Tricyclic sulfonamide compounds and methods of making and using same

A method of treating and/or controlling obesity, comprising administering to a patient in need thereof an effective amount of a tricyclic compound represented by:

• wherein:
• A is phenyl;
• RA1 is selected, independently for each occurrence, from the group consisting of:
• hydrogen, hydroxy, cyano, halogen, C1-4alkyl, and C1-3alkoxy;
• wherein C1-4alkyl or C1-3alkoxy may be optionally substituted by one or more fluorines;
• n is 1 or 2;
• RA2 is selected from the group consisting of:
• hydrogen, RiRjN—, heterocyclyl, heterocyclyloxy, and heterocyclyl-(NRa)—;
• wherein said heterocyclyl may optionally be substituted by one or more substituents selected from Rg;
• and wherein if said heterocyclyl contains a —NH moiety that nitrogen may optionally be substituted by one or more groups Rh;
• or
• RA2 is selected from the group consisting of:
• C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C3-6alkenyloxy, C3-6alkynyloxy, C3-6cycloalkoxy, C1-6alkyl-S(O)w— (wherein w is 0, 1 or 2), C1-6alkyl-N(Ra)—, C1-6alkyl-N(Ra)-carbonyl-, C1-6alkylcarbonyl-N(Ra)—, C1-6alkyl-N(Ra)-carbonyl-N(Ra)—, C1-6alkyl-N(Ra)—SO2—, C1-6alkyl-SO2—N(Ra)—, C1-6alkoxycarbonyl-N(Ra)—, C1-6alkylcarbonyl-N(Ra)—C1-6alkyl-, C1-6alkyl-N(Ra)-carbonyl-C1-6alkyl-, and C1-6alkoxyC1-6alkyl-;
• wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C3-6alkenyloxy, C3-6alkynyloxy, C3-6cycloalkoxy, C1-6alkyl-S(O)w—, C1-6alkyl-N(Ra)—, C1-6alkyl-N(Ra)-carbonyl-, C1-6alkylcarbonyl-N(Ra)—, C1-6alkyl-N(Ra)-carbonyl-N(Ra)—, C1-6alkyl-N(Ra)—SO2—, C1-6alkyl-SO2—N(Ra)—, C1-6alkoxycarbonyl-N(Ra)—, C1-6alkylcarbonyl-N(Ra)C1-6alkyl-, C1-6alkyl-N(Ra)-carbonyl-C1-6alkyl-, or C1-6alkoxy-C1-6alkyl may optionally be substituted by RP, phenyl, phenoxy, heteroaryl, heteroaryloxy, heteroaryl-(NRa)—, heterocyclyl, heterocyclyloxy, or heterocyclyl-N(Ra)—;
• and wherein said heteroaryl or phenyl may optionally be substituted with one or more substituents selected from Rf;
• and wherein said heterocyclyl may optionally be substituted by one or more substituents selected from Rg;
• and wherein if said heterocyclyl contains a —NH moiety that nitrogen may optionally be substituted by one or more groups Rh;
• Ra and Rb are independently selected, for each occurrence, from the group consisting of:
• hydrogen and C1-3alkyl;
• wherein C1-3alkyl may optionally be substituted by one or more substituents selected from the group consisting of:
• fluorine, cyano, oxo, and hydroxy;
• or Ra and Rb, together with the nitrogen to which they are attached, may form a 4-6 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N;
• wherein the 4-6 membered heterocyclic ring may optionally be substituted on carbon by one or more substituents selected from the group consisting of:
• fluorine, cyano, oxo, and hydroxy;
• Rf is independently selected, for each occurrence, from the group consisting of:
• RP, hydrogen, C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkyl-S(O)w— (wherein w is 0, 1 or 2), C1-6alkylcarbonyl-N(Ra)—, and C1-6alkoxycarbonyl-N(Ra)—;
• wherein C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkyl-S(O)w—, C1-6alkylcarbonyl-N(Ra)—, or C1-6alkoxycarbonyl-N(Ra)— may be optionally substituted by one or more substituents selected from RP;
• Rg is independently selected for each occurrence from the group consisting of:
• RP, hydrogen, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkyl-S(O)w— (wherein w is 0, 1 or 2), C1-6alkylcarbonyl-N(Ra)—, and C1-6alkoxycarbonyl-N(Ra)—;
• wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkyl-S(O)w—, C1-6alkylcarbonyl-N(Ra)—, or C1-6alkoxycarbonyl-N(Ra)— may be optionally substituted by one or more substituents selected from RP;
• Rh is independently selected for each occurrence from the group consisting of:
• hydrogen, C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, C1-6alkoxycarbonyl-, RiRjN-carbonyl-, and RiRjN—SO2—;
• wherein C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, or C1-6alkylcarbonyl- may optionally be substituted by one or more substituents selected from RP;
• Ri and Rj are selected independently for each occurrence from the group consisting of:
• hydrogen, C1-4alkyl, and C3-6cycloalkyl;
• wherein C1-4alkyl or C3-6cycloalkyl may be optionally substituted by one or more substituents selected from fluorine, hydroxy, cyano, RaRbN—, RaRbN-carbonyl-, or C1-3alkoxy;
• or Ri and Rj taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N, optionally substituted on carbon by one or more substituents selected from the group consisting of:
• fluorine, hydroxy, oxo, cyano, C1-6alkyl, C1-6alkoxy, RaRbN—, RaRbN—SO2—, and RaRbN-carbonyl-;
• and wherein said C1-6alkyl or C1-6alkoxy may optionally be substituted by fluorine, hydroxy, or cyano;
• and optionally substituted on nitrogen by one or more substituents selected from the group consisting of:
• C1-6alkyl and RaRbN-carbonyl-;
• and wherein said C1-6alkyl may be optionally substituted by fluorine, hydroxy, or cyano;
• and
• RP is independently selected, for each occurrence, from the group consisting of:
• halogen, hydroxy, cyano, C1-6alkoxy, RiRjN—, RiRjN-carbonyl-, RiRjN—SO2—, and RiRjN-carbonyl-N(Ra)—;
• and pharmaceutically acceptable salts and stereoisomers thereof.

A method of treating and/or controlling obesity, comprising administering to a patient in need thereof an effective amount of a tricyclic compound represented by:

• wherein
• D is a 5-7 membered heterocyclic or heteroaromatic ring in which one of the two atoms in common between rings B and D is nitrogen and the other is carbon;
• B is a 4-6 membered saturated or partially unsaturated heterocyclic ring;
• wherein the B ring may optionally be substituted by one or more fluorine atoms on any of the available carbon atoms;
• X is selected from the group consisting of:
• +—C(RD1RD2)—*, +—C(RC1)═*, +—N═*, +—C(RD1RD2)—C(RD5RD6)—*, +—C(RC1)═C(RC2)—*, +—W1—C(RD5RD6)—*, +—W1—C(O)—*, +—C(RD1RD2)—C(RD3RD4)—C(RD5RD6)—*, +—W1—C(RD3RD4)—C(RD5RD6)—*, +—W1—C(O)—C(RD5RD6)—*, +—C(RD1RD2)—W2—C(RD5RD6)—*, and +—C(RD1RD2)—W2—C(O)—*;
• wherein + and * indicate the attachment points of X as indicated in Formula II;
• Y is selected from the group consisting of:
• *—CH2—#, *—CH2—CH2—#, *—CH2—CH2—CH2—#, and *—CH2—O—CH2—#;
• wherein * and # indicate the attachment points of Y as indicated in Formula II;
• W1 is selected from the group consisting of:
• O and N(RN1);
• W2 is selected from the group consisting of:
• O and N(RN2);
• RA1 is selected, independently for each occurrence, from the group consisting of:
• hydrogen, hydroxy, cyano, halogen, C1-4alkyl, and C1-3alkoxy;
• wherein C1-4alkyl, or C1-3alkoxy may be optionally substituted by one or more fluorines;
• n is 1 or 2;
• RA2 is selected from the group consisting of:
• hydrogen, RiRjN—, heterocyclyl, heterocyclyloxy, and heterocyclyl-(NRa)—;
• wherein said heterocyclyl may optionally be substituted by one or more substituents selected from Rg;
• and wherein if said heterocyclyl contains a —NH moiety that nitrogen may optionally be substituted by one or more groups Rh;
• or
• RA2 is selected from the group consisting of:
• C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C3-6alkenyloxy, C3-6alkynyloxy, C3-6cycloalkoxy, C1-6alkyl-S(O)w— (wherein w is 0, 1 or 2), C1-6alkyl-N(Ra)—, C1-6alkyl-N(Ra)-carbonyl-, C1-6alkylcarbonyl-N(Ra)—, C1-6alkyl-N(Ra)-carbonyl-N(Ra)—, C1-6alkyl-N(Ra)—SO2—, C1-6alkyl-SO2—N(Ra)—, C1-6alkoxycarbonyl-N(Ra)—, C1-6alkylcarbonyl-N(Ra)—C1-6alkyl-, C1-6alkyl-N(Ra)-carbonyl-C1-6alkyl-, and C1-6alkoxyC1-6alkyl-;
• wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C3-6alkenyloxy, C3-6alkynyloxy, C3-6cycloalkoxy, C1-6alkyl-S(O)w—, C1-6alkyl-N(Ra)—, C1-6alkyl-N(Ra)-carbonyl-, C1-6alkylcarbonyl-N(Ra)—, C1-6alkyl-N(Ra)-carbonyl-N(Ra)—, C1-6alkyl-N(Ra)—SO2—, C1-6alkyl-SO2—N(Ra)—, C1-6alkoxycarbonyl-N(Ra)—, C1-6alkylcarbonyl-N(Ra)C1-6alkyl-, C1-6alkyl-N(Ra)-carbonyl-C1-6alkyl-, or C1-6alkoxy-C1-6alkyl may optionally be substituted by RP, phenyl, phenoxy, heteroaryl, heteroaryloxy, heteroaryl-(NRa)—, heterocyclyl, heterocyclyloxy or heterocyclyl-N(Ra)—;
• and wherein said heteroaryl or phenyl may optionally be substituted with one or more substituents selected from Rf;
• and wherein said heterocyclyl may optionally be substituted by one or more substituents selected from Rg;
• and wherein if said heterocyclyl contains a —NH moiety that nitrogen may optionally be substituted by one or more groups Rh;
• RD1 and RD2 are each independently selected from the group consisting of:
• hydrogen, fluorine, hydroxy, C1-2alkyl, and C1-2alkoxy;
• wherein the C1-2alkyl and C1-2alkoxy may optionally be substituted by one or more fluorine atoms or a group selected from cyano or hydroxy;
• RD3 and RD4 are each independently selected from the group consisting of:
• hydrogen, fluorine, hydroxy, cyano, C1-3alkyl, and C1-3alkoxy;
• wherein the C1-3 alkyl and C1-3 alkoxy may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxy or N(RaRb);
• RD5 and RD6 are each independently selected from the group consisting of:
• hydrogen, fluorine, hydroxy, cyano, C1-2alkyl, and C1-2alkoxy;
• wherein the C1-2alkyl and C1-2alkoxy may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxy, or N(RaRb);
• RC1 is selected from the group consisting of:
• hydrogen, halogen, C1-2alkyl, and C1-2alkoxy;
• wherein the C1-2alkyl or C1-2alkoxy may optionally be substituted by one or more fluorine atoms;
• RC2 is selected from the group consisting of:
• hydrogen, halogen, hydroxy, cyano, C1-2alkyl, and C1-2alkoxy;
• wherein the C1-2alkyl and C1-2alkoxy may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxy, or N(RaRb);
• RN1 is selected from hydrogen or C1-2alkyl;
• RN2 is selected from the group consisting of:
• hydrogen, C1-3alkyl, and C1-2alkylcarbonyl;
• wherein the C1-3alkyl and C1-2alkylcarbonyl may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxy, or N(RaRb);
• Ra and Rb are independently selected, for each occurrence, from the group consisting of:
• hydrogen and C1-3alkyl;
• wherein C1-3alkyl may optionally be substituted by one or more substituents selected from the group consisting of:
• fluorine, cyano, oxo, and hydroxy;
• or Ra and Rb, together with the nitrogen to which they are attached, may form a 4-6 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N;
• wherein the 4-6 membered heterocyclic ring may optionally be substituted on carbon by one or more substituents selected from the group consisting of:
• fluorine, cyano, oxo, and hydroxy;
• Rf is independently selected, for each occurrence, from the group consisting of:
• RP, hydrogen, C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkyl-S(O)w— (wherein w is 0, 1 or 2), C1-6alkylcarbonyl-N(Ra)—, and C1-6alkoxycarbonyl-N(Ra)—;
• wherein C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkyl-S(O)w—, C1-6alkylcarbonyl-N(Ra)—, or C1-6alkoxycarbonyl-N(Ra)— may be optionally substituted by one or more substituents selected from RP;
• Rg is independently selected for each occurrence from the group consisting of:
• RP, hydrogen, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkyl-S(O)w— (wherein w is 0, 1 or 2), C1-6alkylcarbonyl-N(Ra)—, and C1-6alkoxycarbonyl-N(Ra)—;
• wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkoxy, C1-6alkyl-S(O)w—, C1-6alkylcarbonyl-N(Ra)—, or C1-6alkoxycarbonyl-N(Ra)— may be optionally substituted by one or more substituents selected from RP;
• Rh is independently selected for each occurrence from the group consisting of:
• hydrogen, C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, C1-6alkoxycarbonyl-, RiRjN-carbonyl-, and RiRjN—SO2—;
• wherein C1-6alkyl, C3-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C1-6alkyl-S(O)2—, or C1-6alkylcarbonyl- may optionally be substituted by one or more substituents selected from RP;
• Ri and Rj are selected independently for each occurrence from the group consisting of:
• hydrogen, C1-4alkyl, and C3-6cycloalkyl;
• wherein C1-4alkyl and C3-6cycloalkyl may be optionally substituted by one or more substituents selected from fluorine, hydroxy, cyano, RaRbN—, RaRbN-carbonyl-, or C1-3alkoxy;
• or Ri and Rj taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N, optionally substituted on carbon by one or more substituents selected from the group consisting of:
• fluorine, hydroxy, oxo, cyano, C1-6alkyl, C1-6alkoxy, RaRbN—, RaRbN—SO2—, and RaRbN-carbonyl-;
• and wherein said C1-6alkyl or C1-6alkoxy may optionally be substituted by fluorine, hydroxy, or cyano;
• and optionally substituted on nitrogen by one or more substituents selected from the group consisting of:
• C1-6alkyl and RaRbN-carbonyl-;
• and wherein said C1-6alkyl may be optionally substituted by fluorine, hydroxy, or cyano;
• RP is independently selected, for each occurrence, from the group consisting of:
• halogen, hydroxy, cyano, C1-6alkoxy, RiRjN—, RiRjN-carbonyl-, RiRjN—SO2—, and RiRjN-carbonyl-N(Ra)—;
• and pharmaceutically acceptable salts and stereoisomers thereof.

A method of treating and/or controlling obesity, comprising administering to a patient in need thereof an effective amount of a tricyclic compound selected from the group consisting of:

• (R)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid;
• (S)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid;
• 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylic acid;
• 7-benzenesulfonylamino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylic acid;
• 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylic acid;
• (R)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylic acid;
• (S)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indole-8-carboxylic acid;
• 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline-6-carboxylic acid;
• (R)-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzen-esulfonylamino]-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta-[a]naphthalene-5-carboxylic acid;
• and
• 6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylic acid;
• and pharmaceutically acceptable salts and stereoisomers thereof.