# US 2013/0158018 A1 · Heteroaryl Nitrile Compounds Useful as Inhibitors of Cathepsin-S

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2013/0158018 A1
- Document ID: US20130158018A1
- Status: Published application
- Kind: A1
- Application number: 13/581,829
- Filed: 2011-03-02
- Published: 2013-06-20
- Earliest claimed: 2010-03-05
- Assignees: Boehringer Ingelheim International GmbH
- Inventors: Michael J. Burke; Derek Cogan; Donghong Amy Gao; Alexander Heim-Riether; Eugene Richard Hickey; Matthew Russell Netherton; Philip Dean Ramsden; David Charles Thompson; Zhaoming Xiong
- Web page: https://patentgrep.com/patent/US20130158018A1

## CPC

- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- A61P 17/00: Drugs for dermatological disorders
- 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 37/00: Drugs for immunological or allergic disorders
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are Cathepsin-S reversible inhibitor compounds of the formula (I) which are useful in the treatment of autoimmune and other diseases. Also disclosed are pharmaceutical compositions containing the same, and methods of making and using the same.

## Claims

### Claim 1

A compound of the formula (I):
wherein the
ring is chosen from:
each optionally substituted by C1-3 alkyl;
R1 is C1-7alkyl, C3-7cycloalkyl, aryl, heterocyclyl or heteroaryl each optionally substituted by one or more Rc;
R2 is hydrogen or C1-7alkyl;
or R1 and R2 taken together form a C3-7cycloalkyl or C3-7heterocyclyl ring optionally substituted by one or more halogen or C1-7alkyl;
R3 is —C(O)C1-7alkyl, —C(O)C3-7cycloalkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)heterocyclyl, —C(O)NRaRb, —C(O)ORa, —CH(Rf)-heteroaryl, —CH(Rf)-aryl, —CH(Rf)-heterocyclyl, aryl, C3-7cycloalkyl or heteroaryl, each ring is optionally substituted by one or more Rd;
R4 and R5 are each independently hydrogen, C1-7alkyl, aryl, or heteroaryl, or
R4 and R5 taken together may form a C3-7cycloalkyl or C3-7 heterocyclyl ring each ring being optionally substituted by C1-5alkyl;
Ra, Rb each independently are hydrogen, C1-7alkyl, aryl or heteroaryl, or may be taken together to form a saturated or unsaturated C3-7cycloalkyl or C3-7 heterocyclyl ring;
Rc is C1-7alkyl, C1-7alkoxy, C3-7cycloalkyl, aryl, benzyl, halogen or —C(O)—O-benzyl;
Rd each is independently chosen from C1-7alkyl, C1-7alkoxy, C1-7acyl, —C(O)NRaRb, —NH—C(O)—C1-7alkyl, halogen, —CN, —S(O)m—Re, —NH—S(O)m—Re;
Re is chosen from C1-7alkyl and amino;
Rf each is independently chosen from hydrogen or C1-7alkyl;
m is 0-2;
wherein one or more hydrogens on any one or more of R1, R2, R3, R2, R4, R5, Ra, Rb Rc, Rd, Re, Rf or
may be replaced by a halogen or deuterium atom;
with the proviso that
when
is (i), and
neither R1 nor R2 is hydrogen, and
R3 is —C(O)C1-7alkyl, —C(O)C3-7cycloalkyl, —C(O)aryl, —C(O)heteroaryl, —C(O)heterocyclyl, —CH(Rf)-heteroaryl, —CH(Rf)-aryl, —CH(Rf)-heterocyclyl, aryl, C3-7cycloalkyl or heteroaryl
then R4 and R5 must either both be hydrogen or they must form a ring.
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of the formula (I) according claim 1 and wherein
R2=hydrogen or C1-7alkyl if
a)
is (i), or
b) R4 and R5 are hydrogen, or
c) R4 and R5 form a ring, or
d) R3 is —C(O)NRaRb or —C(O)ORa,
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of the formula (I) according claim 2 and wherein
R1 is C1-7alkyl, C3-7cycloalkyl, cyclohexyl-D11, phenyl, oxiranyl, azepanyl, diazepanyl, azetidinyl, pyrrolidinyl, pyrrolinyl, thiomorpholinyl, dioxalanyl, piperazinyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxo-hexahydro-1λ6-thiopyranyl, 1-oxo-hexahydro-1λ4-thiopyranyl, aziridinyl, thiadiazolyl, tetrazolyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl, purinyl, benzofuranyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, furanyl, pyrazolyl and pyridinyl, each optionally substituted by an Rc;
R2 is hydrogen or C1-5alkyl;
or R1 and R2 taken together form a C3-7cycloalkyl;
R3=—C(O)C1-7alkyl, —C(O)C3-6cycloalkyl, —C(O)phenyl, —C(O)heterocyclyl wherein the heterocyclyl is chosen from oxiranyl, azepanyl, diazepanyl, azetidinyl, pyrrolidinyl, pyrrolinyl, thiomorpholinyl, dioxalanyl, piperazinyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, —C(O)heteroaryl wherein the heteroaryl is chosen from benzofuranyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, furanyl, pyrazolyl and pyridinyl,
—C(O)NH-phenyl, heterocyclyl chosen from oxiranyl, azepanyl, diazepanyl, azetidinyl, pyrrolidinyl, pyrrolinyl, thiomorpholinyl, dioxalanyl, piperazinyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, piperidinyl, tetrahydropyranyl 1,1-Dioxo-1λ6-thiomorpholine, tetrahydrofuranyl, 1,1-dioxo-hexahydro-1λ6-thiopyranyl, piperidinyl and 2-oxo-imidazolidinyl, phenyl, C3-7cycloalkyl, —CH2-2-oxo-imidazolidinyl and —CH(Rf)-heteroaryl wherein the heteroaryl is chosen from thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, furanyl, pyrazolyl and pyridinyl, each ring is optionally substituted by one or more Rd;
R4 and R5 are each independently hydrogen or C1-7alkyl, or
R4 and R5 taken together may form a C3-6cycloalkyl, oxiranyl, azepanyl, diazepanyl, azetidinyl, pyrrolidinyl, pyrrolinyl, thiomorpholinyl, dioxalanyl, piperazinyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl, tetrahydropyrimidonyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, piperidinyl or tetrahydropyranyl each ring being optionally substituted by C1-3alkyl;
Ra, Rb are each independently hydrogen, C1-5alkyl or phenyl;
Rc is C1-5alkyl, C1-5alkoxy, C3-6cycloalkyl, phenyl, benzyl, fluoro or —C(O)—O-benzyl;
Rd is independently chosen from C1-5alkyl, C1-5alkoxy, C1-5acyl, —C(O)NRaRb, —NH—C(O)—C1-5alkyl, halogen, —CN, —S(O)2—Re, —NH—S(O)2—Re;
Re is chosen from C1-5alkyl and amino;
Rf is independently chosen from hydrogen and C1-5alkyl;
wherein one or more hydrogens on any one or more of R1, R2, R3, R2, R4, R5, Ra, Rb, Rc, Rd, Re, Rf or
may be replaced by a halogen or deuterium atom;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The compound of the formula (I) according claim 3 and wherein
R1 is t-butyl, sec-butyl, 3-pentyl, cyclohexyl, —CH2-cyclohexyl, cyclopentyl, cyclopropyl, phenyl, cyclohexyl-D11, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxo-hexahydro-1λ6-thiopyranyl or 1-oxo-hexahydro-1λ4-thiopyranyl, each optionally substituted by an Rc;
R2 is hydrogen or methyl;
or R1 and R2 taken together form a cyclohexyl;
R3 is —C(O)C1-7alkyl, —C(O)cyclopropyl, —C(O)cyclopentyl, —C(O)phenyl, —C(O)heterocyclyl wherein the heterocyclyl is chosen from morpholinyl, piperidinyl, tetrahydrofuranyl and tetrahydropyranyl, —C(O)heteroaryl wherein the heteroaryl is chosen from benzofuranyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, furanyl, pyrazolyl and pyridinyl,
—C(O)NH-phenyl, heterocyclyl chosen from 1,1-Dioxo-1λ6-thiomorpholine, tetrahydrofuranyl, 1,1-dioxo-hexahydro-1λ6-thiopyranyl, piperidinyl and 2-oxo-imidazolidinyl, phenyl, cyclohexyl and —CH2-thienyl;
R4 and R5 are each independently hydrogen, methyl or n-butyl or
R4 and R5 taken together may form cyclopropyl, piperidinyl, tetrahydropyranyl or 1-methyl-piperidinyl;
Ra, Rb are each independently hydrogen, methyl or phenyl;
Rc is methyl, methoxy, cyclohexyl, phenyl, benzyl, fluoro or —C(O)—O-benzyl;
Rd is independently chosen from methyl, —CF3, —CH2CF3, methoxy, acetyl, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2, —NH—C(O)-methyl, —S(O)2—CH3, —S(O)2—NH2, —NH—S(O)2—CH3, F, Cl and —CN;
Rf is independently chosen from hydrogen, methyl and CF3;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The compound of the formula (I) according claim 4 and wherein
wherein the
ring is chosen from:
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The compound of the formula (I) according claim 5 and wherein
wherein the
ring is
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 5)

The compound of the formula (I) according claim 5 and wherein
wherein the
ring is
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 5)

The compound of the formula (I) according claim 5 and wherein
wherein the
ring is:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 5)

The compound of the formula (I) according claim 5 and wherein
R1 is cyclohexyl, —CH2-cyclohexyl, 4,4-difluorocyclohexyl, 3-methoxycyclohexyl, 4-methylcyclohexyl, 4-trifluoromethylcyclohexyl, cyclohexyl-D11, cyclopentyl, 3-pentyl, sec-butyl, tetrahydropyranyl, or tetrahydrothiopyranyl;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The compound of the formula (I) according claim 9 and wherein
R2 is hydrogen or methyl;
or R1 and R2 taken together form a cyclohexyl;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The compound of the formula (I) according claim 10 and wherein
R3 is —C(O)cyclopropyl, —C(O)phenyl, —C(O)heterocyclyl wherein the heterocyclyl is chosen from morpholinyl and piperidinyl, —C(O)heteroaryl wherein the heteroaryl is chosen from imidazo[2,1-b]thiazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thienyl, furanyl, pyrazolyl and pyridinyl,
or R3 is
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The compound of the formula (I) according claim 11 and wherein
R4 and R5 are each independently hydrogen, methyl or n-butyl or
R4 and R5 taken together may form cyclopropyl, piperidinyl, or tetrahydropyranyl;
or a pharmaceutically acceptable salt thereof.

### Claim 13

A compound chosen from
or the pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and one or more pharmaceutically acceptable carriers and/or adjuvants.

### Claim 15 (depends on 1)

A method of treating a disease or condition chosen from rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, Guillain-Barre syndrome, psoriasis, Grave's disease, myasthenia gravis, scleroderma, glomerulonephritis, dermatitis including contact and atopic dermatitis, insulin-dependent diabetes mellitus, endometriosis, chronic obstructive pulmonary disease, asthma, Alzheimer's disease and atherosclerosis comprising administering to a patient in need of such treatment a pharmaceutically effect amount of a compound according to claim 1.