COMPOUNDS AS CDK2/4/6 INHIBITORS
20230135215 · 2023-05-04
Inventors
- Huajie Zhang (Chongqing, CN)
- Hua XU (Chongqing, CN)
- Chengxi He (Chongqing, CN)
- Ling Chen (Chongqing, CN)
- Lijun Yang (Chongqing, CN)
- Lihua JIANG (Chongqing, CN)
- Shu Lin (San Leandro, CA, US)
- Xingdong Zhao (Chongqing, CN)
- Weibo Wang (Moraga, CA)
Cpc classification
A61K45/06
HUMAN NECESSITIES
C07D519/00
CHEMISTRY; METALLURGY
C07D475/00
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D475/00
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
Abstract
Provided are certain CDK2/4/6 inhibitors, pharmaceutical compositions thereof, and methods of use thereof.
Claims
1. A compound of formula (I): ##STR00137## or a pharmaceutically acceptable salt thereof, wherein: A is selected from N and CR.sup.5; B is selected from N and CR.sup.3; Ring Qis selected from C.sub.2-10 alkenyl, cycloalkyl and heterocyclyl, which is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; When A is N and B is CR.sup.3, Ring Q is selected from multicyclic cycloalkyl and multicyclic heterocyclyl, which is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; R.sup.1 is selected from hydrogen, C.sub.3-10 cycloalkyl, heterocyclyl and heterocyclyl-C.sub.1-4 alkyl, wherein the alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X1; R.sup.2 is selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, NO.sub.2, —NR.sup.A2R.sup.B2, —OR.sup.A2, —C(O)R.sup.A2, —C(═NR.sup.E2)R.sup.A2, —C(═N—OR.sup.B2)R.sup.A2, —C(O)OR.sup.A2, —OC(O)R.sup.A2, —C(O)NR.sup.A2R.sup.B2, —NR.sup.A1R.sup.A2C(O)R.sup.B2, —C(═NR.sup.E2)NR.sup.A2R.sup.B2, —NR.sup.A2C(═NR.sup.E2)R.sup.B2, —OC(O)NR.sup.A2R.sup.B2, —NR.sup.A2C(O)OR.sup.B2, —NR.sup.A2C(O)NR.sup.A2R.sup.B2, —NR.sup.A2C(S)NR.sup.A2R.sup.B2, —NR.sup.A2C(═NR.sup.E2)NR.sup.A2R.sup.B2, —S(O).sub.rR.sup.A2, —S(O)(═NR.sup.E2)R.sup.B2, —N═S(O)R.sup.A2R.sup.B2, —S(O).sub.2OR.sup.A2, —OS(O).sub.2R.sup.A2, —NR.sup.A2S(O).sub.rR.sup.B2, —NR.sup.A2S(O)(═NR.sup.E2)R.sup.B2, —S(O).sub.rNR.sup.A2R.sup.B2, —S(O)(═NR.sup.E2)NR.sup.A2R.sup.B2, —NR.sup.A2S(O).sub.2NR.sup.A2R.sup.B2, —NR.sup.A2S(O)(═NR.sup.E2)NR.sup.A2R.sup.B2, —P(O)R.sup.A2R.sup.B2 and —P(O)(OR.sup.A2)(OR.sup.B2), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X2; R.sup.3 is selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, NO.sub.2, —NR.sup.A3R.sup.B3, —OR.sup.A3, —C(O)R.sup.A3, —C(═NR.sup.E3)R.sup.A3, —C(═N—OR.sup.B3)R.sup.A3, —C(O)OR.sup.A3, —OC(O)R.sup.A3, —C(O)NR.sup.A3R.sup.B3, —NR.sup.A3C(O)R.sup.B3, —C(═NR.sup.E3)NR.sup.A3R.sup.B3, —NR.sup.A3C(═NR.sup.E3)R.sup.B3, —OC(O)NR.sup.A3R.sup.B3, —NR.sup.A3C(O)OR.sup.B3, —NR.sup.A3C(O)NR.sup.A3R.sup.B3, —NR.sup.A3C(S)NR.sup.A3R.sup.B3, —NR.sup.A3C(═NR.sup.E3)NR.sup.A3R.sup.B3, —S(O).sub.rR.sup.A3, —S(O)(═NR.sup.E3)R.sup.B3, —N═S(O)R.sup.A3R.sup.B3, —S(O).sub.2OR.sup.A3, —OS(O).sub.2R.sup.A3, —NR.sup.A3S(O).sub.rR.sup.B3, —NR.sup.A3S(O)(═NR.sup.E3)R.sup.B3, —S(O).sub.rNR.sup.A3R.sup.B3, —S(O)(═NR.sup.E3)NR.sup.A3R.sup.B3, —NR.sup.A3S(O).sub.2NR.sup.A3R.sup.B3, —NR.sup.A3S(O)(═NR.sup.E3)NR.sup.A3R.sup.B3, —P(O)R.sup.A3R.sup.B3 and —P(O)(OR.sup.A3)(OR.sup.B3), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X3; R.sup.4 is selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, NO.sub.2, —NR.sup.A4R.sup.B4, —OR.sup.A4, —C(O)R.sup.A4, —C(═NR.sup.E4)R.sup.A4, —C(═N—OR.sup.B4)R.sup.A4, —C(O)OR.sup.A4, —OC(O)R.sup.A4, —C(O)NR.sup.A4R.sup.B4, —NR.sup.A4C(O)R.sup.B4, —C(═NR.sup.E4)NR.sup.A4R.sup.B4, —NR.sup.A4C(═NR.sup.E4)R.sup.B4, —OC(O)NR.sup.A4R.sup.B4, —NR.sup.A4C(O)OR.sup.B4, —NR.sup.A4C(O)NR.sup.A4R.sup.B4, —NR.sup.A4C(S)NR.sup.A4R.sup.B4, —NR.sup.A4C(═NR.sup.E4)NR.sup.A4R.sup.B4, —S(O).sub.rR.sup.A4, —S(O)(═NR.sup.E4)R.sup.B4, —N═S(O)R.sup.A4R.sup.B4, —S(O).sub.2OR.sup.A4, —OS(O).sub.2R.sup.A4, —NR.sup.A4S(O).sub.rR.sup.B4, —NR.sup.A4S(O)(═NR.sup.E4)R.sup.B4, —S(O).sub.rNR.sup.A4R.sup.B4, —S(O)(═NR.sup.E4)NR.sup.A4R.sup.B4, —NR.sup.A4S(O).sub.2NR.sup.A4R.sup.B4, —NR.sup.A4S(O)(═R.sup.E4)NR.sup.A4R.sup.B4, —P(O)R.sup.A4R.sup.B4 and —P(O)(OR.sup.A4)(OR.sup.B4), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X4; R.sup.5 is selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, CN, NO.sub.2, —NR.sup.A5R.sup.B5, —OR.sup.A5, —C(O)R.sup.A5, —C(═NR.sup.E5)R.sup.A5, —C(═N—OR.sup.B5)R.sup.A5, —C(O)OR.sup.A5, —OC(O)R.sup.A5, —C(O)NR.sup.A5R.sup.B5, —NR.sup.A5C(O)R.sup.B5, —C(═NR.sup.E5)NR.sup.A5R.sup.B5, —NR.sup.A5C(═NR.sup.E5)R.sup.B5, —OC(O)NR.sup.A5R.sup.B5, —NR.sup.A5C(O)OR.sup.B5, —N.sup.A5C(O)NR.sup.A5R.sup.B5, —NR.sup.A5C(S)NR.sup.A5R.sup.B5, —NR.sup.A5C(═R.sup.E5)NR.sup.A5R.sup.B5, —S(O).sub.rR.sup.A5, —S(O)(═NR.sup.E5)R.sup.B5, —N═S(O)R.sup.A5R.sup.B5, —S(O).sub.2OR.sup.A5, —OS(O).sub.2R.sup.A5, —NR.sup.A5S(O).sub.rR.sup.B5, —NR.sup.A5S(O)(═NR.sup.E5)R.sup.B5, —S(O).sub.rNR.sup.A5R.sup.B5, —S(O)(═NR.sup.E5)NR.sup.A5R.sup.B5, —NR.sup.A5S(O).sub.2NR.sup.A5R.sup.B5, —NR.sup.A5S(O)(═NR.sup.E5)NR.sup.A5R.sup.B5, —P(O)R.sup.A5R.sup.B5 and —P(O)(OR.sup.A5)(OR.sup.B5), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X5; each R.sup.A2 and R.sup.B2 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X2; or each “R.sup.A2 and R.sup.B2” together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X2 groups; each R.sup.A3 and R.sup.B3 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X3; or each “R.sup.A3 and R.sup.B3” together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X3 groups; each R.sup.A4 and R.sup.B4 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X4; or each “R.sup.A4 and R.sup.B4” together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X4 groups; each R.sup.A5 and R.sup.B5 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X5; or each “R.sup.A5 and R.sup.B5” together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.X5 groups; each R.sup.E2 is selected from hydrogen, C.sub.1-10 alkyl, CN, NO.sub.2, —OR.sup.a1, —SR.sup.a1, —S(O).sub.rR.sup.a1, —C(O)R.sup.a1, —C(O)OR.sup.a1, —C(O)NR.sup.a1R.sup.b1 and —S(O).sub.rNR.sup.a1R.sup.b1, wherein the alkyl is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X2; each R.sup.E3 is selected from hydrogen, C.sub.1-10 alkyl, CN, NO.sub.2, —OR.sup.a1, —SR.sup.a1, —S(O).sub.rR.sup.a1, —C(O)R.sup.a1, —C(O)OR.sup.a1, —C(O)NR.sup.a1R.sup.b1 and —S(O).sub.rNR.sup.a1R.sup.b1, wherein the alkyl is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X3; each R.sup.E4 is selected from hydrogen, C.sub.1-10 alkyl, CN, NO.sub.2, —OR.sup.a1, —SR.sup.a1, —S(O).sub.rR.sup.a1, —C(O)R.sup.a1, —C(O)OR.sup.a1, —C(O)NR.sup.a1R.sup.b1 and —S(O).sub.rNR.sup.a1R.sup.b1, wherein the alkyl is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X4; each R.sup.E5 is selected from hydrogen, C.sub.1-10 alkyl, CN, NO.sub.2, —OR.sup.a1, —SR.sup.a1, —S(O).sub.rR.sup.a1, —C(O)R.sup.a1, —C(O)OR.sup.a1, —C(O)NR.sup.a1R.sup.b1 and —S(O).sub.rNR.sup.a1R.sup.b1, wherein the alkyl is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X5; each R.sup.X, R.sup.X1, R.sup.X2, R.sup.X3, R.sup.X4 and R.sup.X5 is independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, halogen, CN, NO.sub.2, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(O)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(═NR.sup.c1)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(═N—OR.sup.b1)R.sup.a1, —(CR.sup.c1R.sup.d1).sub.tC(O)OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOC(O)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tC(═NR.sup.c1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(═NR.sup.c1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOC(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(O)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(S)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1C(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O)(═NR.sup.c1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tN═S(O)R.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.2OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tOS(O).sub.2R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(═NR.sup.e1)R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rNR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O)(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.2NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O)(═NR.sup.e1)NR.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tP(O)R.sup.a1R.sup.b1 and —(CR.sup.c1R.sup.d1).sub.tP(O)(OR.sup.a1)(OR.sup.b1), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.Y; each R.sup.a1 and each R.sup.b1 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.Y; or R.sup.a1 and R.sup.b1 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R.sup.Y groups; each R.sup.c1 and each R.sup.d1 are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.Y; or R.sup.c1 and R.sup.d1 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R.sup.Y groups; each R.sup.c1 is independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, CN, NO.sub.2, —OR.sup.a2, —SR.sup.a2, —S(O).sub.rR.sup.a2, —C(O)R.sup.a2, —C(O)OR.sup.a2, —S(O).sub.rNR.sup.a2R.sup.b2 and —C(O)NR.sup.a2R.sup.b2; each R.sup.Y is independently selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, halogen, CN, NO.sub.2, —(CR.sup.c2R.sup.d2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(O)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(═NR.sup.e2)R.sup.a2, —(CR.sup.e2R.sup.d2).sub.tC(═N—OR.sup.b2)R.sup.a2, —(CR.sup.c2R.sup.d2).sub.tC(O)OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOC(O)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2)NR.sup.a2C(O)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tC(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOC(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(O)OR.sup.b2, —(CR.sup.c2R.sup.d2)NR.sup.a2C(O)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(S)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2C(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.rR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O)(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tN═S(O)R.sup.a2R.sup.b2, (CR.sup.c2R.sup.d2).sub.tS(O).sub.2OR.sup.b2, —(CR.sup.c2R.sup.d2).sub.tOS(O).sub.2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O).sub.rR.sup.b2, —(CR.sup.c2R.sup.d2)R.sup.a2S(O)(═NR.sup.e2)R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O).sub.rNR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tS(O)(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O).sub.2NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tNR.sup.a2S(O)(═NR.sup.e2)NR.sup.a2R.sup.b2, —(CR.sup.c2R.sup.d2).sub.tP(O)R.sup.a2R.sup.b2 and —(CR.sup.c2R.sup.d2).sub.tP(O)(OR.sup.a2)(OR.sup.b2), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from OH, CN, amino, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.a2 and each R.sup.b2 are independently selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino, di(C.sub.1-10 alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; or R.sup.a2 and R.sup.b2 together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.c2 and each R.sup.d2 are independently selected from hydrogen, halogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino, di(C.sub.1-10 alkyl)amino, heterocyclyl, heterocyclyl-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl and heteroaryl-C.sub.1-4 alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; or R.sup.c2 and R.sup.d2 together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, OH, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, C.sub.1-10 alkylthio, C.sub.3-10 cycloalkylthio, amino, C.sub.1-10 alkylamino, C.sub.3-10 cycloalkylamino and di(C.sub.1-10 alkyl)amino; each R.sup.e2 is independently selected from hydrogen, CN, NO.sub.2, C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkyl-C.sub.1-4 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkoxy, —C(O)C.sub.1-4 alkyl, —C(O)C.sub.3-10 cycloalkyl, —C(O)OC.sub.1-4 alkyl, —C(O)OC.sub.3-10 cycloalkyl, —C(O)N(C.sub.1-4 alkyl).sub.2, —C(O)N(C.sub.3-10 cycloalkyl).sub.2, —S(O).sub.2C.sub.1-4 alkyl, —S(O).sub.2C.sub.3-10 cycloalkyl, —S(O).sub.2N(C.sub.1-4 alkyl).sub.2 and —S(O).sub.2N(C.sub.3-10 cycloalkyl).sub.2; each r is independently selected from 0, 1 and 2; each t is independently selected from 0, 1, 2, 3 and 4.
2.-5. (canceled)
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is N and B is CR.sup.3, and the compound has the formula (II): ##STR00138## wherein Q is selected from multicyclic cycloalkyl and multicyclic heterocyclyl, which is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in Formula (I).
7. (canceled)
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is selected from hydrogen, halogen, methyl, ethyl, CN, NO.sub.2, —NH.sub.2 and —OH, wherein methyl and ethyl are unsubstituted or substituted with at least one substituent, independently selected from R.sup.X3.
9. (canceled)
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is selected from hydrogen, F Cl, Br and CN.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring Q is selected from C.sub.2-10 alkenyl, which is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X; or Ring Q is selected from 3- to 12-membered cycloalkyl and 3- to 12-membered heterocyclyl, which is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X.
12. (canceled)
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring Q is selected from ##STR00139## which is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X.
14.-15. (canceled)
16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the R.sup.X is selected from methyl, ethyl, isopropyl, F, Cl, Br, CN, NO.sub.2, NH.sub.2, OH, methoxy and ethoxy, wherein the methyl, ethyl, isopropyl, methoxy and ethoxy are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.Y.
17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring Q is selected from ##STR00140##
18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, when A is N and B is CR.sup.3, Ring Q is selected from 8- to 12-membered multicyclic cycloalkyl and 8- to 12-membered multicyclic heterocyclyl, which is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X.
19.-20. (canceled)
21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from C.sub.3-10 cycloalkyl and heterocyclyl, wherein the cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R.sup.X1.
22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from ##STR00141## which is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X1.
23. (canceled)
24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.X1 is selected from halogen, OH, —(CR.sup.c1R.sup.d1).sub.tC(O)OR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tNR.sup.a1S(O).sub.rR.sup.b1, —(CR.sup.c1R.sup.d1).sub.tN═S(O)R.sup.a1R.sup.b1, —(CR.sup.c1R.sup.d1).sub.tS(O)(═NR.sup.c1)R.sup.b1 and —(CR.sup.c1R.sup.d1).sub.tS(O).sub.rNR.sup.a1R.sup.b1.
25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from ##STR00142## ##STR00143##
26.-27. (canceled)
28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is selected from hydrogen, F, Cl, Br, CN, methyl, vinyl, difluoromethyl, trifluoromethyl, methoxy and cyclopropyl.
29. (canceled)
30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is selected from hydrogen, halogen, C.sub.1-10 alkyl, CN, NO.sub.2, NH.sub.2 and OH, wherein the alkyl is unsubstituted or substituted with at least one substituent, independently selected from R.sup.X4.
31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159## and pharmaceutically acceptable salts thereof.
32. A pharmaceutical composition, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
33. (canceled)
34. A method of treating a cell-proliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
35. The method of claim 34, wherein the cell-proliferative disorder is characterized by amplification or overexpression of CCNE1 and/or CCNE2.
36. The method of claim 34, wherein the cell-proliferative disorder is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer and thyroid cancer.
Description
EXAMPLES
[0336] Various methods may be developed for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that others may devise.
[0337] It will be readily recognized that certain compounds of formula (I) have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers). It is recognized that synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
[0338] A compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) can be prepared by, for example, reacting the free acid form of the at least one compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.
[0339] The free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc).
[0340] The N-oxides of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80° C. Alternatively, the N-oxides of the compounds of formula (I) can be prepared from the N-oxide of an appropriate starting material.
[0341] Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80° C.
[0342] Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
[0343] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliters); psi (pounds per square inch); M (molar); mM (millimolar); i.v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); RT (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); Rt (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (N,N-dimethylformamide); DMPU (N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et.sub.2O (diethyl ether); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (high pressure liquid chromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF (tetra-n-butylammonium fluoride); m-CPBA (meta-chloroperbenzoic acid).
For example, the following abbreviations in table 1 may be used in the examples and throughout the specification.
[0344] References to ether or Et.sub.2O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions were conducted under an inert atmosphere at RT unless otherwise noted.
[0345] .sup.1H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).
[0346] Low-resolution mass spectra (MS) and compound purity data were acquired on a Shimadzu LC/MS single quadrupole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm), and evaporative light scattering detector (ELSD). Thin-layer chromatography was performed on 0.25 mm Superchem group silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co., Ltd).
Synthetic Schemes
[0347] In the reactions described herein after it may be necessary to protect reactive functional groups, for example hydroxyl, amino, imino, thio or carboxyl groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991
[0348] Synthetic methods for preparing the compounds of the present invention are illustrated in the following Schemes and Examples. Starting materials are commercially available or may be made according to procedures known in the art or as illustrated herein.
[0349] The intermediates shown in the following schemes are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art.
[0350] One synthetic approach of compounds of formula I of the present disclosure is shown in Scheme 1. Compounds of formula I can be synthesized from the intermediates III, and amine IV, which are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art. Coupling of the intermediates III with amine IV in the presence of a base or using transitional metal catalyzed cross coupling reactions known in the literature provide compounds of formula I.
##STR00056##
[0351] As an illustration of the preparation of intermediate III. One synthetic route of IIIa is shown in Scheme 2. The preparation starts with IIIa-A and IIIa-B, which are either commercially available or can be synthesized following the procedure known in the literature. Intermediate IIIa-C can be obtained by the coupling of IIIa-A with amine IIIa-B through a substitution reaction. Oxidation of the hydroxyl group in IIIa-C gives IIIa-D. The Intermediate heterocyclic-fused pyridin-2-ones IIIa-E can be prepared from IIIa-D upon treatment with a lithium enolate of ethyl acetate or α-substituted acetates. Oxidation of the methylthio group in IIIa-E gives compounds of formula IIIa.
##STR00057##
[0352] As a further illustration of the preparation of intermediates of formula III, a preparation of compound IIIb is illustrated in Scheme 3. The preparation starts with IIIb-A and IIIa-B, which are commercially available or can be synthesized following the procedure known in the literature. Intermediate IIIb-B can be obtained by the coupling of IIIb-A with amine IIIa-B through a substitution reaction. Ester IIIb-B can be converted into aldehyde IIIb-D via a sequence of LiAlH.sub.4 reduction and MnO.sub.2 oxidation. Compounds of heterocyclic-fused pyridin-2-ones IIIb can be prepared from IIIb-D upon treatment with a lithium enolate of ethyl acetate or α-substituted acetates.
##STR00058##
[0353] In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
Example 1
2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1)
[0354] ##STR00059##
(4-Chloro-2-(methylthio)pyrimidin-5-yl)methanol (1a)
[0355] The title compound (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (1a) was prepared according to the method described in WO2009 85185. MS-ESI (m/z): 191 [M+1].sup.+.
Spiro[2,4]heptan-4-amine hydrochloride (1b)
[0356] The title compound spiro[2,4]heptan-4-amine hydrochloride (1b) was prepared according to the method described in Journal of Medicinal Chemistry. 2018. Vol 61. Nb. 6p. 2518-2532. MS-ESI (m/z): 112 [M+1].sup.+.
(2-(Methylthio)-4-(spiro[2,4]heptan-4-ylamino)pyrimidin-5-yl)methanol (1c)
[0357] To a solution of (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (1a) (100 mg, 0.530 mmol) and spiro[2,4]heptan-4-amine hydrochloride (1b) (93 mg, 0.64 mmol) in IPA (3 mL) was added DIPEA (336 mg, 2.60 mmol). After that the mixture was stirred at 80° C. for overnight. The mixture was concentrated and extracted with EtOAc (2×30 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (2:1˜1:1.5) to give (2-(methylthio)-4-(spiro[2,4]heptan-4-ylamino)pyrimidin-5-yl)methanol (1c). MS-ESI (m/z): 266 [M+1].sup.+.
2-(Methylthio)-4-(spiro[2,4]heptan-4-ylamino)pyrimidine-5-carbaldehyde (1d)
[0358] To a solution of (2-(methylthio)-4-(spiro[2,4]heptan-4-yl amino)pyrimidin-5-yl)methanol (1c) (142 mg, 0.540 mmol) in EtOAc (25 mL) was added MnO.sub.2 (1.40 g, 16.1 mmol). After that the mixture was stirred at 50° C. for overnight. The reaction was cooled to room temperature, and the mixture was filtered and washed with EtOAc (2×100 mL). The extracts were concentrated to give 2-(methylthio)-4-(spiro[2,4]heptan-4-ylamino)pyrimidine-5-carbaldehyde (1d). MS-ESI (m/z): 264 [M+1].sup.+.
2-(Methylthio)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1e)
[0359] To a solution of 2-(methylthio)-4-(spiro[2,4]heptan-4-yl amino)pyrimidine-5-carbaldehyde (1d) (30 mg, 0.11 mmol) and EtOAc (26 mg, 0.30 mmol) in THF (2 mL) at −10° C. was added dropwise LiHMDS (0.36 mL, 0.36 mmol). After that the mixture was slowly warmed up to 25° C. and stirred for overnight. The reaction was cooled to 0° C., quenched by sat. NH.sub.4Cl (2 mL) and the mixture was extracted with EtOAc (2×20 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give 2-(methylthio)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1e). MS-ESI (m/z): 288 [M+1].sup.+.
2-(Methylsulfonyl)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1f)
[0360] To a solution of 2-(methylthio)-8-(spiro[2,4]heptan-4-yl)pyrido-[2,3-d]pyrimidin-7(8H)-one (1e) (40 mg, 0.13 mmol) in DCM (4.0 mL) was added m-CPBA (121 mg, 0.520 mmol). After that the mixture was stirred at 20° C. for 2.5 h. The mixture was extracted with DCM (2×20 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with PE/EtOAc (1:1.5) to give 2-(methylsulfonyl)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (if). MS-ESI (m/z): 320 [M+1].sup.+.
1-(Methylsulfonyl)piperidin-4-amine (1i)
[0361] The title compound 1-(methylsulfonyl)piperidin-4-amine (1j) was prepared according to the method described in WO2014/184327. MS-ESI (m/z): 179 [M+1].sup.+.
2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1)
[0362] To a solution of 2-(methylsulfonyl)-8-(spiro[2,4]heptan-4-yl)pyrido-[2,3-d]pyrimidin-7(8H)-one (if) (17.2 mg, 0.0600 mmol) in 2-MeTHF (1 mL) was added 1-(methylsulfonyl)piperidin-4-amine (1j) (18.9 mg, 0.110 mmol). After that the mixture was stirred at 65° C. for overnight. The mixture was concentrated and extracted with EtOAc (2×30 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with DCM/MeOH (30:1) to give 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1). MS-ESI (m/z): 418 [M+1].sup.+.
Example 2
6-Methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2)
[0363] ##STR00060##
6-Methyl-2-(methylthio)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2a)
[0364] To a solution of 2-(methylthio)-4-(spiro[2,4]heptan-4-ylamino)pyrimidine-5-carbaldehyde (1d) (30 mg, 0.11 mmol) and ethyl propionate (30 mg, 0.30 mmol) in THF (2 mL) at −10° C. was added dropwise LiHMDS (0.36 mL, 0.36 mmol). After that the mixture was slowly warmed up to 25° C. and stirred for overnight. The reaction was cooled to 0° C. and quenched by sat. NH.sub.4Cl (2 mL) and the mixture was extracted with EtOAc (2×20 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give 6-methyl-2-(methylthio)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2a). MS-ESI (m/z): 302 [M+1].sup.+.
6-Methyl-2-(methylsulfonyl)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2b)
[0365] To a solution of 6-methyl-2-(methylthio)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2a) (29 mg, 0.10 mmol) in DCM (4.0 mL) was added m-CPBA (93 mg, 0.40 mmol). After that the mixture was stirred at 20° C. for 2.5 h. The mixture was extracted with DCM (2×20 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with PE/EtOAc (1:1) to give 6-methyl-2-(methylsulfonyl)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2b). MS-ESI (m/z): 334 [M+1].sup.+.
6-Methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2)
[0366] To a solution of 6-methyl-2-(methylsulfonyl)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2b) (18 mg, 0.060 mmol) in 2-MeTHF (1 mL) was added 1-(methylsulfonyl)piperidin-4-amine (1j) (19 mg, 0.11 mmol). After that the mixture was stirred at 65° C. for overnight. The mixture was concentrated and extracted with EtOAC (2×30 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with DCM/MeOH (30:1) to give 6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (2). MS-ESI (m/z): 432 [M+1].sup.+.
Example 3
(R)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(4-oxaspiro[2,4]heptan-7-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (3)
[0367] ##STR00061##
tert-butyl (R)-(3-hydroxy-1-(I-hydroxycyclopropyl)propyl)carbamate (3a)
[0368] The title compound tert-butyl (R)-(3-hydroxy-1-(1-hydroxycyclopropyl)-propyl)carbamate (3a) was prepared according to the method described in J Org. Chem., Vol. 65, No. 26, 2000. MS-ESI (m/z): 232 [M+1].sup.+.
(R)-3-((tert-butoxycarbonyl)amino)-3-(1-hydroxycyclopropyl)propyl methanesulfonate (3b)
[0369] To a mixture of tert-butyl (R)-(3-hydroxy-1-(1-hydroxycyclopropyl)-propyl)carbamate (3a) (0.56 g, 2.4 mmol) in pyridine (5 mL) at 25° C. was added MsCl(280 mg, 1.21 mmol). After stirring at 25° C. for 2 h, the mixture was diluted with water (20 mL), and then extracted with EtOAc (2×30 mL), washed with brine, dried and concentrated to give the title compound (R)-3-((tert-butoxycarbonyl)amino)-3-(1-hydroxycyclopropyl)propyl methanesulfonate (3b). MS-ESI (m/z): 310 [M+1].sup.+.
tert-butyl (R)-(4-oxaspiro[2,4]heptan-7-yl)carbamate (3c)
[0370] To a mixture of (R)-3-((tert-butoxycarbonyl)amino)-3-(1-hydroxycyclopropyl)-propyl methanesulfonate (3b) (0.70 g, 2.2 mmol) in THF (10 mL) at 0° C. was added NaH (453 mg, 11.0 mmol). After stirring at 0° C. for 1 h, the mixture was diluted with water (20 mL), and then extracted with EtOAc (2×30 mL), washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel eluting with DCM/MeOH (50:1) to give the title compound tert-butyl (R)-(4-oxaspiro[2,4]heptan-7-yl)carbamate (3c). MS-ESI (m/z): 214 [M+1].sup.+.
((R)-4-oxaspiro[2,4]heptan-7-amine hydrochloride (3d)
[0371] A mixture of tert-butyl (R)-(4-oxaspiro[2,4]heptan-7-yl)carbamate (3c) (300 mg, 1.4 mmol) in HCl/dioxane (20 mL) was stirred at RT for 1 h. The mixture was concentrated to give the title compound (R)-4-oxaspiro[2,4]heptan-7-amine hydrochloride (3d). MS-ESI (m/z): 114 [M+1].sup.+.
(R)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(4-oxaspiro[2,4]heptan-7-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (3)
[0372] The title compound 3 was prepared according to the synthetic method of 1 by replacing spiro[2,4]heptan-4-amine hydrochloride (1b) with (R)-4-oxaspiro[2,4]heptan-7-amine hydrochloride (3d). MS-ESI (m/z): 420 [M+1].sup.+.
Example 4
(R)-6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(4-oxaspiro[2,4]heptan-7-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (4)
[0373] ##STR00062##
[0374] The title compound 4 was prepared according to the synthetic method of 2 by replacing spiro[2,4]heptan-4-amine hydrochloride (1b) with (R)-4-oxaspiro[2,4]heptan-7-amine hydrochloride (3d). MS-ESI (m/z): 434 [M+1].sup.+.
Example 5
8-(1-hydroxybicyclo[3.1.0]hexan-2-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (5)
[0375] ##STR00063##
ethyl 2-((tert-butoxycarbonyl)amino)hex-5-enoate (5a)
[0376] The title compound ethyl 2-((tert-butoxycarbonyl)amino)hex-5-enoate (5a) was prepared according to the method described in Journal of Medicinal Chemistry. 2006. Vol 49. Nb. 20 p. 6074-6086. MS-ESI (m/z): 258 [M+1].sup.+.
tert-butyl (1-hydroxybicyclo[3.1.0]hexan-2-yl)carbamate (5b)
[0377] To a solution of ethyl 2-((tert-butoxycarbonyl)amino)hex-5-enoate (5a) (1.20 g, 4.67 mmol) in THF (20 mL) at 5° C.-10° C. was added titanium isopropoxide (2.38 mL, 11.0 mmol) and cyclohexyl magnesium chloride (12.5 mL, 25 mmol) slowly. After that stirred at room temperature for overnight. The mixture was cooled to 0° C., quenched with sat. NH.sub.4Cl (50 mL), and then extracted with EtOAc (2×100 mL), washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel eluting with PE/EA (10:1 to 3:1) to give the title compound tert-butyl (1-hydroxybicyclo[3.1.0]hexan-2-yl)carbamate (5b). MS-ESI (m/z): 214 [M+1].sup.+.
2-Aminobicyclo[3.1.0]hexan-1-ol (5e)
[0378] To a solution of tert-butyl (1-hydroxybicyclo[3.1.0]hexan-2-yl)carbamate (5b) 427 mg, 2.0 mmol) in DCM (8 mL) at 0° C. was added 4N HCl/EtOAC (10 mL). After that the mixture was stirred at room temperature for 2.5 h and concentrated. The residue was dissolved in DCM (30 mL), then added 160 mg NaOH in 0.5 mL H.sub.2O, stirred at room temperature for 40 mins. The mixture was filtered, washed with DCM, dried and concentrated to give the title compound 2-aminobicyclo[3.1.0]hexan-1-ol (5c). MS-ESI (m/z): 114 [M+1].sup.+.
4-Chloro-2-(methylthio)pyrimidine-5-carbaldehyde (5d)
[0379] The title compound 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (5d) was prepared according to the method described in WO2009 85185. MS-ESI (m/z): 189 [M+1].sup.+.
(E)-2-(((4-((1-hydroxybicyclo[3.1.0]hexan-2-yl)amino)-2-(methylthio)pyrimidin-5-yl)methylene)amino)bicyclo[3.1.0]hexan-1-ol (5e)
[0380] To a solution of 2-aminobicyclo[3.1.0]hexan-1-ol (5c) (193 mg, 0.860 mmol) and 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (5d) (81 mg, 0.43 mmol) in CH3CN (10 mL) was added Et.sub.3N (170 mg, 1.68 mmol). After that the mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with water (20 mL), and then extracted with EtOAc (2×30 mL), washed with brine, dried and concentrated to give the title crude compound (E)-2-(((4-((1-hydroxybicyclo[3.1.0]hexan-2-yl)amino)-2-(methylthio)-pyrimidin-5-yl)methylene)amino)bicyclo[3.1.0]hexan-1-ol (5e). MS-ESI (m/z): 361 [M+1].sup.+.
4-((1-Hydroxybicyclo[3.1.0]hexan-2-yl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (5f)
[0381] To a solution of (E)-2-(((4-((1-hydroxybicyclo[3.1.0]hexan-2-yl)amino)-2-(methylthio)pyrimidin-5-yl)methylene)amino)bicyclo[3.1.0]hexan-1-ol (5e) (219 mg, 0.610 mmol) in THF (12 mL) at room temperature was added 4N HCl/Dioxane (3.5 mL) and 1 N HCl (2.0 mL). After that the mixture was stirred at room temperature for 2.5 h and concentrated. The residue was diluted with water (20 mL), and then extracted with EtOAc (2×30 mL), washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel eluting with PE/EA (5:1 to 1:1) to give the title compound 4-((1-hydroxybicyclo[3.1.0]hexan-2-yl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (5f). MS-ESI (m/z): 266 [M+1].sup.+.
8-(1-Hydroxybicyclo[3.1.0]hexan-2-yl)-2-((1-(methylsulfonyl)piperidin-4-yl) amino)pyrido[2,3-d]pyrimidin-7(8H)-one (5)
[0382] The title compound 5 was prepared according to the synthetic method of 1 by replacing 2-(methylthio)-4-(spiro[2,4]heptan-4-ylamino)pyrimidine-5-carbaldehyde (1d) with 4-((1-hydroxybicyclo[3.1.0]hexan-2-yl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (5f). MS-ESI (m/z): 420 [M+1].sup.+.
Example 6
8-(1-Hydroxybicyclo[3.1.0]hexan-2-yl)-6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (6)
[0383] ##STR00064##
[0384] The title compound 6 was prepared according to the synthetic method of 2 by replacing 2-(methylthio)-4-(spiro[2,4]heptan-4-ylamino)pyrimidine-5-carbaldehyde (1d) with 4-((1-hydroxybicyclo[3.1.0]hexan-2-yl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (5f). MS-ESI (m/z): 434 [M+1].sup.+.
Example 7
6-Chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (7)
[0385] ##STR00065##
[0386] To a solution of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1) (9.3 mg, 0.022 mmol) in 2-MeTHF (1 mL) was added NCS (6.0 mg, 0.033 mmol). After that the mixture was stirred at room temperature for 1 h. The mixture was extracted with EtOAC (2×15 mL) and washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with DCM/MeOH (30:1) to give 6-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (7). MS-ESI (m/z): 452 [M+1].sup.+.
Example 8
6-Bromo-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (8)
[0387] ##STR00066##
[0388] To a solution of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1) (11.2 mg, 0.027 mmol) in 2-MeTHF (1 mL) was added NBS (7.1 mg, 0.04 mmol). After that the mixture was stirred at room temperature for 1 h. The mixture was extracted with EtOAc (2×15 mL) and washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with DCM/MeOH (30:1) to give 6-bromo-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (8). MS-ESI (m/z): 496, 498 [M+1].sup.+.
Example 9
2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-oxo-8-(spiro[2,4]heptan-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (9)
[0389] ##STR00067##
[0390] To a solution of 6-bromo-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(spiro[2,4]heptan-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (8) (6.0 mg, 0.012 mmol) in DMF (1 mL) was added Zn(CN).sub.2 (6.0 mg, 0.052 mmol) and Pd(PPh.sub.3).sub.4 (1.5 mg, 0.002 mmol). After that the mixture was stirred at 100° C. under N2 overnight. The mixture was extracted with EtOAC (2×15 mL) and washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with DCM/MeOH (30:1) to 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-oxo-8-(spiro[2,4]heptan-4-yl)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (9). MS-ESI (m/z): 443 [M+1].sup.+.
Example 10
8-(Bicyclo[3.1.0]hexan-1-yl)-6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (10)
[0391] ##STR00068##
Methyl bicyclo[3.1.0]hexane-1-carboxylate (10a)
[0392] To the suspension of NaH (2 g, 50.0 mmol) in DMSO (40.0 ml) was added Trimethylsulfoxonium iodide (11 g, 50 mmol) portionwise at 0° C., the mixture was warmed up to rt and stirred for 1 h. Then the mixture was added methyl cyclopent-1-ene-1-carboxylate (2.4 g, 20.0 mmol) in DMSO (20.0 ml) dropwise and stirred at 50° C. for 15 h. The reaction was quenched with H.sub.2O (200 ml), extracted with EtOAc (2×100 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give methyl bicyclo[3.1.0]hexane-1-carboxylate (10a). MS-ESI (m/z): 141 [M+1].sup.+.
Bicyclo[3.1.0]hexane-1-carboxylic acid (10b)
[0393] To the solution of methyl bicyclo[3.1.0]hexane-1-carboxylate (10a) (0.9 g, 6.4 mmol) in MeOH (15 mL) and H.sub.2O (5 ml) was added LiOH.H.sub.2O (1.6 g, 30.7 mmol). The mixture was stirred at 40° C. for 1 h. Then the mixture was extracted with EtOAc (2×30 mL), the water phase was adjust pH=3-4 with HCl (3M) and extracted with EtOAc (2×40 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give bicyclo[3.1.0]hexane-1-carboxylic acid (10b). MS-ESI (m/z): 127 [M+1].sup.+.
Benzyl bicyclo[3.1.0]hexan-1-ylcarbamate (10c)
[0394] The mixture of bicyclo[3.1.0]hexane-1-carboxylic acid (10b) (125 mg, 1.0 mmol), DPPA (330 mg, 1.2 mmol) and Et.sub.3N (121 mg, 1.2 mmol) in toluene (5 ml) was stirred at 80° C. to 100° C. for 2h. Then added BnOH (540 mg, 5 mmol) and stirred at 100° C. for 12h. The reaction mixture was concentrate, diluted with NaHCO.sub.3(sat. 50.0 ml), then the mixture was extracted with EtOAc (2×30 mL). The extracts were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (50:1 to 25:1) to give benzyl bicyclo[3.1.0]hexan-1-ylcarbamate (10c). MS-ESI (m/z): 232 [M+1].sup.+.
Bicyclo[3.1.0]hexan-1-amine hydrochloride (10d)
[0395] To a solution of benzyl bicyclo[3.1.0]hexan-1-ylcarbamate (10c) (200 mg, 0.86 mmol) in EtOAc (5 mL) was added 10% Pd/C (200 mg). The mixture was heated to 40° C. under H2 for 1 h. The reaction was filtered with celite, the filtrate was adjust pH=1 with HCl/EA (4 M), then concentrated to give bicyclo[3.1.0]hexan-1-amine hydrochloride (10d). MS-ESI (m/z): 98 [M+1].sup.+.
8-(Bicyclo[3.1.0]hexan-1-yl)-6-methyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (10)
[0396] The title compound 10 was prepared according to the synthetic method of 2 by replacing spiro[2,4]heptan-4-amine hydrochloride (1b) with bicyclo[3.1.0]hexan-1-amine hydrochloride (10d). MS-ESI (m/z): 418 [M+1].sup.+.
Example 11
1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (11)
[0397] ##STR00069##
Ethyl 6-chloro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)nicotinate
[0398] To a solution of ethyl 4,6-dichloronicotinate (700 mg, 3.18 mmol) and (1R,2R)-2-amino-1-methylcyclopentanol (330 mg, 2.86 mmol) in DMAC (10 mL) was added DIPEA (1.2 mL, 6.78 mmol). After that the mixture was stirred at 90° C. for 3 h. The mixture was quenched with water and extracted with EtOAc (3×20 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give Ethyl 6-chloro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)nicotinate (11a). MS-ESI (m/z): 299 [M+1].sup.+.
(1R,2R)-2-((2-chloro-5-(hydroxymethyl)pyridin-4-yl)amino)-1-methylcyclopentanol (11b)
[0399] To a solution of Ethyl 6-chloro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl) amino)nicotinate (11a) (300 mg, 1 mmol) in THF (4 mL) was added LiAlH.sub.4 (100 mg, 2.63 mmol) portions at 0° C. and then stirred at room temperature for 1 h. The mixture was cooled to 0° C., quenched with water and stirred for another 0.5 h at room temperature. The mixture was filtered and the cake was washed with THF, the filtrate was concentrated to give (1R,2R)-2-((2-chloro-5-(hydroxymethyl) pyridin-4-yl)amino)-1-methylcyclopentanol (11b). MS-ESI (m/z): 257 [M+1].sup.+.
6-chloro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)nicotinaldehyde
[0400] To a solution of (1R,2R)-2-((2-chloro-5-(hydroxymethyl) pyridin-4-yl)amino)-1- methylcyclopentanol (11b) (257 mg, 1 mmol) in DCM(4 mL) was added MnO.sub.2 (2.3 g) and stirred at room temperature for overnight. The mixture was filtered through celite, the cake washed with DCM and the filtrate was concentrated to give 6-chloro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)nicotinaldehyde (11c). MS-ESI (m/z): 255 [M+1].sup.+.
7-chloro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-1,6-naphthyridin-2(1H)-one (11d)
[0401] To a solution of 6-chloro-4-(((1R,2R)-2-hydroxy-2-methyl cyclopentyl)amino)nicotinaldehyde (11c) (45 mg, 0.17 mmol) in EtOAc (5 mL) was added NaOEt (530 mg, 1.56 mmol, 20% in EtOH) and stirred at 65° C. for 10 min. The mixture was quenched with water, separated, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/EtOAc (5:1 to 1:2) to give 7-chloro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-1,6-naphthyridin-2(1H)-one (11d). MS-ESI (m/z): 279 [M+1].sup.+.
1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (11)
[0402] The suspension of 7-chloro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-1,6-naphthyridin-2(1H)-one (11d) (75 mg, 0.26 mmol), 1-(methylsulfonyl)piperidin-4-amine (1j) (72 mg, 0.40 mmol), Pd.sub.2(dba).sub.3 (49 mg, 0.053 mmol), rac-BINAP(34 mg, 0.053 mmol) and K.sub.3PO.sub.4 (170 mg, 0.80 mmol) in toluene (10 mL) was stirred at 110° C. under nitrogen atmosphere for overnight. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/EtOAc (2:1 to 1:10) to give 1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (11). MS-ESI (m/z): 421 [M+1].sup.+.
Example 12
3-(difluoromethyl)-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (12)
[0403] ##STR00070##
[0404] To the suspension of sodium difluoromethanesulfinate (27 mg, 0.2 mmol), 1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (11) (20 mg, 0.047 mmol) and FeCl.sub.2 (0.6 mg, 0.0047 mmol) in DMSO (2.5 mL) and water (0.2 mL) was added TBHP (30 mg, 0.23 mmol, 70% in water) at 0 5° C., then the mixture was warmed to room temperature and stirred for 0.5 h. The mixture was added water (5 ml), extracted with EtOAc (2×20 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM/EtOAc (2:1 to 1:10) to give 3-(difluoromethyl)-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl) piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (12). MS-ESI (m/z): 471 [M+1].sup.+.
Example 13
8-fluoro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (13)
[0405] ##STR00071##
ethyl 6-chloro-5-fluoro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-nicotinate (13a)
[0406] To a solution of ethyl 4,6-dichloro-5-fluoronicotinate (260 mg, 1.09 mmol) and (1R,2R)-2-amino-1-methylcyclopentan-1-ol (130 mg, 1.13 mmol) in DMAc (3 mL) was added DIPEA (0.37 mL, 2.24 mmol). After that the mixture was stirred at RT for 6 h. The mixture was extracted with EtOAc (2×30 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give ethyl 6-chloro-5-fluoro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)nicotinate (13a). MS-ESI (m/z): 317 [M+1].sup.+.
(1R,2R)-2-((2-chloro-3-fluoro-5-(hydroxymethyl)pyridin-4-yl)amino)-1-methylcyclopentan-1-ol (13b)
[0407] To a solution of ethyl 6-chloro-5-fluoro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)nicotinate (13a) (306 mg, 0.97 mmol) in THF (5 mL) at 0° C. was added LiAlH.sub.4 (62 mg, 1.63 mmol). After that the mixture was stirred for 1 h. The mixture was quenched with H.sub.2O and extracted with EtOAc (2×50 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give (1R,2R)-2-((2-chloro-3-fluoro-5-(hydroxymethyl)pyridin-4-yl)amino)-1-methylcyclopentan-1-ol (13b). MS-ESI (m/z): 275 [M+1].sup.+.
6-chloro-5-fluoro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)nicotinaldehyde (13c)
[0408] To a solution of (1R,2R)-2-((2-chloro-3-fluoro-5-(hydroxymethyl)pyridin-4-yl)amino)-1-methylcyclopentan-1-ol (13b) (258 mg, 0.97 mmol) in EtOAc (30 mL) was added MnO.sub.2 (1.70 g, 19.5 mmol). After that the mixture was stirred at RT for overnight. The reaction mixture was filtered and washed with EtOAc (2×100 mL) and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (5:1 to 3:1) to give 6-chloro-5-fluoro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)nicotinaldehyde (13c). MS-ESI (m/z): 273 [M+1].sup.+.
7-chloro-8-fluoro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-1,6-naphthyridin-2(1H)-one (13d)
[0409] To a solution of 6-chloro-5-fluoro-4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)-amino)nicotinaldehyde (13c) (20 mg, 0.074 mmol) and EtOAc (26 mg, 0.20 mmol) in THF (1.5 mL) at −10° C. was added LiHMDS (0.24 mL, 0.24 mmol) dropwise. After that the mixture was slowly warmed up to 25° C. and stirred for overnight. The reaction was cooled to 0° C., quenched by sat. NH.sub.4Cl (2 mL) and the mixture was extracted with EtOAc (2×20 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with DCM/MeOH(35:1) to give 7-chloro-8-fluoro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-1,6-naphthyridin-2(1H)-one (13d). MS-ESI (m/z): 297 [M+1].sup.+.
8-fluoro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (13)
[0410] To a solution of 7-chloro-8-fluoro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-1,6-naphthyridin-2(1H)-one (13d) (13 mg, 0.044 mmol) and 1-(methylsulfonyl)piperidin-4-amine (1j) (16 mg, 0.088 mmol) in toluene (3.0 mL) at RT was added Pd.sub.2(dba).sub.3 (8 mg, 0.009 mmol), BINAP (6 mg, 0.009 mmol) and K.sub.3PO.sub.4 (8 mg, 0.13 mmol) under N2. After that the mixture was heated to 110° C. and stirred for overnight. The reaction was cooled to RT and the mixture was extracted with EtOAc (2×20 mL). The extracts were washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with DCM/MeOH(40:1) to give 8-fluoro-1-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,6-naphthyridin-2(1H)-one (13). MS-ESI (m/z): 439 [M+1].sup.+.
Example 14
8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pteridin-7(8H)-one (14)
[0411] ##STR00072##
(1R,2R)-2-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (14a)
[0412] To a solution of 2,4-dichloro-5-nitropyrimidine (207 mg, 1.06 mmol) and DIPEA (0.18 mL, 1.09 mmol) in DCM (3 mL) at −60° C. was added a solution of (1R,2R)-2-amino-1-methylcyclopentan-1-ol (126 mg, 1.09 mmol) in DCM (1 mL) dropwise. After that the mixture was slowly warmed up to 0° C. The mixture was extracted with DCM (2×30 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated to give (1R,2R)-2-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (14a). MS-ESI (m/z): 273 [M+1].sup.+.
(1R,2R)-1-methyl-2-((2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclopentan-1-ol (14b)
[0413] To a solution of (1R,2R)-2-((2-chloro-5-nitropyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (14a) (154.0 mg, 0.57 mmol) and DIPEA (0.18 mL, 1.09 mmol) in DMF (2 mL) was added 1-(methylsulfonyl)piperidin-4-amine (1j) (121.0 mg, 0.68 mmol). After that the mixture was stirred at RT for overnight. The mixture was extracted with EtOAc (2×30 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (50:1 to 25:1) to give (1R,2R)-1-methyl-2-((2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclopentan-1-ol (14b). MS-ESI (m/z): 415 [M+1].sup.+.
(1R,2R)-2-((5-amino-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (14c)
[0414] To a solution of (1R,2R)-1-methyl-2-((2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclopentan-1-ol (14b) (100.0 mg, 0.241 mmol) in MeOH (10 mL) at RT was added 10% Pd/C (100 mg) under H2 (1 atm). After that the mixture was stirred at RT for overnight. The mixture was filtered, washed with MeOH and concentrated to give (1R,2R)-2-((5-amino-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (14c). MS-ESI (m/z): 385 [M+1].sup.+.
ethyl (E)-2-((4-(((R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)imino)acetate (14d)
[0415] To a solution of (1R,2R)-2-((5-amino-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (14c) (16.0 mg, 0.42 mmol) in EtOH (2 mL) at RT was added ethyl 2-oxoacetate (16 mg, 0.078 mmol). After that the mixture was stirred at RT for 2 h and heated at 80° C. for overnight. The mixture was cooled to RT and concentrated. to give crude ethyl (E)-2-((4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)imino)acetate (14d). MS-ESI (m/z): 469 [M+1].sup.+.
8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pteridin-7(8H)-one (14)
[0416] To a solution of crude ethyl (E)-2-((4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)imino) acetate (14d) in dry THF (2 mL) at rt was added KO.sup.tBu(14 mg, 0.11 mmol). After that the mixture was stirred at rt for overnight. The mixture was cooled to 0° C. and quenched with sat. NH.sub.4Cl, extracted with EtOAc (2×30 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by PTLC with DCM/MeOH (35:1) to give 8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pteridin-7(8H)-one (14). MS-ESI (m/z): 423 [M+1].sup.+.
[0417] Following essentially the same procedures described for Examples 1˜14 or using similar synthetic strategies or methods. Examples 15˜75 listed in Table 1 were prepared using appropriate intermediates, which can be readily synthesized by methods known in the art, and sequential modifications as necessary. The structures and names of Examples 15˜75 are given in table 1.
TABLE-US-00001 TABLE 1 EXAMPLE STRUCTURE NAME DATA 15
Cell Proliferation Assays
[0418] MTS testing kit was purchased from Promega (Madison, Wis., USA). The RPMI-1640, DMEM, Fetal bovine serum and Penicillin-Streptomycin were purchased from BI (Biological Industries, Beit Haemek, Israel). Dimethyl sulfoxide (DMSO) was purchased from Sigma (St. Louis, Mo., USA).
[0419] To investigate whether a compound is able to inhibit the activity of CDK2/4/6 in cells, we developed a mechanism-based assay using HCC1806 (CDK4/6 independent) and Hs68 (CDK4/6 dependent) cell lines. In this assay, inhibition of CDK2/4/6 was detected by the cell proliferation inhibition of HCC1806 and Hs68 cells. HCC806 and HS68 cells cultured in PRMI-1640 and DMEM supplemented with 10% fetal bovine serum respectively to 40-80% confluence were collected and plated into 96-well plates at desired cell density of 5×10.sup.3/mL. Plates were incubated at 37° C., with 5% CO.sub.2 for 24 h. Compounds were serially diluted and added to the plates with the final concentrations as 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM. Plates were incubated at 37° C., with 5% CO.sub.2 for 120 h. A mixture of 20 μl MTS/100 μl medium were added to each well and the plates were incubated at 37° C., with 5% CO.sub.2 for exactly 2 h. The absorbance was measured by a microplate reader at 490 nm. IC.sub.50 was calculated using GraphPad Prism 5.0 software.
[0420] Selected compounds prepared as described above were assayed according to the biological procedures described herein. The results are shown in the table below:
TABLE-US-00002 TABLE 2 Example HCC1806 IC.sub.50 (nM) Hs68 IC.sub.50 (nM) 1 379 318 2 / 322 7 308 233 8 305 105 18 233 / 19 139 / 20 211 / 22 318 / 23 150 489 24 78 437 30 409 / 31 118 418