US 8,772,480 B2 · Inhibitors of PI3 kinase and/or mTOR

Abstract

The present invention relates to compounds of Formula I, or a pharmaceutically acceptable salt thereof; methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds, wherein the variables are as defined herein.

A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein Ar1 is a 5 to 10 membered monocyclic or bicyclic ring that can contain from zero to four heteroatoms independently selected from O, N or S, and which ring can be unsubstituted or substituted with groups independently selected from C1-4haloalkyl, halo, oxo, —OCHF2, —CN, nitro, —C(═O)NRaRa, —C(═O)Rb, —C(═O)ORb, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —O—C1-6alkylN(Ra)C(═O)ORb, —OC(═O)N(Ra)S(═O)2Rb, —OC2-6alkyl NRaRa, —OC2-6alkylORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Rb, —S(═O)2N(Ra)C(═O)ORb, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa, —NRaC2-6alkylORa, —C1-6alkyl, —C2-6alkenyl, or —C2-6 alkynyl, wherein —C1-6alkyl, —C2-6alkenyl, or —C2-6alkynyl are substituted by 0, 1, 2 or 3 substituents independently selected from C1-4haloalkyl, halo, cyano, nitro, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Rb, —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Rb, —S(═O)2N(Ra)C(═O)ORb, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa, —NRaC2-6alkylORa, —N(Ra)(CRaRa)n—Y, —(CRaRa)nY, or —(CRaRa)nORa;
Y is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic ring or 6-, 7-, 8-, 9-, or 10-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, which is substituted with 0, 1, or 2 substitutents independently selected from C1-8alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, halo, —CN, nitro, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Rb, —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Rb, —S(═O)2N(Ra)C(═O)ORb, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa or —NRaC2-6alkylORa;
each Ra is independently hydrogen or Rb;
each Rb is independently phenyl, benzyl, C1-6alkyl, C4-8heterocycloalkyl, or C3-8cycloalkyl, wherein the phenyl, benzyl, C1-6alkyl, C4-8heterocycloalkyl or C3-8cycloalkyl is substituted by 0, 1, 2 or 3 substituents independently selected from halo, —OH, —S(═O)2Rb, —OC2-6alkylORa, C1-4alkyl, C1-3haloalkyl, —OC1-4alkyl, —NH2, —CN, or —NRaRa;
each Rc is independently hydrogen, —ORa, —NRaRa, —CF3, C1-6alkyl, or the group CRcRc can form a C3-8cycloalkyl ring;
each n is independently 0, 1, 2, or 3;
one of Z1, Z2, Z3 or Z4 is N and the others are CR;
each R is independently selected from hydrogen, oxo, C1-4haloalkyl, halo, —OCHF2, —CN, nitro, —C(═O)NRaRa, —C(═O)Rb, —C(═O)ORb, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —(CRaRa)nORa, —OC(═O)NRaRa, —O—C1-6alkylN(Ra)C(═O)ORb, —OC(═O)N(Ra)S(═O)2Rb, —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Rb, —S(═O)2N(Ra)C(═O)ORb, —S(═O)2N(Ra)C(═O)NRaRa, —(CRcRc)nNRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa, —NRaC2-6alkylORa, —(CRcRc)nC4-8heterocycloalkyl, —(CRcRc)nC6-8aryl, —(CRcRc)nC5-8heteroaryl, —(CRcRc)nO(CRcRc)nC6-8aryl, —(CRcRc)nC3-8cycloalkyl, —(CRcRc)nC4-8heterocycloalkyl, —(CRcCRc)nO(CRcCRc)nCF3, —(CRcCRc)nN(CRcRc)nORa, —(CRcRc)nN(Ra)(CRcRc)nC6-8aryl, —(CRcRc)nN(Ra)(CRcRc)nC5-8heteroaryl, —(CRcRc)nO(CRcRc)nC5-8heteroaryl, —C1-6alkyl, —C2-6alkenyl, or —C2-6alkynyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-8aryl, C4-8heterocycloalkyl, C3-8cycloalkyl or C5-8heteroaryl are substituted by 0, 1, 2 or 3 substituents independently selected from C1-4haloalkyl, halo, oxo, C1-6alkyl, cyano, nitro, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Rb, —OC2-6alkylNRaRa, —OC2-6alkylORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Rb, —S(═O)2N(Ra)C(═O)ORb, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkylNRaRa, —NRaC2-6alkylORa, —N(Ra)(CRaRa)n—Y, —(CRaRa)nY, —(CRaRa)nC3-8cycloalkyl, or —(CRaRa)nORa;
Q is
R2 is methyl or ethyl;
Z5 is N;
Z9 is N;
Z10 is CR;
and the group NRaRa, either alone or a part of a larger group, can be a 4 to 6 membered heterocyclic ring wherein the two Ras taken together with the nitrogen atom to which they are attached form a ring that can have from zero to one additional heteroatom selected from N, O or S, and the ring can be substituted or unsubstituted with from 1 to 3 substitutents independently selected from oxo, halo, —CN, nitro, —C(═O)Rc, —C(═O)ORc, —ORc, —OC(═O)Rc, —SRc, —S(═O)Rc, —S(═O)2Rc, —S(═O)2NRcRc, —NRcRc, —C1-6alkyl, —C2-6alkenyl, or —C2-6alkynyl.

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Inhibitors of PI3 kinase and/or mTOR

Life of this patent

Inhibitors of PI3 kinase and/or mTOR

Life of this patent

Abstract

Claims25