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Details for Patent: 8,993,567

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Details for Patent: 8,993,567

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 (Franklin Park, NJ), Norris; Derek (Pennington, NJ), Doweyko; Arthur M. P. (Long Valley, NJ), Barrish; Joel C. (Richboro, PA), Wityak; John (Carlsbad, CA)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Filing Date:Mar 27, 2014
Application Number:14/226,868
Claims:1. A compound of formula I or salt thereof ##STR00640## 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 (1) hydrogen or R.sub.6, where 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 and 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.13--NR.sub.7R.sub.8 where Z.sub.13 is --C(O)--; 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 R.sub.7 is alkyl; R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 (1) are each independently hydrogen or R.sub.6; 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; or (14) --O--C(O)--Z.sub.6; 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 (1) are each independently hydrogen or Z.sub.6; 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 said compound is other than a compound of formula (ix) ##STR00641## where R.sub.2i is hydrogen or alkyl; R.sub.3i is --C(O)--NH-(alk); and R.sub.58 and R.sub.59 are independently hydrogen, alkyl or halogen.

2. A compound of claim 1 wherein R.sub.1 is hydrogen, alkyl, or aryl.

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

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

5. A compound of claim 2 wherein R.sub.4 is hydrogen.

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

7. A compound of claim 2 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 and one or more groups Z.sub.3.

8. A compound of claim 7 wherein R.sub.5 is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.

9. A pharmaceutical composition, comprising a pharmaceutically acceptable vehicle or diluent and at least one compound of claim 1.

10. A compound of formula II or salt thereof ##STR00642## where n is 1; X.sub.3 is oxygen; A is nitrogen; B is sulfur; R.sub.1 is (1) hydrogen or R.sub.6, where 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 and 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 R.sub.3 is --Z.sub.13--NR.sub.7R.sub.8 where Z.sub.13 is --C(O)--; 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 R.sub.7 is alkyl; R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 (1) are each independently hydrogen or R.sub.6; 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; (14) --O--C(O)--Z.sub.6; 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 (1) are each independently hydrogen or Z.sub.6; 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 said compound is other than a compound of formula (ix) ##STR00643## where R.sub.2i is hydrogen or alkyl; R.sub.3i is --C(O)--NH-(alk); and R.sub.58 and R.sub.59 are independently hydrogen, alkyl or halogen.

11. 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 and one or more groups Z.sub.3.

12. A compound of claim 11 wherein R.sub.5 is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.
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