# US 2012/0108505 A1 · Thiophenes as glucagon receptor antagonists, compositions, and methods for their use

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- Number: US 2012/0108505 A1
- Document ID: US20120108505A1
- Status: Published application
- Kind: A1
- Application number: 13/377,707
- Filed: 2010-06-10
- Published: 2012-05-03
- Earliest claimed: 2009-06-12
- Assignees: Schering Corporation
- Inventors: Eric J. Gilbert; Michael W. Miller; Andrew W. Stamford; William J. Greenlee
- Web page: https://patentgrep.com/patent/US20120108505A1

## CPC

- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/48: of the pancreatic hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- 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 13/12: of the kidneys
- A61P 25/02: for peripheral neuropathies
- 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
- 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

The present invention relates to compounds of the general formula (I): wherein R1, R2, R3, R5, s, and Z are selected independently of each other and are as defined herein, to compositions comprising the compounds, and methods of using the compounds as glucagon receptor antagonists and for the treatment or prevention of type 2 diabetes and conditions related thereto.

## Claims

### Claim at position 1

1-18. (canceled)

### Claim 19

A compound or pharmaceutically acceptable salt thereof, having the general structure shown in Formula (A):
wherein R1, R2, R3, R5, s, and Z are selected independently of each other and wherein:
the * shown in the N* represents a valence optionally filled by R1, R2, or H;
s is an integer from 1 to 5;
R1 is selected from the group consisting of:
(a) —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, —C(O)NR8R9, and —NR8R9;
(b) alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl,
wherein each of the alkyl, alkenyl and alkynyl portions of said alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl are unsubstituted or optionally independently substituted with one or more groups each independently selected from the group consisting of:
halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, —OC(O)NR8R9, unsubstituted alkoxy, and alkoxy substituted with one or more groups independently selected from the group consisting of halo, perhaloalkoxy, OH, and —CO2R6;
(c) —O-aryl, —S-aryl, arylalkyl-, —O-heteroaryl, —S-heteroaryl, heteroarylalkyl-, cycloalkyl, aryl-fused cycloalkyl-, cycloalkylalkyl-, —O-cycloalkyl, —S-cycloalkyl, heterocycloalkyl, aryl-fused heterocycloalkyl-, heterocycloalkylalkyl-, —O-heterocycloalkyl, —S-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —S-cycloalkenyl, heterocycloalkenyl, —O-heterocycloalkenyl, and —S-heterocycloalkenyl,
wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl portions of said —O-aryl, —S-aryl, arylalkyl-, —O-heteroaryl, —S-heteroaryl, heteroarylalkyl-, cycloalkyl, aryl-fused cycloalkyl-, cycloalkylalkyl-, —O-cycloalkyl, —S-cycloalkyl, heterocycloalkyl, aryl-fused heterocycloalkyl-, heterocycloalkylalkyl-, —O-heterocycloalkyl, —S-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —S-cycloalkenyl, heterocycloalkenyl, —O-heterocycloalkenyl, and —S-heterocycloalkenyl, and the alkyl portions of said arylalkyl-, said heteroarylalkyl-, said cycloalkylalkyl-, and said heterocycloalkylalkyl-, are each independently unsubstituted or optionally independently substituted with 1 or more groups each independently selected from the group consisting of
(i) halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR8—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9,
(ii) -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl,
wherein the alkyl, alkenyl and alkynyl portions of said -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl are unsubstituted or optionally independently substituted with one or more groups each independently selected from the group consisting of:
halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9, and
(iii) aryl, —O-aryl, —C(O)-aryl, heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, and heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (i) and (ii) above;
and
(d) aryl and heteroaryl,
wherein said aryl and said heteroaryl are substituted with at least one group each independently selected from the group consisting of:
(1) halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, —SF5, —Si(R7)3, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9,
(2)-alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl,
wherein each of the alkyl, alkenyl and alkynyl portions of said -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl are unsubstituted or optionally independently substituted with one or more groups each independently selected from the group consisting of:
halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9, and
(3) aryl, —O-aryl, —C(O)-aryl, heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, and heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1) and (2) above;
R2 is selected from the group consisting of aryl, arylalkyl-, heteroaryl, and heteroarylalkyl-,
wherein the aryl and heteroaryl, and the aryl and heteroaryl portions of said arylalkyl- and said heteroarylalkyl-, are substituted with 1 or more groups each independently selected from the group consisting of:
(A) halo, OH, —CO2R6, —C(O)R6, —SR7, —S(O)R7, —SO2R7, —SF5, —Si(R7)3, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9,
(B) -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl,
wherein each of the alkyl, alkenyl and alkynyl portions of said -alkyl, -heteroalkyl, —C(O)alkyl, —C(O)-heteroalkyl, —O-alkyl, —O-heteroalkyl, -alkenyl, -heteroalkenyl, —C(O)alkenyl, —C(O)-heteroalkenyl, —O-alkenyl, —O-heteroalkenyl, -alkynyl, -heteroalkynyl, —C(O)alkynyl, —C(O)-heteroalkynyl, —O-alkynyl, and —O-heteroalkynyl are unsubstituted or optionally independently substituted with one or more groups each independently selected from the group consisting of:
halo, OH, —CO2R6, —C(O)R6, —S(O)R7, —SO2R7, CN, NO2, —C(O)NR8R9, —NR8R9, haloalkoxy, —NR10—C(O)—NR8R9, —NR10—CO2R6, —NR10—C(O)R6, —NR10—SO2R6, —SO2—NR8R9, —C(O)NR8R9, and —OC(O)NR8R9, and
(C) aryl, —O-aryl, —C(O)-aryl, heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, cycloalkyl, —O-cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, —O-heterocycloalkyl, —C(O)-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —C(O)-cycloalkenyl, and heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (A) and (B) above;
R3 is selected from the group consisting of H and lower alkyl;
Z is a moiety selected from —(C(R11)2)—(C(R12R13)), —C(O)OH, —(C(R11)2)—(C(R14)2)n—C(O)OH, from —(C(R11)2)—(C(R12R13))m—C(O)Oalkyl, —(C(R11)2)—(C(R14)2)n—C(O)Oalkyl,
—(C(R11)2)—(C(R12R13))m-Q, and —(C(R11)2)—(C(R14)2)n-Q,
wherein Q is a moiety selected from the group consisting of:
m is an integer from 0 to 5;
n is an integer from 0 to 5;
p is an integer from 0 to 5;
each R5 is independently selected from the group consisting of H, lower alkyl, hydroxy-substituted lower alkyl;
each R6 is independently selected from the group consisting of H and alkyl;
each R7 is independently selected from the group consisting of H, alkyl, aryl, arylalkyl-;
each R8 is independently selected from the group consisting of H and alkyl;
each R9 is independently selected from the group consisting of H and alkyl,
or alternatively R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocyclic ring, or a 5-, 6-, or 7-membered unsaturated heterocyclic ring, which ring contains (including said nitrogen) from 1 to 2 ring heteroatoms each independently selected from the group consisting of N,N-oxide, O, S, S(O), or S(O)2,
or alternatively R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-membered heteroaromatic ring containing (including the nitrogen to which R8 and R9 are attached) from 1 to 3 ring nitrogens;
each R10 is independently selected from the group consisting of H and alkyl;
each R11 is independently selected from the group consisting of H and lower alkyl;
each R12 is independently selected from the group consisting of H, lower alkyl, —OH, hydroxy-substituted lower alkyl;
each R13 is independently selected from the group consisting of H, unsubstituted lower alkyl, lower alkyl substituted with one or more groups each independently selected from the group consisting of hydroxyl and alkoxy, or R12 and R13 are taken together to form an oxo; and
each R14 is independently selected from the group consisting of H and fluoro.

### Claim 20

A compound or pharmaceutically acceptable salt thereof, having the general structure shown in Formula (VI):
wherein R1, R2, R3, R5, s, and Z are selected independently of each other and wherein:
R1 is selected from the group consisting of:
phenyl and naphthyl,
wherein said phenyl and said naphthyl are substituted with from 1 to 3 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;
R2 is selected from the group consisting of:
phenyl and naphthyl,
wherein said phenyl and said naphthyl are substituted with from 1 to 3 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;
R3 is selected from the group consisting of H and lower alkyl;
R5 is selected from H and alkyl;
s is 1-3; and
Z is selected from the group consisting of —(CH2)—(CH(CH3))—C(O)OH, —(CH2)—(CH2)—(CH2)—C(O)OH, —(CH2)—C(CH3)2—C(O)OH, —(CH2)—C(CH3)(OH)—C(O)OH, —CH2—CH2—C(O)OH, —CH2—CH(OH)—C(O)OH, —CH(CH3)—CH2—C(O)OH, —CH2—CH(F)—C(O)OH, —CH2—CF2—C(O)OH, CH(CH3)—CF2—C(O)OH, —CH2—CH2—CF2—C(O)OH,

### Claim 21 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
R1 is selected from phenyl and naphthyl,
wherein said phenyl and said naphthyl are substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; and
R2 is selected from the group consisting of:
phenyl and naphthyl,
wherein said phenyl and said naphthyl are substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl.

### Claim 22 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
one of R1 and R2 is phenyl and the other is naphthyl,
wherein each of said phenyl and said naphthyl is substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl.

### Claim 23 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl,
wherein said phenyl is substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; and
R2 is naphthyl,
wherein said naphthyl is substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl.

### Claim 24 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
R1 is naphthyl,
wherein said naphthyl is substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; and
R2 is phenyl,
wherein said phenyl is substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl.

### Claim 25 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl,
wherein said phenyl is substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; and
R2 is phenyl,
wherein said phenyl is substituted with from 1 to 2 groups each independently selected from:
halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl.

### Claim 26 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
R3 is selected from the group consisting of H and methyl.

### Claim 27 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
Z is selected from the group consisting of —(CH2)—(CH(CH3))—C(O)OH, —(CH2)—(CH2)—(CH2)—C(O)OH, —(CH2)—C(CH3)2—C(O)OH, —(CH2)—C(CH3)(OH)—C(O)OH, —CH2—CH2—C(O)OH, —CH2—CH(OH)—C(O)OH, —CH(CH3)—CH2—C(O)OH, —CH2—CH(F)—C(O)OH, —CH2—CF2—C(O)OH, —CH(CH3)—CF2—C(O)OH, and —CH2—CH2—CF2—C(O)OH.

### Claim 28 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
R3 is H; and
Z is selected from the group consisting of —(CH2)—(CH(CH3))—C(O)OH, —(CH2)—(CH2)—(CH2)—C(O)OH, —(CH2)—C(CH3)2—C(O)OH, —(CH2)—C(CH3)(OH)—C(O)OH, —CH2—CH2—C(O)OH, —CH2—CH(OH)—C(O)OH, —CH(CH3)—CH2—C(O)OH, —CH2—CH(F)—C(O)OH, —CH2—CF2—C(O)OH, —CH(CH3)—CF2—C(O)OH, and —CH2—CH2—CF2—C(O)OH.

### Claim 29 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
R3 is H; and
Z is

### Claim 30 (depends on 20)

A compound of claim 20 or pharmaceutically acceptable salt thereof, wherein:
R3 is H; and
Z is

### Claim 31

A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 32 (depends on 1)

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

### Claim 33 (depends on 1, 32)

A pharmaceutical composition according to claim 32, further comprising at least one antidiabetic agent other than a compound of claim 1.

### Claim 34 (depends on 1, 33)

A pharmaceutical composition according to claim 33, wherein said at least one antidiabetic agent other than a compound of claim 1 is selected from: a DPP-IV inhibitor, an insulin sensitizer, insulin, an insulin mimetic, an insulin secretagogue, a glucosidase inhibitor, an alpha glucosidase inhibitor, a glucagon receptor antagonist other than a compound of claim 1, glucophage, glucophage XR, an antihypertensive agent, a meglitinide, an alpha-glucosidase inhibitor, amlintide, pramlintide, exendin, a histamine H3 receptor antagonist, dapagliflozin, sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku), a cholesterol lowering agent, a PACAP, a PACAP mimetic, a PACAP receptor 3 agonist, a PPAR delta agonist, an antiobesity agent, an ileal bile acid transporter inhibitor, an NSAID, and a CBI receptor antagonist, and a CB1 receptor inverse agonist.

### Claim 35 (depends on 1)

A method for treating or delaying the onset of type 2 diabetes mellitus in a patient in need thereof comprising administering to said patient a compound of claim 1 in an amount that is effective to treat type 2 diabetes mellitus.

### Claim 36 (depends on 1)

A method for treating a condition, or a combination of conditions, selected from hyperglycemia, low glucose tolerance, insulin resistance, obesity, abdominal obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and/or high LDL levels, atherosclerosis, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X and other conditions where insulin resistance or hyperglycemia is a component, in a patient in need thereof, comprising administering to said patient a compound of claim 1 in an amount effective to treat said condition.