US 2008/0167288 A1 · Substituted cyclic hydroxamates as lnhibitors of matrix metalloproteinases

Abstract

The present invention provides compounds of the formula: its enantiomers, diastereomers, racemic mixtures thereof, prodrugs, crystalline forms, non-crystalline forms, amorphous forms thereof, solvates thereof, metabolites thereof, and pharmaceutically acceptable salts, wherein the ring A substituent groups are fully defined in the following disclosure. The compounds of formula are inhibitors of metalloproteases such as matrix metalloproteases and sheddases, and are useful in treating diseases such as rheumatoid arthritis, psoriasis, neoplastic diseases, allergies and all those diseases wherein inhibition of MMPs is desirable.

A compound of the formula IA:

its enantiomers, diastereomers, enantiomerically enriched mixtures, racemic mixtures thereof, prodrugs, crystalline forms, non-crystalline forms, amorphous forms thereof, solvates thereof, metabolites thereof, and pharmaceutically acceptable salts, wherein:
ring A is a 3-13 membered carbocycle or heterocycle comprising carbon atoms, 0-3 carbonyl groups, 0-4 double bonds, and from 0-4 ring heteroatoms selected from the group consisting of O, N, NR, and S(O)p, provided that ring A contains other than a S—S, O—O, or S—O bond;
n′ is an integer from 1-3;
Z is selected from the group consisting of —COR5, —CO2H, —CH2CO2H, —CO2R6, —CONHOH, —CONHOR5, —CON(R6)OH, —CONHOR6, —NHRa, —N(OH)C(O)R5, —N(OH)CHO, —SH, —CH2SH, —S(O)(═NH)Ra, —SN2H2Ra, —PO(ORg)2, —PO(OH)NHRa,
Rg is independently selected from the group consisting of H, CH2OCORa,
P is -D-E-G-Q-L-T-X—Y, wherein
D is absent or is selected from the group consisting of O, NRa1, C(O), C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
E is absent or is selected from the group consisting of C1-10alkylene, C2-10 alkenylene, and C2-10 alkynylene;
G is absent or is selected from the group consisting of O, NRa1, S(O)p, and C(O);
Q is absent or is selected from the group consisting of a C3-13 carbocycle substituted with 0-5 Rb, and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and said heterocycle being substituted with 0-5 Rb;
L is absent or is selected from the group consisting of O, NRa1, C(O), C(O)O, OC(O), C(O)NRa1, NRa1C(O), OC(O)O, OC(O)NRa1, NRa1C(O)O, NRa1C(O)NRa1, S(O)p, S(O)pNRa1, NRa1S(O)p, and NRa1SO2NRa1;
T is absent or is selected from the group consisting of C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
X is absent or is selected from the group consisting of O, NRa1, S(O)p, and C(O);
Y is selected from the group consisting of H, a C3-13 carbocycle substituted with 0-5 Rc and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and said heterocycle being substituted with 0-5 Rc;
provided that D, E, G, Q, L, T, X and Y do not combine to form a N—N, N—O, O—N, O—O, S(O)p—O, O—S(O)p or S(O)p—S(O)p group;
R, at each occurrence, is independently selected from (C1-10 alkylene substituted with 1-3 Rb1)r-M, (C2-10 alkenylene substituted with 1-3 Rb1)-M, (C2-10 alkynylene substituted with 1-3 Rb1)-M, OH, Cl, F, Br, I, —CN, NO2, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCF2CF3, OCHF2, O(CRdRd1)r-M, NRa(CRdRd1)r-M, OC(O)(CRdRd1)r-M, NRaC(O)(CRdRd1)r-M, OC(O)O(CRdRd1)r-M, OC(O)NRa(CRdRd1)r-M, NRaC(O)O(CRdRd1)r-M, NRaC(O)NRa1(CRdRd1)r-M, S(O)p(CRdRd1)rM, S(O)2NRa(CRdRd1)r-M, NRaS(O)2(CRdRd1)r-M, and NRaS(O)2NRa1(CRdRd1)r-M, (CRdRd1)rP(O)(ORa)2, (CRdRd1)rP(O)(ORa)(NRdRd1), (CRdRd1)rP(O)(NRaRa1)2, (CRdRd1)rOP(O)(ORa)2, (CRdRd1)rOP(O)(ORa)(NRaRa1), (CRdRd1)rOP(O)(NRaRa1)2, (CRdRd1)rNRaP(O)(ORa)2, (CRdRd1)rNRaP(O)(ORa)(NRaRa1), (CRdRd1)rNRaP(O)(NRaRa1)2;
C(═NRa)NRa1Ra2;
C(═CRdRd1)NRa1Ra2;
a C3-13 carbocycle
substituted with 0-5 Rd, and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, S(O)p and said heterocycle being substituted with 0-5 Rd;
alternatively, two R, together with a carbon atom on A, form the group CA=CRdRd1, where the atom CA is said atom on A;
M is selected from the group consisting of H, C2-10 alkenylene substituted with 0-3 Rb1, C2-10 alkynylene substituted with 0-3 Rb1, ORa, Cl, F, Br, I, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, NRaC(O)ORa, NRaC(O)Ra, S(O)2NRaRa1, NRaS(O)2Ra, NRaS(O)2NRaRa1, OS(O)2NRaRa1, S(O)pRa2, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCF2CF3, OCHF2, a C3-13 carbocycle substituted with 0-5 Rd, and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, S(O)p and said heterocycle being substituted with 0-5 Rd;
alternatively, R, at each occurrence, is independently selected from (CRdRd1)rO(CRdRd1)r-M1, (CRdRd1)rNRa(CRdRd1)r-M1, (CRdRd1)rC(O)(CRdRd1)r-M1, (CRdRd1)rC(O)O(CRdRd1)r-M1, (CRdRd1)rOC(O)(CRdRd1)r-M1, (CRdRd1)rC(O)NRa(CRdRd1)r-M1, (CRdRd1)rNRaC(O)(CRdRd1)r-M1, (CRdRd1)rOC(O)O(CRdRd1)r-M1, (CRdRd1)rOC(O)NRa(CRdRd1)r-M1, (CRdRd1)rNRaC(O)O(CRdRd1)r-M1, (CRdRd1)rNRaC(O)NRa1(CRdRd1)r-M1, (CRdRd1)rS(O)p(CRdRd1)r-M1, (CRdRd1)rS(O)2NRa(CRdRd1)r-M1, (CRdRd1)rNRaS(O)2(CRdRd1)r-M1, and (CRdRd1)rNRaS(O)2NRa1(CRdRd1)r-M1;
M1 is selected from the group consisting of C1-10 alkylene-M1, C2-10 alkenylene-M1, C2-10 alkynylene-M1, ORa, Cl, F, Br, I, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa1, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, S(O)pRa2, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCF2CF3, and a 5-14 membered non-aromatic heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, S(O)p and said heterocycle being substituted with 0-5 Rd;
a C3-C13 carbocycle, C4-C14 heterocycle and wherein said C3-C13 carbocycle and C4-C14 heterocycle are substituted with 1-3 Rh, and CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCHF2, OCF2CF3 and OCH2CF3;
alternatively, when two R groups are attached to adjacent ring A atoms, together with the atoms to which they are attached they may form a 3-8 membered saturated, partially saturated or unsaturated ring comprised of carbon atoms and 0-3 heteroatoms selected from the group consisting of N, NRa, O, and S(O)p, wherein said ring may be benzene-fused and/or substituted with Rd;
alternatively, when two R groups are attached to the same ring A carbon, together with the carbon to which they are attached they may form a 3-8 membered saturated, partially saturated or unsaturated spiro-ring comprised of carbon atoms and 0-3 heteroatoms selected from the group consisting of N, NRa, O, and S(O)p, wherein said spiro-ring may be benzene-fused and/or substituted with Rd;
provided that either two or more R or M, M1 and the atom to which they are attached do not combine to form a N—N, N—O, O—N, O—O, N-halogen, O-halogen, S-halogen, S(O)p—O, O—S(O)p, S(O)p—S(O)p group, or C(O)F, C(O)Cl, C(O)Br, or C(O)I reactive group;
Ra, Ra1, and Ra2 at each occurrence are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with O(primary, secondary, or tertiary)C1-C8, OH, Cl, F, Br, I, ═O, —CN, NO2, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCF2CF3 and OCH2CF3;
C3-C10 carbocycle, heterocycles, C3-C10 carbocyclylalkyl, heterocyclylalkyl and wherein said C3-C10 carbocycle, heterocycles, C3-C10 carbocyclylalkyl, and heterocyclylalkyl may be optionally substituted with one or more substituents selected from the group consisting of C1-C8 alkyl, O(primary, secondary, or tertiary)C1-C8, OH, Cl, F, Br, I, ═O, —CN, NO2, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamido-alkyl, N-alkylsulfonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCF2CF3 and OCH2CF3;
alternatively, Ra and Ra1 taken together with the nitrogen to which they are attached form a 4 to 8 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S, wherein said ring may be substituted with Rd;
Rb at each occurrence is independently selected from the group consisting of C1-6alkyl optionally substituted with Rc1, O(primary, secondary, or tertiary)C1-C8, OH, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa, OC(O)NRaRa1, RaNC(O)O Ra1, S(O)2 NRaRa1, NRaS(O)2Ra2, NRaS(O)2 NRaRa1, OS(O)2 NRaRa1, S(O)pRa2, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCHF2, OCF2CF3 and OCH2CF3;
C3-10 carbocyclic residue, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, C3-C10 carbocyclyl(C1-8)alkyl, and 5-14 heterocyclyl-(C1-8)alkyl and said C3-10 carbocyclic residue, heterocyclic system, C3-C10 carbocyclyl(C1-8)alkyl, and 5-14 heterocyclyl(C1-8)alkyl are optionally substituted with Rc1;
Rb1 at each occurrence is independently selected from the group consisting of ORa, F, ═O, —CN, NO2, NRaRa1 and S(O)pRa;
Rc at each occurrence is independently selected from the group consisting of C1-6alkyl optionally substituted with Rc1, ORa, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa, OC(O)NRaRa1, RaNC(O)ORa1, S(O)2 NRaRa1, NRaS(O)2Ra2, NRaS(O)2 NRaRa1, OS(O)2 NRaRa1, S(O)pRa2, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCHF2, OCF2CF3 and OCH2CF3;
a C3-10 carbocyclic residue, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, C3-C10 carbocyclyl(C1-8)alkyl, and 5-14 heterocyclyl(C1-8)alkyl;
said C3-10 carbocyclic residue, heterocyclic system C3-C10 carbocyclyl(C1-8)alkyl, and 5-14 heterocyclyl(C1-8)alkyl are optionally substituted with Rc1;
Rc1 at each occurrence is independently selected from the group consisting of C1-6alkyl, ORa, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, S(O)pRa2, CF3, and CF2CF3, CH2F, and CHF2;
Rd at each occurrence is independently selected from the group consisting of H, C1-6alkyl optionally substituted with Rc1, ORa, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa, C(O)NRaRa1, RaNC(O)O Ra1, S(O)2 NRaRa1, NRaS(O)2Ra2, NRaS(O)2 NRaRa1, OS(O)2 NRaRa1, S(O)pRa2, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCHF2, OCF2CF3 and OCH2CF3;
C3-10 carbocyclic residue, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, C3-C10 carbocyclyl(C1-8)alkyl, and 5-14 heterocyclyl(C1-8)alkyl;
said C3-10 carbocyclic residue, heterocyclic system C3-C10 carbocyclyl(C1-8)alkyl, and 5-14 heterocyclyl(C1-8)alkyl optionally substituted with Rc1;
Rd1 at each occurrence is independently selected from the group consisting of H, C1-6alkyl optionally substituted with Rc1, ORa, Cl, F, Br, I, ═O, —CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa, OC(O)NRaRa1, RaNC(O)O Ra1, S(O)2 NRaRa1, NRaS(O)2Ra2, NRaS(O)2 NRaRa1, OS(O)2 NRaRa1, S(O)pRa2, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCHF2, OCF2CF3 and OCH2CF3;
C3-10 carbocyclic residue, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S, C3-C10 carbocyclyl(C1-8)alkyl, and 5-14 heterocyclyl(C1-8)alkyl;
said C3-10 carbocyclic residue, heterocyclic system C3-C10 carbocyclyl(C1-8)alkyl, and 5-14 heterocyclyl(C1-8)alkyl optionally substituted with Rc1;
alternatively, Rd and Rd1 taken together with the atom to which they are attached form a 4 to 8 membered ring containing from 0-1 heteroatoms selected from the group consisting of N, O, and S, wherein said ring may be substituted with Rd;
Rh at each occurrence is independently selected from the group consisting of ORj, NRjRa, CORj, C(O)ORj, C(O)NRjRa, NRaC(O)NRjRa1, OC(O)NRjRa, S(O)pNRjRa1, NRaS(O)pRj, NRaS(O)pNRjRa, C1-6alkyl substituted with Rc;
Rj at each occurrence is independently selected from the group consisting of CF3, CHF2, CFH2, CF2CF3, C1-C8 alkyl substituted with O(primary, secondary, or tertiary)C1-C8, OH, Cl, F, Br, I, ═O, —CN, NO2, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCHF2, OCF2CF3 and OCH2CF3;
C2-C8 alkenyl, C2-C8 alkynyl, wherein said alkenyl and alkynyl groups are optionally substituted with C1-C8 alkyl, O(primary, secondary, or tertiary)C1-C8, OH, Cl, F, Br, I, ═O, —CN, NO2, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCHF2, OCF2CF3 and OCH2CF3;
C3-C10 carbocycle, heterocycles, C3-C10 carbocyclylalkyl, heterocyclylalkyl and wherein said C3-C10 carbocycle, heterocycles, C3-C10 carbocyclylalkyl, and heterocyclylalkyl may be optionally substituted with one or more substituents selected from the group consisting of O(primary, secondary, or tertiary)C1-C8, OH, Cl, F, Br, I, ═O, —CN, NO2, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamido-alkyl, N-alkylsulfonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF3, CF2CF3, CH2F, CHF2, CF2CH3, C(CH3)2F, OCF3, OCF2CF3 and OCH2CF3, with the proviso that said C3-C10 carbocycle can not be a phenyl group and C3-C10 carbocyclylalkyl can not be a benzyl group;
R3 is H or C1-6alkyl ORa, NRaRa1, and S(O)pRa;
R4 is selected from the group consisting of H, C1-6alkyl, ORa, NRaRa1, and S(O)pRa;
R5 at each occurrence is selected from the group consisting of C1-10alkyl substituted with 0-2Rb, and C1-8 alkyl substituted with 0-2 Re;
Re at each occurrence is selected from the group consisting of phenyl substituted with 0-2 Rb and biphenyl substituted with 0-2 Rb;
R6 at each occurrence is selected from the group consisting of phenyl, naphthyl, C1-10alkyl-phenyl-C1-6alkyl-, C3-11cycloalkyl, C1-6alkylcarbonyloxy-C1-3 alkyl-, C1-6alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, [5-(Ra)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C1-10 alkyl-NR7, R7a, —CH(R8)OC(O)R9, and —CH(R8)OC(O)OR9;
alternatively, R4 and R6 can be taken together to form a 5-10 membered ring optionally substituted with Rc;
R7 is selected from the group consisting of H, C1-10 alkyl, C2-6 alkenyl, C3-6cycloalkyl-C1-3 alkyl-, and phenyl-C1-6alkyl-;
R7a is selected from the group consisting of H, C1-10 alkyl, C2-6 alkenyl, C3-6cycloalkyl-C1-3 alkyl-, and phenyl-C1-6alkyl-;
R8 is selected from the group consisting of H and C1-4 linear alkyl;
R9 is selected from the group consisting of H, C1-8 alkyl substituted with 1-2 Rf, C3-8 cycloalkyl substituted with 1-2 Rf, and phenyl substituted with 0-2 Rb;
Rf at each occurrence is selected from the group consisting of H, C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, and phenyl substituted with 0-2 Rb;
p at each occurrence is 0, 1, and 2;
and
r at each occurrence is 0, or an integer from 1 to 10.

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Substituted cyclic hydroxamates as lnhibitors of matrix metalloproteinases

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Substituted cyclic hydroxamates as lnhibitors of matrix metalloproteinases

Life of this patent

Abstract

Claims24