# US 2013/0158009 A1 · Piperidinyl-substituted lactams as gpr119 modulators

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- Number: US 2013/0158009 A1
- Document ID: US20130158009A1
- Status: Published application
- Kind: A1
- Application number: 13/698,257
- Filed: 2011-05-13
- Published: 2013-06-20
- Earliest claimed: 2010-05-17
- Assignees: Array BioPharma Inc.
- Inventors: Thomas Daniel Aicher; Josef Roland Bencsik; Kevin Ronald Condroski; Jay Bradford Fell; John P. Fischer; Ronald Jay Hinklin; Scott Alan Pratt; Ajay Singh; Timothy M. Turner; Steven Armen Boyd
- Web page: https://patentgrep.com/patent/US20130158009A1

## CPC

- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- C07D 413/14: containing three or more hetero rings
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 9/12: Antihypertensives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of Formula (I): and pharmaceutically acceptable salts thereof in which X1, X2, L, R3, R4, R5, R6, R6a, R7, R9, R9a, and n have the meanings given in the specification, are modulators of GPR119 and are useful in the treatment or prevention of diseases such as such as, but not limited to, type 2 diabetes, diabetic complications, symptoms of diabetes, metabolic syndrome, obesity, dyslipidemia, and related conditions.

## Claims

### Claim 1

A compound having the general formula I
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L is O or NRx;
Rx is H or (1-3C)alkyl;
X1 is N or CR1 and X2 is N or CR2, wherein only one of X1 and X2 may be N;
R1, R2, R3 and R4 are independently selected from H, halogen, CF3, (1-6C)alkyl and (1-6C)alkoxy;
R5 is (1-3C)alkylsulfonyl, (3-6C)cycloalkylsulfonyl, (cyclopropylmethyl)sulfonyl, phenylsulfonyl, CN, Br, CF3, triazolyl, (1-4C)alkoxycarbonyl, RxRyNHC(═O)—, oxadiazolyl optionally substituted with (1-3C)alkyl, and tetrazolyl optionally substituted with (1-3C)alkyl;
or when X1 is CR1 and X2 is CR2, then R4 and R5 optionally together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O and S and optionally substituted with an oxo group, wherein the S when present is optionally oxidized;
Rx and Ry are independently (1-4C)alkyl optionally substituted with OH, or
Rx and Ry together with the atom to which they are attached form a 5-6 membered saturated azacyclic ring optionally substituted with OH;
R6 is H, OH or methyl;
R6a is H or methyl;
R7 is a group having the structure
A1 is N or CRa;
A2 is N or CRb;
A3 is N or CRc;
A4 is N or CRd,
wherein at least one of A1, A2, A3 and A4 is N, and no more than two of A1, A2, A3 and A4 may be N;
Ra, Rb, Rc and Rd are independently H, CF3, halogen, (1-4C)alkyl or CN;
R8 is selected from hydrogen, halogen, CF3, CN, (1-10C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy, (1-6C alkyl)sulfanyl, phenyl, pyridyl, pyrimidyl, pyrazolyl, and di(1-3C)alkylcarbamyl, wherein each of said phenyl, pyridyl, pyrimidyl, and pyrazolyl is optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy and CF3;
R9 and R9a are independently hydrogen or methyl; and
n is 1, 2 or 3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein:
L is O or NRx;
Rx is H or (1-3C)alkyl;
X1 is N or CR1 and X2 is N or CR2, wherein only one of X1 and X2 may be N;
R1, R2, R3 and R4 are independently selected from H, halogen, CF3, (1-6C)alkyl and (1-6C)alkoxy;
R5 is (1-3C)alkylsulfonyl, (3-6C)cycloalkylsulfonyl, (cyclopropylmethyl)sulfonyl-, phenylsulfonyl-, CN, Br, CF3, oxadiazolyl optionally substituted with (1-3C)alkyl, or tetrazolyl optionally substituted with (1-3C)alkyl;
or when X1 is CR1 and X2 is CR2, then R4 and R5 optionally together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O and S and optionally substituted with an oxo group, wherein the S when present is optionally oxidized;
R6 is H or OH;
R6a is H;
R7 is a group having the structure:
A1 is N or CRa;
A2 is N or CRb;
A3 is N or CRc;
A4 is N or CRd;
wherein at least one of A1, A2, A3 and A4 is N, and no more than two of A1, A2, A3 and A4 may be N;
Ra, Rb, Rc and Rd are independently H, CF3, halogen, (1-4C)alkyl or CN;
R8 is selected from hydrogen, halogen, CF3, CN, (1-10C)alkyl, hydroxy(1-6C)alkyl-, (1-6C)alkoxy, (1-6C alkyl)sulfanyl, phenyl, pyridyl, pyrimidyl, and pyrazolyl, wherein each of said phenyl, pyridyl, pyrimidyl, and pyrazolyl is optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy and CF3;
R9 and R9a are hydrogen; and
n is 1, 2 or 3.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein:
X1 is N or CR1 and X2 is N or CR2, wherein only one of X1 and X2 may be N;
R1, R2, R3 and R4 are independently selected from H, halogen, CF3, (1-6C)alkyl and (1-6C)alkoxy; and
R5 is (1-3C)alkylsulfonyl, (3-6C)cycloalkylsulfonyl, (cyclopropylmethyl)sulfonyl-, phenylsulfonyl-, CN, Br, CF3, oxadiazolyl optionally substituted with (1-3C)alkyl, or tetrazolyl optionally substituted with (1-3C)alkyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein:
X1 is CR1;
X2 is CR2; and
R1, R2, R3 and R4 are independently selected from H, (1-6C)alkyl, CF3 and halogen.

### Claim 5 (depends on 4)

The compound of claim 4, wherein:
R1 and R2 are independently selected from H, F and Cl; and
R3 and R4 are independently selected from H, Me, F, Cl and CF3.

### Claim 6 (depends on 4)

The compound of claim 4, wherein:
R1 is H or F;
R2 is H, F or Cl;
R3 is H, F or CF3; and
R4 is H, Me, F or Cl.

### Claim 7 (depends on 4)

The compound of claim 4, wherein:
R1 and R4 are H; and
R2 and R3 are F.

### Claim 8 (depends on 4)

The compound of claim 4, wherein:
R1, R2 and R4 are H; and
R3 is F.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein:
X1 is N; and
X2 is CR2.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R2, R3 and R4 are independently selected from H, halogen, and (1-6C)alkyl.

### Claim 11 (depends on 9)

The compound of claim 9, wherein R2, R3 and R4 are each H.

### Claim 12 (depends on 9)

The compound of claim 9, wherein R2 and R4 are H and R3 is Cl.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein:
X1 is CR1; and
X2 is N.

### Claim 14 (depends on 13)

The compound according to claim 13, wherein R1, R3 and R4 are independently selected from H, F, Cl and Me.

### Claim 15 (depends on 13)

The compound according to claim 13, wherein each of R1, R3 and R4 is H.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein R5 is selected from (1-3C)alkylsulfonyl, (3-6C)cycloalkylsulfonyl-, (cyclopropylmethyl)sulfonyl, and phenylsulfonyl (C6H5SO2—).

### Claim 17 (depends on 16)

The compound according to claim 16, wherein R5 is (1-3C)alkylsulfonyl.

### Claim 18 (depends on 17)

The compound according to claim 17, wherein R5 is methylsulfonyl.

### Claim 19 (depends on 1)

The compound according to claim 1, wherein R5 is selected from CN, Br and CF3.

### Claim 20 (depends on 1)

The compound according to claim 1, wherein R5 is oxadiazolyl optionally substituted with (1-3C)alkyl.

### Claim 21 (depends on 1)

The compound according to claim 1, wherein R5 is tetrazolyl optionally substituted with (1-3C)alkyl.

### Claim 22 (depends on 1)

The compound according to claim 1, wherein X1 is CR1, X2 is CR2, and R4 and R5 together with the atoms to which they are attached form a 5-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from O and S, wherein the heterocyclic ring is optionally substituted with an oxo group, and the S is optionally oxidized.

### Claim 23 (depends on 1)

The compound according to claim 1, wherein R7 is a group having the structure:
wherein
A1 is CRa,
A2 is CRb,
A3 is CRc,
A4 is N; and
Ra, Rb and Rc are independently H, CF3, halogen, (1-4C)alkyl or CN.

### Claim 24 (depends on 23)

The compound of claim 23, wherein Ra, Rb and Rc are independently selected from hydrogen, Cl and (1-4C)alkyl.

### Claim 25 (depends on 24)

The compound of claim 24, wherein two of Ra, Rb and Rc are hydrogen and the other is selected from hydrogen, Cl and methyl.

### Claim 26 (depends on 25)

The compound of claim 25, wherein each of Ra, Rb and Rc is hydrogen.

### Claim 27 (depends on 1)

The compound according to claim 1, wherein R7 is a group having the structure:
wherein:
A1 is N;
A2 is CRb;
A3 is CRc;
A4 is N; and
Rb and Rc are independently H, CF3, halogen, (1-4C)alkyl or CN.

### Claim 28 (depends on 27)

The compound of claim 27, wherein one of Rb and Rc is hydrogen and the other is selected from hydrogen and (1-4C)alkyl.

### Claim 29 (depends on 28)

The compound of claim 28, wherein Rb and Rc are both hydrogen.

### Claim 30 (depends on 1)

The compound according to claim 1, wherein R7 is a group having the structure:
wherein
A1 is CRa;
A2 is N;
A3 is CRc;
A4 is N; and
Ra and Rc are independently selected from H, CF3, halogen, (1-4C)alkyl and CN.

### Claim 31 (depends on 30)

The compound of claim 30, wherein one of Ra and Rc is hydrogen and the other is selected from hydrogen, halogen, CN and (1-4C)alkyl.

### Claim 32 (depends on 31)

The compound of claim 31, wherein one of Ra and Rc is hydrogen and the other is selected from hydrogen, chloro, CN and methyl.

### Claim 33 (depends on 32)

The compound of claim 32, wherein each of Ra and Rc is hydrogen.

### Claim 34 (depends on 1)

The compound according to claim 1, wherein R7 is a group having the structure:
wherein:
A1 is CRa;
A2 is CRb;
A3 is N;
A4 is N; and
Ra and Rb are independently selected from H, CF3, halogen, (1-4C)alkyl and CN.

### Claim 35 (depends on 34)

The compound of claim 34, wherein one of Ra and Rb is hydrogen and the other is selected from hydrogen and (1-4C)alkyl.

### Claim 36 (depends on 35)

The compound of claim 35, wherein one of Ra and Rb is hydrogen and the other is selected from hydrogen and methyl.

### Claim 37 (depends on 36)

The compound of claim 36, wherein each of Ra and Rb is hydrogen.

### Claim 38 (depends on 1)

The compound according to claim 1, wherein R8 is hydrogen.

### Claim 39 (depends on 1)

The compound according to claim 1, wherein R8 is halogen.

### Claim 40 (depends on 39)

The compound according to claim 39, wherein R8 is selected from Cl, Br and I.

### Claim 41 (depends on 40)

The compound according to claim 40, wherein R8 is Cl.

### Claim 42 (depends on 1)

The compound according to claim 1, wherein R8 is CF3.

### Claim 43 (depends on 1)

The compound according to claim 1, wherein R8 is CN.

### Claim 44 (depends on 1)

The compound according to claim 1, wherein R8 is (1-10C)alkyl.

### Claim 45 (depends on 44)

The compound according to claim 44, wherein R8 is selected from methyl, ethyl, propyl, isopropyl, butyl, heptyl and decyl.

### Claim 46 (depends on 45)

The compound according to claim 45, wherein R8 is selected from methyl and ethyl.

### Claim 47 (depends on 46)

The compound according to claim 46, wherein R8 is methyl.

### Claim 48 (depends on 46)

The compound according to claim 46, wherein R8 is ethyl.

### Claim 49 (depends on 1)

The compound according to claim 1, wherein R8 is hydroxy(1-6C)alkyl-.

### Claim 50 (depends on 1)

The compound according to claim 1, wherein R8 is (1-6C)alkoxy.

### Claim 51 (depends on 1)

The compound according to claim 1, wherein R8 is (1-6C alkyl)sulfanyl.

### Claim 52 (depends on 1)

The compound according to claim 1, wherein R8 is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy and CF3.

### Claim 53 (depends on 1)

The compound according to claim 1, wherein R8 is phenyl, pyrimidyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from (1-4C)alkyl.

### Claim 54 (depends on 53)

The compound according to claim 53, wherein R8 is pyridyl, pyrimidyl, or pyrazolyl, wherein each of said phenyl, pyridyl, pyrimidyl, and pyrazolyl are optionally substituted with one or more substituents independently selected from (1-4C)alkyl.

### Claim 55 (depends on 1)

The compound according to claim 1, wherein L is O.

### Claim 56 (depends on 1)

The compound according to claim 1, wherein L is NRx.

### Claim 57 (depends on 56)

The compound according to claim 56, wherein L is NH.

### Claim 58 (depends on 1)

The compound according to claim 1, wherein n is 1 or 3.

### Claim 59 (depends on 1)

The compound according to claim 1, wherein n is 1.

### Claim 60 (depends on 1)

The compound according to claim 1, wherein n is 2.

### Claim 61 (depends on 1)

The compound according to claim 1, wherein n is 2 and at least two of R1, R2, R3 and R4 is not H.

### Claim 62 (depends on 1)

The compound according to claim 1, wherein n is 3.

### Claim 63 (depends on 1)

The compound according to claim 1, wherein R6 is H.

### Claim 64 (depends on 1)

The compound according to claim 1, wherein R6 is OH.

### Claim 65 (depends on 1)

The compound according to claim 1, wherein R6a is H.

### Claim 66 (depends on 1)

The compound according to claim 1, wherein R9 and R9a are hydrogen.

### Claim 67 (depends on 1)

The compound according to claim 1, wherein R9 and R9a are methyl.

### Claim 68 (depends on 1)

A compound of claim 1, selected from any one of Examples 1-166, or a pharmaceutically acceptable salt thereof.

### Claim 69 (depends on 1)

A pharmaceutical composition, which comprises a compound of Formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.

### Claim 70 (depends on 1)

A method of treating a disease or condition selected from type 2 diabetes, symptoms of diabetes, diabetic complications, metabolic syndrome (including hyperglycemia, impaired glucose tolerance, and insulin resistance), obesity, dyslipidemia, dyslipoproteinemia, vascular restenosis, diabetic retinopathy, hypertension, cardiovascular disease, Alzheimer's disease, schizophrenia, and multiple sclerosis in a mammal in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 71 (depends on 70)

The method of claim 70, wherein the disease is type 2 diabetes.

### Claim 72

(canceled)

### Claim 73

(canceled)

### Claim 74 (depends on 1)

A process for the preparation of a compound of claim 1, which comprises:
(a) coupling a corresponding compound having the formula II
with a corresponding compound having the formula III
wherein L1 is a leaving atom or group, in the presence of a base and optionally further in the presence of a metal catalyst and optionally in the presence of a ligand; or
(b) coupling a corresponding compound having the formula IV
wherein L3 is a leaving atom or group, with a compound having the formula (R8)2Zn or R8ZnBr in the presence of a metal catalyst and a base; or
(c) for a compound of Formula I wherein L is NRx, coupling a corresponding compound having the formula V
with a corresponding compound having the formula VI
wherein L4 is a leaving atom or group, in the presence of a base and optionally further in the presence of a metal catalyst; or
(d) for a compound of Formula I wherein R5 is a group having the R5aSO2— where R5a is (1-3C) alkyl, (3-6C)cycloalkyl, cyclopropylmethyl- or phenyl, reacting a corresponding compound having the formula VII
wherein L5 is a leaving atom or group, with a reagent having the formula R5aSO2Na in the presence of a metal catalyst and a ligand; or
(e) for a compound of Formula I wherein R8 is phenyl, pyridyl, pyrimidyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy and CF3, reacting a corresponding compound having the formula IV
wherein L3 is a leaving atom or group, with a corresponding compound having the formula R8aB(OReRf)2, where R8a is phenyl, pyridyl, pyrimidyl or pyrazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy and CF3, and Re and Rf are H or (1-6C)alkyl, or Re and Rf together with the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (1-3C alkyl), wherein said coupling takes place in the presence of a palladium catalyst and a base; or
(f) for a compound of Formula I wherein R5 is CN, reacting a corresponding compound having the formula VII
wherein L5 is a leaving atom or group, in the presence of a metal catalyst CuCN; or
(g) for a compound of Formula I wherein R8 is CH(OH)(1-5C alkyl), reacting a corresponding compound having the formula VIII
with a reducing agent; or
(h) for a compound of Formula I wherein R8 is (1-6C alkyl)sulfanyl, reacting a corresponding compound having the formula IV
wherein L3 is a leaving atom or group, with a reagent having the formula NaS(1-6C alkyl) in the presence of a palladium catalyst, a ligand and a base; and
optionally removing any protecting groups and optionally preparing a salt thereof.