# US 8,785,477 B2 · Hexahydropyrrolo[3,4-b]pyrrole derivatives, preparation methods and pharmaceutical uses thereof

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

- Number: US 8,785,477 B2
- Document ID: US8785477B2
- Status: Granted
- Kind: B2
- Application number: 13/685,454
- Filed: 2012-11-26
- Published: 2013-07-11
- Granted: 2014-07-22
- Earliest claimed: 2010-05-24
- Assignees: Shanghai Sun-Sail Pharmaceutical Science & Technology Co., Ltd.
- Applicants: Peng Lu; Rui Zhang; Wansong Yu; Mingjie Zhu; Yilang Chen
- Inventors: Peng Lu; Rui Zhang; Wansong Yu; Mingjie Zhu; Yilang Chen
- Web page: https://patentgrep.com/patent/US8785477B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Hexahydropyrrolo[3,4-b]pyrrole derivatives, preparation methods and pharmaceutical uses thereof are provided. Specifically, dipeptidyl peptidase IV inhibitors presented by following formula (I) are provided. Such compounds can be used for treating or preventing the diseases associated with dipeptidyl peptidase IV, such as diabetes, obesity and hyperlipemia. The compounds presented by formula (I) and pharmaceutically acceptable salts thereof, a method for preparing a pharmaceutical composition thereof and their uses in the manufacture of medicaments for treating or preventing the disease associated with dipeptidyl peptidase IV are provided.

## Claims

### Claim 1

A compound according to formula (I) or optical isomers, crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof:
wherein,
X is selected from the group consisting of:
(1) —C1-C3 alkylidene;
(2) —C(O)—;
(3) —S(O)2—;
(4) —C(O)O—; and
(5) —C(O)NR1—;
R is selected from the group consisting of:
(1) H;
(2) C1-C6 alkyl, which is unsubstituted or substituted by one to three substituents selected from the following group: fluorine, chlorine or hydroxyl;
(3) C3-C6 cycloalkyl, which is unsubstituted or substituted by one to two substituents selected from the following group: C1-C3 alkyl, fluorine, chlorine, hydroxyl, cyano, C(O)NH2;
(4) Phenyl, which is unsubstituted or substituted by one to three substituents selected from the followings: C1-C3 alkyl, fluorine, chlorine, cyano, S(O)2R2; and
(5) 6-membered heterocycle containing one to two atoms independently selected from N atom, above-mentioned 6-membered heterocycle is unsubstituted or substituted by one to three substituents selected from the followings: C1-C3 alkyl, fluorine, chlorine, cyano, S(O)2R2;
wherein, R1 is H or C1-C3 alkyl;
R2 is C1-C3 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein, said compound is a compound of formula (Ia):
wherein,
X is selected from the group consisting of:
(1) —C1-C3 alkylidene-;
(2) —C(O)—;
(3) —S(O)2—;
(4) —C(O)O—; and
(5) —C(O)NR1—;
R is selected from the group consisting of:
(1) H;
(2) C1-C6 alkyl, which is unsubstituted or substituted by one to three substituents selected from the following group: fluorine, chlorine or hydroxyl;
(3) C3-C6 cycloalkyl, which is unsubstituted or substituted by one to two substituents selected from the following group: C1-C3 alkyl, fluorine, chlorine, hydroxyl, cyano, C(O)NH2;
(4) Phenyl, which is unsubstituted or substituted by one to three substituents selected from the followings: C1-C3 alkyl, fluorine, chlorine, cyano, S(O)2R2; and
(5) 6-membered heterocycle containing one to two N atoms, said 6-membered heterocycle is unsubstituted or substituted by one to three substituents selected from the followings: C1-C3 alkyl, fluorine, chlorine, cyano, S(O)2R2;
wherein, R1 is H or C1-C3 alkyl;
R2 is C1-C3 alkyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein, said compound is the salt formed by the compound of formula (Ia) having general formula (Ib):
wherein, A is selected from acid radical of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, aspartic acid, or glutamic acid.

### Claim 4 (depends on 1)

The compound of claim 1, wherein, X is selected from —C(O)—.

### Claim 5 (depends on 1)

The compound of claim 1, wherein, said R is selected from: C1-C6alkyl, which is unsubstituted or substituted by one to three substituents selected from the group consisting of fluorine, chlorine and hydroxyl; and C3-C6 cycloalkayl, which is unsubstituted or substituted by one to two substituents selected from the group consisting of C1-C3 alkyl, fluorine, chlorine, hydroxyl, cyano, and C(O)NH2.

### Claim 6 (depends on 1)

The compound of claim 1, wherein, said compound is selected from the following compounds shown in the following table:
compound
compound structure
compound name
1
(R)-3-amino-1-((3aS,6aS)-hexahydro-5- methylpyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)but-1-anone fumarate
2
(R)-3-amino-1-((3aS,6aS)-5- methoxycarbonylhexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5-trifluorophenyl)but- 1-anone fumarate
3
(R)-3-amino-1-((3aS,6aS)-5-(N,N- dimethylaminoformyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
4
(R)-3-amino-1-((3aS,6aS)-5-(N- methylaminoformyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
5
(R)-3-amino-1-((3aS,6aS)-5- (methylaminoformyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
6
(R)-3-amino-1-((3aS,6aS)-5- (cyclopropcarbonyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
7
(R)-3-amino-1-((3aS,6aS)-5-(2-fluoro-2- methylpropionyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one
8
(R)-3-amino-1-((3aS,6aS)-5-(2-fluoro-2- methylpropionyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
9
(R)-3-amino-1-((3aS,6aS)-5-(2-fluoro-2- methylpropionyl)-hexapyrrolo[3,4-b]pyrrol- 1(2H)-yl)-4-(2,4,5-trifluorophenyl)butane-1- one hydrochloride
10
(R)-3-amino-1-((3aS,6aS)-5-(2-fluoro-2- methylpropionyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one phosphate
11
(R)-3-amino-1-((3aS,6aS)-5-(2-fluoro-2- methylpropionyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one methane sulfonate
12
(R)-3-amino-1-((3aS,6aS)-5- (cyclopropcarbonyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
13
(R)-3-amino-1-((3aS,6aS)-5-(1- fluorocyclopropylcarbonyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
14
(R)-3-amino-1-((3aS,6aS)-5-(1- hydroxylcyclopropylcarbonyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
15
(R)-3-amino-1-((3aS,6aS)-5-(1- methylcyclopropylcarbonyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
16
(R)-3-amino-1-((3aS,6aS)-5- (cyclopropylmethylidenecarbonyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
17
(R)-3-amino-1-((3aS,6aS)-5-(1- cyanocyclopropylcarbonyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
18
(R)-3-amino-1-((3aS,6aS)-5- (isopropylcarbonyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
19
(R)-3-amino-1-((3aS,6aS)-5-(3- methylbutyryl)-hexahydropyrrolo[3,4-b]pyrrol- 1(2H)-yl)-4-(2,4,5-trifluorophenyl)butane-1- one fumarate
20
(R)-3-amino-1-((3aS,6aS)-5-(tertvaleryl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
21
(R)-3-amino-1-((3aS,6aS)-5-(3,3- dimethylbutyryl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
22
(R)-3-amino-1-((3aS,6aS)-5-(2-hydroxyl-2- methylpropionyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
23
(R)-3-amino-1-((3aS,6aS)-5-(hydroxylacetyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
24
(R)-3-amino-1-((3aS,6aS)-5-(1- hydroxymethyl2-hydroxypropionyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
25
(R)-3-amino-1-((3aS,6aS)-5-(pyrrol-2-yl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
26
(R)-3-amino-1-((3aS,6aS)-5-(3- mesylbenzoyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
27
(R)-3-amino-1-((3aS,6aS)-5-(3- acetylbenzoyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
28
(R)-3-amino-1-((3aS,6aS)-5-(1- aminocarbonylcyclopropylcarbonyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
29
(R)-3-amino-1-((3aS,6aS)-5-(acetyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
30
(R)-3-amino-1-((3aS,6aS)-5-(trifluoroacetyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
31
(R)-3-amino-1-((3aS,6aS)-5-(3,3,3- trifluoropropionyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
32
(R)-3-amino-1-((3aS,6aS)-5-(benzoyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
33
(R)-3-amino-1-((3aS,6aS)-5-(3- fluorobenzoyl)-hexahydropyrrolo[3,4-b]pyrrol- 1(2H)-yl)-4-(2,4,5-trifluorophenyl)butane-1- one fumarate
34
(R)-3-amino-1-((3aS,6aS)-5-(3- chlorobenzoyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
35
(R)-3-amino-1-((3aS,6aS)-5-(3- methylbenzoyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
36
(R)-3-amino-1-((3aS,6aS)-5-(3- cyanobenzoyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
37
(R)-3-amino-1-((3aS,6aS)-5- (cyclopropylsulfonyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
38
(R)-3-amino-1-((3aS,6aS)-5-(mesyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
39
(R)-3-amino-1-((3aS,6aS)-5-(trifluoromesyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate
40
(R)-3-amino-1-((3aS,6aS)-5- (benzenesulfonyl)-hexahydropyrrolo[3,4- b]pyrrol-1(2H)-yl)-4-(2,4,5- trifluorophenyl)butane-1-one fumarate
41
(R)-3-amino-1-((3aS,6aS)-5-(p-tosyl)- hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4- (2,4,5-trifluorophenyl)butane-1-one fumarate.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising pharmaceutically acceptable excipients or carriers, and the compound of claim 1, or various optical isomers, various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof.

### Claim 8

A method for preparing a compound according to formula (I), wherein, the method comprises the steps of:
(a) reacting a compound of formula (1c) with a compound of formula (1d) under a peptide coupling condition to produce a compound of formula (1e),
(b) deprotecting the compound of formula (1e) under a basic condition to produce a compound of formula (1f),
(c) converting the compound of formula (1f) to a compound of formula (1g) by a coupling reaction or acylation reaction, and
(d) deprotecting the compound of formula (1 g) to a compound of formula (Ia) in the presence of an acid;
wherein,
X is selected from the group consisting of:
(1) —C1-C3 alkylidene-;
(2) —C(O)—;
(3) —S(O)2—;
(4) —C(O)O—; and
(5) —C(O)NR1—;
R is selected from the group consisting of:
(1) H;
(2) C1-C6 alkyl, which is unsubstituted or substituted by one to three substituents selected from the following group: fluorine, chlorine or hydroxyl;
(3) C3-C6 cycloalkane, which is unsubstituted or substituted by one to two substituents selected from the following group: C1-C3 alkyl, fluorine, chlorine, hydroxyl, cyano, C(O)NH2;
(4) Phenyl, which is unsubstituted or substituted by one to three substituents selected from the following: C1-C3 alkyl, fluorine, chlorine, cyano, S(O)2R2; and
(5) 6-membered heterocycle containing one to two atoms independently selected from N atom, above-mentioned 6-membered heterocycle is unsubstituted or substituted by one to three substituents selected from the followings: C1-C3 alkyl, fluorine, chlorine, cyano, S(O)2R2;
Wherein, R1 is H or C1-C3 alkyl;
R2 is C1-C3 alkyl.

### Claim 9 (depends on 1)

A method for the treatment of a disease associated with DPP-IV comprising the step of administering to a patient in need a pharmaceutical composition comprising the compound according to claim 1, or various optical isomers, various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein the said disease is diabetes, obesity, or hyperlipemia.

### Claim 11 (depends on 1)

The compound of claim 1, wherein
X is selected from the group consisting of:
(1) —C(O)—;
(2) —S(O)2—;
(3) —C(O)O—; and
(4) —C(O)NR1.