Compounds and methods for kinase modulation

Patent metadata

Field	Value
Publication number	US-2018354946-A1
Application number	US-201816001534-A
Country	US
Kind code	A1
Filing date	Jun 6, 2018
Priority date	Jun 7, 2017
Publication date	Dec 13, 2018
Grant date	—

Abstract

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, compositions thereof, and uses thereof.

First claim

1 . A compound having Formula I:

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or a deuterated analog thereof, wherein:
A is N or —C(Z 3 )═;
W is —C(R 2 )═ or N;
Z 3 is hydrogen or halo;
Z 2 is:

L is —SO 2 —NR 6 R 7 , —NHC(O)R 4 , or —C(O)NR 3 R 4 ;
R 1 is C 1-6 alkyl, halo, or halo-C 1-6 alkyl;
R 2 is hydrogen, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , or halo;
R 3 is hydrogen or C 1-6 alkyl;
R 4 is C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, cyano-C 3-6 cycloalkyl, cyano-C 3-6 cycloalkyl-C 1-3 alkyl, cyano-C 1-6 alkylene, heterocycloalkyl, heteroaryl, or —(CH 2 )—[(CR 10 )] 2 —OH, wherein the C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, cyano-C 3-6 cycloalkyl, cyano-C 3-6 cycloalkyl-C 1-3 alkyl, cyano-C 1-6 alkylene, heterocycloalkyl, and heteroaryl are optionally substituted with 1-2 G groups;
or R 3 and R 4 , together with the N atom to which they are attached, join to form a 4-6 membered heterocycloalkyl moiety substituted with 1-2 G groups;
R 6 is hydrogen, C 1-6 alkyl, cyano-C 1-6 alkylene optionally substituted with 1-2 G groups, or C 3-6 cycloalkyl optionally substituted with 1-2 G 2 groups;
R 7 is hydrogen or C 1-6 alkyl;
or R 6 and R 7 , together with the N atom to which they are attached, join to form a heterocycloalkyl moiety substituted with 1-2 G groups;
R 8 is C 1-3 alkyl, hydroxy-C 1-6 alkyl, halo-C 1-6 alkyl, cyano-C 1-6 alkylene, —[C(R 9 ) 2 ] 1-2 —C 3-6 cycloalkyl, —[C(R 9 ) 2 ] 1-2 -heterocycloalkyl, —[C(R 9 ) 2 ] 1-2 -heteroaryl, —[C(R 9 ) 2 ] 1-2 —SO 2 —C 1-3 alkyl, —[C(R 9 ) 2 ] 1-2 —C(O)—C 1-3 alkyl, —[C(R 9 ) 2 ] 1-2 —C(O)—N(C 1-3 alkyl) 2 , —[C(R 9 ) 2 ] 1-2 —C(O)—NH 2 , —[C(R 9 ) 2 ] 1-2 —C(O)—C 3-6 cycloalkyl, or —[C(R 9 ) 2 ] 1-2 —C(O)-heterocycloalkyl;
each R 9 is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo, and halo-C 1-6 alkyl;
each R 10 is C 1-3 alkyl or two R 10 , together with the C atom to which they are attached, join to form a C 3-6 cycloalkyl;
each G is independently hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, or heterocycloalkyl;
each G 2 is independently C 1-6 alkyl, halogen, or cyano;
m is 0-2; and
n is 0-1;
provided that the compound is not
N-(2-cyano-2-methyl-propyl)-6-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,
N-(2-cyano-2-methyl-propyl)-6-[2-[1-(difluoromethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,
N-(1-cyano-1-methyl-ethyl)-6-[2-[1-(difluoromethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,
N-(1-cyano-1-methyl-ethyl)-6-[2-(2-isopropyl-4-methyl-thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,
6-[2-[1-(2-cyanoethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide,
N-(1-cyano-1-methyl-ethyl)-6-[2-[1-(2-morpholinoethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,
N-(1-cyano-1-methyl-ethyl)-6-[2-(1-isopropyl-3-methyl-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,
6-[3-chloro-2-[1-(difluoromethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide,
6-[3-chloro-2-(1-isopropyl-3-methyl-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide,
N-(1-cyano-1-methyl-ethyl)-6-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridine-2-carboxamide,
N-(2-cyanopropan-2-yl)-6-(2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide,
N-(2-cyanopropan-2-yl)-6-(2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide,
N-(2-cyanopropan-2-yl)-6-(2-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide, and
N-(2-cyanopropan-2-yl)-6-(2-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide.

2 . The compound according to claim 1 , wherein W is —C(R 2 )═, and R 2 is —CH 3 , F, Cl, or Br.

3 . The compound according to claim 1 , wherein W is —C(R 2 )═, and R 2 is hydrogen.

4 . The compound according to claim 1 , wherein W is N.

5 . The compound according to claim 1 , wherein A is —C(Z 3 )═, and L is —C(O)NR 3 R 4 .

6 . The compound according to claim 1 , wherein A is —C(Z 3 )═, and L is:

7 . The compound according to claim 1 , wherein A is —C(Z 3 )═, and L is:

8 . The compound according to claim 1 having one of the following Formulae:

wherein R 2 is —CH 3 , Cl, or F.

9 . The compound according to claim 8 having one of Formulae I(a), I(e), I(g), I(k), I(m), I(t), I(u), I(x), I(aa), I(dd), I(gg), I(jj), or I(oo).

10 . The compound according to claim 8 having one of Formulae I(c), I(f), I(i), (l), I(o), I(q), I(w), I(z), I(cc), I(ff), I(ii), I(ll), or I(pp).

11 . The compound according to claim 8 having one of Formulae I(b), I(d), I(h), I(j), I(n), I(r), I(v), I(y), I(bb), I(ee), I(hh), I(kk), or I(mm).

12 . The compound according to claim 8 having one of Formulae I(a), I(b), I(c), I(d), I(e), or I(f).

13 . The compound according to claim 1 , wherein R 8 is —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —C(CH 3 ) 2 —OH, —CH 2 C(CH 3 ) 2 —OH, —CH 2 —S(O) 2 —CH 3 , —CH 2 —CN, —CH 2 -oxetanyl, —CH 2 —C(O)—NH 2 , —CH 2 —C(O)—N(C 1 -C 3 alkyl) 2 , or —CH 2 —C(O)-heterocycloalkyl.

14 . The compound according to claim 1 , wherein R 8 is —CHF 2 , —C(CH 3 ) 2 —OH, —CH 2 C(CH 3 ) 2 —OH, —CH 2 —S(O) 2 —CH 3 , —CH 2 —C(O)—NH 2 , —CH 2 —C(O)—N(CH 3 ) 2 , or —CH 2 —C(O)-pyridyl.

15 . The compound according to claim 1 , wherein Z 3 is F or Cl.

16 . A compound having the structure:

Assignees

• Plexxikon Inc

Inventors

• Zhang Chao
• Wu Guoxian
• Spevak Wayne
• Guo Zuojun
• Zhang Ying

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title