Inhibitors of IMPDH enzyme technical field of the invention

A compound of the formula:

• wherein:
• X is selected from —C(O)—N(R6)—, —N(R6)—C(O)—, —N(R6)—S(O)2—, —S(O)2—N(R6)—, —C(R12)(R12)—C(O)—, —C(O)—C(R12)(R12)—, —C(R12)(R12)—S(O)2—, —S(O)2—C(R12)(R12)—, —S(O)2—O—, —O—S(O)2—, —NR6—C(O)—Y— or Y—C(O)—NR6—;
• wherein
• each R6 is independently selected from hydrogen, C1-C4 straight or branched alkyl, C2-C4 straight or branched alkenyl or alkynyl, Ar-substituted-C1-C4 straight or branched alkyl, or Ar-substituted-C2-C4 straight or branched alkenyl or alkynyl;
• wherein
• each R6, except hydrogen, is optionally substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino;
• each R12 is independently selected from R6, W—(C1-C4 straight or branched alkyl), W—(C2-C4 straight or branched alkenyl or alkynyl), Ar-substituted-(W—(C1-C4 straight or branched alkyl)), Ar-substituted-(W—(C2-C4 straight or branched alkenyl or alkynyl)), O—Ar, N(R6)—Ar, S—Ar, S(O)—Ar, S(O)2—Ar, S—C(O)H, N(R6)—C(O)H, or O—C(O)H;
• wherein
• W is O—, O—C(O)—, S—, S(O)—, S(O)2—, S—C(O)—, N(R6)—, or N(R6)—C(O)—;
• and wherein
• each R12 is optionally and independently substituted with up to 3 substituents independently selected from halo, hydroxy, nitro, cyano or amino;
• Y is selected from —O—, —S—, —C≡C—, —C(R12)2—C(R12)2—, —C(R12)2— or —C(R12)═C(R12)—;
• each of R1, R2, R3, R4, R5, R7, R8, R9, R10 and R11 is independently selected from hydrogen, halo, hydroxy, cyano, nitro, amino, —C(O)NH2, Z—((C1-C4)-straight or branched alkyl), Z—((C2-C4)-straight or branched alkenyl or alkynyl), Ar-substituted-((C1-C4)-straight or branched alkyl), Ar-substituted-((C2-C4)-straight or branched alkenyl or alkynyl), Ar, Q—Ar, ((C1-C4)-straight or branched alkyl)-Q—Ar, ((C2-C4)-straight or branched alkenyl or alkynyl)-Q—Ar, O—((C1-C4)-straight or branched alkyl)-Q—Ar, O—((C2-C4)-straight or branched alkenyl or alkynyl)-Q—Ar, or any two adjacent R groups may be taken together with the carbon atoms to which they are bound to form a 5 to 6-membered aromatic carbocyclic ring or a 5 to 6-membered heterocyclic ring containing 0 to 3 heteroatoms selected from O, N, or S;
• wherein
• Z is selected from a bond, O—, S—, S(O)2—, C(O)—, OC(O)—, or N(H)C(O)—;
• Q is selected from O, —O—C(O)—, —C(O)—O—, —N(H)—C(O)—O—, —O—N(H)—C(O)—, —N(H)—C(O)—, —C(O)—N(H)—, —O—C(O)—N(H)—, or —C(O)—N(H)—O—;
• Ar is selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, (pyraxolyl) pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo(b)furanyl, benzo(b)thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, piperidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl or other chemically feasible monocyclic, bicyclic or tricyclic ring systems, wherein each ring consists of 5 to 7 ring atoms and wherein each ring contains 0 to 3 heteroatoms independently selected from N, O and S;
• R13 is selected from (C1-C12 straight or branched alkyl) or, (C2-C12 straight or branched alkenyl or alkynyl);
• wherein R13 is optionally substituted with 1 to 4 substituents independently selected from R14 or R15, wherein
• each R14 is a monocyclic or a bicyclic ring system consisting of 3 to 7 members per ring, wherein said ring system optionally contains up to 4 heteroatoms selected from N, O, and S;
• wherein a CH2 adjacent to said N, O or S may be substituted with C(O);
• and wherein R14 optionally contains up to 2 substituents independently selected from (C1-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, (CH2)n—R16, —S—(CH2)n—R16, —S(O)—(CH2)n—R16, —S(O)2—(CH2)n—R16, —O—(CH2)n—R16, or —N(R18)—(CH2)n—R16
• wherein n is 0, 1 or 2;
• R16 is selected from halogen, —CN, —NO2—CF3, —OCF3, —OH, —S—(C1-C4)-alkyl, —S(O)—(C1-C4)-alkyl, —S(O)2—(C1-C4)-alkyl, —NH2, —NH—(C1-C4)-alkyl, —N((C1-C4)-alkyl)2, COOH, C(O)—O—(C1-C4)-alkyl or O—(C1-C4)-alkyl;
• and
• each R15 is independently selected from —OR17, or —N(R18)2;
• R1, is selected from hydrogen, —(C1-C6)-straight alkyl, —(C1-6)-straight alkyl-Ar, —C(O)—(C1-C6)-straight or branched alkyl, —C(O)—Ar, or —(C1-C6)-straight alkyl-CN;
• and
• each R18 is independently selected from —(C1-C6)-straight or branched alkyl, —(C1-C6)-straight or branched alkyl-Ar, —(C1-C6)-straight alkyl-CN, —(C1-C6)-straight alkyl-OH, —(C1-C6)-straight alkyl-OR17, —C(O)—(C1-C6)-straight or branched alkyl, —C(O)—Ar, —S(O)2—(C1-C6)-straight or branched alkyl, or —S(O)2—Ar;
• wherein
• any alkyl, alkenyl or alkynyl group is optionally substituted with 1 to 3 independently selected halo groups;
• and
• any Ar, aromatic carbocyclic ring or heterocyclic 5 to 6-membered ring containing 0 to 3 heteroatoms selected from N, O, or S is optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, nitro, cyano, amino, (C1-C4)-straight or branched alkyl;
• O—(C1-C4)-straight or branched alkyl, (C2-C4)-straight or branched alkenyl or alkynyl, or O—(C2-C4)-straight or branched alkenyl or alkynyl;
• any Ar, aromatic carbocyclic ring or heterocyclic 5 to 6-membered ring containing 0 to 3 heteroatoms selected from N, O, or S is optionally benzofused;
• with the provisos that:
• at least two of R1, R2, R3, R4, or R5 is hydrogen;
• no more than two of R1, R2, R3, R4, or R5 are taken together to form an Ar group;
• at least two of R7, R8, R9, R10 or R11 is hydrogen;
• and
• no more than two of R7, R8, R9, R10, or R11, are taken together to form an Ar group;
• when X is —C(O)—N(R6)— or —N(R6)—C(O)—, then
• two adjacent groups, selected from either R1, R2 R3, R4 and R5, or from R7, R8, R9 R10 and R11, may not be taken together with the carbon atoms to which they are bound to form a 6-membered aromatic carbocyclic ring;
• when X is —NH—S(O)2— or —S(O)2—N(H)—,
• one of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 is O—(C1-C4)-straight or branched alkyl, and
• seven of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 are hydrogen, then
• the remaining two of R1, R2 R3, R4, R5, R7, R8, R9, R10 or R11 are not bound together to form a 5 to 6-membered aromatic carbocyclic or heterocyclic ring;
• when X is —NH—S(O)2— or —S(O)2—N(H)—,
• two of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 are O—(C1-C4)-straight or branched alkyl, and
• seven of R1, R2 R3, R4, R5, R7, R8, R9, R10 or R11 are hydrogen, then
• the remaining one of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 is not —NO2, —CN or —Ar;
• when X is —NH—S(O)2— or —S(O)2—N(H)—,
• two of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 are O—(C1-C4)-straight or branched alkyl, and
• six of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 are hydrogen, then
• the remaining two of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 are not both halo;
• when X is —NH—S(O)2— or —S(O)2—N(H)—, and
• one of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 is Ar, then
• the remaining 9 of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 are not each hydrogen;
• when X is —N(H)—C(O)—S— or —S—C(O)—N(H)—,
• one of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 is —OH, and
• eight of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 are hydrogen, then
• the remaining one of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 is not halo;
• when wherein X is —N(H)—C(O)—S— or —S—C(O)—N(H)—,
• one of R1, R2, R3, R4, R5, R7, R5, R9, R10 or R11 is —OH,
• seven of R1, R2, R3, R4, R5, R7, R5, R9, R10 or R11 are hydrogen, and
• one of R1, R2, R3, R4, R5, R7, R8, R9, R10 or R11 is O—(C1-C4)-straight or branched alkyl, then
• the remaining one of R1, R2, R3, R4, R5, R7, R8, R9 R10 or R11 is not halo or (C1-C4)-straight or branched alkyl.