# US 2016/0257671 A2 · Ship1 modulators and methods related thereto

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- Number: US 2016/0257671 A2
- Document ID: US20160257671A2
- Status: Published application
- Kind: A2
- Application number: 14/759,622
- Filed: 2014-01-07
- Published: 2016-09-08
- Earliest claimed: 2013-01-09
- Assignees: Aquinox Pharmaceuticals (Canada) Inc.
- Applicants: Aquinox Pharmaceuticals (Canada) Inc.
- Inventors: Lloyd F. MACKENZIE; Thomas B. MACRURY; Curtis HARWIG; David BOGUCKI; Jeffery R. RAYMOND; Jeremy D. PETTIGREW; Vladimir KHLEBNIKOV; Rudong SHAN
- Web page: https://patentgrep.com/patent/US20160257671A2

## CPC

- A61K 31/4965: Non-condensed pyrazines
- A61K 31/085: having an ether linkage to aromatic ring nuclear carbon
- A61K 31/09: having two or more such linkages
- A61K 31/095: Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K 31/10: Sulfides; Sulfoxides; Sulfones
- A61K 31/12: Ketones
- A61K 31/122: having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/277: having a ring, e.g. verapamil
- A61K 31/4164: 1,3-Diazoles
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/443: containing a five-membered ring with oxygen as a ring hetero atom
- 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 31/4465: only substituted in position 4
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/16: Anti-Parkinson drugs
- 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 27/02: Ophthalmic agents
- 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 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 39/17: containing other rings in addition to the six-membered aromatic rings {, e.g. cyclohexylphenol}
- C07C 43/21: containing rings other than six-membered aromatic rings
- C07C 43/215: having unsaturation outside the six-membered aromatic rings
- C07C 43/23: containing hydroxy or O-metal groups
- C07C 49/83: polycyclic
- C07C 49/835: having unsaturation outside an aromatic ring
- C07C 49/84: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07C 62/32: containing hydroxy or O-metal groups
- C07C 62/34: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07C 217/84: the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
- C07C 225/20: having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
- C07C 233/26: having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
- C07C 233/28: having the carbon atom of the carboxamide group bound to an acyclic carbon atom of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
- C07C 233/31: with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C 233/32: with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
- C07C 233/60: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C 233/76: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C 235/82: with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C 237/08: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C 255/47: to carbon atoms of rings being part of condensed ring systems
- C07C 275/26: having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C 275/64: having nitrogen atoms of urea groups singly-bound to oxygen atoms
- C07C 279/16: having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C 311/07: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C 311/17: to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C 311/18: to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C 317/22: with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C 323/20: with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07D 211/66: having a hetero atom as the second substituent in position 4
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 213/81: Amides; Imides
- C07D 213/82: in position 3
- C07D 213/89: with hetero atoms directly attached to the ring nitrogen atom
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 241/24: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 295/112: with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 295/215: Radicals derived from nitrogen analogues of carbonic acid
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07B 2200/07: Optical isomers
- C07C 2602/28: Hydrogenated naphthalenes
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Compounds of formula (I): where n, R1, R4a, R4b, R5, R7 and R8 are defined herein, or pharmaceutically acceptable salts thereof, are described herein. The disclosed compounds have activity as SHIP1 modulators, and thus may be used to treat any of a variety of diseases, disorders or conditions that would benefit from SHIP1 modulation. Compositions comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or diluent are also disclosed, as are methods of SHIP1 modulation by administration of such compounds to an animal in need thereof.

## Claims

### Claim 1

A compound of formula (I):
wherein:
is selected from:
n is 1, 2, 3, 4, 5, or 6;
R1 is —R9a—C(R10)2—R9b—, —R9a—C(O)—R9b—, —R9a—S(O)t—R9b— (where t is 0, 1 or 2), —R9a—O—R9b—, —R9a—C(O)N(R11a)—R9b—, —R9a—N(R11a)C(O)—R9b— or —R9a—N(R11a)—R9b—;
R2 and R3 are each independently selected from hydrogen, alkyl or —R9—OR11, provided that at least one of R2 and R3 is —R9—OR11 when R6 is hydrogen;
R4a and R4b are each independently selected from hydrogen, alkyl, —R9—OR11 or —C(O)OR11,
or R4a is selected from hydrogen, alkyl, —R9—OR11, or —C(O)OR11 and R4b is a direct bond to the carbon at numeral 1 or a direct bond to the carbon at numeral 3;
R5 is independently selected from hydrogen, oxo, cyano, nitro, halo, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R9—OR11, —R9—C(O)R11, —R9—C(O)OR11, —R9—N(R11)R12, —R9—C(O)N(R11)R12, —R9—N(R11)C(O)R12, —R9—N(R11)—R14—N(R11)R12, —R9—N(R11)C(O)—R9—N(R11)R12, —R9—N(R11)C(O)N(R11)—OR12, —R9—N(R11)C(═NR11)N(R11)R12, —R9—N(R11)S(O)pR11 (where p is 1 or 2), —R9—N(R11)C(S)N(R11)R12 or —R9—N(R11)C(O)—R9—N(R11)S(O)pR12 (where p is 1 or 2);
each R6 and R8 is independently selected from hydrogen, alkyl, halo or haloalkyl;
R7 is hydrogen, alkyl, halo or haloalkyl;
each R9, R9a and R9b is independently a direct bond or a straight or branched alkylene chain;
each R10 is independently hydrogen, alkyl, —OR11, —C(O)OR11, —C(O)N(R11)R12, —N(R11)R12 or —N(R11)C(O)R11;
each R11, R11a and R12 is independently hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and
R14 is a straight or branched alkylene chain;
or a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
provided that compounds of formula (I) do not include the following compounds:
(1 S,2S,4aS,8aR)-decahydro-1-[2-(3-methoxyphenyl)ethyl]-5,5,8a-trimethyl-2-naphthalenecarboxylic acid;
(1 S,2S,4aS,8aR)-decahydro-1-[2-(3-methoxyphenyl)ethyl]-5,5,8a-trimethyl-2-naphthalenemethanol;
α-(3,5-dimethoxyphenyl)decahydro-2-hydroxy-2,5,5,8a-tetramethyl-1-naphthalenemethanol;
(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-α-(3-methoxy-5-methylphenyl)-2,5,5,8a-tetramethyl-1-naphthalenemethanol;
(1 S,2R,4aS,8aS)-decahydro-2-hydroxy-α-(3-methoxy-5-methylphenyl)-2,5,5,8a-tetramethyl-1-naphthalenemethanol;
(1R,2R,4aS,8aS)-decahydro-1-[(3-methoxy-5-methylphenyl)methyl]-2,5,5,8a-tetramethyl-2-naphthalenol;
(1S,2R,4aS,8aS)-1-(3-methoxy-5-methylphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol;
(1S,2R,4aS,8aS)-1-(3,5-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol;
(1S,2R,4aS,8aS)-1-[3,5-bis(propan-2-yloxy)phenoxymethyl]-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol;
(1R,2R,8aS)-1-((3,5-dimethoxyphenylsulfonyl)methyl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol;
(1R,2R,4aS,8aS)-1-{[(3-methoxy-5-methylphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol;
(1R,2R,4aS,8aS)-1-{[(3-methoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol; and
(1R,2R, 4aS,8aS)-1-{[(3,5-dimethoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol.

### Claim 2 (depends on 1)

The compound of claim 1 having the formula (Ia):
wherein n, R1, R2, R3, R4a, R4b, R5, R6, R7 and R8 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1, 2)

The compound of claim 2 where R1 is —R9a—C(O)—R9b—, i.e., a compound of formula (Ia1):
wherein R9a and R9b are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1, 2)

The compound of claim 2 wherein R1 is —R9a—C(R10)2—R9b—, i.e., the compound of formula (Ia2):
wherein R9a, R9b and R10 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1, 2)

The compound of claim 2, wherein R1 is —R9—S(O)t—R9—, i.e., a compound of formula (Ia3):
wherein t, R9a, R9b are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1, 2)

The compound of claim 2, wherein R1 is —R9a—O—R9b—, i.e., a compound of formula (Ia4):
wherein R9a, R9b are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1, 2)

The compound of claim 2, wherein R1 is —R9a—C(O)N(R11a)—R9b—, i.e., a compound of formula (Ia5):
wherein R9a, R9b and R11a are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1, 2)

The compound of claim 2 where R1 is —R9a—N(R11a)C(O)—R9b—, i.e., a compound of formula (Ia6):
wherein R9a, R9b and R11a are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1, 2)

The compound of claim 2 wherein R1 is —R9a—N(R11a)—R9b—,
i.e., a compound of formula (Ia7):
wherein R9a, R9b and R11a are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1 having the formula (Ic):
wherein n, R1, R4a, R4b, R5, R6, R7 and R8 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1, 10)

The compound of claim 10 wherein R1 is —R9a—N(R11a)C(O)—R9b—, i.e., a compound of formula (Ic1):
wherein R9a, R9b and R11a are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1 having the formula (Id):
wherein n, R1, R4a, R4b, R5, R6, R7 and R8 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1, 12)

The compound of claim 12 wherein R1 is —R9a—C(R10)2—R9b—, i.e., a compound of formula (Id1):
wherein R9a, R9b and R10 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The compound of claim 1 having the formula (Ie):
wherein n, R1, R4a, R4b, R5, R6, R7 and R8 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1, 14)

The compound of claim 14 wherein R1 is —R9a—C(R10)2—R9b—, i.e., a compound of formula (lei):
wherein R9a, R9b and R10 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound of claim 1 having the formula (If):
wherein n, R1, R4a, R4b, R5, R6, R7 and R8 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1, 16)

The compound of claim 16 wherein R1 is —R9a—C(R10)2—R9b—, i.e., a compound of formula (If1):
wherein R9a, R9b and R10 are as defined above in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The compound of claim 1 wherein:
is selected from:
n is 1, 2, 3, 4, 5, or 6;
R1 is —R9a—C(R10)2—R9b—, —R9a—C(O)—R9b—, —R9a—S(O)t—R9b— (where t is 0, 1 or 2), —R9a—O—R9b—, or —R9a—C(O)N(R11a)—R9b— or —R9a—N(R11a)C(O)—R9b—;
R4a and R4b are each independently selected from hydrogen, alkyl, —R9—OR11 or —C(O)OR11,
or R4a is selected from hydrogen, alkyl, —R9—OR11, or —C(O)OR11 and R4b is a direct bond to the carbon at numeral 1 or a direct bond to the carbon at numeral 3;
R5 is independently selected from hydrogen, oxo, cyano, nitro, halo, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R9—OR11, —R9—C(O)R11, —R9—C(O)OR11, —R9—N(R11)R12, —R9—C(O)N(R11)R12, —R9—N(R11)C(O)R12, —R9—N(R11)—R14—N(R11)R12, —R9—N(R11)C(O)—R9—N(R11)R12, —R9—N(R11)C(O)N(R11)—OR12, —R9—N(R11)C(═NR11)N(R11)R12, —R9—N(R11)S(O)pR11 (where p is 1 or 2), —R9—N(R11)C(S)N(R11)R12 or —R9—N(R11)C(O)—R9—N(R11)S(O)pR12 (where p is 1 or 2);
each R6 and R8 is independently selected from hydrogen, alkyl, halo or haloalkyl;
R7 is hydrogen, alkyl, halo or haloalkyl;
each R9, R9a and R9b is independently a direct bond or a straight or branched alkylene chain;
each R10 is independently hydrogen, alkyl, —OR11, —C(O)OR11, —C(O)N(R11)R12, —N(R11)R12 or —N(R11)C(O)R11;
each R11, R11a and R12 is independently hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and
R14 is a straight or branched alkylene chain;
or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

### Claim 19

(canceled)

### Claim 20 (depends on 1)

A composition comprising a compound of claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 1)

A method for modulating SHIP1 activity in a mammal comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, to a mammal in need thereof.

### Claim 22 (depends on 1)

A method for treating a disease, disorder or condition in a mammal comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, to a mammal in need thereof, where the disease, disorder or condition is an autoimmune disease, disorder or condition, an inflammatory disease, disorder or condition, or a neoplastic or cell proliferative disease, disorder or condition.