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Last Updated: March 28, 2024

Details for Patent: 8,716,323


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Title:Cyclic protein tyrosine kinase inhibitors
Abstract: Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.
Inventor(s): Das; Jagabandhu (Mercerville, NJ), Padmanabha; Ramesh (Hamden, CT), Chen; Ping (Belle Mead, NJ), Norris; Derek J. (Trenton, NJ), Doweyko; Arthur M. P. (Long Valley, NJ), Barrish; Joel C. (Holland, PA), Wityak; John (Robbinsville, NJ)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Filing Date:Nov 10, 2005
Application Number:11/271,626
Claims:1. A compound of formula I or salt thereof ##STR00622## where Q is thiazole optionally substituted with R.sub.1; Z is a single bond; X.sub.1 and X.sub.2 together form .dbd.O; R.sub.1 is hydrogen or alkyl, R.sub.6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z.sub.1, Z.sub.2 or one or more groups Z.sub.3; q is 1 or 2; R.sub.2 is hydrogen, R.sub.6, --Z.sub.4--R.sub.6 or --Z.sub.13--NR.sub.7R.sub.8; R.sub.3 is --Z.sub.4--R.sub.6' where Z.sub.4 is a single bond and R.sub.6' is heteroaryl optionally substituted with groups Z.sub.1, Z.sub.2 or one or more groups Z.sub.3; R.sub.4 is independently (1) hydrogen or R.sub.6; (2) --Z.sub.4--N(R.sub.9)--Z.sub.5--NR.sub.10R.sub.11; (3) --N(R.sub.9)Z.sub.4R.sub.6; or (4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; R.sub.5 is an aryl group which is substituted with Z.sub.1, Z.sub.2 or one or more groups Z.sub.3; R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 are each independently (1) hydrogen or R.sub.6; (2) R.sub.7 and R.sub.8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; or (3) any two of R.sub.9, R.sub.10 and R.sub.11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached; which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; R.sub.13 is (1) cyano; (2) nitro; (3) --NH.sub.2; (4) --NHOalkyl; (5) --OH; (6) --NHOaryl; (7) --NHCOOalkyl; (8) --NHCOOaryl; (9) --NHSO.sub.2alkyl; (10) --NHSO.sub.2aryl; (11) aryl; (12) heteroaryl; (13) --Oalkyl; or (14) --Oaryl; R.sub.14 is (1) --NO.sub.2; (2) --COOalkyl; or (3) --COOaryl; Z.sub.1, Z.sub.2 and Z.sub.3 are each independently (1) hydrogen or Z.sub.6, where Z.sub.6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z.sub.1, Z.sub.2 and Z.sub.3; (2) --OH or --OZ.sub.6; (3) --SH or --SZ.sub.6; (4) --C(O).sub.qH, --C(O).sub.qZ.sub.6, or --O--C(O).sub.qZ.sub.6; (5) --SO.sub.3H, --S(O).sub.qZ.sub.6; or S(O).sub.qN(Z.sub.9)Z.sub.6; (6) halo; (7) cyano; (8) nitro; (9) --Z.sub.4--NZ.sub.7Z.sub.8; (10) --Z.sub.4--N(Z.sub.9)--Z.sub.5--NZ.sub.7Z.sub.8; (11) --Z.sub.4--N(Z.sub.10)--Z.sub.5--Z.sub.6; (12) --Z.sub.4--N(Z.sub.10)--Z.sub.5--H; (13) oxo; (14) --O--C(O)--Z.sub.6; (15) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or (16) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together be --O--(CH.sub.2).sub.r--O--, where r is 1 to 5, completing a 4- to 8-membered ring together with the atoms to which they are attached; Z.sub.4 and Z.sub.5 are each independently (1) a single bond; (2) --Z.sub.11--S(O).sub.q--Z.sub.12--; (3) --Z.sub.11--C(O)--Z.sub.12--; (4) --Z.sub.11--C(S)--Z.sub.12--; (5) --Z.sub.11--O--Z.sub.12--; (6) --Z.sub.11--S--Z.sub.12--; (7) --Z.sub.11--O--C(O)--Z.sub.12--; or (8) --Z.sub.11--C(O)--O--Z.sub.12--; Z.sub.7, Z.sub.8, Z.sub.9 and Z.sub.10 are each independently (1) hydrogen or Z.sub.6; (2) Z.sub.7 and Z.sub.8, or Z.sub.6 and Z.sub.10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; or (3) Z.sub.7 or Z.sub.8, together with Z.sub.9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; Z.sub.11 and Z.sub.12 are each independently (1) a single bond; (2) alkylene; (3) alkenylene; or (4) alkynylene; and Z.sub.13 is (1) a single bond; (2) --Z.sub.11--S(O).sub.q--Z.sub.12--; (3) --Z.sub.11--C(O)--Z.sub.12--; (4) --Z.sub.11--C(S)--Z.sub.12--; (5) --Z.sub.11--O--Z.sub.12--; (6) --Z.sub.11--S--Z.sub.12--; (7) --Z.sub.11--O--C(O)--Z.sub.12--; (8) --Z.sub.11--C(O)--O--Z.sub.12--; (9) --C(NR.sub.13)--; (10) --C(CHR.sub.14)--; or (11) --C(C(R.sub.14).sub.2)--; provided that the compound is other than 'N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-m- ethyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

2. A compound of claim 1 wherein R.sub.1 is hydrogen.

3. A compound of claim 1 wherein R.sub.2 is hydrogen.

4. A compound of claim 1 wherein R.sub.4 is hydrogen.

5. A compound of claim 1 wherein R.sub.2 and R.sub.4 are independently hydrogen or alkyl.

6. A compound of claim 5 wherein R.sub.5 is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.

7. A compound of claim 6 wherein R.sub.3 is heteroaryl substituted optionally substituted with Z.sub.1 and Z.sub.2 and substituted with at least one group Z.sub.3 where Z.sub.3 is Z.sub.6.

8. A compound of claim 7 wherein Z.sub.6 is heterocyclo optionally substituted with one or more hydroxyalkyl.

9. A compound of formula I or salt thereof ##STR00623## where Q is thiazole optionally substituted with R.sub.1; Z is a single bond; X.sub.1 and X.sub.2 together form .dbd.O; R.sub.1 is hydrogen or alkyl; R.sub.6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z.sub.1, Z.sub.2 or one or more groups Z.sub.3; q is 1 or 2; R.sub.2 is hydrogen, R.sub.6, --Z.sub.4--R.sub.6 or --Z.sub.13--NR.sub.7R.sub.8; R.sub.3 is heteroaryl optionally, substituted with groups Z.sub.1, Z.sub.2 or one or more groups Z.sub.3; R.sub.4 and R.sub.5 are each independently (1) hydrogen or R.sub.6; (2) --Z.sub.4--N(R.sub.9)--Z.sub.5--NR.sub.10R.sub.11; (3) --N(R.sub.9)Z.sub.4R.sub.6; or (4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 are each independently (1) hydrogen or R.sub.6; (2) R.sub.7 and R.sub.8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; or (3) any two of R.sub.9, R.sub.10 and R.sub.11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; R.sub.13 is (1) cyano; (2) nitro; (3) --NH.sub.2; (4) --NHOalkyl; (5) --OH; (6) --NHOaryl; (7) --NHCOOalkyl; (8) --NHCOOaryl; (9) --NHSO.sub.2alkyl; (10) --NHSO.sub.2aryl; (11) aryl; (12) heteroaryl; (13) --Oalkyl; or (14) --Oaryl; R.sub.14 is (1) --NO.sub.2; (2) --COOalkyl; or (3) --COOaryl; Z.sub.1, Z.sub.2 and Z.sub.3 are each independently (1) hydrogen or Z.sub.6, where Z.sub.6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (3) of the definition of Z.sub.1, Z.sub.2 and Z.sub.3; (2) --OH; or (3) halo; Z.sub.4 and Z.sub.5 are each independently (1) a single bond; (2) --Z.sub.11--S(O).sub.q--Z.sub.12--; (3) --Z.sub.11--C(O)--Z.sub.12--; (4) --Z.sub.11--C(S)--Z.sub.12--; (5) --Z.sub.11--O--Z.sub.12--; (6) --Z.sub.11--S--Z.sub.12--; (7) --Z.sub.11--O--C(O)--Z.sub.12--; or (8) --Z.sub.11--C(O)--O--Z.sub.12--; Z.sub.11 and Z.sub.12 are each independently (1) a single bond; (2) alkylene; (3) alkenylene; or (4) alkynylene; and Z.sub.13 is (1) a single bond; (2) --Z.sub.11--S(O).sub.qZ.sub.12--; (3) --Z.sub.11--C(O)--Z.sub.12--; (4) --Z.sub.11--C(S)--Z.sub.12--; (5) --Z.sub.11--O--Z.sub.12--; (6) --Z.sub.11--S--Z.sub.12--; (7) --Z.sub.11--O--C(O)--Z.sub.12--; (8) --Z.sub.11--C(O)--O--Z.sub.12--; (9) --C(NR.sub.13)--; (10) --C(CHR.sub.14)--; or (11) --C(C(R.sub.14).sub.2)--; provided that the compound is other than 'N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-m- ethyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

10. A compound of formula II or salt thereof ##STR00624## where n is 1; X.sub.3 is oxygen; A is nitrogen; B is sulfur; R.sub.1 is hydrogen or alkyl; R.sub.6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z.sub.1, Z.sub.2 or one or more groups Z.sub.3; q is 1 or 2; R.sub.2 is hydrogen, R.sub.6, --Z.sub.4--R.sub.6 or --Z.sub.13--NR.sub.7R.sub.8; R.sub.3 is heteroaryl optionally substituted with groups Z.sub.1, Z.sub.2 or one or more groups Z.sub.3; R.sub.4 and R.sub.5 (1) are each independently hydrogen or R.sub.6; (2) --Z.sub.4--N(R.sub.9)--Z.sub.5--NR.sub.10R.sub.11; (3) --N(R.sub.9)Z.sub.4R.sub.6; or (4) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; R.sub.7, R.sub.8, R.sub.9, R.sub.10, and R.sub.11 are each independently (1) hydrogen or R.sub.6; (2) R.sub.7 and R.sub.9 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; or (3) any two of R.sub.9, R.sub.10 and R.sub.11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3; R.sub.13 is (1) cyano; (2) nitro; (3) --NH.sub.2; (4) --NHOalkyl; (5) --OH; (6) --NHOaryl; (7) --NHCOOalkyl; (8) --NHCOOaryl; (9) --NHSO.sub.2alkyl; (10) --NHSO.sub.2aryl; (11) aryl; (12) heteroaryl; (13) --Oalkyl; or (14) --Oaryl; R.sub.14 is (1) --NO.sub.2; (2) --COOalkyl; or (3) --COOaryl; Z.sub.1, Z.sub.2 and Z.sub.3 are each independently (1) hydrogen or Z.sub.6, where Z.sub.6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (3) of the definition of Z.sub.1, Z.sub.2 and Z.sub.3; (2) --OH; or (3) halo; Z.sub.4 and Z.sub.5 are each independently (1) a single bond; (2) --Z.sub.11--S(O).sub.q--Z.sub.12--; (3) --Z.sub.11--C(O)--Z.sub.12--; (4) --Z.sub.11--C(S)--Z.sub.12--; (5) --Z.sub.11--O--Z.sub.12--; (6) --Z.sub.11--S--Z.sub.12; (7) --Z.sub.11--O--C(O)--Z.sub.12--; or (8) --Z.sub.11--C(O)--O--Z.sub.12--; Z.sub.11 and Z.sub.12 are each independently (1) a single bond; (2) alkylene; (3) alkenylene; or (4) alkynylene; and Z.sub.13 is (1) a single bond; (2) --Z.sub.11--S(O).sub.q--Z.sub.12--; (3) --Z.sub.11--C(O)--Z.sub.12--; (4) --Z.sub.11--C(S)--Z.sub.12--; (5) --Z.sub.11--O--Z.sub.12--; (6) --Z.sub.11--S--Z.sub.12--; (7) --Z.sub.11--O--C(O)--Z.sub.12--; (8) --Z.sub.11--C(O)--O--Z.sub.12--; (9) --C(NR.sub.13)--; (10) --C(CHR.sub.14)--; or (11) --C(C(R.sub.14).sub.2)--; provided that the compound is other than 'N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-m- ethyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

11. A compound of claim 10 wherein R.sub.1 is hydrogen.

12. A compound of claim 10 wherein R.sub.2 is hydrogen.

13. A compound of claim 10 wherein R.sub.4 is hydrogen.

14. A compound of claim 10 wherein R.sub.5 is an aryl group which is substituted with Z.sub.1, Z.sub.2 or one or more groups Z.sub.3.

15. A compound of claim 10 wherein R.sub.1 is hydrogen or alkyl, R.sub.2 and R.sub.4 are independently hydrogen or alkyl, and R.sub.5 is aryl which is unsubstituted or substituted with Z.sub.1, Z.sub.2 or one or more groups Z.sub.3.

16. A compound of claim 15 wherein R.sub.5 is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.

17. A compound of claim 16 wherein R.sub.3 is heteroaryl substituted optionally substituted with Z.sub.1 or Z.sub.2 and substituted with at least one group Z.sub.3 where Z.sub.3 is Z.sub.6.

18. A compound of claim 17 wherein Z.sub.6 is heterocyclo optionally substituted with one or more hydroxyalkyl.

19. A compound of claim 7, wherein R.sub.3 is heteroaryl substituted with groups Z.sub.1, Z.sub.2 and one or more Z.sub.3; wherein the heteroaryl is selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, or indazolyl.

20. A compound of claim 17 wherein R.sub.3 is is heteroaryl substituted optionally substituted with Z.sub.1 or Z.sub.2 and substituted with at least one group Z.sub.3, wherein the heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, or indazolyl.

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