IP Library › Patent Application 14690219

Patent Application

App. No. 14/690,219

Tricyclic Lactams for Use in the Protection of Normal Cells During Chemotherapy

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Patent No.: US None
App. No.: 14/690,219

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Abstract

This invention is in the area of tricyclic lactam compounds, compositions and methods of protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC) as well as renal cells, from damage associated with DNA damaging chemotherapeutic agents. In one aspect, protection of healthy cells is disclosed using compounds that act as cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects undergoing DNA damaging chemotherapeutic regimens for the treatment of proliferative disorders.

Claims (319)

1 . A method of reducing the effect of chemotherapy on healthy cells in a subject being treated for cyclin-dependent kinase 4/6 (CDK4/6) replication independent cancer or abnormal cell proliferation, wherein said healthy cells are hematopoietic stem cells, hematopoietic progenitor cells, or renal epithelial cells, the method comprising administering to the subject, an effective amount of an compound selected from the group consisting of Formula I, II, III, IV, or V:

wherein:

Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;

each X is independently CH or N;

each X′ is independently CH or N;

X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;

R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O)n-NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

each R 1 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 1 's on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;

y is 0, 1, 2, 3 or 4;

R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1 or 2 and n is 0, 1 or 2;

R 3 and R 4 at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;

R 5 and R 5 * at each occurrence is:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance;

R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 ) -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:

said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *,

n is 0, 1 or 2, and

m is 0, 1 or 2;

R 3 * and R 4 * at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance; and

R 6 is H or lower alkyl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring; and

R 10 is (i) NHR A , wherein R A is unsubstituted or substituted C 1 -C 8 alkyl, cycloalkylalkyl, or -TT-RR, C 1 -C 8 cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C 1 -C 6 alkoxy, amino, unsubstituted or substituted C 1 -C 6 alkylamino, unsubstituted or substituted di-C 1 -C 6 alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R 12 or —C(O)O—R 13 , wherein R 12 is NHR A or R A and R 13 is R A ;

when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present and are as defined above;

when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present and are as defined above;

or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein each R 8 is independently hydrogen or C 1 -C 3 alkyl.

3 . The method of claim 1 , wherein the compound has the formula selected from the structures shown in FIG. 5 .

4 . The method of claim 1 , wherein the compound has the formula selected from the structures shown in FIG. 6 .

5 . The method of claim 1 , wherein the compound has the formula selected from the structures shown in FIG. 7 .

6 . The method of claim 1 , wherein the compound has the formula selected from the structures shown in FIG. 8 .

7 . The method of claim 1 , wherein the compound has the formula selected from the structures shown in FIG. 9 .

8 . The method of claim 1 , wherein the compound has the formula:

9 . The method of claim 1 , wherein the compound has the formula:

10 . The method of claim 1 , wherein the compound has the formula:

11 . The method of claim 1 , wherein the compound has the formula:

12 . The method of claim 1 , wherein the compound has the formula:

13 . The method of claim 1 , wherein the compound has the formula:

14 . The method of claim 1 , wherein the compound has the formula:

15 . The method of claim 1 , wherein the compound has the formula:

16 . The method of claim 1 , wherein the compound has the formula:

17 . The method of claim 1 , wherein the compound has the formula:

18 . The method of claim 1 , wherein the compound has the formula:

19 . The method of claim 1 , wherein the compound has the formula:

20 . The method of claim 1 , wherein the compound has the formula:

21 . The method of claim 1 , wherein the compound has the formula:

22 . The method of claim 1 , wherein the compound has the formula:

23 . The method of claim 1 , wherein the compound has the formula:

24 . The method of claim 1 , wherein the compound is selected from the group consisting of:

Structure

Reference

Structure

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX

25 . The method of claim 1 , wherein the subject is a human.

26 . The method of claim 1 , wherein the compound is administered to the subject 24 hours or less prior to exposure to the cytotoxic compound.

27 . The method of claim 1 , wherein the subject has cancer.

28 . The method of claim 1 , wherein the subject has an abnormal cell proliferation.

29 . The method of claim 1 , wherein the cancer or abnormal cell proliferation is characterized by a loss or absence of retinoblastoma tumor suppressor protein (RB).

30 . The method of claim 1 , wherein the cancer is small cell lung cancer, retinoblastoma, triple negative breast cancer, human papillomavirus (HPV) positive head and neck cancer, or HPV positive cervical cancer.

31 . The method of claim 1 , wherein the chemotherapy is selected from an alkylating agent, DNA intercalator, protein synthesis inhibitor, inhibitor of DNA or RNA synthesis, DNA base analog, topoisomerase inhibitor, telomerase inhibitor or telomeric DNA binding compound.

32 . The method of claim 1 , wherein the cancer is small cell lung carcinoma and the chemotherapy is selected from the group consisting of etoposide, cisplatin, and carboplatin, or a combination thereof.

33 . The method of claim 1 , wherein at least 80% or more of the HSPCs re-enter the cell cycle in less than 36 hours from the last administration of the compound.

34 . The method of claim 1 , wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

35 . The method of claim 1 , wherein the healthy cells are renal epithelial cells.

36 . A method of treating an Rb-negative cancer or abnormal cell proliferation in a subject with combination therapy, comprising administering to the subject an effective amount of a combination of chemotherapy and a compound selected from the group consisting of Formula I, II, III, IV, or V:

wherein:

Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;

each X is independently CH or N;

each X′ is independently CH or N;

X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;

R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

y is 0, 1, 2, 3 or 4;

R 3 and R 4 at each occurrence are independently:

(i) hydrogen or

R 5 and R 5 * at each occurrence is:

(i) hydrogen or

n is 0, 1 or 2, and

m is 0, 1 or 2;

R 3 * and R 4 * at each occurrence are independently:

(i) hydrogen or

R 10 is 1 (i) NHR A , wherein R A is unsubstituted or substituted C 1 -C 8 alkyl, cycloalkylalkyl, or -TT-RR, C 1 -C 8 cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C 1 -C 6 alkoxy, amino, unsubstituted or substituted C 1 -C 6 alkylamino, unsubstituted or substituted di-C 1 -C 6 alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R 12 or —C(O)O—R 13 , wherein R 12 is NHR A or R A and R 13 is R A ;

when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present and are as defined above;

when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present and are as defined above;

or a pharmaceutically acceptable salt thereof.

37 . The method of claim 36 , wherein the compound is selected from the group consisting of:

Structure

Reference

Structure

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX

38 . A method of reducing the effect of chemotherapy on healthy cells in a subject being treated for cyclin-dependent kinase 4/6 (CDK4/6) replication independent cancer or abnormal cell proliferation, wherein said healthy cells are hematopoietic stem cells, hematopoietic progenitor cells, or renal epithelial cells, the method comprising administering to the subject, an effective amount of an compound selected from the group consisting of Formula VI:

wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , Z, m, n, and y are as defined in claim 1 ;

each R 14 is independently H, C 1 -C 3 alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

or two R 14 groups bonded to the same carbon can form an exocyclic double bond;

or two R 14 groups bonded to the same carbon can form a carbonyl group; and

when the compound of Formula VI has a double bond, as indicated by the ( - - - - ), in the 6-membered ring fused to the pyrimidine ring, two R 14 groups are present as allowed for in Formula VI above; or

when the compound of Formula VI does not include a double bond, as indicated by the ( - - - - ), in the 6-membered ring fused to the pyrimidine ring, four R 14 groups are present as allowed for in Formula VI above;

or a pharmaceutically acceptable salt thereof.

39 . The method of claim 1 , wherein the compound is selected from the group consisting of:

XXX

ZZZ

BBBB

DDDD

EEEE

or a pharmaceutically acceptable salt thereof.

40 . The method of claim 38 , wherein the compound is selected from the group consisting of:

YYY

AAAA

CCCC

FFFF

GGGG

HHHH

or a pharmaceutically acceptable salt thereof.

41 . A method of reducing the effect of chemotherapy on healthy cells in a subject being treated for cyclin-dependent kinase 4/6 (CDK4/6) replication independent cancer or abnormal cell proliferation, wherein said healthy cells are hematopoietic stem cells, hematopoietic progenitor cells, or renal epithelial cells, the method comprising administering to the subject, an effective amount of an compound selected from the group consisting of Formula I, II, III, IV, or V:

wherein:

Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;

each X is independently CH or N;

each X′ is independently CH or N;

X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;

R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

y is 0, 1, 2, 3 or 4;

R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1, or 2 and n is 0, 1 or 2;

wherein heterocyclo may be optionally independently substituted with 1 to 3 R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;

R 3 and R 4 at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;

R 5 and R 5 * at each occurrence is:

(i) hydrogen or

R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 , -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:

-(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, and

wherein heterocycle may be further independently substituted with one to three substitutions selected from

n is 0, 1 or 2, and

m is 0, 1; or 2 and

R 3 * and R 4 * at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance;

R 6 is H, absent, or lower alkyl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 ,

-(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring; and

when the compound of Formula I, II, III, IV, or V has a double bond, as indicated by the ( - - - - ), in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present as allowed for in Formula I, II, III, IV, or V above; or

when the compound of Formula I, II, III, IV, or V does not include a double bond, as indicated by the ( - - - - ), in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present as allowed for in Formula I, II, III, IV, or V above;

wherein each heteroaryl is an aryl ring system that contains one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized;

wherein each aryl is a carbocyclic aromatic system containing one or two rings, wherein such rings may be attached together in a fused manner, and wherein each aryl may have 1 or more R x substituents;

wherein each heterocyclo is a saturated or partially saturated heteroatom-containing ring radical, where the heteroatoms may be selected from nitrogen, sulfur and oxygen, wherein each heterocyclo is a monocyclic 6-8 membered ring or a 5-16 membered bicyclic ring system, and wherein each heterocyclo may have 1 to 3 R x substituents;

or a pharmaceutically acceptable salt thereof.

42 . A method of reducing the effect of chemotherapy on healthy cells in a subject being treated for cyclin-dependent kinase 4/6 (CDK4/6) replication independent cancer or abnormal cell proliferation, wherein said healthy cells are hematopoietic stem cells, hematopoietic progenitor cells, or renal epithelial cells, the method comprising administering to the subject, an effective amount of an compound selected from the group consisting of Formula VI:

wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , Z, m, n, and y are as defined in claim 41 ;

each R 14 is independently H, C 1 -C 3 alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

or two R 14 groups bonded to the same carbon can form an exocyclic double bond;

or two R 14 groups bonded to the same carbon can form a carbonyl group; and

or a pharmaceutically acceptable salt thereof.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 10, 2016

From: GASTON, RICKY D.; GADWOOD, ROBERT C.

To: KALEXSYN, INC.

Reel/Frame 039396/0682 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 10, 2016

From: STRUM, JAY COPELAND; BISI, JOHN EMERSON; ROBERTS, PATRICK JOSEPH

To: G1 THERAPEUTICS, INC.

Reel/Frame 039396/0958 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 10, 2016

From: KALEXSYN, INC.

To: G1 THERAPEUTICS, INC.

Reel/Frame 039397/0287 →