Claims for Patent: 7,994,190

Summary for Patent: 7,994,190

Title:	Modulators of glucocorticoid receptor, AP-1, and/or NF-.kappa.B activity and use thereof
Abstract:	Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, and/or AP-1 and/or NF-.kappa.B activity including inflammatory and immune diseases, obesity and diabetes having the structure of formula (I):, its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, wherein the group X is O or (R.sup.x)(R.sup.y); is heterocyclo or heteroaryl; E is --N--, --NR.sub.1--, --O--, --C(.dbd.O), --S--, --SO.sub.2--, or --CR.sub.2--; F is --N--, --NR.sub.1a, --O--, --C(.dbd.O), --S--, --SO.sub.2--, or --CR.sub.2a--; G is independently N, --NR.sub.1b--, --O--, --C(.dbd.O), --S--, --SO.sub.2-- or --CR.sub.2b-- provided that the heterocyclic ring formed does not contain a S--S or S--O bond and at least one of E, F and G is a hetero atom; and Ma, R.sup.x, R.sup.y, R.sub.1, R.sub.1a, R.sub.1b, R.sub.2, R.sub.2a, R.sub.2b, R.sub.4, R.sub.5a, R.sub.6, R.sub.7, X, Z.sub.a and Z are as defined herein. Also provided are pharmaceutical compositions and methods of treating inflammatory- or immune-associated diseases employing said compounds. ##STR00001##
Inventor(s):	Dhar; T. G. Murali (Newtown, PA), Xiao; Hai-Yun (Belle Mead, NJ), Sheppeck; James E. (Newtown, PA)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	12/513,228
Patent Claims:	1. A compound according to formula I, ##STR00069## its enantiomer, diastereomers, and tautomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, wherein the side chain group: ##STR00070## is attached to the benzo ring at the 5- or 6-position; ##STR00071## is heterocyclo or heteroaryl; E is --CR.sub.2--; F is selected from --N-- and --CR.sub.2a--; G is selected from N and --CR.sub.2b--; X is selected from O and (R.sup.x)(R.sup.y); M is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclo, and heteroaryl; M.sub.a is a linker between C and M and is selected from a bond; C.sub.1-C.sub.5 alkylene; C.sub.1-C.sub.5 alkylene which includes at any position in the chain a) a nitrogen which is substituted with alkyl, b) an oxygen, c) a sulfur, or d) an SO.sub.2 group; --C(R.sub.m.sub.1)(R.sub.m.sub.2)C(.dbd.O)N(R.sub.m.sub.3)--; --C(.dbd.O)N(R.sub.m.sub.1)C(R.sub.m.sub.2)(R.sub.m.sub.3)--; --N(R.sub.m.sub.3)C(.dbd.O)C(R.sub.m.sub.1)(R.sub.m.sub.2)--; --C(R.sub.m.sub.1)(R.sub.m.sub.2)S(.dbd.O).sub.2N(R.sub.m.sub.3)--; --S(.dbd.O).sub.2N(R.sub.m.sub.1)C(R.sub.m.sub.2)(R.sub.m.sub.3)--; and --N(R.sub.m.sub.1)C(.dbd.O)N(R.sub.m.sub.2)--; (R.sub.m where R.sub.m.sub.1, R.sub.m.sub.2 and R.sub.m.sub.3 are the same or different and at each occurrence independently selected from H and C.sub.1-C.sub.4 alkyl, or R.sub.m.sub.1 and R.sub.m.sub.2 combine to form a C.sub.3-6 carbocyclic or heterocyclo ring; Q is selected from (i) hydrogen, halogen, nitro, cyano, hydroxy, unsubstituted C.sub.1-C.sub.4 alkyl, and substituted C.sub.1-C.sub.4 alkyl; or (ii) Q and R.sub.6 are combined with the carbons to which they are attached to form a 3- to 6-membered cycloalkyl or heterocyclo ring; (iii) Q and M-M.sub.a are combined with the carbon to which they are attached to form a 3-7 membered ring optionally containing of 0, 1 or 2 heteroatoms which are the same or different and are independently selected form the group consisting of O, S, SO, SO.sub.2, and N--R.sub.5b, provided that the heterocyclic ring formed does not contain a S--S or S--O bond, wherein this ring may be optionally substituted with 0, 1 or 2 R.sub.3 groups or carbonyl; where X is O, Z is selected from (i) alkyl, cycloalkyl, heterocyclo, alkylsulfonyl, aryl, and heteroaryl; and (ii) Z is combined with R.sub.5a and to the carbon to which they are attached to form a 3-6 membered heterocyclic ring which is optionally substituted with 1-2 R.sub.3 groups or carbonyl; or when X.dbd.(R.sup.x)(R.sup.y), Z is selected from (i) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, --C(.dbd.O)NR.sub.8R.sub.9, --C(.dbd.O)R.sub.8, --C(NCN)NR.sub.8R.sub.9, C(.dbd.O)OR.sub.8, --SO.sub.2R.sub.8, and --SO.sub.2NR.sub.8R.sub.9; or (ii) Z is combined with R.sub.5a to form a 3-6 membered heterocyclic ring which is optionally substituted with 1-2 R.sub.3 or carbonyl; Z.sub.a is a linker between N and Z and is selected from a bond; C.sub.1-C.sub.5 alkylene; C.sub.1-C.sub.5 alkylene which includes at any position in the chain a) a nitrogen which is substituted with alkyl, b) an oxygen, c) a sulfur, or d) an SO.sub.2 group; --C(R.sub.z.sub.1)(R.sub.z.sub.2)C(.dbd.O)N(R.sub.z.sub.3)--; --C(.dbd.O)N(R.sub.z.sub.1)C(R.sub.z.sub.2)(R.sub.z.sub.3)--; --C(R.sub.z.sub.1)(R.sub.z.sub.2)S(.dbd.O).sub.2N(R.sub.z.sub.3)--; and --S(.dbd.O).sub.2N(R.sub.z.sub.1)C(R.sub.z.sub.2)(R.sub.z.sub.3)--; where R.sub.z.sub.1, R.sub.z.sub.2 and R.sub.z.sub.3 at each occurrence are independently selected from H and C.sub.1-C.sub.4 alkyl; R.sub.1, R.sub.1a, R.sub.1b, R.sup.x and R.sup.y are the same or different and at each occurrence are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; R.sub.2, R.sub.2a and R.sub.2b are the same or different and at each occurrence are independently selected from (i) hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, --OR.sub.10, --NR.sub.10R.sub.11, --C(.dbd.O)R.sub.10, --CO.sub.2R.sub.10, --C(.dbd.O)NR.sub.10R.sub.11, --O--C(.dbd.O)R.sub.10, --NR.sub.10C(.dbd.O)R.sub.11, --NR.sub.10C(O)OR.sub.11, --NR.sub.10C(S)OR.sub.11, --S(O).sub.pR.sub.12, --NR.sub.8SO.sub.2R.sub.12, --SO.sub.2NR.sub.10R.sub.11, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl; or (ii) two R.sub.2, R.sub.2a and R.sub.2b groups that are located on adjacent carbon atoms may be taken together with the carbons to which they are attached to form a fused ring; R.sub.3 at each occurrence is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, --OR.sub.13, --NR.sub.13R.sub.14, --C(.dbd.O)R.sub.13, --CO.sub.2R.sub.13, --C(.dbd.O)NR.sub.13R.sub.14, --O--C(.dbd.O)R.sub.13, --NR.sub.13C(.dbd.O)R.sub.14, --NR.sub.13C(O)OR.sub.14, --NR.sub.13C(S)OR.sub.14, --S(O).sub.pR.sub.15, --NR.sub.13SO.sub.2R.sub.15, --SO.sub.2NR.sub.13R.sub.14, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl; R.sub.4 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, and C.sub.1-C.sub.4 alkoxy; R.sub.5a is selected from hydrogen and alkyl; and R.sub.6 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, --OR.sub.16, --NR.sub.16R.sub.17, --C(.dbd.O)R.sub.17, --CO.sub.2R.sub.17, --C(.dbd.O)NR.sub.16R.sub.17, --O--C(.dbd.O)R.sub.16, --NR.sub.16C(.dbd.O)R.sub.17, --NR.sub.16C(.dbd.O)OR.sub.17, --NR.sub.16C(.dbd.S)OR.sub.17, --S(O).sub.pR.sub.18, --NR.sub.16SO.sub.2R.sub.18, --SO.sub.2NR.sub.16R.sub.17, cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl; R.sub.7 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, OR.sub.19, NR.sub.19R.sub.20, --C(.dbd.O)R.sub.19, --CO.sub.2R.sub.19, --C(.dbd.O)NR.sub.19R.sub.20, --O--C(.dbd.O)R.sub.19, --NR.sub.19C(.dbd.O)R.sub.20, --NR.sub.19C(.dbd.O)OR.sub.20, --NR.sub.19C(.dbd.S)OR.sub.20, --S(O).sub.pR.sub.21, --NR.sub.19SO.sub.2R.sub.21, --SO.sub.2NR.sub.19R.sub.20, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl; or R.sub.6 and R.sub.7 are taken together with the carbon to which they are attached to form a cycloalkyl, cycloalkenyl, or heterocyclo ring; R.sub.5b, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.13, R.sub.13a, R.sub.14, R.sub.16, R.sub.17, R.sub.19 and R.sub.20 are the same or different and at each occurrence are independently selected from (i) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) with respect to Z, R.sub.8 taken together with R.sub.9, and/or with respect to R.sub.3 and R.sub.6, R.sub.15 is taken together with R.sub.16, and/or with respect to R.sub.6 and R.sub.7, R.sub.18 is taken together with R.sub.19, and/or with respect to R.sub.7, R.sub.20 is taken together with R.sub.21 to form a 4- to 6-membered heteroaryl or heterocyclo ring; R.sub.12, R.sub.15, R.sub.18 and R.sub.21 are the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo; and p is 0, 1 or 2, provided that where the ring system ##STR00072## and Q and M.sub.a-M are independently H, CH.sub.3 or C.sub.2H.sub.5, then Z.sub.a--Z is other than ##STR00073## where G.sub.1 is a heteroaryl, acetyl, carbamoyl, or --C(.dbd.S)CH.sub.3 or --C(.dbd.S)C.sub.2H.sub.5. 2. The compound according to claim 1 having the structure ##STR00074## 3. The compound according to claim 1 having the structure ##STR00075## 4. The compound as defined in claim 1 where in ##STR00076## E is CR.sub.2; F is N; and G is CR.sub.2b; X is (R.sup.x)(R.sup.y) where R.sup.x and R.sup.y are the same or different and are independently selected from H and alkyl; or X is O; R.sub.6 is alkyl or H; R.sub.7 is alkyl or H; M is aryl or H; M.sub.a is a bond; Q is H; or E is CR.sub.2 where R.sub.2 is H, aryl or alkyl; F is N or CR.sub.2a; G is CR.sub.2b where R.sub.2b is selected from haloaryl, halo, cyanoaryl, H, dihaloaryl, hydroxyalkylaryl and heteroaryl, or G is N; where X is (R.sup.x)(R.sup.y) then Z is selected from cycloalkyl, heteroaryl, aryl, heterocyclo, --C(.dbd.O)NR.sub.8R.sub.9, --C(.dbd.O)R.sub.8, --C(NCN)NR.sub.8R.sub.9, and --C(.dbd.O)OR.sub.8; where X is O then Z is selected from heteroaryl, cycloalkyl, aryl, heterocyclo, and alkyl; and Z.sub.a is a bond. 5. The compound as defined in claim 1 wherein ##STR00077## is selected from ##STR00078## 6. The compound as defined in claim 1 wherein ##STR00079## where R.sub.2 is selected from aryl, H and alkyl, R.sub.2b is selected from H, halogen, aryl, and heteroaryl; and R.sub.4 is selected from H and methyl; or ##STR00080## where R.sub.2 is selected from H, alkyl and aryl; and R.sub.4 is selected from H and methyl. 7. A compound as defined in claim 1 wherein: Z is selected from ##STR00081## R.sup.m and R.sup.n are the same or different and at each occurrence are independently selected from hydrogen, halogen, cycloalkyl, cyano, --CO.sub.2R.sup.c, --NR.sup.aR.sup.b, --C(.dbd.O)R.sup.c, --C(O)N(R.sup.a)(R.sup.b), OR.sup.c, alkyl, substituted alkyl, aryl, heteroaryl and heterocyclo; or R.sup.m and R.sup.n combine to form a 5-, 6- or 7-membered carbocyclic, aryl, heteroaryl or cycloheteroalkyl ring which contains 0, 1, 2 or 3 hetero atoms which can be N, O, or S; R.sup.a and R.sup.b are the same or different and at each occurrence are independently selected from (1) hydrogen, alkyl, C(.dbd.O)alkyl, CO.sub.2(alkyl), SO.sub.2alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkenyl, heterocyclo, and cycloalkyl, provided R.sup.a and R.sup.b are not both alkoxy, amino, or substituted amino, or (2) where possible R.sup.a is taken together with R.sup.b to form a heteroaryl or heterocyclo ring; and R.sup.c is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, heteroaryl, heterocyclo, cycloalkyl, and aryl. 8. The compound as defined in claim 4 wherein G is N or G is CR.sub.2b and R.sub.2b is ##STR00082## E is CR.sub.2 and R.sub.2 is ##STR00083## H or CH.sub.3; F is N; and R.sub.6 is CH.sub.3 or H; R.sub.7 is CH.sub.3 or H; and M-M.sub.a is ##STR00084## or H. 9. The compound as defined in claim 5 wherein Z is ##STR00085## 10. The compound as defined in claim 1 wherein ##STR00086## 11. The compound as defined in claim 1 having the structure ##STR00087## where G is N or CR.sub.2b; R.sub.2 is H, CH.sub.3 or ##STR00088## R.sub.2b is Br, ##STR00089## R.sub.4 is H or CH.sub.3; R.sub.6 is H or CH.sub.3; R.sub.7 is H or CH.sub.3; Q is ##STR00090## M is H; M.sub.a is a bond; R.sub.5a is H; Z is ##STR00091## R.sup.x is H; R.sup.y is H; and Z.sub.a is a bond; or a pharmaceutically acceptable salt thereof. 12. The compound as defined in claim 1 having the structure ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor. 14. A pharmaceutical combination comprising a compound as defined in claim 1 and an antidiabetic agent, an anti-obesity agent, an antihypertensive agent, and/or an antiosteoporosis agent, wherein the antidiabetic agent is 1, 2, 3 or more of a metformin, a sulfonyl urea, a glucosidase inhibitor, a PPAR .gamma. agonist, a PPAR .alpha./.gamma. dual agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or a meglitinide, wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor agonist, an aP2 inhibitor and/or an anorectic agent, wherein the antihypertensive agent is an ACE inhibitor, angiotensin II receptor antagonist, NEP/ACE inhibitor, calcium channel blocker and/or .beta.-adrenergic blocker, and the antiosteoporosis agent is parathyroid hormone or a biphosphonate.

Details for Patent 7,994,190

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2039-03-29