CCR5 modulators

A compound of the formula

• [Region α]-[Region β]-[Region γ]-[Region δ] (I)
• or a pharmaceutically acceptable salt thereof, wherein [Region α] is a moiety of the formula
• wherein the symbol ‘*’ indicates the point of attachment of the moiety of the formula (2.0.0) to Region β;
• R4 is H or C1-C2 alkyl;
• R6 is H, C1-C2 alkyl, C1-C2 alkoxy, —CN, —OH, or —CONH2;
• A is phenyl optionally substituted by up to 4 substituents independently selected from fluoro, chloro, —CO2R4, —OH, —CN, —CONR4aR4b, —NR4aR4b, —NR4aCOR4b, —NR4aCO2R4b, —NR4aS(O)pR4b, —S(O)pNR4aR4b, C1-C4 alkyl, C1-C4 alkoxy, C1-C2 alkoxycarbonyl, C1-C2 alkylcarbonyl and C1-C2 alkylcarbonyloxy, said C1-C4 alkyl and C1-C4 alkoxy being optionally substituted by up to 3 substituents independently selected from fluoro and chloro;
• p is 0, 1 or 2;
• R4a and R4b are each independently H or C1-C2 alkyl;
• R5a is a direct bond, —CO— or —SO2—;
• W1 is
• (i) a direct bond, or
• (ii) in the case where R5a is —CO— or —SO2—, C1-C3 alkylene optionally substituted by up to 2 substituents R23, or
• (iii) a moiety independently selected from formulas (2.0.6) through (2.0.16) inclusive;
• wherein the symbol ‘→’ indicates the point of attachment of the moiety W1 to the nitrogen atom in partial formula (2.0.0) and the symbol ‘*’ indicates the point of attachment of the moiety W1 to the other, remaining portions of partial formula (2.0.0);
• R23 is fluoro, chloro, —CO2R4, —OH, —CN, C2-C4 alkoxy, C3-C7 cycloalkyl or phenyl, said C1-C4 alkoxy, C3-C7 cycloalkyl and phenyl being optionally substituted by up to two substituents R11;
• R11 is fluoro, chloro, —CO2R4, —OH, —CN, —CONR4aR4b, —NR4aR4b, —NR4aCOR4b, —NR4aCO2R4b, —NR4aS(O)pR4b, —S(O)pNR4aR4b, C1-C4 alkyl including dimethyl, C1-C4 alkoxy, C1-C2 alkoxycarbonyl, C1-C2 alkylcarbonyl or C1-C2 alkylcarbonyloxy, said C1-C4 alkyl and C1-C4 alkoxy each being optionally substituted by up to 3 substituents independently selected from fluoro and chloro;
• R24 is H or C1-C4 alkyl;
• R25 and R26 are each independently —OH, C1-C2 alkyl or C1-C2 alkoxy, said C1-C2 alkyl being optionally substituted by up to 3 substituents selected from fluoro and —OH;
• R27 is
• (i) C2-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, each optionally substituted by up to 3 substituents R28;
• or
• (ii) —(CH2)n—(C3-C7 cycloalkyl) wherein
• (a) said C3-C7 cycloalkyl is optionally substituted by up to 3 substituents R28,
• (b) n is 0, 1 or 2,
• (c) in the event that n is 0, the α-carbon of said C3-C7 cycloalkyl is optionally substituted by one substituent selected from C1-C4 alkyl and phenyl wherein said C1-C4 alkyl and phenyl are optionally substituted by 1 or 2 substituents selected from —CH3, —OCH3, —OH or —NH2, and
• (d) in the event that n is 1 or 2, the resulting methylene or ethylene is optionally substituted by 1 substituent selected from fluoro, —NH2, —N(CH3)2, —OH, —OCH3, C1-C4 alkyl or phenyl, said C1-C4 alkyl and phenyl being optionally substituted by 1 or 2 substituents selected from —CH3, —OCH3, —OH and —NH2;
• or
• (iii) phenyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, piperazinyl, pyrimidinyl, pyranyl, azetidinyl, morpholinyl, thiomorpholino, indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl or quinoxalinyl, each optionally substituted
• (a) on any one or more carbon atoms by up to 3 substituents R28, or
• (b) on any one or more nitrogen atoms that is not a point of attachment of said heterocyclic moiety by up to 3 substituents R13b, or
• (c) on any sulphur atom that is not a point of attachment of said heterocyclic moiety by up to 2 oxygen atoms;
• R28 is phenyl, fluoro, chloro, oxo, —OH, C1-C2 alkyl, C1-C3 alkoxy, —CO2R29, —CO(C1-C4)alkyl, —SO2(C1-C4)alkyl, —CONR29R30, —NR29R30, —NR29COR30, —NR29CO2R30, —NR29S(O)pR30 or —SO2NR 29R30;
• R29 and R30 are each independently H or C1-C4 alkyl optionally substituted by up to 3 substituents selected from fluoro and chloro;
• R13b is H, C1-C4 alkyl, C2-C4 alkenyl, C1-C2 alkoxy, C3-C7 cycloalkyl, —CO(C1-C4) alkyl, —SO2(C1-C4)alkyl or phenyl wherein said C1-C4 alkyl, C2-C4 alkenyl, C1-C2 alkoxy, C3-C7 cycloalkyl and phenyl are optionally substituted by up to 2 substituents R11;
• [Region β] is an alkyl bridging element of partial Formula (3.0.0):
• wherein:
• “*” is a symbol which represents the point of attachment of the moiety of partial Formula (3.0.0) to Region α;
• “→” is a symbol which represents the point of attachment of the moiety of partial Formula (3.0.0) to Region γ;
• R40 and R41 are independently selected from the group consisting of hydrogen;
• (C1-C2) alkyl including dimethyl;
• hydroxy;
• and (C1-C3) alkoxy;
• [Region γ] is an aza-bicyclic moiety of partial Formula (4.2.0):
• wherein
• “*” is a symbol which represents the point of attachment of the moiety of partial Formula (4.2.0) to Region β;
• “→” is a symbol representing a covalent bond from any of the carbon atoms of the moiety of partial Formula (4.2.0) to Region δ;
• W4 is a direct bond;
• or is a member independently selected from the group consisting of partial Formulas (4.2.1) through (4.2.6):
• where:
• R52 is a member selected from the group consisting of hydrogen;
• phenyl;
• (C1-C4)alkyl substituted by 0 or 1 substituent independently selected from (C1-C2)alkoxy and —CO2R4;
• (C3-C6)cycloalkyl;
• —CO2R4;
• →O;
• C(═O) (C1-C3)alkyl;
• —C(═O)NR4aR4b;
• —S(═O) (C1-C4)alkyl;
• and (C1-C2)alkylcarbonyl;
• where R4, R4a, and R4b;
• are as defined above, but selected on an independent basis;
• R51 is absent or is a member selected from the group consisting of (C1-C4)alkyl substituted by 0 or 1 substituent independently selected from (C1-C2) alkoxy and —CO2R4 where R4 is as defined above;
• and →O;
• it being understood that in the case where substituent R51 is present, the nitrogen atom is in quaternary form;
• and
• k, l and m are each an integer selected from 0, 1, 2, and 3;
• [Region δ] is a member selected from the group consisting of:
• A. a two-nitrogen-atom-containing five-membered heterocyclic moiety of partial Formulas (5.0.0) through (5.0.10):
• wherein:
• the symbol:
• “*” indicates the point of attachment of each of the moieties of partial Formulas (5.0.0) through (5.0.10), inclusive, to Region γ;
• R60b through R60g, inclusive, R60k, and R60l are each a member selected from the group consisting of hydrogen;
• —CO2R4;
• —C(═O)NR4aR4b;
• —S(═O)pNR4aR4b;
• where:
• R4;
• R4a;
• and R4b are as defined above but selected on an independent basis;
• →O;
• (C1-C2)alkylcarbonyl;
• —(C1-C4)alkyl;
• —(CH2)n—(C3-C7)cycloalkyl;
• —(C2-C3)alkenyl;
• —(CH2)n-(phenyl);
• and —(CH2)n-(HET1), where n is an integer independently selected from 0, 1, and 2;
• wherein said (C1-C4)alkyl, alkenyl, cycloalkyl, phenyl and HET1 (heterocyclyl) groups are independently substituted with 0 to 3 substituents R66, where:
• HET1 is a heterocyclyl group selected from the group consisting of thienyl;
• oxazolyl;
• isoxazolyl;
• thiazolyl;
• isothiazolyl;
• pyrazolyl;
• oxadiazolyl;
• thiadiazolyl;
• triazolyl;
• pyridyl;
• pyrazinyl;
• pyridazinyl;
• pyrimidinyl;
• thiomorpholino;
• and morpholinyl;
• where:
• R66 is a member selected from the group consisting of —F;
• —Cl;
• —OH;
• cyano;
• —C(═O)OR68;
• —C(═O)NR68R69;
• —NR68R69;
• —NR68C(═O)R69;
• —NR68C(═O)OR69;
• —NR68S(═O)2R69;
• —S(═O)2NR68R69;
• (C1-C4)alkyl including dimethyl, and (C1-C4)alkoxy wherein said alkyl and alkoxy are each independently substituted with 0 to 3 substituents independently selected from F and Cl;
• (C1-C2)alkoxycarbonyl;
• (C1-C2)alkylcarbonyl;
• and (C1-C2)alkylcarbonyloxy, where:
• R68 and R69 are each a member selected from the group consisting of hydrogen;
• and (C1-C2)alkyl;
• and where said:
• R61a;
• R61d;
• R61e;
• and R61h through R61l inclusive;
• R64a through R64l inclusive;
• R65a through R65c inclusive;
• and R65g through R65i inclusive are each a member selected from the group consisting of hydrogen;
• —OH;
• —CF3;
• cyano;
• —(C1-C3)alkoxy;
• —C(═O)OR4;
• —C(═O)NR4aR4b;
• —NR4aR4b;
• —NR4aC(═O)R4b;
• —NR4aC(═O)OR4b;
• —NR4aS(═O)pR4b;
• —S(═O)pNR4aR4b;
• where:
• R4;
• R4a;
• and R4b are as defined further above but selected on an independent basis;
• —(C1-C4)alkyl;
• —(CH2)n-(C3-C7)cycloalkyl;
• —(C2-C3)alkenyl;
• —(CH2)n-(phenyl);
• and —(CH2)n-(HET1), where n is an integer selected from 0, 1, and 2;
• wherein said (C1-C4)alkyl, alkenyl, cycloalkyl, phenyl, and HET1(heterocyclyl) groups where HET1(heterocyclyl) groups is as defined above, are independently substituted with 0 to 3 substituents R66 where:
• R66 is as defined above, or:
• R64a through R64c inclusive;
• R64g through R64i inclusive;
• R65a through R65c inclusive;
• and R65g through R65l inclusive may be taken together in their same subscript denominated pairs along with the remaining portions of the moieties of partial Formulas (5.0.0) through (5.0.2), and (5.0.6) through (5.0.8), to form a fused bicyclic ring system comprising a member independently selected from the group consisting of benzimidazolyl;
• purinyl, i.e., imidazopyrimidinyl;
• and imidazopyridinyl;
• wherein said fused bicyclic ring system is independently substituted with 0 to 3 substituents R66, where R66 has the same meaning as set out further above, except that it is independently selected therefrom;
• B. a (substituted)-amide, carbamate, or urea moiety selected from the group consisting of:
• 1, alkyl-, cycloalkyl-, and alkenyl-(substituted)-amide, carbamate, or urea moieties of partial Formula (5.1.0):
• wherein:
• the symbol “*” as defined above;
• R73 is a member selected from the group consisting of hydrogen and (C1-C2)alkyl;
• W5 is selected from the group consisting the moieties of partial Formulas (5.1.1) through (5.1.12):
• wherein:
• the symbol:
• “→” indicates the point of attachment of the moiety W5 represented by partial Formulas (5.1.1) through (5.1.12), inclusive, to the nitrogen atom in partial Formula (5.1.0), and the symbol:
• “*” indicates the point of attachment of the moiety W5 to R77 as defined further below;
• R74 and R75 are each selected from the group consisting of hydrogen;
• (C1-C2)alkyl substituted by 0 or 1 substituent independently selected from OH;
• and (C1-C2)alkoxy;
• and
• R77 is a member selected from the group consisting of (C1-C6)alkyl;
• (C2-C6)alkenyl;
• and —(CH2)n-(C3-C7)cycloalkyl, where n is an integer selected from 0, 1, and 2;
• and wherein said alkyl, alkenyl, and cycloalkyl groups comprising R77 are substituted with 0 to 3 substituents R78, where:
• R78 is a member selected from the group consisting of oxo;
• —OH;
• —(C1-C2)alkyl;
• —(C1-C3)alkoxy;
• —CF3;
• —C(═O)OR79;
• —C(═O)NR79R80;
• —NR79R80;
• —NR79C(═O)R80;
• —NR79C(═O)OR80;
• —NR79S(═O)2R80;
• and —S(═O)2NR79R80, where:
• R79 and R80 are each a member independently selected from the group consisting of hydrogen;
• and (C1-C4)alkyl;
• and
• 2. aryl and heterocyclyl-(substituted)-amide, carbamate, or urea moieties of partial Formula (5.2.0):
• wherein:
• the symbol:
• “*”;
• R73;
• and W5 have the same meanings as under the definitions of partial Formula (5.1.0) above, except that they are independently selected therefrom;
• and under W5 the symbols:
• “→” and “*” are as defined under partial Formula (5.1.0);
• and
• R82 is a member selected from the group consisting of phenyl;
• cinnolinyl;
• furyl;
• thienyl;
• pyrrolyl;
• oxazolyl;
• isoxazolyl;
• thiazolyl;
• isothiazolyl;
• imidazolyl;
• imidazolinyl;
• pyrazolyl;
• pyrazolinyl;
• oxadiazolyl;
• thiadiazolyl;
• triazolyl;
• pyridyl;
• pyrazinyl;
• pyridazinyl;
• pyrimidinyl;
• thiomorpholino;
• indolyl;
• isoindolyl;
• indolinyl;
• benzo[b]furanyl;
• 2;3-dihydrobenzofuranyl;
• benzo[b]thiophenyl;
• 1H-indazolyl;
• benzimidazolyl;
• benzthiazolyl;
• quinolinyl;
• isoquinolinyl;
• phthalazinyl;
• quinazolinyl;
• quinoxalinyl;
• wherein:
• the aryl or heterocyclyl moiety is substituted by 0 to 3 substituents R78 where R78 is as defined above, but selected on an independent basis;
• or
• C. a (substituted)-heterocyclyl moiety independently selected from the group consisting of:
• 1. a heterocyclyl moiety of partial Formula (5.3.0):
• wherein:
• the symbol:
• “*” indicates the point of attachment of partial Formula (5.3.0) to Region γ;
• Q is N, O or S and
• partial Formula (5.3.0) represents:
• a. a monocyclic heterocyclic group containing a total of 5- members of which one said member is nitrogen and a second said member is selected from O and S where said S may optionally be in the sulfonate form, wherein said heterocyclic group is selected from the group consisting of oxazolyl;
• isoxazolyl;
• thiazolyl;
• and iso-thiazolyl;
• or
• b. a monocyclic heterocyclic group containing a total of 5- members of which two said members are nitrogen and a third or fourth said member is independently selected from N, O, and S where said S may optionally be in the sulfonate form, —S(═O)2;
• wherein said heterocyclic group is independently selected from the group consisting of triazolyl;
• tetrazolyl;
• oxadiazolyl;
• and thiadiazolyl;
• and
• R90a and R90b are each a member independently selected from the group consisting of hydrogen, —(C1-C2)alkylcarbonyl;
• —(C1-C4)alkyl;
• —(CH2)n-(C3-C7)cycloalkyl;
• —(C2-C3)alkenyl;
• —(CH2)n-(phenyl);
• and —(CH2)n-(HET2), where n is an integer independently selected from 0, 1, and 2;
• wherein said (C1-C4)alkyl, alkenyl, cycloalkyl, phenyl, and HET2 groups are independently substituted with 0 to 3 substituents R91, where:
• j is 0, 1 or 2;
• HET2 is a heterocyclyl group selected from the group consisting of thienyl;
• oxazolyl;
• isoxazolyl;
• thiazolyl;
• isothiazolyl;
• pyrazolyl;
• oxadiazolyl;
• thiadiazolyl;
• triazolyl;
• pyridyl;
• pyrazinyl;
• pyridazinyl;
• pyrimidinyl;
• thiomorpholino;
• and morpholinyl;
• where:
• R91 is selected from the group consisting of —F;
• —Cl;
• —CO2R4;
• —OH;
• —CN;
• —CONR93R94;
• —NR93R94;
• C(═O)(C1-C4)alkyl;
• —NR93C(═O)R94;
• —NR93C(═O)OR94;
• —NR93S(═O)R94;
• —S(═O)NR93R94;
• (C1-C4)alkyl including dimethyl, and (C1-C4)alkoxy wherein said alkyl and alkoxy are each independently substituted with 0 to 3 substituents independently selected from F and Cl;
• (C1-C2)alkoxycarbonyl;
• (C1-C2)alkylcarbonyl;
• and (C1-C2)alkylcarbonyloxy;
• wherein:
• R93 and R94 are each a member independently selected from the group consisting of hydrogen;
• and (C1-C2)alkyl;
• and
• 2. a heterocyclyl moiety of partial Formula (5.4.0):
• wherein:
• R90a, R90b and j have the same meanings as set out above and Q is N, O or S.