Substituted ureas and carbamates

A compound of the formula:

• or pharmaceutically acceptable salts or esters thereof;
• wherein X is —(C═O)—, —(C═S)—, or —(C═N—Z), wherein Z is R20 or —OR20;
• T is NR20;
• wherein each R20 is independently H, —CN, C1-C6 alkyl C2-C6alkenyl, C1-C6 haloalkyl or C4-C7 cycloalkyl, with the proviso that when Z is R20 or —OR20, R20 is not —CN;
• wherein R1 is —(CH2)1-2—S(O)0-2—(C1-C6 alkyl), or
• C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, ═O, —SH, —C≡N, —CF3, —C1-C3 alkoxy, amino, mono or dialkylamino, —N(R)C(O)R′—, —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or
• C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- or dialkylamino, or
• aryl, heteroaryl, heterocyclyl, —C1-C6 alkyl-aryl, —C1-C6 alkyl-heteroaryl, or —C1-C6 alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —OH, —SH, —C≡N, —NR105R′105, —CO2R, —N(R)COR′, —N(R)SO2R′, —C(═O)—(C1-C4) alkyl, —SO2-amino, —SO2-mono or dialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO2—(C1-C4) alkyl, or
• C1-C6 alkoxy optionally substituted with 1, 2, or 3 halogens, or
• C3-C7 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, —C1-C6 alkyl and mono- or dialkylamino, or
• C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF3, —C1-C3 alkoxy, amino, mono- or dialkylamino and —C1-C3 alkyl, or
• C2-C10 alkenyl or C2-C10 alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, C1-C6 alkyl and mono- or dialkylamino;
• and the heterocyclyl group is optionally further substituted with oxo;
• R and R′ independently are hydrogen, C1-C10 alkyl, C1-C10 alkylaryl or C1-C10 alkylheteroaryl;
• wherein Rc is
• (I) —[—(CH2)(0-8)—(CH)(alkyl1) (alkyl2)], where alkyl1 and alkyl2 are stratight or branched C2-10 alkanyl, alkenyl or alkynyl, and wherein alkyl1 and alkyl2 attach to the same or different methylene carbon with the remaining open methylene valences occupied by hydrogen, thus forming a branched alkyl chain having between 8 and 20 carbon atoms in total;
• the alkyl groups, alkyl1 and alkyl2 being optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, —O-phenyl, —C(O)C1-C3 alkyl, —NR1-aR1-b where R1-a and R1-b are —H or C1-C6 alkyl, —OC═O NR1-aR1-b, —S(═O)0-2, —NR1-aC═O NR1-aR1-b, —C═O NR1-aR1-b, and —S(═O)2 NR1-aR1-b;
• (II) —(C(Rc-x)(Rc-y))(0-4)-Rc-cycle
• wherein each Rc-x and Rc-y is independently chosen from:
• H
• C1-C6 alkyl
• C1-C6 alkoxy
• C2-C6 alkenyl or alkynyl
• —(CH2)0-4-Rc-cycle where Rc-cycle is as defined below or Rc-x and Rc-y may be taken together with the methylene carbon to which they jointly attach to form a spirocyclic ring of 3 to 7 atoms comprising carbon and up to 2 of O, S(O)(0-2) and NRa′, wherein is Ra′ is H or C1-4 alkyl;
• wherein the spirocyclic ring may be fused to another ring to provide a bicyclic ring system comprising carbon and up to 2 of O, S(O)(0-2) and NRa′, and comprising up to 9 atoms in total including,
• Rc-cycle is aryl, heteroaryl, cycloalkyl or a fused-ring system consisting of no more than three rings where each of the rings is the same or different and is an aryl, heteroaryl, or cycloalkyl ring
• wherein Rc-cycle is optionally substituted with up to four substituents independently selected from:
• (1) C1-C6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
• (2) C2-C6 alkenyl or alkynyl with one or two unsaturated bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
• (3) halogen,
• (4) C1-C6 alkoxy,
• (5) —C1-C6 alkoxy optionally substituted with one, two, or three of —F,
• (6) —NRN-6RN-7 where RN-6 and RN-7 are the same or different and are selected from the group consisting of:
• (a) —H,
• (b) —C1-C6 alkyl optionally substituted with one substitutent selected from the group consisting of:
• (i) —OH, and
• (ii) —NH2,
• (c) —C1-C6 alkyl optionally substituted with one to three —F, —Cl, —Br, or —I,
• (d) —C3-C7 cycloalkyl,
• (e) —(C1-C2 alkyl)-(C3-C7 cycloalkyl),
• (f) —(C1-C6 alkyl)-O—(C1-C3 alkyl),
• (g) —C2-C6 alkenyl with one or two double bonds,
• (h) —C2-C6 alkynyl with one or two triple bonds,
• (i) —C1-C6 alkyl chain with one double bond and one triple bond,
• (j) aryl, and
• (k) heteroaryl,
• (7) —OH,
• (8) —C≡N,
• (9) C3-C7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b,
• (10) —CO—(C1-C4 alkyl),
• (11) —SO2—NR1-aR1-b,
• (12) —CO—NR1-aR1-b,
• (13) —SO2—(C1-C4 alkyl),
• and when there is a saturated carbon atom in Rc-cycle
• (14) oxo,
• (15) oxime
• (16) ketal rings of 5 to 7 members, and
• (17) a spirocyclic ring having from 3 to 7 atoms comprising carbon and when the ring size is 4-7 atoms optionally up to 2 of O, S(O)(0-2) and NRa′
• (III) —(CRC-xRC-y)0-4-aryl-aryl,
• (IV) —(CRC-xRC-y)0-4-aryl-heteroaryl,
• (V) —(CRC-xRC-y)0-4-heteroaryl-aryl,
• (VI) —(CRC-xRC-y)0-4-heteroaryl-heteroaryl,
• (VII) —(CRC-xRC-y)0-4-aryl-heterocycle,
• (VIII) —(CRC-xRC-y)0-4-heteroaryl-heterocycle,
• (IX) —(CRC-xRC-y)0-4-heterocycle-aryl,
• (X) —(CRC-xRC-y)0-4-heterocycle-heteroaryl,
• (XI) —(CRC-xRC-y)0-4-heterocycle-heterocycle,
• (XII) —[C(RC-1)(RC-2)]1-3—[CO]0-1—N—(RC-3)2 where each RC-1 is the same or different and is selected from the group consisting of H, C1-4 alkyl and C1-4 alkoxy where each RC-2 and RC-3 is independently selected from
• (A) —C1-C6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C6 alkoxy, —O— phenyl, and —NR1-aR1-b,
• (B) C2-C6 alkenyl or alkynyl with one or two unsaturated bonds, optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C6 alkoxy, —O-phenyl, and —NR1-aR1-b,
• (C) —(CH2)1-2—S(O)0-2—(C1-C6 alkyl),
• (D) —(CH2)0-4—C3-C7 cycloalkyl optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C6 alkoxy, —O— phenyl, —NR1-aR1-b,
• (E) —(CH2)0-4-5-7 membered heterocycle optionally substituted with one, two or three substituents selected from the group consisting of C1-C3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF3, C1-C6 alkoxy, —O— phenyl, oxo, and —NR1-aR1-b,
• (XIII) —CH(aryl)2 where each aryl is the same or different,
• (XIV) —CH(heteroaryl)2 where each heteroaryl is the same or different and are as defined above,
• (XVIII) —CH(aryl)(heteroaryl);
• wherein RN is R′100, —(CRR′)1-6R′100, —(CRR′)0-6R100, —(CRR′)1-6—O—R′100, —(CRR′)1-6—S—R′100, —(CRR′)1-6—C(═O)—R100, —(CRR′)1-6—SO2—R100, —(CRR′)1-6—NR100—R′100 or —SO2R′100, with the proviso that when RN is —SO2R′100, X is not —S(═O)n— or —C(═S)—;
• wherein
• R100 and R′100 are independently represent aryl, heteroaryl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, —CH [(CH2)0-2—O—R150]—(CH2)0-2-aryl, —CH [(CH2)0-2—O—R150]—(CH2) 0-2-heterocyclyl or —CH[(CH2)0-2—O—R150]—(CH2)0-2-heteroaryl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from
• —OR, —NO2, halogen, —C≡N, —OCF3, —CF3, —(CH2)0-4—O—P(═O)(OR)(OR′), —(CH2)0-4—CO—NR105R′105, —(CH2)0-4—O—(CH2)0-4—CONR102R102′, —(CH2)0-4—CO—(C1-C12 alkyl), —(CH2)0-4—CO—(C2-C12 alkenyl), —(CH2)0-4—CO—(C2-C12 alkynyl), —(CH2)0-4—CO—(CH2)0-4 (C3-C7 cycloalkyl), —(CH2)0-4—R110, —(CH2)0-4—R120, —(CH2)0-4—R130, —(CH2)0-4—CO—R110, —(CH2)0-4—CO—R120, —(CH2)0-4—CO—R130, —(CH2)0-4—CO—R140, —(CH2)0-4—CO—O—R150, —(CH2)0-4—SO2—NR105R′105, —(CH2)0-4—SO—(C1-C8 alkyl), —(CH2)0-4—SO2—(C1-C12 alkyl), —(CH2)0-4—SO2—(CH2)0-4—(C3-C7 cycloalkyl), —(CH2)0-4—N(R150)—CO—O—R150, —(CH2)0-4—N(R150)—CO—N(R150)2, —(CH2)0-4—N(R150)—CS—N(R150)2, —(CH2)0-4—N(R150)—CO—R105, —(CH2)0-4—NR105R′105, —(CH2)0-4—R140, —(CH2)0-4—O—CO—(C1-C6 alkyl), —(CH2)0-4—O—P(O)—(O—R110)2, —(CH2)0-4—O—CO—N(R150)2, —(CH2)0-4—O—CS—N(R150)2, —(CH2)0-4—O—(R150), —(CH2)0-4—O—R150′-COOH, —(CH2)0-4—S—(R150), —(CH2)0-4—N(R150)—SO2—R105, —(CH2)0-4—C3-C7 cycloalkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl, or
• R100 is C1-C10 alkyl optionally substituted with 1, 2, or 3 R115 groups, or
• R100 is —(C1-C6 alkyl)—O—C1-C6 alkyl) or —(C1-C6 alkyl)—S—(C1-C6 alkyl), each C1-C6 alkyl is optionally substituted with 1, 2, or 3 R115 groups, or
• R100 is C3-C8 cycloalkyl optionally substituted with 1, 2, or 3 R115 groups;
• W is a bond —(CH2)1-4—, —O—, —S(O)0-2—, —N(R135)—, —CR(OH)— or —C(O)—;
• R102 and R102′ independently are hydrogen, or
• C1-C10 alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, aryl or —R110;
• R105 and R′105 independently are —H, —R110, —R120, C3-C7 cycloalkyl, —(C1-C2 alkyl)-(C3-C7 cycloalkyl), —(C1-C6 alkyl)—O—(C1-C3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkyl chain with one double bond and one triple bond, C1-C6 alkyl optionally substituted with —OH or —NH2;
• or C1-C6 alkyl optionally substituted with 1, 2, or 3 halogen, or
• R105 and R′105 together with the atom to which they are attached form a 3 to 7 membered carbocylic ring, where one member is optionally a heteratom selected from —O—, —S(O)0-2—, —N(R135)—, the ring being optionally substituted with 1, 2 or three R140 groups;
• R115 at each occurrence is independently halogen, —OH, —CO2R102, —C1-C6 thioalkoxy, —CO2-phenyl, —NR105R′135, —SO2—(C1-C8 alkyl), —C(═O)R180, R180, —CONR105R′105, —SO2NR105R′105, —NH—CO—(C1-C6 alkyl), —NH—C(═O)—OH, —NH—C(═O)—OR, —NH—C(═O)—O-phenyl, —O—C(═O)—(C1-C6 alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl, —O—(C1-C6 alkyl)—CO2H, —NH—SO2—(C1-C6 alkyl), C1-C6 alkoxy or C1-C6 haloalkoxy;
• R135 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, —(CH2)0-2-(aryl), —(CH2)0-2-(heteroaryl), or —(CH2)0-2-(heterocyclyl);
• R140 is heterocyclyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, and ═O;
• R150 is hydrogen, C3-C7 cycloalkyl, —(C1-C2 alkyl)-(C3-C7 cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl with one double bond and one triple bond, —R110, —R120, or
• C1-C6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH2, C1-C3 alkoxy, R110, and halogen;
• R150′ is C3-C7 cycloalkyl, —(C1-C3 alkyl)-(C3-C7 cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl with one double bond and one triple bond, —R110, —R120, or
• C1-C6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH2, C1-C3 alkoxy, R110, and halogen;
• R180 is selected from morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6) alkyl, and ═O;
• R110 is aryl optionally substituted with 1 or 2 R125 groups;
• R125 at each occurrence is independently halogen, amino, mono- or dialkylamino, —OH, —C≡N, —SO2—NH2, —SO2—NH—C1-C6 alkyl, —SO2—N(C1-C6 alkyl) 2, —SO2—(C1-C4 alkyl), —CO—NH2, —CO—NH—C1-C6 alkyl, or —CO—N(C1-C6 alkyl)2, or
• C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein each C1-C6alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with 1, 2, or 3 groups that are independently selected from C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, amino, and mono- and dialkylamino, or
• C1-C6 alkoxy optionally substituted with one, two or three halogens;
• R120 is heteroaryl optionally substituted with 1 or 2 R125 groups;
• and
• R130 is heterocyclyl optionally substituted with 1 or 2 R125 groups;
• R2 is selected from the group consisting of H;
• C1-C6 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b;
• wherein R1-a and R1-b are —H or C1-C6 alkyl;
• —(CH2)0-4-aryl;
• —(CH2)0-4-heteroaryl;
• C2-C6 alkenyl;
• C2-C6 alkynyl;
• —CONRN-2RN-3;
• —SO2NRN-2RN-3;
• —CO2H;
• and —CO2—(C1-C4 alkyl);
• R3 is selected from the group consisting of H;
• C1-C6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C3 alkyl, halogen, —OH, —SH, —C≡N, —CF3, C1-C3 alkoxy, and —NR1-aR1-b;
• —(CH2)0-4-aryl;
• —(CH2)0-4-heteroaryl;
• C2-C6 alkenyl;
• C2-C6 alkynyl;
• —CO—NRN-2RN-3;
• —SO2—NRN-2RN-3;
• —CO2H;
• and —CO—O—(C1-C4 alkyl);
• wherein
• RN-2 and RN-3 at each occurrence are independently selected from the group consisting of —C1-C8 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —OH, —NH2, phenyl and halogen;
• —C3-C8 cycloalkyl;
• —(C1-C2 alkyl)-(C3-C8 cycloalkyl);
• —(C1-C6 alkyl)—O—(C1-C3 alkyl);
• —C2-C6 alkenyl;
• —C2-C6 alkynyl;
• —C1-C6 alkyl chain with one double bond and one triple bond;
• aryl;
• heteroaryl;
• heterocycloalkyl;
• or
• RN-2, RN-3 and the nitrogen to which they are attached form a 5, 6, or 7 membered heterocycloalkyl or heteroaryl group, wherein said heterocycloalkyl or heteroaryl group is optionally fused to a benzene, pyridine, or pyrimidine ring, and said groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at each occurrence are independently C1-C6 alkyl, C1-C6 alkoxy, halogen, halo C1-C6 alkyl, halo C1-C6 alkoxy, —CN, —NO2, —NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl) (C1-C6 alkyl), —OH, —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl) (C1-C6 alkyl), C1-C6 alkoxy C1-C6 alkyl, C1-C6 thioalkoxy, and C1-C6 thioalkoxy C1-C6 alkyl;
• or
• R2, R3 and the carbon to which they are attached form a carbocycle of three thru seven carbon atoms, wherein one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO2—, or —NRN-2—.