US 2026/0297042 A1 · BIARYLAMIDE DERIVATIVES AND THEIR USE AS PKMYT1 INHIBITORS

Abstract

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain biarylamide compounds of the following formula (also referred to herein as “BAA compounds”) which inhibit Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PKMYT1 kinase; to treat disorders (e.g., diseases) that are ameliorated by the inhibition of PKMYT1 kinase; to treat a proliferative disorder, cancer, etc.

A compound of the following formula:

or a pharmaceutically acceptable salt or solvate thereof;
wherein:
—Ring A is:
wherein:
—RA1 is —RA11;
—RA11 is —RA111, —F, —Cl, —Br, —I, —CF3, —CHF2, —OH, —ORA111, —OCF3, —NH2, —NHRA111, —NRA1112, —CN, —C(═O)RA111, —C(═O)OH, —C(═O)ORA111, —C(═O)NH2, —C(═O)NHRA111, —C(═O)NRA1112, or —S(═O)2RA111;
each —RA111 is independently linear or branched saturated C1-4alkyl;
—RA2 is —RA22;
—RA22 is —RA222, —F, —Cl, —Br, —I, —CF3, —CHF2, —OH, —ORA222, —OCF3, —NH2,
—NHRA222, —NRA2222, —CN, —C(═O)RA222, —C(═O)OH, —C(═O)ORA222, —C(═O)NH2,
—C(═O)NHRA222, —C(═O)NRA2222, or —S(═O)2RA222;
each —RA222 is independently linear or branched saturated C1-4alkyl;
—RA3 is —H or —RA33;
—RA33 is —RA333, —F, —Cl, —Br, —I, —CF3, —OH, —ORA333, or —OCF3;
each —RA333 is independently linear or branched saturated C1-4alkyl;
—RA4 is —H or —RA44;
—RA44 is —RA444, —F, —Cl, —Br, —I, —CF3, —OH, —ORA444, or —OCF3;
each —RA444 is independently linear or branched saturated C1-4alkyl;
and:
—Ring B is selected from:
wherein:
Y1 is S, O, NH, or NRY1;
Y2 is CH, CRY2, or N;
Y3 is N, CH, or CRY3;
Y4 is N, CH, or CRY4;
Y5 is S, O, NH, or NRY5;
Y6 is N, CH, or CRY6;
Y7 is N, CH, or CRY7;
Y8 is N, CH, or CRY8;
Y9 is S, O, NH, or NRY9;
wherein:
each —RY2, —RY3, —RY4, —RY6, —RY7, and —RY8 is independently —H, —F, —Cl, —Br, —I, —RYY, —CF3, —OH, —ORYY, —OCF3, —NH2, —NHRYY, or —NRYY2;
each —RYY is independently linear or branched saturated C1-4alkyl;
and wherein:
each —RY1, —RY5, and —RY9 is independently —RYYN, —C(═O)RYYN, —C(═O)ORYYN, —C(═O)NH2, —C(═O)NHRYYN, —C(═O)NRYYN2, or —S(═O)2RYYN;
each —RYYN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl,
wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2,
—NH(CH3), and —N(CH3)2;
and wherein:
-Q is -Q1, -LQ1-Q1, -Q2, -LQ2-Q2, -Q3, -LQ3-Q3, -Q4, -LQ4-Q4, -Q5, or —H;
wherein:
Q1 is C5-10heteroaryl;
and is:
optionally substituted on carbon with one or more groups —RQ1C;
and
optionally substituted on secondary nitrogen, if present, with one or more groups —RQ1N;
-LQ1- is linear or branched saturated C1-4alkylene;
Q2 is C3-10heterocyclyl;
and is:
optionally substituted on sulfur, if present, with one or two groups ═O;
optionally substituted on carbon with one or more groups —RQ2C;
and
optionally substituted on secondary nitrogen, if present, with one or more groups —RQ2N;
-LQ2- is linear or branched saturated C1-4alkylene;
Q3 is phenyl or naphthyl;
and is optionally substituted with one or more groups —RQ3C;
-LQ3- is linear or branched saturated C1-4alkylene;
Q4 is C3-10carbocyclyl;
and is optionally substituted with one or more groups —RQ4C;
-LQ4- is linear or branched saturated C1-4alkylene;
Q5 is linear or branched saturated C1-6alkyl;
and is optionally substituted with one or more groups —RQ5C;
and wherein:
each —RQ1C is independently:
—F, —Cl, —Br, —I,
—RQ1CX, —ORQ1CX,
—OH, —ORQ1CC,
-LQ1C—OH, -LQ1C-ORQ1CC,
—NH2, —NHRQ1CC, —NRQ1CC2, —RQ1CM,
-LQ1C—NH2, -LQ1C-NHRQ1CC, -LQ1C—NRQ1CC2, -LQ1C-RQ1CM,
—NHC(═O)RQ1CC, —N(RQ1CC)C(═O)RQ1CC, —NHC(═O)ORQ1CC,
-LQ1C—NHC(═O)RQ1CC, -LQ1C—NHC(═O)ORQ1CC,
—C(═O)NH2, —C(═O)NHRQ1CC, —C(═O)NRQ1CC2, —C(═O)RQ1CM, ═O
—NHC(═O)NH2, —NHC(═O)NHRQ1CC, —NHC(═O)NRQ1CC2, —NHC(═O)RQ1CM,
-LQ1C—C(═O)NH2, LQ1C—C(═O)NHRQ1CC, -LQ1C—C(═O)NRQ1CC2, LQ1C—C(═O)RQ1 CM
—C(═O)OH, —C(═O)ORQ1CC,
—OC(═O)RQ1CC,
—OC(═O)NH2, —OC(═O)NHRQ1CC, —OC(═O)NRQ1CG2, —OC(═O)RQ1 CM
—S(═O)2RQ1CC, —S(═O)2RQ1CX,
—S(═O) 2NH2, —S(═O)2NHRQ1CC, —S(═O)2NRQ1CC2, —S(═O)2RQ1 CM
—NHS(═O)RQ1CC, —NHS(═O)2RQ1CC,
—CN, —C≡CH, or —NO2;
and two adjacent-RQ1C, if present, taken together may form —(CH2)n1—O—(CH2)m1—or
—O—(CH2)p1—O—, wherein:
n1 is 0, 1, 2, or 3;
m1 is 0, 1, 2, or 3;
and p1 is 1 or 2;
with the proviso that m1+n1 is 2 or 3;
wherein:
each —RQ1CC is independently linear or branched saturated C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-6alkyl is optionally substituted with —OH, —CN or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected
from:
—F, —Cl, —C1-4alkyl, —CHF2, —CF3, —OH, —OCH3, —NH2,
—NH(CH3), and —N(CH3)2;
each —RQ1CX is independently linear or branched saturated C1-4haloalkyl;
each -LQ1C- is independently linear or branched saturated C1-4alkylene;
each —RQ1CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom;
and is:
optionally substituted on carbon with one or more groups —RQ1CMM;
optionally substituted on sulfur, if present, with one or two ═O groups;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
RQ1CMM, —C(═O)RQ1CMM, —C(═O)ORQ1CMM, —C(═O)NH2, —C(═O)NHRQ1CMM;
—C(═O)NRQ1CMM2, and —S(═O)2RQ1CMM;
and
each —RQ1CMM is independently —F, —NH2, linear or branched saturated C1-4alkyl, C1-4alkyIOC(═O)NH—, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2,
—NH(CH3), and —N(CH3)2;
and wherein:
each —RQ1N is independently:
—RQ1NC-LQ1N-RQ1NC;
—RQ1NC,
—RQ1Nhet, -LQ1N-RQ1Nhet,
-LQ1N-OH, -LQ1N-ORQ1NC,
-LQ1N—C(═O)RQ1NC,
—S(═O)2RQ1NC,
-LQ1N-C(═O)OH, -LQ1N—C(═O)ORQ1NC,
-LQ1N-C(═O)NH2, -LQ1N-C(═O)NHRQ1NK, -LQ1N—C(═O)NRQ1NC2, -LQ1N-C(═O)RQ1NP,
-LQ1N-NH2, -LQ1N-NHRQ1NC, -LQ1N-NRQ1NC2, -LQ1N-RQ1NM;
or -LQ1N—NHC(═O)ORQ1NC;
wherein:
each —RQ1NC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl,
wherein each C1-4alkyl is optionally substituted by —F, —OH, -CEN, —SO2—CH3, or —OCH3,
wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —Br, linear or branched saturated C1-4alkyl, —CHF2, —CF3, —OH, —OCH3, —CH2—O—CH3, —OCH2CH3, —C(═O)—NH—phenyl, —NH2, —N H(CH3), and —N(CH3)2;
wherein C1-4alkyl and phenyl are independently optionally substituted by —CH3 or —OH;
each —RQ1NX is independently linear or branched saturated C1-4haloalkyl;
each -LQ1N- is independently linear or branched saturated C1-4alkylene;
wherein C1-4alkylene is optionally substituted by —OH or —OMe
each —RQ1NM is independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom;
and is:
optionally substituted on carbon with one or more groups —RQ1NMM,
optionally substituted on sulfur, if present, with one or two ═O groups;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RQ1NMM, —C(═O)RQ1NMM, —C(═O)ORQ1NMM, —C(═O)NH2, —C(═O)NHRQ1NMM, —C(═O)NRQ1NMM2, and —S(═O)2RQ1NMM;
and
each —RQ1NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl,
wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
and wherein:
each —RQ1Nhet is independently non-aromatic C3-7heterocyclyl;
and is:
optionally substituted on sulfur, if present, with one or two groups ═O;
optionally substituted on carbon with one or more groups —RQ1NHH or ═O;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RQ1NHH, —C(═O)RQ1NJJ, —C(═O)ORQ1NHH, —C(═O)NH2, —C(═O)NHRQ1NHH, —C(═O)NRQ1NHH2, and —S(═O)2RQ1NHH,
wherein:
each —RQ1NHH is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and
each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
and wherein:
—RQ1NJJ is —RJ1, —RJ2, -LJ-RJ2, —RJ3, -LJ-RJ3, —RJ4, -LJ-RJ4, —RJ5, or -LJ-RJ5;
—RJ1 is linear or branched saturated C1-6alkyl;
and is optionally substituted with one or more groups selected from:
—F, —OH, —ORJJ, —O-phenyl, —C(═O)OH, —C(═O)ORJJ, —NH2, —NHRJ, and —NRJJ2;
each —RJ2 is independently C3-6cycloalkyl;
and is optionally substituted with one or more groups selected from:
—F, —RJ, —CF3, —OH, —ORJ, —NH2, —NHRJ, and —NRJ2;
each —RJ3 is independently non-aromatic C3-7heterocyclyl;
and is:
optionally substituted on sulfur, if present, with one or two groups ═O;
optionally substituted on carbon with one or more groups selected from —F, —RJ, —CF3, —OH, —ORJ, —NH2, —NHRJ, and —NRJJ2;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RJJ, —C(═O)RJ, —C(═O)ORJJ, and —S(═O)2RJJ;
each —RJ4 is phenyl;
and is optionally substituted with one or more groups selected from:
—F, —Cl, —RJ, —CF3, —OH, —ORJJ, —NH2, —NHRJ, and —NRJJ2;
each —RJ5 is independently C5-6heteroaryl;
and is:
optionally substituted on carbon with one or more groups selected from —F, —RJ, —CF3, —OH, —ORJ, —NH2, —NHRJJ, and —NRJJ2;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RJ, —C(═O)RJJ, —C(═O)ORJ, and —S(═O)2RJJ;
each -LJ- is independently linear or branched saturated C1-4alkylene, and is optionally substituted with one or more —F;
each —RJ is linear or branched saturated C1-4alkyl;
and wherein:
—RQ1NK is —RK1, —RK2, -LKRK2, —RK3, —K—RK3, —RK4, -LK-RK4, —RK5, or -LK-RK5;
—RK1 is linear or branched saturated C1-7alkyl;
and is optionally substituted with one or more groups selected from:
—F, —OH, —ORKK, —OCH2CH2OCH3, —O-phenyl, —C(═O)OH, —C(═O)ORKK, —NH2, —NHRKK, and —NRKK2;
each —RK2 is independently C3-6cycloalkyl;
and is optionally substituted with one or more groups selected from:
—F, —RKK, —CF3, —OH, —ORKK, —NH2, —NHRKK, and —NRKK2;
each —RK3 is independently non-aromatic C3-7heterocyclyl;
and is:
optionally substituted on carbon with one or more groups selected from —F, —RKK, —CF3, —OH, —ORKK, —NH2, —NHRKK, and —NRKK2;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RKK, —C(═O)RKK, —C(═O)ORKK, and —S(═O)2RKK;
each —RK4 is phenyl;
and is optionally substituted with one or more groups selected from:
—F, —Cl, —RKK, —CF3, —OH, —ORKK, —NH2, —NHRKK, and —NRKK2;
each —RK5 is independently C5-6heteroaryl;
and is:
optionally substituted on carbon with one or more groups selected from —F, —RKK, —CF3, —OH, —ORKK, —NH2, —NHRKK, and —NRKK2;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RKK, —C(═O)RKK, —C(═O)ORKK, and —S(═O)2RKK;
each -LK- is linear or branched saturated C1-4alkylene, and is optionally substituted with one or more —F;
each —RKK is linear or branched saturated C1-4alkyl;
and wherein:
—RQ1NP is non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom;
and is:
optionally substituted on sulfur, if present, with one or two ═O groups;
optionally substituted on carbon with one or more groups selected from —RQ1NPP, —F, —OH, —ORQ1NPP, and ═O;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RQ1NPP, —RQ1NPPX, —C(═O)RQ1NPP, —C(═O)ORQ1NPP, —C(═O)NH2, —C(═O)NHRQ1NPP, —C(═O)NRQ1NPP2, and —S(═O)2RQ1NPP;
each —RQ1NPP is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —F, —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
—RQ1NPPX is linear or branched saturated C1-4haloalkyl;
and wherein:
each —RQ2C is independently:
—F,
—RQ2CC, —RQ2CX,
—OH, —ORQ2CC, —ORQ2CX,
—NH2, —NHRQ2CC, —NRQ2CC2, —RQ2CM,
—NHC(═O)RQ2CC, —NHC(═O)ORQ2CC,
—C(═O)NH2, —C(═O)NHRQ2CC, —C(═O)NRQ2CC2, —C(═O)RQ2CM,
—C(═O)OH, —C(═O)ORQ2CC,
—OC(═O)RQ2CC,
—OC(═O)NH2, —OC(═O)NHRQ2CC, —OC(═O)NRQ2CG2, —OC(═O)RQ2CM, or ═O;
wherein:
each —RQ2CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, C3-7heterocyclyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and
each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
each —RQ2CX is independently linear or branched saturated C1-4haloalkyl;
each —RO2 CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom;
and is:
optionally substituted on carbon with one or more groups —RQ2CMM;
optionally substituted on sulfur, if present, with one or two ═O groups;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RQ2CMM, —C(═O)RQ2CMM, —C(═O)ORQ2CMM, —C(═O)NH2, —C(═O)NHRQ2CMM, —C(═O)NRQ2CMM2, and —S(═O)2RQ2CMM;
and
each —RQ2CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl,
wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
and wherein:
each —R92N is independently:
—RQ2NC,
═O, —C(═O)RQ2NC,
—C(═O)-LQ2N—OH, —C(═O)-LQ2N-ORQ2NC,
—C(═O)-LQ2N-NH2, —C(═O)-LQ2N-NHRQ2NC, —C(═O)-LQ2N-NRQ2NC2, —C(═O)-LQ2N-RQ2NM,
—C(═O)ORQ2NC,
LQ2N-NH2, -LQ2N-NHRQ2NC-LQ2N-NRQ2NC2, -LQ2N-RQ2NM,
—C(═O)NH2, —C(═O)NHRQ2NC, —C(═O)NRQ2NC2, —C(═O)RQ2NM,
LQ2N-C(═O)NH2, -LQ2N-C(═O)NHRQ2NC, -LQ2N-C(═O)NRQ2NC2, -LQ2N-C(═O)RQ2NM, or —S(═O)2RQ2NC;
wherein:
each —RQ2NC is independently linear or branched saturated C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-6alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
each -LQ2N- is independently linear or branched saturated C1-4alkylene;
each —RQ2NM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom;
and is:
optionally substituted on carbon with one or more groups —RQ2NMM;
optionally substituted on sulfur, if present, with one or two ═O groups;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RQ2NMM, —C(═O)RQ2NMM, —C(═O)ORQ2NMM, —C(═O)NH2, —C(═O)NHRQ2NMM, —C(═O)NRQ2NMM2, and —S(═O)2RQ2NMM;
and
each —RQ2NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
and wherein:
each —RQ3C is independently:
—F, —Cl, —Br, —I,
—RQ3CC,
—RQ3CX CX—ORQ3CX CX
—OH, —ORQ3CC,
-LQ3C—OH, -LQ3C-ORQ3CC,
—NH2, —NHRQ3CC, —NRQ3CX CC2, -RQ3 CM
-LQ3C-NH2, -LQ3C-NHRQ3CC, -LQ3C-NRQ3CX CC2, -LQ3C-Q3 CM,
—NHC(═O)RQ3CC, —NHC(═O)ORQ3CC,
LQ3C-C(═O)RQ3CXC, -LQ3C—NHC(═O)ORQ3CC,
—C(═O)NH2, —C(═O)NHRQ3CC, —C(═O)NRQ3CXCC2, —C(═O)RQ3CM,
-LQ3C-C(═O)NH2, -LQ3C-C(═O)NHRQ3CC, -LQ3C—C(═O)NRQ3CXCC2, -LQ3C-C(═O)RQ3 CM
—C(═O)OH, —C(═O)ORQ3CC,
—OC(═O)RQ3CC,
—OC(═O)NH2, —OC(═O)NHRQ3CC, —OC(═O)NRQ3CXCC2, —OC(═O)RQ3 CM,
—S(═O)2RQ3CC, S(═O)2RQ3CM,
—CN, or —NO2;
and two adjacent-RO3C, if present, taken together may
form —(CH2)n3—O—(CH2)m3—, —(CH2)n3—NH—(CH2)m3—, —(CH2)q3 (C(O))—NH—(CH2)v3—, —NH—(CH2)q3C(O)(CH2)v3—O—, —NH—(CH2)p3—NH—or —O—(CH2)p3—O—, wherein:
n3 is 0, 1, 2, or 3;
m3 is 0, 1, 2, or 3;
p3 is 1 or 2;
q3 is 0, 1, 2, or 3;
v3 is 0, 1, 2, or 3 with the proviso that
m3+n3 is 2 or 3;
wherein:
each —RQ3CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6Cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —F, —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2,
—NH(CH3), and —N(CH3)2;
each —RQ3CX is independently linear or branched saturated C1-4haloalkyl;
each -LQ3C- is independently linear or branched saturated C1-4alkylene;
each -RQ3 CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom;
and is:
optionally substituted on carbon with one or more groups —RQ3CCMM, optionally substituted on sulfur, if present, with one or two ═O groups;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RQ3CCMM, —C(═O)RQ3CCMM, —C(═O)ORQ3CCMM, —C(═O)NH2, —C(═O)NHRQ3CMM, —C(═O)NRQ3CMM2, and —S(═O)2RQ3CCMM;
and
each —RQ3CMM is independently linear or branched saturated-F, C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl,
wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
and wherein:
each —RQ4C is independently:
—F,
—RQ4CC, —RQ4CX,
—OH, —ORQ4CC, —ORQ4CX,
—NH2, —NHRQ4CC, —NRQ4CC2, -RQ4 CM
—NHC(═O)RQ4CC, —NHC(═O)ORQ4CC,
—C(═O)NH2, —C(═O)NHRQ4CC, —C(═O)NRQ4CC2, —C(═O)RQ4 CM,
—C(═O)OH, —C(═O)ORQ4CC,
—OC(═O)RQ4CC,
—OC(═O)NH2, —OC(═O)NHRQ4CC, —OC(═O)NRQ4CC2, —OC(═O)RQ4 CM, or
═O;
wherein:
each —RQ4CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6Cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and
each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
each —RQ4CX is independently linear or branched saturated C1-4haloalkyl;
each -RQ4 CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom;
and is:
optionally substituted on carbon with one or more groups —RQ4CMM;
optionally substituted on sulfur, if present, with one or two ═O groups;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
-RQ4 CM, —C(═O)RQ4CMM, —C(═O)ORQ4CM, —C(═O)NH2, —C(═O)NHRQ4CMM, —C(═O)NRQ4CMM2, and —S(═O)2RQ4CMM;
each —RQ4CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl,
wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
and wherein:
each —RQ5C is independently:
—F, —OH, —ORQ5CC, —OCF3,
—NH2, —NHRQ5CC, —NRQ5CC2, -RQ5 CM
—NHC(═O)RQ5CC, —NHC(═O)ORQ5CC,
—C(═O)NH2, —C(═O)NHRQ5CC, —C(═O)NRQ5CC2, —C(═O)RQ5CM,
—C(═O)OH, —C(═O)ORQ5CC,
—OC(═O)RQ5CC,
—OC(═O)NH2, —OC(═O)NHRQ5CC, —OC(═O)NRQ5CC2, or —OC(═O)RQ5CM,
wherein:
each —RQ5CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and
each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2, —NH(CH3), and —N(CH3)2;
each —RO5 CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom;
and is:
optionally substituted on carbon with one or more groups —RQ5CMM,
optionally substituted on sulfur, if present, with one or two ═O groups;
and
optionally substituted on secondary nitrogen, if present, with a group selected from:
—RQ5CMM, —C(═O)RQ5CMM, —C(═O)ORQ5CMM, —C(═O)NH2, —C(═O)NHRQ5CMM, —C(═O)NRQ5CMM2, and —S(═O)2RQ5CMM;
each —RQ5CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with —OH or —OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from:
—F, —Cl, —CH3, —CF3, —OH, —OCH3, —NH2,
—NH(CH3), and —N(CH3)2.

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Biarylamide derivatives and their use as pkmyt1 inhibitors

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Biarylamide derivatives and their use as pkmyt1 inhibitors

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Abstract

Claims17