# US 10,246,450 B2 · Modulators of calcium release-activated calcium channel

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- Number: US 10,246,450 B2
- Document ID: US10246450B2
- Status: Granted
- Kind: B2
- Application number: 15/892,229
- Filed: 2018-02-08
- Published: 2018-08-09
- Granted: 2019-04-02
- Earliest claimed: 2009-10-08
- Assignees: Rhizen Pharmaceuticals SA
- Applicants: Rhizen Pharmaceuticals SA
- Inventors: Meyyappan Muthuppalaniappan; Srikant Viswanadha; Gayatri S. Merikapudi; Swaroop K. Vakkalanka
- Web page: https://patentgrep.com/patent/US10246450B2

## CPC

- A61K 31/433: Thidiazoles
- A61K 31/415: 1,2-Diazoles
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/455: Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 207/327: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 207/337: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 295/195: Radicals derived from nitrogen analogues of carboxylic acids
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C12N 5/0634: {Cells from the blood or the immune system}
- C12N 2500/46: Amines, e.g. putrescine
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer.

## Claims

### Claim 1

A method of treating an autoimmune disorder comprising the step of administering to a subject in need thereof an effective amount of a compound of formula
or a pharmaceutically acceptable salt thereof, wherein
Ring Hy represents
optionally substituted with R′″;
R1 and R2 are the same or different and are independently selected from CH3, CH2F, CHF2, CF3, substituted or unsubstituted C(3-5)cycloalkyl, CH2—ORa, CH2—NRaRb, CN and COOH with the proviso that:
a) both R1 and R2 at the same time do not represent CF3,
b) both R1 and R2 at the same time do not represent CH3,
c) when R1 is CF3 then R2 is not CH3; and
d) when R1 is CH3 then R2 is not CF3;
Ring Ar represents:
L1 and L2 together represent NH—C(═O)—;
A is absent;
R′″ is selected from hydrogen, hydroxy, cyano, halogen, —ORa, —COORa, —S(═O)q—Ra, —NRaRb, C(═X)—Ra, substituted or unsubstituted C(1-6) alkyl group, substituted or unsubstituted C(1-6) alkenyl, substituted or unsubstituted C(1-6) alkynyl, and substituted or unsubstituted C(3-5)cycloalkyl;
each occurrence of X is independently selected from O, S and —NRa;
Cy is selected from monocyclic substituted or unsubstituted cycloalkyl group, monocyclic substituted or unsubstituted aryl; and substituted or unsubstituted pyridyl;
each occurrence of Ra and Rb are the same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, —ORc, —S(═O)q—Rc, —NRcRd, —C(═Y)—Rc, —CRcRd—C(═Y)—Rc, —CRcRd—Y—CRcRd—, —C(═Y)—NRcRd—, —NRRd—C(═Y)—NRcRd—, —S(═O)q—NRcRd—, —NRcRd—S(═O)q—NRcRd—, —NRcRd—NRcRd—, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocylyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, or when Ra and Rb are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRc and S;
each occurrence of Rc and Rd may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or when two Rc and/or Rd substitutents are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which are the same or different and are selected from O, NH and S;
each occurrence of Y is selected from O, S and —NRa; and
each occurrence of q independently represents 0, 1 or 2;
wherein the autoimmune disorder is chronic obstructive pulmonary disease, inflammatory bowel disease, allergic rhinitis, multiple sclerosis, psoriasis, Crohn's disease, colitis, ulcerative colitis, arthritis, bone diseases associated with increased bone resorption, or chronic obstructive airway disease.

### Claim 2 (depends on 1)

The method of claim 1, wherein the autoimmune disorder is multiple sclerosis, chronic obstructive pulmonary disease, chronic obstructive airway disease, or psoriasis.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 2)

The method of claim 2, wherein the subject is a human subject.

### Claim 5

A method of modulating store-operated calcium (SOC) channel activity comprising contacting the SOC channel complex, or portion thereof, with a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 6

A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 7

A method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 8

A method of decreasing cytokine release by inhibiting the SOCE activation of NFAT in a mammal comprising administering to the mammal a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 9

A method of inhibiting immune cell activation comprising administering to an immune cell a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 10

A method of inhibiting T-cell and/or B-cell proliferation in response to an antigen, comprising administering to a T-cell and/or B-cell cell a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 11

A method of inhibiting cytokine production in a cell comprising administering to the cell a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The method of claim 11, wherein the cytokine is selected from IL-2, IL-4, IL-5, IL-13, GM-CSF, IFN-γ, TNFα, and combinations thereof.

### Claim 13

A method of modulating an ion channel in a cell, wherein the ion channel is involved in immune cell activation, comprising administering to the cell a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the ion channel is a Ca2+-release-activated Ca2+ channel (CRAC).

### Claim 15

A method of reducing an inflammation in a subject in need thereof comprising administering to the subject an effective amount of a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 16

A method of treating an autoimmune disorder comprising the step of administering to a subject in need thereof an effective amount of a compound N-{6-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}-3-fluoroisonicotinamide or a pharmaceutically acceptable salt thereof, wherein the autoimmune disorder is chronic obstructive pulmonary disease, inflammatory bowel disease, allergic rhinitis, asthma, multiple sclerosis, psoriasis, Crohn's disease, colitis, ulcerative colitis, arthritis, bone diseases associated with increased bone resorption, or chronic obstructive airway disease.

### Claim 17 (depends on 16)

The method of claim 16, wherein the autoimmune disorder is multiple sclerosis, asthma, chronic obstructive pulmonary disease, chronic obstructive airway disease, or psoriasis.

### Claim 18 (depends on 16)

The method of claim 16, wherein the subject is a human subject.

### Claim 19 (depends on 17)

The method of claim 17, wherein the subject is a human subject.