q-phos, Pd(dba)2 and zinc enolate were added and the mixture heated for 1 hour at 700C to bring the reaction to com- pletion. The desired product (2 g ; 95.6% yield) was isolated by flash chromatography using silica gel column chromatography with 10% - 40% ethylacetate in hexane as eluent.
Example 27: 2-(4-Methoxy-benzyl)-l-oxo-l,2,3?4-tetrahydro-isoquinolin-6-yl]-acetic acid (II)
The tert-butyl ester (I) ( 1 g, 5.7 mmole ) was dissolved in 40 ml methanol and to this solu- tion was added LiOH monohydrate ( 0.72 g , 17.3 mmole ) in 6 ml water. The mixture was stirred at RT for 16 hours, then concentrated in vacuo, acidified with HCl 2N and extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue (1.8 g; 97% yield ) was used in the next step without further purification.
Example 28: 2-[2-(4-Methoxy-benzyl)-l-oxo-l,2,3,4-tetrahydro-isoquinolin-6-yl]- acetamide (III)
To the carboxylic acid (II) ( 2.3 g,7 mmole) in 22 ml chloroform was added EEDQ (2.07 g, 8.4 mmole ) and ammonium bicarbonate ( 1.66 g, 21 mmole ). After stirring the mixture at RT for 16 hours, the amide was precipitated by addition of water (20 ml). The solid was filtered, washed with water and dried in vacuo. The residue was triturated with 50% ethylacetate in hexane, filtered and dried in vacuo to afford 1.4 g amide (III), 63% yield.
Example 29: [2-(4-Methoxy-benzyl)-l-oxo-l,2,3,4 -tetrahydro-isoquinolin-6-yl]- acetonitrile (IV):
The amide (III) (1.3 g, 4 mmole ) was suspended in 5 ml THF and 10 ml DMF. To this mixture was added cyanuric chloride (0.370 g, 2 mmole) and after stirring at RT for 0.5 hour, the reaction mixture was partitioned between ethylacetate and brine; the organic layer was washed with 5% sodium bicarbonate, followed by brine and then dried over sodium sulfate. Purification by flash chromatograpy on silica gel column using 75% ethylacetate in hexane as eluent afforded 1.2 g ( 98% yield) of nitrile (IV).
Example 30: l-[2-(4-Methoxy-benzyl)-l-oxo-l,2,3,4-tetrahydro-isoquinolin-6-yl]- cyclopropanecarbonitrile (V)
To a suspension of sodium hydrate (0.228 g, 60%, 5.72 mmole) in 15 ml DMF was added nitrile (IV) ( 1.2 g, 3.9 mmole ) and after stirring for 15 minutes at RT 1,2-dibromo-ethane (1.1 g, 5.8 mmole ) in 1.5 ml DMF was added. The resulting mixture was stirred 0.5 hour at RT and then more sodium hydrate (0.114 g, 2.86 mmole ) was added and the reaction mixture heated for about 10 minutes at 30-350C. After cooling the mixture was partitioned between ethylacetate and brine, the organic layer was dried over sodium acetate and concentrated in vacuo. Purification by silica gel column chromatography with 30% - 50% ethylacetate in hexane afforded compound (V ) 1 g ( 77% yield).
Example 31: l-[2-(4-Methoxy-benzyl)-l-oxo-l,2,3,4-tetrahydro-isoquinolin-6-yl]- cyclopropanecarbaldehyde (VI)
To a solution of nitrile (V) (0.722 g, 2.17 mmole) in 3 ml DCM and 9 ml toluene, cooled at - 500C was added dropwise DIBAH (4.8 ml, 4.77 mmole). After stirring 1 hour at -500C, the reaction was quenched with 5 ml HCl IN, left to warm to RT and stirred 0.5 hour. Next the mixture was extracted with ethylacetate; the organic layer was washed with HCl 0.5N, sodium carbonate 5% solution, brine, next dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography using 30%-60% ethylacetate in hexane to provide aldehyde (VI) 0.075 g ( 10.3% yield). Example 32: 6-(l-Difluoromethyl-cyclopropyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H- isoquinolin-1-one (VII)
To a solution of DAST ( 0.042 g, 0.26 mmole) in 1.5 ml dichloromethylene was added aldehyde (VI) (0.075 g, 0.22 mmole ) in 0.5 ml dichloromethylene. This mixture was stirred at RT for 16 hours. After cooling in an ice bath, water 5 ml was added to the reaction mixture followed by ethylacetate. The organic layer was washed with 5% sodium bicarbonate solution and brine, then dried over sodium sulfate and concentrated in vacuo. The residue was purified silica gel prep TLC affording compound (VII) 0.068 g, 87% yield.
Example 33: 6-(l-Difluoromethyl-cyclopropyl)-3,4-dihidro-2H-isoqinolin-l-one (VIII)
Compound (VII) ( 0.068 g, 0.19 mmole) was dissolved in TFA 1 ml and heated to 700C for 1.5 hours. To the reaction mixture cooled to RT was added ethylacetate and the solution was washed with brine followed by sodium bicarbonate 5% solution, and again with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel prep TLC with 5% methanol in dichloromethylene affording compound (VIII) 0.030 g, 66% yield.
Example 34: 2-Bromo-6-[6-(l-difluoromethyl-cyclopropyl)-l-oxo-3,4-dihydro-lH- isoquinolin-benzaldehyde (IX)
To a mixture of compound (VIII) (0.030 g, 0.12 mmole ), 2,6-dibromo-benzaldehyde ( 0.064 g, 0.25 mmole ), cesium carbonate ( 0.054 g, 0.16 mmole) and Xantphos (0.002 G, 0.004 mmole) in a microwave tube under argon was added Pd(dba)2 (0.0014 g, 0.0024 mmole). The tube was sealed and the reaction mixture was heated at 1000C for 16 hours. After cooling the mixture was partitioned between ethylacetate and brine, the organic layer dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel prep TLC with 40% ethylacetate in hexane as eluent affording 0.024 g, 48% yield. General Scheme 2.
Figure imgf000087_0001
Example 35: 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-l-one
6-Dimethylamino-2H-isoquinolin-l-one (50mg, 0.27mmol), cuprous iodide (lOmg, 0.053mmol), and potassium carbonate (37mg, 0.27mmol) were deposited in sealed vessel. 3mL DMSO and 2,6-dibromotoluene (133mg, 0.532mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 1500C for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (30% ethyl acetate/hexanes) to yield 2-(3- Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-l-one (43mg, 0.12mmol). MS (ESI) 357 (M+H)+.
Example 36: Acetic acid 2-(6-dimethylamino-l-oxo-lH-isoquinolin-2-yl)-6-(4,4,5,5- tetramethyl-[l,3?2]dioxaborolan-2-yl)-benzyl ester
To Acetic acid 2-bromo-6-(6-dimethylamino-l-oxo-lH-isoquinolin-2-yl)-benzyl ester (420mg, l .Olmmol), bis(pinacolato)diboron (308mg, 1.21mmol), and potassium acetate (298mg, 3.03mmol) in a sealed tube was added 5 mL dimethylsulfoxide. Argon was bubbled through this mixture for 3 minutes. [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladi- um(II) complex with DCM (25mg, 0.030mmol) was added. Argon was continued to bubble through the mixture for one more minute and the lid was tightly closed. This was heated at 800C for 18 hours. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield acetic acid Acetic acid 2-(6-dimethylamino-l-oxo-lH-isoquinolin-2-yl)-6-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl ester (183mg, 0.396mmol). MS (ESI) 463.1 (M+H)+.
Example 37: 4-Isopropenyl-2-methyl-benzoic acid methyl ester
4-Bromo-2-methyl-benzoic acid methyl ester (4g, 17.46 mmol), isopropenylboronic acid pinacol ester (3.228g, 19.21 mmol) and cesium carbonate (19.913g, 61.11 mmol) were treated with a degassed solution of 15 ml dioxane/5 ml water. After 5 min stirring [l,l'-bis- (diphenylphosphino)ferrocene]dichloropalladium(II) complex (0.718 g, 0.873 mmol) was added and heated to 1200C for 40 min in the microwave. The reaction mixture was filtered over cellulose; washed with 20 ml dioxane and concentrated in vacuo. The residue was purified by 120 g silica gel chromatography (gradient elution 0-50% ethyl acetate in hexane during 50 min) to yield 4-Isopropenyl-2-methyl-benzoic acid methyl ester (2.94 g, 15.45 mmol). MS (ESI) 191.3 (M+H) +
Example 38: 2-Methyl-4-(l-methyl-cyclopropyl)-benzoic acid methyl ester
Formation of Diazomethane: N-Nitroso-N-methylurea (9.1g, 61.8 mmol) was added under stirring in portions to a two phase mixture of 50 ml potassium hydroxide solution (23.9g in 50 ml water) and 50 ml diethyl ether at 00C. The color of the organic phase changed from colorless to yellow. The two phase mixture was vigorously stirred for 40 min at 00C. The organic layer that contains diazomethane was separated. Cyclopropanation by adding diazo- methane solution to methyl styrene: 4-Isopropenyl-2-methyl-benzoic acid methyl ester (2.94g, 15.45 mmol) was dissolved in 15 ml diethyl ether and cooled to 00C. Palladium (II) acetate (0.173g, 0.773 mmol) was added. The yellow organic phase (containing diazomethane) was added dropwise. In total 20 ml of the organic phase (approximately 4 eq. of diazomethane) was added until the reaction was done. You observe releasing nitrogen by adding diazomethane to the methyl styrene intermediate. The reaction mixture was filtered over cellulose; washed with diethyl ether; concentrated; The residue (brown liquid) was purified by 40 g silica gel chromatography (gradient elution 0-100% ethyl acetate in hexane for 15 min) 2.9 g of a crude light yellow liquid was obtained. NMR shows 8% 2-methylbenzoic acid methyl ester. The crude residue was purified again by 110 g flash chromatography (gradient elution 0-20% EtOAc in Hex for 30 min) to give 2-Methyl-4-(l-methyl-cyclopropyl)-benzoic acid methyl ester (2.75g, 13.46 mmol) MS (ESI) 268.9 (M+ Na+ + ACN)
Example 39: 2-Methyl-4-(l-methyl-cyclopropyl)-benzoic acid
2-Methyl-4-(l-methyl-cyclopropyl)-benzoic acid methyl ester (2.75g, 13.46 mmol) was treated with methanol and 5 M aqueous sodium hydroxide solution (20.46 ml, 102.32 mmol). This solution was heated to 800C for 4 hours. The reaction mixture was concentrated until methanol was evaporated. A white solid was obtained. The solid was dissolved in 50 ml water under heating then cooled with an ice bath; acidified with 10 ml cone, hydrochloric acid. A white precipitate was formed; filtered; washed with water; dried under high vacuum overnight to yield 2-Methyl-4-(l-methyl-cyclopropyl)-benzoic acid (2.18g, 11.46 mmol) MS (ESI) 189.1 (M-H)
Example 40: 2-Methyl-4-(l-methyl-cyclopropyl)-benzoyl chloride
2-Methyl-4-(l-methyl-cyclopropyl)-benzoic acid (2.139g, 11.243 mmol) and phosphorus- pentachloride (2.575g, 12.37 mmol) were charged into a 50 ml flask under stirring. These both solids dissolved at 1000C. The reaction mixture was stirred 2 hours at 1200C with an reflux condenser in a N2 atmosphere. After that the resulting phosphorus oxylchloride was distilled off at 1400C from the reaction mixture. The whole reaction mixture was cooled to RT and the reaction mixture still remained as a solution. The desired product was distilled by Kugelrohr distillation (1500C / 4 mbar) to give 2-Methyl-4-(l-methyl-cyclopropyl)-benzoyl chloride (1.92g, 9.2 mmol)
Example 41: N-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-methyl- 4-(l-methyl-cyclopropyl)-benzamide
3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenylamine (2.91g, 9.2mmol), 2-methyl- 4-(l-methyl-cyclopropyl)-benzoyl chloride (1.92g, 9.2 mmol) (Example 40), N,N-diiso- propylethylamine (2.41 ml, 13.8 mmol) and 4-dimethylaminopyridine (0.112 g, 0.92 mmol) were dissolved in 20 ml anhydrous THF. The reaction mixture was refluxed overnight; filtered off the precipitate; concentrated and extracted with ethyl acetate; washed with 2 M phosphate buffer pH 5.5, then with water and brine; dried over sodium sulfate; filtered; concentrated. 4.69g of an oil was obtained. The crude was purified by 80g silica gel chromatography (gradient elution 0-20% ethyl acetate in hexane for 25 min, then 20-100 % ethyl acetate in hexane for 30 min) to give N-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)- phenyl]-2-methyl-4-(l-methyl-cyclopropyl)-benzamide (3.5 Ig, 7.185 mmol) MS (ESI) 510 (M+ Na+)
Example 42: 2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-3-hydroxy- T-Cl-methyl-cyclopropyl^^-dihydro^H-isoquinolin-l-one
2,2,6,6-tetramethylpiperidine (2.28g, 16.17 mmol) was dissolved in 13 ml anhydrous THF under stirring; cooled by means of an ethylen glycol/ice bath mixture to -15°C. Buthyllithium, 2.5 M in hexanes (6.16 ml, 15.4 mmol) was added dropwise and the temperature was kept around -15°C and stirred additionally 30 min at -15°C. A solution of N-[3-Bromo-2-(tert- butyl-dimethyl-silanyloxymethyl)-phenyl]-2-methyl-4-(l-methyl-cyclopropyl)-benzamide in 20 ml anhydrous THF was added dropwise over a period of 10 minutes to the reaction mix- ture at -15°C. The reaction mixture was stirred for 2 hours. After that 3.55 ml of DMF was added in one portion. The reaction mixture was allowed to warm up to RT. It was stirred for 2 hours at RT, then cooled to 00C, quenched with 25 ml of 1 M potassium hydrogen sulfate solution; extracted with ethyl acetate/water; organic phase was washed with brine; dried over sodium sulfate; filtered and concentrated. 2.71 g of a brown oil was obtained. Crystallization with DCM and hexane gave 2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-3- hydroxy-7-(l-methyl-cyclopropyl)-3,4-dihydro-2H-isoquinolin-l-one (1.134g, 2.2 mmol) MS (ESI) SIoO (M-H)
Example 43 : 2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-7-(l- methyl-cyclopropyl)-2H-isoquinolin-l-one
2 - [3 -Bromo -2 -(tert-butyl-dimethyl-s ilanyloxymethyl)-phenyl] -3 -hydroxy-7 -(I -methyl-cyc Io - propyl)-3,4-dihydro-2H-isoquinolin-l-one (1.134g, 2.2 mmol) (Example 42) was dissolved in 13 ml DCM at RT; TEA (1.31 ml, 9.44 mmol) followed by addition of methanesulfonyl chloride (0.478g, 4.171 mmol) were added. It was stirred for 1.5 hours at RT but it's already done in 10 minutes according to LCMS. The reaction mixture was extracted with DCM /water; organic phase was washed with brine; dried over sodium sulfate; filtered; concentrated to give 2-[3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-7-(l-methyl- cyclopropyl)-2H-isoquinolin-l-one (1.094g, 2.2 mmol) MS (ESI) 520.0 (M+ Na+).
General Scheme 3.
Figure imgf000091_0001
Example 44: 2-(3-Bromo-2-methyl-phenyl)-3-(3-dimethylamino-phenylamino)-acrylic acid ethyl ester
(3-Bromo-2-methyl-phenyl)-acetic acid benzyl ester (421mg, 1.32mmol) was dissolved in ethyl formate (2.5mL, 31mmol). Sodium hydride (95%, 67mg, 2.6mmol) was added. After stirring for 30 minutes, this was quenched with IM aq. HCl. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. A portion of this material and N,N-Dimethyl-benzene- 1,3 -diamine (96mg, 0.70mmol) were stirred in ImL ethanol for 18 hours. This was concentrated in vacuo and purified by flash chromatography (gradient elution 5 to 20% ethyl acetate/hexanes) to yield 2-(3-Bromo-2- methyl-phenyl)-3-(3-dimethylamino-phenylamino)-acrylic acid ethyl ester (164mg, 0.407mmol). MS (ESI) 405.0 (M+H)+.
Example 45: 3-(3-Bromo-2-methyl-phenyl)-7-dimethylamino-lH-quinolin-4-one
To 2-(3-Bromo-2-methyl-phenyl)-3-(3-dimethylamino-phenylamino)-acrylic acid ethyl ester (lOOmg, 0.248mmol) (Example 44) was added 4g polyphosphoric acid. This stirred at 1400C for 10 minutes. 50 ml water was added and the mixture was stirred. The resulting precipitate was filtered and washed with water. The filtrate was extracted with 10%methanol/ DCM solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was combined with the precipitate and purified by flash chro- matography (gradient elution 2 to 5% methanol/ DCM) to yield 3-(3-Bromo-2-methyl- phenyl)-7-dimethylamino-lH-quinolin-4-one (22mg, 0.062mmol). MS (ESI) 357.0 (M+H)+.
General Scheme 4.
Figure imgf000093_0001
General Scheme 5.
Figure imgf000094_0001
Example 46: 4-Bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride
Chlorosulfonic acid (17 niL) was added dropwise to l-bromo-3-(2-bromo-ethyl)-benzene (5 g, 19 mmol) at 00C. The mixture was stirred at 00C for Ih then an additional 3h at rt. The mixture was poured into an ice-water slowly and extracted with methylene chloride, and the combined organic layers were evaporated under reduced pressure to give 4.3 g of crude A- bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride which was used directly for the next reaction (see Scheme 5). MS (ESI) 342.9 (M-C1+0H)".
Example 47: Bruton's tyrosine kinase (Btk) inhibition Assay
The assay is a capture of radioactive 33τ P phosphorylated product through filtration. The interactions of Btk, biotinylated SH2 peptide substrate (Src homology), and ATP lead to phosphorylation of the peptide substrate. Biotinylated product is bound streptavidin sepharose beads. All bound, radiolabeled products are detected by scintillation counter. Plates assayed are 96-well polypropylene (Greiner) and 96-well 1.2 μm hydrophilic PVDF filter plates (Millipore). Concentrations reported here are final assay concentrations: 10- 100 μM compounds in DMSO (Burdick and Jackson), 5-10 nM Btk enzyme (His-tagged, full- length), 30 μM peptide substrate (Biotin-Aca- AAAEEIYGEI-NH2), 100 μM ATP (Sigma), 8 mM imidazole (Sigma, pH 7.2), 8 mM glycerol-2 -phosphate (Sigma), 200 μM EGTA (Roche Diagnostics), 1 mM MnCl2 (Sigma), 20 mM MgCl2 (Sigma), 0.1 mg/ ml BSA (Sigma), 2 niM DTT (Sigma), 1 μCi 33P ATP (Amersham), 20% streptavidin sepharose beads (Amers- ham), 50 niM EDTA (Gibco), 2 M NaCl (Gibco), 2 M NaCl w/ 1% phosphoric acid (Gibco), microscint-20 (Perkin Elmer).
IC50 determinations are calculated from 10 data points per compound utilizing data produced from a standard 96-well plate assay template. One control compound and seven unknown inhibitors were tested on each plate and each plate was run twice. Typically, compounds were diluted in half-log starting at 100 μM and ending at 3 nM.The control compound was staurosporine. Background was counted in the absence of peptide substrate. Total activity was determined in the presence of peptide substrate. The following protocol was used to determine Btk inhibition.
1) Sample preparation: The test compounds were diluted at half-log increments in assay buffer (imidazole, glycerol-2 -phosphate, EGTA, MnCl2, MgCl2, BSA).
2) Bead preparation a.) rinse beads by centrifuging at 500 g b.) reconstitute the beads with PBS and EDTA to produce a 20% bead slurry
3) Pre-incubate reaction mix without substrate (assay buffer, DTT, ATP, 33P ATP) and mix with substrate (assay buffer, DTT, ATP, 33P ATP, peptide substrate) 300C for 15 min.
4) To start assay, pre-incubate 10 μL Btk in enzyme buffer (imidazole, glycerol-2-phos- phate, BSA) and lOμL of test compounds for 10 min at RT.
5) Add 30 μL reaction mixture without or with substrate to Btk and compounds.
6) Incubate 50 μL total assay mix for 30 min at 300C.
7) Transfer 40 μL of assay to 150 μL bead slurry in filter plate to stop reaction.
8) Wash filter plate after 30 min, with following steps a. 3 x 250 μL NaCl b. 3 x 250 μL NaCl containing 1% phosphoric acid c. 1 x 250 μL H2O
9) Dry plate for 1 h at 65°C or overnight at RT
10) Add 50 μL microscint-20 and count 33P cpm on scintillation counter. Calculate percent activity from raw data in cpm percent activity = (sample - bkg) / (total activity - bkg) x 100 Calculate IC50 from percent activity, using one-site dose response sigmoidal model y = A + ((B - A) / (l + ((x / C)D)))) x = cmpd cone, y = % activity, A = min, B = max, C = IC50, D = I (hill slope)
Representative results are in Table II below:
TABLE II.
Compound Btk inhibition IC50 (μM) II-5 0.016
II-6 0.015
11-11 0.01 π-12 0.01
Example 48: Inhibition of B-cell Activation - B cell FLIPR assay in Ramos cells
Inhibition of B-cell activation by compounds of the present invention is demonstrated by determining the effect of the test compounds on anti-IgM stimulated B cell responses. The B cell FLIPR assay is a cell based functional method of determining the effect of potential inhibitors of the intracellular calcium increase from stimulation by an anti-IgM antibody. Ramos cells (human Burkitt's lymphoma cell line. ATCC-No. CRL-1596) were cultivated in Growth Media (described below). One day prior to assay, Ramos cells were resuspended in fresh growth media (same as above) and set at a concentration of 0.5 x 106/mL in tissue culture flasks. On day of assay, cells are counted and set at a concentration of 1 x 106/mLl in growth media supplemented with lμM FLUO-3AM(TefLabs Cat-No. 0116, prepared in anhydrous DMSO and 10% Pluronic acid) in a tissue culture flask, and incubated at 37°C (4% CO2) for one h. To remove extracellular dye, cells were collected by centrifuga- tion (5 min, 1000 rpm), resuspended in FLIPR buffer (described below) at 1 x 106 cells/mL and then dispensed into 96-well poly-D-lysine coated black/clear plates (BD Cat-No. 356692) at 1 x 105 cells per well. Test compounds were added at various concentrations ranging from 100 μM to 0.03 μM (7 concentrations, details below), and allowed to incubate with cells for 30 min at RT Ramos cell Ca2+ signaling was stimulated by the addition of 10 μg/mL anti- IgM (Southern Biotech, Cat-No. 2020-01) and measured on a FLIPR (Molecular Devices, captures images of 96 well plates using a CCD camera with an argon laser at 48OnM excitation). Media/Buffers:
Growth Medium: RPMI 1640 medium with L-glutamine (Invitrogen, Cat-No. 61870-010),
10% Fetal Bovine Serum (FBS, Summit Biotechnology Cat-No. FP-100-05); ImM Sodium
Pyruvate (Invitrogen Cat. No. 11360-070). FLIPR buffer: HBSS (Invitrogen, Cat-No. 141175-079), 2mM CaCl2 (Sigma Cat-No. C-
4901), HEPES (Invitrogen, Cat-No. 15630-080), 2.5mM Probenecid (Sigma, Cat-No. P-
8761), 0.1% BSA (Sigma, Cat-No A-7906), 1 ImM Glucose (Sigma, Cat-No.G-7528)
Compound dilution details:
In order to achieve the highest final assay concentration of 100 μM, 24 μL of 10 mM compound stock solution (made in DMSO) is added directly to 576 μL of FLIPR buffer. The test compounds are diluted in FLIPR Buffer (using Biomek 2000 robotic pipettor) resulting in the following dilution scheme: vehicle, 1.00 x 10"4 M, 1.00 x 10"5, 3.16 x 10"6, 1.00 x 10"6,
3.16 x 10"7, 1.00 x lθ~7, 3.16 x lθ~8.
Intracellular increases in calcium were reported using a max - min statistic (subtracting the resting baseline from the peak caused by addition of the stimulatory antibody using a
Molecular Devices FLIPR control and statistic exporting software. The IC50 was determined using a non-linear curve fit (GraphPad Prism software).
Example 49: Mouse In Vivo Collagen-induced arthritis (mCIA)
On day 0 mice are injected at the base of the tail or several spots on the back with an emul- sion of Type II Collagen (i.d.) in Complete Freund's adjuvant (CFA). Following collagen immunization, animals will develop arthritis at around 21 to 35 days. The onset of arthritis is synchronized (boosted) by systemic administration of collagen in Incomplete Freund's adjuvant (IFA; i.d.) at day 21. Animals are examined daily after day 20 for any onset of mild arthritis (score of 1 or 2; see score description below) which is the signal to boost. Follow- ing boost, mice are scored and dosed with candidate therapeutic agents for the prescribed time ( typically 2 — 3 weeks) and dosing frequency, daily (QD) or twice-daily (BID).
Example 50: Rat/« Vivo Collagen-induced arthritis (rCIA)
On day 0, rats are injected with an emulsion of Bovine Type II Collagen in Incomplete Freund's adjuvant (IFA) is injected intradermally (i.d.) on several locations on the back. A booster injection of collagen emulsion is given around day 7, (i.d.) at the base of the tail or alternative sites on the back. Arthritis is generally observed 12-14 days after the initial collagen injection. Animals may be evaluated for the development of arthritis as described below (Evaluation of arthritis) from day 14 onwards. Animals are dosed with candidate therapeutic agents in a preventive fashion starting at the time of secondary challenge and for the pre- scribed time ( typically 2 — 3 weeks) and dosing frequency, daily (QD) or twice-daily (BID).
Example 51: Evaluation of Arthritis:
In both models (Examples 38 and 39), developing inflammation of the paws and limb joints is quantified using a scoring system that involves the assessment of the 4 paws following the criteria described below: Scoring: 1= swelling and/or redness of paw or one digit.
2= swelling in two or more joints.
3= gross swelling of the paw with more than two joints involved.
4= severe arthritis of the entire paw and digits.
Evaluations are made on day 0 for baseline measurement and starting again at the first signs or swelling for up to three times per week until the end of the experiment. The arthritic index for each mouse is obtained by adding the four scores of the individual paws, giving a maximum score of 16 per animal.
Example 52: Rat In Vivo Asthma Model
Male Brown-Norway rats are sensitized i.p. with 100 μg of OA (ovalbumin) in 0.2 ml alum once every week for three weeks (day 0, 7, and 14). On day 21 (one week following last sensitization) , the rats are dosed q.d. with either vehicle or compound formulation subcutane- ously 0.5 hour before OA aerosol challenge (1% OA for 45 minutes) and terminated 4 or 24 hours after challenge. At time of sacrifice, serum and plasma are collected from all animals for serology and PK, respectively. A tracheal cannula is inserted and the lungs are lavaged 3X with PBS. The BAL fluid is analyzed for total leukocyte number and differential leukocyte counts. Total leukocyte number in an aliquot of the cells (20-100 μl) is determined by Coulter Counter. For differential leukocyte counts, 50-200 μl of the sample is centrifuged in a Cytospin and the slide stained with Diff-Quik. The proportions of monocytes, eosinophils, neutrophils and lymphocytes are counted under light microscopy using standard morphologi- cal criteria and expressed as a percentage. Representative inhibitors of Btk show decreased total leucocyte count in the BAL of OA sensitized and challenged rats as compared to control levels.
Example 53: Pharmaceutical compositions
Composition for Oral Administration (A)
Ingredient % wt./wt.
Active ingredient 20.0%
Lactose 79.5%
Magnesium stearate 0.5% The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.
Composition for Oral Administration (B)
Ingredient % wtJwt
Active ingredient 20.0%
Magnesium stearate 0.5%
Crosscarmellose sodium 2.0%
Lactose 76.5%
PVP (polyvinylpyrrolidine) 1.0%
The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.
Composition for Oral Administration (C)
Ingredient % wtJwt
Active compound 1.0 g
Fumaric acid 0.5 g
Sodium chloride 2.O g
Methyl paraben 0.15 g
Propyl paraben 0.05 g
Granulated sugar 25.5 g
Sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g
Flavoring 0.035 ml
Colorings 0.5 mg
Distilled water q.s. to 100 ml
The ingredients are mixed to form a suspension for oral administration.
Parenteral Formulation (D)
Ingredient % wtJwt
Active ingredient 0.25 g
Sodium Chloride qs to make isotonic
Water for injection to 100 ml
The active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.
Suppository Formulation (E)
Ingredient % wtJwt.
Active ingredient 1.0%
Polyethylene glycol 1000 74.5%
Polyethylene glycol 4000 24.5%
The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight. Topical Formulation (F)
Ingredients grams
Active compound 0.2-2
Span 60 2
T ween 60 2
Mineral oil 5
Petrolatum 10
Methyl paraben 0.15
Propyl paraben 0.05
BHA (butylated hydroxy anisole) 0.01
Water q.s. 100
The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims.
Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.
All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Claims

Claims
1. A compound of Formula I, II, III, IV or V
Figure imgf000102_0001
IV
wherein
R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R1 ; wherein each R1 is independently lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, cycloalkyl lower alkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -(CH2)qC(=O)O, -C(=O)N(R2')2, -(CH2),, -O(CH2)q, -
CH2C(=O), -CH2C(=O)N(R2')2, or-S(=O)2; wherein each R2' is independently H, lower alkyl, lower alkoxy, lower haloalkyl, or lower hydroxyalkyl; and q is 1, 2, or 3; R3 is H or R4; wherein R4 is lower alkyl, lower heteroalkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydro xyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
Q is CH2, CH(Y ) or NH; wherein Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; Y1 is H or lower alkyl; Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3; Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; γ4 is γ4a^ γ4b^ γ4c^ Qr γ4d. wherdn
Y4"1 is H or halogen;
Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
Y40 is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and Y411 is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment, the invention provides a compound of Formula I, wherein: R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R1 ; wherein each R1 is independently lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -C(=O)N(R2'), -(CH2),, -O(CH2)q, -(CH2)qC(=O)O, -O(CH2)q C(=O)N(R2'), -CH2C(=O)N(R2'),or -S(=O)2; wherein R2' is H or lower alkyl; and q is 1, 2, or 3;
R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl; Q is CH or N; Y1 is H or lower alkyl;
Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3;
Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; Y4 is Y4a, Y4b, Y4c, or Y4d; wherein Y4"1 is H or halogen;
Y413 is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y40 is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y411 is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
2. The compound of formula I according to claim 1 , wherein: R is H, -R1, -R!-R2-R3, -R!-R3, or -R2-R3; R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R1 ; wherein each R1 is independently lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -C(=O)N(R2'), -(CH2),, -O(CH2)q, -(CH2)qC(=O)O, -O(CH2)q
C(=O)N(R2'), -CH2C(=O)N(R2'),or -S(=O)2; wherein R2' is H or lower alkyl; and q is 1, 2, or 3;
R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
Q is CH or N;
Y1 is H or lower alkyl; Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3; Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; γ4 is γ4a^ γ4b^ γ4c^ Qr γ4d. wherdn Y43 is H or halogen;
Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy;
Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y411 is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
3. The compound of Formula II according to claim 1, wherein: R is H, -R1, -R!-R2-R3, -R!-R3, or-R2-R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with one or more R1 ; each R1 is independently lower alkyl, hydroxy, lower hydro xyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, cycloalkyl lower alkyl, heterocycloalkyl, cyano, nitro, or lower haloalkyl; R2 is -C(=O), -C(=O)O, -C(=O)N(R2')2, -(CH2),, -O(CH2)q, -
CH2C(=O), -CH2C(=O)N(R2')2, or-S(=O)2; wherein each R2' is independently H, lower alkyl, lower alkoxy, lower haloalkyl, or lower hydroxyalkyl; and q is 1, 2, or 3; R3 is H or R4; wherein R4 is lower alkyl, lower alkoxy, amino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl; Q is CH2, CH(Y ) orNH;
Y is halogen, hydroxy, or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; Y1 is H or lower alkyl; Y2 is Y2a or Y2b; wherein Y2a is H or halogen; Y2b is lower alkyl, optionally substituted with one or more Y2b ; wherein Y2b is hydroxy, lower alkoxy, or halogen; each Y2 is independently Y2 a or Y2 b; wherein Y2 a is halogen; Y2 b is lower alkyl, optionally substituted with one or more Y2 b ; wherein Y2 b is hydroxy, lower alkoxy, or halogen; n is 0, 1, 2, or 3; Y3 is halogen or lower alkyl, wherein the lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen; m is 0 or 1 ; γ4 is γ4a^ γ4b^ γ4c^ Qr γ4d. wherdn Y4a is H or halogen;
Y4h is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; Y40 is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y4d is amino, optionally substituted with one or more lower alkyl; or a pharmaceutically acceptable salt thereof.
4 .The compound of formula I or II according to claim 2 or 3, wherein Y1 is methyl, Y2 is hydroxymethyl, n is 0, and m is 0.
5. The compound of formula I or II according to claim 2 or 3, wherein Q is CH.
6. The compound of formula I or II according to claim 2 or 3, wherein Y4 is Y4c or Y4d; wherein Y4cis lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl and lower haloalkyl; and Y4*1 is amino, optionally substituted with one or more lower alkyl.
7. A method for treating an inflammatory and/or autoimmune condition, e.g. arthritis, or of inhibiting B-cell proliferation comprising administering to a patient in need thereof a therapeutically effective amount of the Btk inhibitor compound of any one of claims 1-6.
8. A pharmaceutical composition comprising the Btk inhibitor compound of any one of claims 1-6, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.
9. The use of a compound of formula I according to any one of claims 1-6 for the preparation of a medicament for the treatment of an inflammatory and/or autoimmune condition.
10. The invention as hereinbefore described.
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