# US 2020/0399274 A1 · Tetrazole-substituted pyrazolopyrimidine inhibitors of jak kinases and uses thereof

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- Number: US 2020/0399274 A1
- Document ID: US20200399274A1
- Status: Published application
- Kind: A1
- Application number: 16/902,490
- Filed: 2020-06-16
- Published: 2020-12-24
- Earliest claimed: 2019-06-18
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Mark Edward Zak; Naomi S. Rajapaksa; Yun-Xing Cheng; Jessica Grandner; Daniel G.M. Shore; F. Anthony Romero; Marian C. Bryan
- Web page: https://patentgrep.com/patent/US20200399274A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles}
- A61K 9/16: Agglomerates; Granulates; Microbeadlets {; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction (A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A61P 11/06: Antiasthmatics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I) wherein R1, R2, R3, R4, R5 and R6 are as defined herein, and salts thereof, that are useful as JAK kinase inhibitors are described herein. Also provided are pharmaceutical compositions that include such a JAK inhibitor and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.

## Claims

### Claim 1

A compound of Formula (I)
or a stereoismer or pharmaceutically acceptable salt thereof,
wherein:
R1 is: hydroxyl-C1-C6alkyl; —(CRa1Ra2)m-het1; —(CRa1Ra2)nNRbRc; or —(CRa1Ra2)m—C3-6 cycloalkyl wherein the C3-6cycloalkyl moiety is substituted once with Rd;
R2 is: halo; halo C1-C6alkoxy; C1-C6alkylthio; —SF2; or C3-C6cycloalkyl;
R3 is: hydrogen; or C1-C6alkyl;
R4 is: hydrogen; or C1-C6alkyl;
R5 is: hydrogen; or C1-C6alkyl;
R6 is: hydrogen; or C1-C6alkyl;
or R2 and R6 together with the atoms to which they are attached may form a six-membered ring containing two heteroatoms each independently selected from O, N and S;
m is from 0 to 2;
n is from 0 to 3;
each Ra1 is independently: hydrogen; or C1-C6alkyl;
each Ra2 is independently: hydrogen; halo; or C1-C6alkyl;
Rb is: hydrogen; or C1-C6alkyl;
Rc is: hydrogen; C1-C6alkyl; an amino protecting group; or azetidinyl which may be unsubstituted or substituted once with C1-C6alkyl;
het1 is a heterocyclyl selected from: azetidinyl; pyrrolidinyl; piperazinyl; piperidinyl; morpholinyl; and oxetanyl; each of which may be unsubstituted or substituted once with Rd and once or twice with Rg;
Rd is: —(CRa1Ra2)p-het2; —(CRa1Ra2)q—NReRf; or —(CRa1Ra2)p—C3-6cycloalkyl wherein the C3-6cycloalkyl moiety is substituted once with —NReRf;
p is from 0 to 2;
q is from 0 to 4;
Re is: hydrogen; or C1-C6alkyl;
Rf is: hydrogen; C1-C6alkyl; or —CH2C2N(CH3)2;
each Rg is: C1-C6alkyl; or halo; and
Het2 is a heterocycle selected from: tetrahydropyranyl; azetidinyl; and pyrrolidinyl; each of which may be unsubstituted or substituted once with C1-C6alkyl or —NReRf.

### Claim 2 (depends on 1)

The compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R1 is —(CHRa)m-het1; or —(CHRa)n—NRbRc, wherein the het1 may be unsubstituted or substituted once with Rd.

### Claim 3 (depends on 1)

The compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R2 is: chloro; difluoromethoxy; methylethio; or cyclopropyl.

### Claim 4 (depends on 1)

The compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R3, R4, R5, R6 and Ra are hydrogen.

### Claim 5 (depends on 1)

The compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R2 and R6 together with the atoms to which they are attached form a six-membered ring containing two heteroatoms each independently selected from O, N and S.

### Claim 6 (depends on 1)

The compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein het1 is azetidinyl, which may be unsubstituted or substituted once with Rd.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R is selected from:
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is of formula (II)
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound is of formula (IV)
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein X is —O— or —S—, and Rg is hydrogen or C1-C6alkyl.

### Claim 10 (depends on 1)

A method of preventing, treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein the disease or condition is cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation (e.g., transplant rejection), immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, CNS disorders or a myeloproliferative disorder.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises microparticles of the compound suitable for inhaled delivery.

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12, wherein the microparticles are prepared by spray-drying, freeze-drying or micronisation.

### Claim 14 (depends on 1)

A kit comprising:
(a) a first pharmaceutical composition comprising a compound of claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof; and
(b) instructions for use.

### Claim 15 (depends on 14)

The kit of claim 14, further comprising a second pharmaceutical composition comprising an agent for treatment of an inflammatory disorder, or a chemotherapeutic agent.