US 10,308,615 B2 · Heterocyclic compounds as inhibitors of Vanin-1 enzyme

Abstract

Compounds, pharmaceutically acceptable salts thereof, are disclosed wherein the compounds have the structure of as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
A1 is C(R3), A2 is N and A3 is C(R3);
R1 is selected from the group consisting of:
(i) 6 to 10 membered aryl optionally substituted with one, two, three or four E;
and
(ii) 5 to 11 membered heteroaryl optionally substituted with one, two, three or four E, wherein said 5 to 11 membered heteroaryl (a) comprises one, two or three heteroatoms independently selected for each occurrence from the group consisting of —N═, —N(J)-, —O—, and —S— and (b) is not bound to the carbonyl of Formula (I) through a nitrogen;
W is selected from the group consisting of:
(i) —NHCG2-R2;
(ii) —NHCG2CG2-R2;
(iii) —OCG2-R2;
(iv) —OCG2CG2-R2;
R2 is selected from the group consisting of:
(i) phenyl optionally substituted with one, two, three or four E;
and
(ii) 5 to 6 membered heteroaryl optionally substituted with one, two, three or four E, wherein said 5 to 6 membered heteroaryl comprises one or two heteroatoms independently selected for each occurrence from the group consisting of —N═, —N(J)-, —O—, and —S—;
(iii) —C3-C7 carbocyclyl optionally substituted with one, two, three, four, five or six E;
(iv) 4 to 7 membered heterocyclyl optionally substituted with one, two, three, four, five or six E, wherein said 4 to 7 membered heterocyclyl comprises one or two heteroatoms independently selected for each occurrence from the group consisting of —N(J)-, —O— and —S—;
and
(v) 4 to 7 membered heterocyclyl optionally substituted with one, two, three, four, five or six E, wherein said 4 to 7 membered heterocyclyl is (i) bound to W through a first heterocyclyl ring heteroatom —N— and (ii) which optionally comprises a second ring heteroatom independently selected from the group consisting of —N(J)-, —O—, and —S—;
R3 is independently selected for each occurrence from the group consisting of —H, —F, —Cl, —CN, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —CF2CF3, —OCH3, —OCH2F, —OCHF2, —OCF3, —SCH3, —SCH2F, —SCHF2, and —SCF3;
E is independently selected for each occurrence from the group consisting of:
(i) —H;
(ii) —halo;
(iii) —CN;
(iv) —OH;
(v) —CO2H;
(vi) —C1-C6alkyl optionally substituted with one, two, three, four, five or six K;
(vii) —OC1-C6alkyl optionally substituted with one, two, three, four, five or six K;
(viii) —SC1-C6alkyl optionally substituted with one, two, three, four, five or six K;
(ix) —C3-C5cycloalkyl optionally substituted with one, two, three, four, five or six K;
(x) —OC3-C5cycloalkyl optionally substituted with one, two, three, four, five or six K;
(xi) —SC3-C5cycloalkyl optionally substituted with one, two, three, four, five or six K;
(xii) —C1-C6alkyl(C3-C5cycloalkyl) optionally substituted with one, two, three, four, five or six K;
(xiii) 4 to 7 membered heterocyclyl optionally substituted with one, two, three, four, five or six K, wherein said 4 to 7 membered heterocyclyl comprises one or two heteroatoms independently selected for each occurrence from the group consisting of —N(J)-, —O— or —S—;
(xiv) —NH2;
(xv) —NH(C1-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six K;
(xvi) —N(C1-C6alkyl)2, which C1-C6alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K;
(xvii) —C(O)NH2;
(xviii) —C(O)NH(C1-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six K;
(xix) —C(O)N(C1-C6alkyl)2, which C1-C6alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K;
(xx) —NHC(O)(C1-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six K;
(xxi) —N(C1-C6alkyl)C(O)(C1-C6alkyl), which C1-C6alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K;
(xxii) —SO2(C1-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six K;
(xxiii) —SO2NH2;
(xxiv) —SO2NH(C1-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six K;
(xxv) —SO2N(C1-C6alkyl)2, which C1-C6alkyl is, independently for each occurrence optionally substituted with one, two, three, four, five or six K;
(xxvi) —NHSO2(C0-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six K;
and
(xxvii) —N(C1-C6alkyl)SO2(C1-C6alkyl), which C1-C6alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K;
G is independently selected for each occurrence from the group consisting of:
(i) —H;
(ii) —halo;
(iii) —OH;
(iv) —C1-C6alkyl optionally substituted optionally substituted with one, two, three, four, five or six K;
(v) —OC1-C6alkyl optionally substituted with one, two, three, four, five or six K;
(vi) —SC1-C6alkyl optionally substituted with one, two, three, four, five or six K;
(vii) —NH(C1-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six K;
(viii) —N(C1-C6alkyl)2, which C1-C6alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K;
(ix) —C3-C5cycloalkyl optionally substituted with one, two, three, four, five or six K;
and
(x) 4 to 5 membered heterocyclyl optionally substituted with one, two, three, four, five or six K, which said 4 to 5 membered heterocyclyl comprises one or two heteroatoms independently selected for each occurrence from the group consisting of —N(J)-, —O— or —S—;
or two geminal G may, together with the carbon to which they are bound, form a —C3-C5cycloalkylene optionally substituted with one, two, three, four, five or six K or a 4 to 5 membered heterocyclylene optionally substituted with one, two, three, four, five or six K, wherein said 4 to 5 membered heterocyclylene comprises one heteroatom independently selected from the group consisting of —N(J)-, —O—, or —S—;
J is independently selected, for each occurrence, from the group consisting of:
(i) —H;
(ii) —C1-C6alkyl optionally substituted with one, two, three, four, five or six K;
(iii) —C(O)NH2;
(iv) —C(O)NH(C1-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six K;
(v) —C(O)N(C1-C6alkyl)2, which C1-C6alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K;
and
(vi) —SO2(C1-C6alkyl), which C1-C6alkyl is optionally substituted with one, two, three, four, five or six halo;
and
K is independently selected, for each occurrence, from the group consisting of —H, —F, —Cl, —OH, —CN, —CO2H, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —CF2CF3, —OCH3, —OCH2F, —OCHF2, —OCF3, —SCH3, —SCH2F, —SCHF2, —SCF3—NH2, —NH(CH3), —N(CH3)2, and —CONH2.

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Heterocyclic compounds as inhibitors of Vanin-1 enzyme

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Heterocyclic compounds as inhibitors of Vanin-1 enzyme

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Abstract

Claims8