# US 2018/0021346 A1 · Novel glp-1 receptor modulators

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- Number: US 2018/0021346 A1
- Document ID: US20180021346A1
- Status: Published application
- Kind: A1
- Application number: 15/711,858
- Filed: 2017-09-21
- Published: 2018-01-25
- Earliest claimed: 2014-12-10
- Assignees: Celgene International II SÀRL
- Applicants: Celgene International II SÀRL
- Inventors: Marcus F. Boehm; Esther Martinborough; Manisha Moorjani; Junko Tamiya; Liming Huang; Adam R. Yeager; Enugurthi Brahmachary; Thomas Fowler; Andrew Novak; Premji Meghani; Michael Knaggs; Daniel Glynn; Mark Mills
- Web page: https://patentgrep.com/patent/US20180021346A1

## CPC

- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 31/402: 1-aryl substituted, e.g. piretanide
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/421: 1,3-Oxazoles, e.g. pemoline, trimethadione
- A61K 31/4245: Oxadiazoles
- A61K 31/426: 1,3-Thiazoles
- A61K 31/433: Thidiazoles
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- 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 31/4965: Non-condensed pyrazines
- A61K 31/497: containing further heterocyclic rings
- A61K 31/50: Pyridazines; Hydrogenated pyridazines
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 38/26: Glucagons
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- 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 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 207/08: with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D 211/22: by oxygen atoms
- C07D 211/98: Nitrogen atom
- C07D 213/55: Acids; Esters
- C07D 215/14: Radicals substituted by oxygen atoms
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 237/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/34: One oxygen atom
- C07D 239/74: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
- C07D 241/08: with oxygen atoms directly attached to ring carbon atoms
- C07D 241/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 243/08: not condensed with other rings
- C07D 253/06: 1,2,4-Triazines
- C07D 253/065: having three double bonds between ring members or between ring members and non-ring members
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 271/107: with two aryl or substituted aryl radicals attached in positions 2 and 5
- C07D 277/30: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 285/08: 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
- C07D 285/12: 1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D 295/084: with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- 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 403/10: linked by a carbon chain containing aromatic rings
- 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 407/12: 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 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds are provided that modulate the glucagon-like peptide 1 (GLP-1) receptor, as well as methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds can act as modulators or potentiators of GLP-1 receptor on their own, or with incretin peptides such as GLP-1(7-36) and GLP-1(9-36), or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “” represents either or both the R and S form of the compound): where A, B, C, Y1, Y2, Z, R1, R2, R3, R4, R5, W1, n, p and q are as defined herein.

## Claims

### Claim at position 1

1-92. (canceled)

### Claim 93

A method of activation, potentiation, modulation or agonism of a glucagon-like peptide 1 receptor comprising contacting the receptor with an effective amount of a compound having one of the following structures, or a pharmaceutically acceptable diastereomer, enantiomer, racemate, salt, hydrate or solvate thereof:
wherein
R2 is —NR41R42;
R3 is alkyl, alkyl substituted with cyano, or —S(O2)(alkyl);
R41 and R42 taken together with the N atom to which they are attached form a 4-membered heterocyclyl substituted with —COOH; and
R5 is cycloalkyl optionally substituted singly of multiply with halo, alkyl or haloalkyl.

### Claim 94

A method of potentiating a glucagon-like peptide 1 receptor comprising contacting the receptor with a compound having one of the following structures, or a pharmaceutically acceptable diastereomer, enantiomer, racemate, salt, hydrate or solvate thereof:
wherein
R2 is —NR41R42;
R3 is alkyl, alkyl substituted with cyano, or —S(O2)(alkyl);
R41 and R42 taken together with the N atom to which they are attached form a 4-membered heterocyclyl substituted with —COOH; and
R5 is cycloalkyl optionally substituted singly of multiply with halo, alkyl or haloalkyl;
in the presence of GLP-1(7-36), GLP-1(9-36) and/or oxyntomodulin.

### Claim 95

A method of treatment of a malcondition in a patient for which activation, potentiation, modulation or agonism of a glucagon-like peptide 1 receptor is medically indicated, comprising administering an effective amount of the compound having one of the following structures, or a pharmaceutically acceptable diastereomer, enantiomer, racemate, salt, hydrate or solvate thereof:
wherein
R2 is —NR41R42;
R3 is alkyl, alkyl substituted with cyano, or —S(O2)(alkyl);
R41 and R42 taken together with the N atom to which they are attached form a 4-membered heterocyclyl substituted with —COOH; and
R5 is cycloalkyl optionally substituted singly of multiply with halo, alkyl or haloalkyl;
to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient.

### Claim 96 (depends on 95)

The method of claim 95 wherein the malcondition is type I diabetes, type II diabetes, gestational diabetes, obesity, excessive appetite, insufficient satiety, metabolic disorder, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

### Claim 97 (depends on 95)

The method of claim 95 wherein the malcondition is type II diabetes.

### Claim 98 (depends on 95)

The method of claim 95 wherein the malcondition is non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

### Claim 99 (depends on 95)

The method of claim 95, wherein R41 and R42 taken together with the N atom to which they are attached form a 4-membered heterocyclyl having the following structure:

### Claim 100 (depends on 95)

The method of claim 95, wherein 4-membered heterocyclyl is substituted with —COOH to provide the following structure:

### Claim 101 (depends on 95)

The method of claim 95, wherein R3 is ethyl, iso-propyl, cyclopropyl, iso-butyl or tert-butyl.

### Claim 102 (depends on 95)

The method of claim 95, wherein R3 is ethyl, iso-propyl, cyclopropyl, iso-butyl or tert-butyl, each of which is substituted with cyano.

### Claim 103 (depends on 95)

The method of claim 95, wherein R3 is —SO2CH3.

### Claim 104 (depends on 95)

The method of claim 95, wherein R5 is cyclohexyl singly or multiply substituted with halo, alkyl or haloalkyl.

### Claim 105 (depends on 95)

The method of claim 95, wherein R5 is cyclohexyl singly substituted with alkyl.

### Claim 106 (depends on 95)

The method of claim 95, wherein R5 is cyclohexyl singly substituted with methyl, ethyl, n-propyl, iso-propyl or tert-butyl.

### Claim 107 (depends on 95)

The method of claim 95, wherein R5 is cyclohexyl singly or multiply substituted with halo or haloalkyl.

### Claim 108 (depends on 95)

The method of claim 95, wherein the compound has the structure of any one of the following compounds, or a pharmaceutically acceptable diastereomer, enantiomer, racemate, salt, hydrate or solvate thereof.