TrkA kinase inhibitors, compositions and methods thereof
View Patent ↗The present invention is directed to six membered heteroaryl benzamide compounds of formula (I), which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.
1. A compound of formula I:
or pharmaceutically acceptable salts thereof, wherein:
B represents a six membered heteroaryl having at least one heteroatom that is nitrogen, said heteroaryl optionally substituted with 1 to 3 groups of R a ;
R represents hydrogen, OH, or —C 1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of R f ;
R 1 is selected from the group consisting of hydrogen, CN, OH, —C 1-6 alkyl and halogen;
R 2 is hydrogen or (CHR) n C 5-10 heterocycle, said heterocycle optionally substituted with 1 to 3 groups of R a , wherein when R 2 is hydrogen then R 4 is (CHR) n C 5-10 heterocycle;
R 4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, (CHR) n C 6-10 aryl and (CHR) n C 5-10 heterocycle, said alkyl, aryl, and heterocycle optionally substituted with 1 to 3 groups of R a ,
R 3 represents C 1-4 haloalkyl,
R 5 is hydrogen or halogen;
R a is selected from the group consisting of hydrogen, —CN, NO 2 , —(CH 2 ) n C(O)OR f , —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —C 1-6 alkenyl, —C 1-6 alkynyl, —(CH 2 ) n C 3-6 cycloalkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —(CH 2 ) n C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6-10 aryl, —O—(CH 2 ) n C 4-10 heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, SO 2 R d , (CH 2 ) n NHSO 2 R d , —(CH 2 ) n SO 2 N(R d ) 2 , S(O)(NH)R g , —C(O)CF 3 , COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NRC(O)NHR d , —(CH 2 ) n NHC(O)OR d , CHR) n C(O)N(R d ) 2 —OC 1-6 alkyl, —O—, and —OH, said alkyl, cycloalkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein when two R d groups are attached to a nitrogen atom they may combine with that nitrogen to from a 4-8 membered heterocyle that is optionally substituted with 1 to 3 groups of R f ;
R b is selected from the group consisting of halogen, —C 1-6 alkyl, —C 1-6 alkylOR, —C 1-4 haloalkyl, —(CH 2 ) n N(R d ) 2 , —OR c , —O—, —CN, S(O)(NH)R g , —SO 2 R, —SO 2 N(R d ) 2 , —(CH 2 ) n C(O)N(R d ) 2 , —(CH 2 ) n NHC(O)R d , COR, C(O)OR, C 3-6 cycloalkyl, —O—(CH 2 ) n C 4-10 heterocycle, and —C 1-6 alkylN(R d ) 2 , said alkyl and heterocycle optionally substituted with 1 to 3 groups of R f ;
R c is selected from the group consisting of hydrogen, —C 1-6 alkylORg, —C 1-4 haloalkyl and —C 1-6 alkyl;
R d is independently selected from the group consisting of hydrogen, halogen, —C 1-4 haloalkyl —C 1-6 alkyl, COR, —(CH 2 ) n SO 2 R, —(CH 2 ) n NR f C 4-10 heterocycle, —(CH 2 ) n C 3-6 cycloalkyl, —(CH 2 ) n C 4-10 heterocycle said alkyl, cycloalkyl and heterocycle optionally substituted with 1 to 3 groups of R f ; wherein when two R d groups are attached to a nitrogen atom they may combine with that nitrogen to from a 4-8 membered heterocyle that is optionally substituted with 1 to 3 groups of R f ;
R f is selected from the group consisting of hydrogen, C 1-6 alkyl, OR c , CN, —N(R c ) 2 , C(O)N(R g ) 2 , C(O)C 1-6 alkyl, —SO 2 R g , —O—, —C 1-6 alkylSO 2 R g , —C 1-6 alkylOR g , —C 1-6 alkylN(R g ) 2 ,
R g is selected from the group consisting of hydrogen, —C 1-6 alkyl; and
n represents 0-6.
2. The compound according to claim 1 wherein B is an unsubstituted or substituted six membered heterocycle selected from the group consisting of pyridyl, pyrimidinyl, pyradizinyl, and pyrazinyl.
3. The compound according to claim 2 wherein B is unsubstituted or substituted pyridyl.
4. The compound according to claim 2 wherein B is unsubstituted or substituted pyrimidinyl.
5. The compound according to claim 1 wherein one of R 2 and R 4 is hydrogen and the other is optionally substituted (CHR) n C 5-10 heterocycle and R 1 and R 5 are independently selected from hydrogen and halogen.
6. The compound according to claim 5 wherein the heterocycle of R 2 and R 4 is selected from the group consisting of optionally substituted pyrazolyl, pyridyl, thiazolyl, triazolyl, oxazolyl, oxadiazolyl, and pyrimidinyl.
7. The compound according to claim 1 wherein R 3 is CF 3 .
8. The compound according to claim 1 wherein B is a pyrimidinyl substituted with 1 to 3 groups of R a selected from the group consisting of —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6- 10 aryl, —O—(CH 2 ) n C 4-10 heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein n=0-2.
9. The compound according to claim 1 wherein B is a pyridyl substituted with 1 to 3 groups of R a selected from the group consisting of —C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6-10 aryl, —O—(CH 2 ) n C 4-10 heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein n=0-2.
10. The compound according to claim 1 represented by structural formula Ia:
or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as originally described and R a1 , R a2 , R a3 , and R a4 all equal R a and R a is as originally described.
11. The compound according to claim 10 wherein R a1 , R a2 , R a3 , and R a4 are independently selected from hydrogen, C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6-10 aryl, —O—(CH 2 ) n C 4- 10 heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein at least two of R a1 , R a2 , R a3 , and R a4 on the pryidyl are hydrogen, and one of R a1 , R a2 , R a3 , and R a4 is phenyl, R 1 and R 5 are independently selected from hydrogen and halogen, R 3 is CF 3 , or halogen, and one of R 2 and R 4 is hydrogen and the other is (CHR) n C 5-10 heterocycle.
12. The compound according to claim 10 wherein R a4 is phenyl, R 1 is hydrogen, R 3 is CF 3 , R 5 is fluorine, R 2 is optionally substituted pyrazolyl, and R 4 is hydrogen.
13. The compound according to claim 1 represented by structural formula II:
and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as originally described, and R w , R v and R y =R a .
14. The compound according to claim 13 wherein R w , R v , and R y are independently selected from hydrogen, C 1-4 haloalkyl, —OC 1-4 haloalkyl, —C 1-6 alkyl, —(CHR) n C 6-10 aryl, —(CHR) n C 4-10 heterocycle, —C(O)(CHR) n C 4-10 heterocycle, —O—(CH 2 ) n C 6-10 aryl, —O—(CH 2 ) n C 4-10 heterocycle, —O—, —(CH 2 ) n N(R d ) 2 , —(CH 2 ) n C(O)NH(CH 2 ) n C 4-10 heterocycle, COR, —(CH 2 ) n halo, —(CH 2 ) n NHC(O)R d , —(CH 2 ) n NHC(O)NHR d , —(CH 2 ) n NHC(O)OR d , —(CHR) n C(O)N(R d ) 2 —(CH 2 ) n NHSO 2 R d , and —OR, said alkyl, aryl and heterocycle optionally substituted with 1 to 3 groups of R b , wherein at least two of R w , R v , and R y on the pryimidinyl are hydrogen, and one of R w , R v , and R y is phenyl, R 1 and R 5 are independently selected from hydrogen and halogen, R 3 is CF 3 , or halogen, and one of R 2 and R 4 is hydrogen and the other is (CHR) n C 5-10 heterocycle.
15. The compound according to claim 13 wherein R w is phenyl, R 1 is hydrogen, R 3 is CF 3 , R 5 is fluorine, R 2 is optionally substituted pyrazolyl, and R 4 is hydrogen.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.