Substituted pyrimidinyl-amines as protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9018205-B2
Application number	US-201313766075-A
Country	US
Kind code	B2
Filing date	Feb 13, 2013
Priority date	Sep 4, 2007
Publication date	Apr 28, 2015
Grant date	Apr 28, 2015

Abstract

The present invention provides novel substituted pyrimidinyl-amines that are useful as inhibitors of protein kinases, especially c-Jun N-terminal kinases (JNK) and pharmaceutical compositions thereof and methods of using the same for treating conditions responsive to the inhibition of the JNK pathway.

First claim

What is claimed is:

1. A method of treating a disease or condition responsive to the inhibition of the JNK pathway, wherein the disease or condition is any of Parkinson's disease, stroke, diabetes, cancer, myocardial infarction, multiple sclerosis, pulmonary fibrosis, and Alzheimers and pre-Alzheimers diseases, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of formula Ic:

wherein:
Z 1 and Z 2 are each CH;
R 1 is a (4- to 10-membered) heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R 5 ;
R 2 is independently Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , or CON(R a ) 2 ;
R 3 is H, CH 3 , CH 2 CH 3 , cyano, Cl, F, Br, or I;
R 4 is a phenyl group substituted with 1-2 R 4a ;
each R 4a is independently Cl, F, Br, I, CF 3 , OCF 3 , C 1-6 alkyl substituted with 0-3 R 5 , C 2-6 alkenyl substituted with 0-3 R 5 , C 2-6 alkynyl substituted with 0-3 R 5 , (CH 2 ) p NO 2 , (CH 2 ) p CN, (CH 2 ) p OR, (CH 2 ) p N(R) 2 , (CH 2 ) p COR, (CH 2 ) p OCOR, (CH 2 ) p CO 2 R, (CH 2 ) p CON(R) 2 , (CH 2 ) p OCON(R) 2 , (CH 2 ) p NRCOR, (CH 2 ) p NRCO 2 R, (CH 2 ) p NRCON(R) 2 , (CH 2 ) p C(═NH)NH 2 , (CH 2 ) p SO 2 R, (CH 2 ) p SO 2 N(R) 2 , (CH 2 ) p NRSO 2 R, (CH 2 ) p NRSO 2 N(R) 2 , CH(CF 3 )NH 2 , or (CH 2 ) p -(5- to 6-membered heterocyclic ring) having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-3 R 5a , wherein provided that a first R 4a group is a 5- to 6-membered heteroaromatic ring comprising 3 or 4 heteroatom ring members selected from O, S(O) q , and N, and substituted with 0-3 R 5a ;
each R is independently H, C 1-6 alkyl substituted with 0-2 R 5 , C 2-6 alkenyl substituted with 0-2 R 5 , C 2-6 alkynyl substituted with 0-2 R 5 , 3- to 10-membered carbocyclic ring substituted with 0-2 R 5 , or 5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R 5 ; or two R attached to the same N atom are taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered heterocyloalkyl substituted with 0-2 R 5
each R 5 is independently ═O, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , CON(R a ) 2 , NR a COR a , NR a CO 2 R a , NR a CON(R a ) 2 , C(═NH)NH 2 , SO 2 R a , SO 2 N(R a ) 2 , NR a SO 2 R a , NR a SO 2 N(R a ) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R b ), or (CH 2 ) p -(5- to 10-membered) heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with substituted with 0-2 R b ; or two R 5 taken together with a carbon atom to which they are both connected form a 1,3-dioxolane ring wherein the two oxygen ring atoms are attached to the connecting carbon atom;
R 5a is selected from ═O, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, (CH 2 ) p OR a , N(R a ) 2 , COR a , CO 2 R a , CON(R a ) 2 , NR a COR a , NR a CO 2 R a , NR a CON(R a ) 2 , C(═NH)NH 2 , SO 2 R a , SO 2 N(R a ) 2 , NR a SO 2 R a , NR a SO 2 N(R a ) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R b , or (CH 2 ) p -(5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N), wherein the heterocyclic ring is substituted with 0-2 R b ;
each R a is independently H, C 1-4 -alkyl, C 3-6 cycloalkyl, CH 2 —C 3-6 cycloalkyl, phenyl, or benzyl; or two R a attached to the same N atom are taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered heterocycloalkyl;
R b is H, Cl, F, Br, I, CF 3 , OCF 3 , C 1-4 -alkyl optionally substituted with OR a , C 2-4 alkenyl, C 2-4 alkynyl, NO 2 , —CN, OR a , N(R a ) 2 , COR a , CO 2 R a , or CON(R a ) 2 ;
p is 0;
q is 0, 1, or 2; and
m is 1 and n is 0 or 1.

2. The method of claim 1 , wherein the first R 4a is (5-membered heteroaromatic ring).

3. The method of claim 1 , wherein the heteroaromatic ring of R 4a heteroatom ring members are selected from N and O heteroatoms.

4. The method of claim 1 , wherein the heteroaromatic ring of the first R 4a group is substituted with Cl, F, Br, CF 3 , C 1-4 -alkyl, C 2-4 alkenyl, (CH 2 ) p OR a , N(R a ) 2 , (CH 2 ) p -(3- to 10-membered carbocyclic ring substituted with 0-2 R b , or (CH 2 ) p -(5- to 10-membered heterocyclic ring having 1 to 4 heteroatom ring members selected from O, S(O) q , and N, wherein the heterocyclic ring is substituted with 0-2 R b .

5. The method of claim 1 , wherein the heteroaromatic ring of the first R 4a group is substituted with phenyl or benzyl.

6. The method of claim 1 , wherein the heteroaromatic ring of the first R 4a group is substituted with (CH 2 ) p -(5- to 10)-membered heterocyclic ring, and wherein the (CH 2 ) p -(5- to 10-membered)heterocyclic ring is optionally substituted with Cl, F, CF 3 , C 1-4 -alkyl optionally substituted with OR a , —CN, or OR a .

7. The method of claim 1 , wherein the compound of formula (Ic) is selected from the group consisting of

Assignees

• Kamenecka Theodore Mark
• Jiang Rong
• Song Xinyi
• Lograsso Philip
• Cameron Michael Darin
• Duckett Derek R
• Scripps Research Inst

Inventors

• Kamenecka Theodore Mark
• Jiang Rong
• Song Xinyi
• Lograsso Philip
• Cameron Michael Darin
• Duckett Derek R

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title