# US 2019/0375753 A1 · Pyrazolo-pyrimidin-amino-cycloalkyl compounds and their therapeutic uses

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- Number: US 2019/0375753 A1
- Document ID: US20190375753A1
- Status: Published application
- Kind: A1
- Application number: 16/431,504
- Filed: 2019-06-04
- Published: 2019-12-12
- Earliest claimed: 2018-06-05
- Assignees: Rapt Therapeutics, Inc.
- Applicants: Rapt Therapeutics, Inc.
- Inventors: Minna H. T. Bui; Adrian O. Dukes; Xinping Han; Dennis X. Hu; Jeffrey J. Jackson; Yoo Min Ko; Paul R. Leger; Anqi Ma; Jack Maung; Andrew A. Ng; Akinori Okano; Omar Robles; Grant Shibuya; Hunter P. Shunatona; Jacob B. Schwarz; Anton A. Shakhmin; David J. Wustrow; Mikhail Zibinsky
- Web page: https://patentgrep.com/patent/US20190375753A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are pyrozolo-pyrimidin-amino-cycloalkyl compounds, analogs thereof, pharmaceutical compositions comprising thereof and therapeutic uses therefor.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
z is an integer from 0 to 6;
ring A is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
L1 and L2 are independently a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R2 is independently hydrogen, halogen, —CX23, —CHX22, —CH2X2, —OCX23, —OCHX22, —OCH2X2, —CN, —S(O)2R2A, —SR2A, —S(O)R2A, —SO2NR2AR2B, —NHC(O)NR2AR2B, —N(O)2, —NR2AR2B, NHNR2AR2B, —C(O)R2A, —C(O)—OR2A, —C(O)NR2AR2B, —C(O)NHNR2AR2B, —OR2A, —NR2ASO2R2B, —NR2AC(O)R2B, —NR2AC(O)OR2B, NR2AOR2B, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is independently halogen, —CX33, —CHX32, —CH2X3, —OCX33, —OCHX32, —OCH2X3, —CN, —S(O)2R3A, —SR3A, —S(O)R3A, —SO2NR3AR3B, —NHC(O)NR3AR3B, —N(O)2, —NR3AR3B, —NHNR3AR3B, —C(O)R3A, —C(O)—OR3A, —C(O)NR3AR3B, —P(O)R3AR3B, —C(O)NHNR3AR3B, —OR3A, —NR3ASO2R3B, —NR3AC(O)R3B, —NR3AC(O)OR3B, —NR3AOR3B, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R3 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R2A, R2B, R3A, and R3B are independently hydrogen, —F, —Cl, Br, —I, —CF3, —CHF2, —CH2F, —CCl3, —CHCl2, —CH2Cl, —CBr3, —CHBr2, —CH2Br, —CI3, —CHI2, —CH2I, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, —OCH2F, —OCH2Cl, —OCH2Br, —OCH2I, —N3, —CN, —SH, —SCH3, —SO2H, —SO2CH3, —SO2NH2, —SO2NHCH3, —NHC(O)NH2, —NHC(O)NHCH3, —NO2, —NH2, —NHCH3, —C(O)H, —C(O)CH3, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NHCH3, —OH, —OCH3, —NHSO2H, —NHSO2CH3, —NHC(O)H, —NCH3C(O)H, —NHC(O)OH, —NCH3C(O)OH, —NHOH, —NCH3OH, —NCH3OCH3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R2A and R2B may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3A and R3B may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X2 and X3 are independently halogen;
with the proviso that when ring A is cyclohexyl, then R3 is not an ortho-substituted —NH2 or —HNC═(O)t-BuO, or para-substituted —NHSO2CH2CH2CF3, —NHSO2CH3, or —OH.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R3 is not a substituted or unsubstituted amine attached to ring A at the ortho position.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R3 is not attached to ring A at the ortho position.

### Claim 4 (depends on 1)

The compound of claim 1, wherein L1 and L2 are a bond.

### Claim 5 (depends on 1)

The compound of claim 1, wherein L1 and L2 are independently substituted or unsubstituted C1-C8 alkylene or substituted or unsubstituted 2 to 8 membered heteroalkylene.

### Claim 6 (depends on 5)

The compound of claim 5, wherein L1 and L2 are independently unsubstituted C1-C8 alkylene or unsubstituted 2 to 8 membered heteroalkylene.

### Claim 7 (depends on 1)

The compound of claim 1, having the formula:
or a pharmaceutically acceptable salt thereof;
wherein:
m is an integer from 1 to 4;
R3.1 is independently hydrogen, halogen, —CX3.13, —CHX3.12, —CH2X3.1, —OCX3.13, —OCHX3.12, —OCH2X3.1, —CN, —S(O)2R3.1A, —SR3.1A, —S(O)R3.1A, —SO2NR3.1AR3.1B, —NHC(O)NR3.1AR3.1B, —N(O)2, —NR3.1AR3.1B, —NHNR3.1AR3.1B, —C(O)R3.1A, —C(O)—OR3.1A, —C(O)NR3.1AR3.1B, —P(O)R3.1AR3.1B, —C(O)NHNR3.1AR3.1B, —OR3.1A, —NR3.1ASO2R3.1B, —NR3.1AC(O)R3.1B, —NR3.1AC(O)OR3.1B, —NR3.1AOR3.1B, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.1 and R3.2 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R3.2 is independently hydrogen, halogen, —CX3.23, —CHX3.22, —CH2X3.2, —OCX3.23, —OCHX3.22, —OCH2X3.2, —CN, —S(O)2R3.2A, —SR3.2A, —S(O)R3.2A, —SO2NR3.2AR3.2B, —NHC(O)NR3.2AR3.2B, —N(O)2, —NR3.2AR3.2B, —NHNR3.2AR3.2B, C(O)R3.2A, —C(O)—OR3.2A, —C(O)NR3.2AR3.2B, —P(O)R3.2AR3.2B, —C(O)NHNR3.2AR3.2B, OR3.2A, —NR3.2ASO2R3.2B, —NR3.2AC(O)R3.2B, —NR3.2AC(O)OR3.2B, —NR3.2AOR3.2B, —N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.1 and R3.2 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
R3.1A, R3.1B, R3.2A, and R3.2B are independently hydrogen, —F, —Cl, Br, —I, —CF3, —CHF2, —CH2F, —CCl3, —CHCl2, —CH2Cl, —CBr3, —CHBr2, —CH2Br, —CI3, —CHI2, —CH2I, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, —OCH2F, —OCH2Cl, —OCH2Br, —OCH2I, —N3, —CN, —SH, —SCH3, —SO2H, —SO2CH3, —SO2NH2, —SO2NHCH3, —NHC(O)NH2, —NHC(O)NHCH3, —NO2, —NH2, —NHCH3, —C(O)H, —C(O)CH3, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NHCH3, —OH, —OCH3, —NHSO2H, —NHSO2CH3, —NHC(O)H, —NCH3C(O)H, —NHC(O)OH, —NCH3C(O)OH, —NHOH, —NCH3OH, —NCH3OCH3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R3.1A and R3.1B may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R3.2A and R.3.2B may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

### Claim 8 (depends on 7)

The compound of claim 7 having the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein:
ring A is R6-substituted or unsubstituted C4-C7 cycloalkyl, or R6-substituted or unsubstituted 4- to 7-membered heterocycloalkyl;
R6 is independently hydrogen, —F, —Cl, Br, —I, —CF3, —CHF2, —CH2F, —CCl3, —CHCl2, —CH2Cl, —CBr3, —CHBr2, —CH2Br, —CI3, —CHI2, —CH2I, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, —OCH2F, —OCH2Cl, —OCH2Br, —OCH2I, —N3, —CN, —SH, —SCH3, —SO2H, —SO2CH3, —SO2NH2, —SO2NHCH3, —NHC(O)NH2, —NHC(O)NHCH3, —NO2, —NH2, —NHCH3, —C(O)H, —C(O)CH3, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NHCH3, —OH, —OCH3, —NHSO2H, —NHSO2CH3, —NHC(O)H, —NCH3C(O)H, —NHC(O)OH, —NCH3C(O)OH, —NHOH, —NCH3OH, —NCH3OCH3, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

### Claim 10 (depends on 7)

The compound of claim 7, having the formula:
wherein:
R4 and R5 are independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted 3 to 8 membered heterocycloalkyl;
wherein R4 and R5 may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl or substituted or unsubstituted 5 or 6 membered heteroaryl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R4 and R5 are independently hydrogen or substituted or unsubstituted C1-C4 alkyl.

### Claim 12 (depends on 11)

The compound of claim 11, wherein R4 and R5 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, propan-1-ol, 2,2-difluorobutane, or 2-fluorobutane.

### Claim 13 (depends on 10)

The compound of claim 10, wherein R4 and R5 are independently hydrogen or substituted or unsubstituted 2 to 4 membered heteroalkyl.

### Claim 14 (depends on 13)

The compound of claim 13, wherein R4 and R5 are independently hydrogen, 1-methoxypropane, 1-methoxy-2-methylpropane, N,N-dimethylpropan-1-amine, 1-(methylsulfonyl)propane, (2,2-difluorobutyl)-1-oxidane, 1-(1-azaneyl)-2,2-difluoropropan-1-one, methyl(methylimino)(propyl)-6-sulfanone, or 2-methoxy-2-methylbutane.

### Claim 15 (depends on 10)

The compound of claim 10, wherein R4 and R5 are independently hydrogen or substituted or unsubstituted C3-C8 cycloalkyl.

### Claim 16 (depends on 15)

The compound of claim 15, wherein R4 and R5 are independently hydrogen, cyclobutyl or cyclopentyl.

### Claim 17 (depends on 10)

The compound of claim 10, wherein R4 and R5 are independently hydrogen, or substituted or unsubstituted C3-C7 heterocycloalkyl.

### Claim 18 (depends on 17)

The compound of claim 17, wherein R4 and R5 are independently hydrogen, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, 1,4-piperazin-2-one, piperidinyl, 1,3-imidazolidin-4-one, 1,3-imidazolidine, 6-oxa-2-azaspiro [4.5]decane, tetrahydropyranyl, 2-oxa-5,2-azabicyclo[2.2.1]heptane, (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane, 2,6-diazaspiro[3,4]octane, 4-thiomorpholine-1,1-dioxide, 4-thiomorpholine-1-oxide, tetrahydro-2H-thiopyran-1,1-oxide, 1-oxa-8-azaspiro[4,5]decane, 1-pyrrolidin-2-one, 1-imidazolidin-4-one, 2,7-diazaspiro[4.4]nolan-1-one, tetrahydro-1H-8-pyrazino[3,4-c][1,4]oxazin-4(3H)-one, or hexahydro-1H-8-pyrazino[3,4-c][1,4]oxazine.

### Claim 19 (depends on 1)

The compound of claim 1, wherein:
R1 is R7-substituted or unsubstituted C6-C10 aryl or R′-substituted or unsubstituted 5 to 10 membered heteroaryl;
R7 is independently hydrogen, —F, —Cl, Br, —I, —CF3, —CHF2, —CH2F, —CCl3, —CHCl2, —CH2Cl, —CBr3, —CHBr2, —CH2Br, —CI3, —CHI2, —CH2I, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, —OCH2F, —OCH2Cl, —OCH2Br, —OCH2I, —N3, —CN, —SH, —SCH3, —SO2H, —SO2CH3, —SO2NH2, —SO2NHCH3, —NHC(O)NH2, —NHC(O)NHCH3, —NO2, —NH2, —NHCH3, —C(O)H, —C(O)CH3, —C(O)OH, —C(O)OCH3, —C(O)NH2, —C(O)NHCH3, —OH, —OCH3, —NHSO2H, —NHSO2CH3, —NHC(O)H, —NCH3C(O)H, —NHC(O)OH, —NCH3C(O)OH, —NHOH, —NCH3OH, —NCH3OCH3
substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.

### Claim 20 (depends on 19)

The compound of claim 19, wherein:
R1 is R7A-substituted or unsubstituted phenyl or R7A-substituted or unsubstituted quinolone.

### Claim 21 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R2 is halogen or substituted or unsubstituted C1-C2-alkyl.

### Claim 22 (depends on 21)

The compound of claim 21, wherein R2 is halogen.

### Claim 23 (depends on 22)

The compound of claim 22, wherein halogen is Cl or Br.

### Claim 24 (depends on 21)

The compound of claim 21, wherein R2 is substituted or unsubstituted C1-C2-alkyl.

### Claim 25 (depends on 24)

The compound of claim 24, wherein R2 is methyl.

### Claim 26 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable excipient.

### Claim at position 27

-28. (canceled)

### Claim 29 (depends on 1)

A method of treating or preventing a disease or disorder mediated by GCN2, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula (I) of claim 1.

### Claim 30 (depends on 26)

A method of treating or preventing a disease or disorder mediated by GCN2, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 26.

### Claim 31 (depends on 29)

The method of claim 29, comprising administering a compound of Formula (II), a compound of formula (III), a compound of formula (IV), or a pharmaceutically acceptable salt thereof.

### Claim at position 31

-34. (canceled)

### Claim 35 (depends on 29)

The method of claim 29, wherein the disease or disorder is cancer.

### Claim 36 (depends on 35)

The method of claim 35, wherein the cancer is melanoma, non-small cell lung cancer, bladder cancer, pancreatic cancer, head and neck cancer or brain tumor.