# US 9,517,227 B2 · Dihydropyrazoles

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- Number: US 9,517,227 B2
- Document ID: US9517227B2
- Status: Granted
- Kind: B2
- Application number: 14/300,945
- Filed: 2014-06-10
- Published: 2014-10-02
- Granted: 2016-12-13
- Earliest claimed: 2011-07-01
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH
- Inventors: Henry Yu; Thomas E. Richardson; Robert James Foglesong; Lizbeth Celeste Deselm; Andreas Goutopoulos
- Web page: https://patentgrep.com/patent/US9517227B2

## CPC

- A61K 31/415: 1,2-Diazoles
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0031: {Rectum, anus}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61P 5/06: of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/06: having one double bond between ring members or between a ring member and a non-ring member
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- 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 401/10: linked by a carbon chain containing aromatic rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 471/04: 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

Novel dihydropyrazole derivatives of formula (I) wherein L, R, R3, R4, R5, R6, R7, X1, X2, X3, X4, Y, m and n have the meaning according to the claims, are positive allosteric modulators of the FSH receptor, and can be employed, inter alia, for the treatment of fertility disorders.

## Claims

### Claim 1

A compound of formula (I)
wherein
R, L each independently denote Ar1 or Het1;
R1 denotes Hal, A, —(CY2)p—OY, —(CY2)p—NY2, COOY, CONY2, NHCOY, CN, SO2Y, -E-(CY2)p—Ar2, -E-(CY2)p-Het1 or -E-(CY2)p-Het3;
R2 denotes Hal, A, —(CY2)p—OY, —(CY2)p—NY2, COY, COOY, CONY2, —CONY-Cyc, —O-Cyc, NO2, CN, SY, SOY, SO2Y, SO2NY2, NHSO2Y, alkenyl or -E-(CY2)p—Ar2;
R3, R4, R5, R6 denote independently from one another H, A or Ar2;
R7 denotes Y, OY or NY2;
X1 denotes a single bond;
X2 denotes O or a single bond;
X3 denotes O, NY or a single bond;
X4 denotes a single bond;
with the proviso that m denotes 0 if X1 and X2 denote a single bond;
E denotes —C≡C—, SO2, —SO2—NY—, O, NY or a single bond;
Y denotes H or A;
A denotes unbranched or branched alkyl having 1-10 C atoms,
in which 1-7 H atoms can be replaced by Hal;
Cyc denotes cycloalkyl having 3-7 C atoms,
in which 1-4 H atoms can be replaced independently from one another by Hal or A;
Ar1 denotes a saturated, unsaturated or aromatic, mono- or bicyclic carbocycle having 3-10 C atoms,
which can be substituted by at least one substituent selected from the group of R1, R2 and —C≡C—C(A)2OH, and/or which can be fused to Cyc, Het1 or Het3;
Ar2 denotes an aromatic, mono- or bicyclic carbocycle having 6-10 C atoms, which can be substituted by at least one substituent selected from the group of Hal, A and —(CY2)p—OY;
Het1 denotes an unsaturated or aromatic mono- or bicyclic heterocycle having 3-8 C atoms and 1-4 N, O and/or S atoms,
which can be substituted by at least one substituent selected from the group of Hal, A, —(CY2)p—OY, —(CY2)p—NY2, —(CY2)p—Ar2, —CO—Ar2, SO2—Ar2, —(CY2)p-Het2, Het3 and CN;
Het2 denotes an aromatic monocyclic heterocycle having 5-7 C atoms and 1-3 N atoms,
which can be substituted by at least one substituent selected from the group of Hal, A and —(CY2)p—OY;
Het3 denotes a saturated monocyclic heterocycle having 3-7 C atoms and 1-4 N, O and/or S atoms,
which can be substituted by at least one substituent selected from the group of Hal, A, —(CY2)p—OY, —(CY2)p—NY2, COOY, COY, —CONY2, ═O and CN;
Hal denotes F, Cl, Br or I; and
m is 0 or 1;
n is 0 or 1;
p is 0, 1, 2, 3 or 4
wherein at least one of m or n is not 0;
and/or a physiologically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein
R, L denote Ar1.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein
X2 is O,
X1 is a single bond, and
X3 and X4 denote a single bond.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein
Ar1 denotes an aromatic, monocyclic carbocycle having 5-8 C atoms, which is mono-, di- or trisubstituted by at least one substituent selected from the group of R1 and R2.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein
Het1 denotes an unsaturated or aromatic monocyclic heterocycle having 3-6 C atoms and 1-3 N, O and/or S atoms, which is substituted by at least one substituent selected from the group of Hal, A and OA.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein
X3 is O or NY,
X4 is a single bond, and
X1 and X2 denote a single bond.

### Claim 7 (depends on 1)

The compound according to claim 1, which is selected from the group of:
and/or a physiologically acceptable salt thereof.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising at least one compound according to claim 1 and/or a physiologically acceptable salt thereof.

### Claim 9 (depends on 8)

The pharmaceutical composition according to claim 8, comprising pharmaceutically tolerable adjuvants for oral administration.

### Claim 10 (depends on 8)

The pharmaceutical composition according to claim 8, comprising at least a second active pharmaceutical ingredient.

### Claim 11

A method for modulating an FSH receptor comprising the steps of:
(a) providing (i) a system expressing said FSH receptor and (ii) at least one compound of formula (I)
wherein
R, L denote independently from one another Ar1, Het1, A or OY;
R1 denotes Hal, A, —(CY2)p—OY, —(CY2)p—NY2, COOY, CONY2, NHCOY, CN, SO2Y, -E-(CY2)p—Ar2, -E-(CY2)p-Het1 or -E-(CY2)p-Het3;
R2 denotes Hal, A, —(CY2)p—OY, —(CY2)p—NY2, COY, COOY, CONY2, —CONY-Cyc, —O-Cyc, NO2, CN, SY, SOY, SO2Y, SO2NY2, NHSO2Y, alkenyl or
-E-(CY2)p—Ar2;
R3, R4, R5, R6 denote independently from one another H, A or Ar2;
R7 denotes Y, OY or NY2;
X1, X2, X3, X4 denote independently from one another O, NY or a single bond;
E denotes —C≡C—, SO2, —SO2—NY—, O, NY or a single bond;
Y denotes H or A;
A denotes unbranched or branched alkyl having 1-10 C atoms,
in which 1-7 H atoms can be replaced by Hal;
Cyc denotes cycloalkyl having 3-7 C atoms,
in which 1-4 H atoms can be replaced independently from one another by Hal or A;
Ar1 denotes a saturated, unsaturated or aromatic, mono- or bicyclic carbocycle having 3-10 C atoms,
which can be substituted by at least one substituent selected from the group of R1, R2 and —C≡C—C(A)2OH, and/or which can be fused to Cyc, Het1 or Het3;
Ar2 denotes an aromatic, mono- or bicyclic carbocycle having 6-10 C atoms, which can be substituted by at least one substituent selected from the group of Hal, A and —(CY2)p—OY;
Het1 denotes an unsaturated or aromatic mono- or bicyclic heterocycle having 3-8 C atoms and 1-4 N, O and/or S atoms,
which can be substituted by at least one substituent selected from the group of Hal, A, —(CY2)p—OY, —(CY2)p—NY2, —(CY2)p—Ar2, —CO—Ar2, SO2—Ar2, —(CY2)p-Het2, Het3 and CN;
Het2 denotes an aromatic monocyclic heterocycle having 5-7 C atoms and 1-3 N atoms,
which can be substituted by at least one substituent selected from the group of Hal, A and —(CY2)p—OY;
Het3 denotes a saturated monocyclic heterocycle having 3-7 C atoms and 1-4 N, O and/or S atoms,
which can be substituted by at least one substituent selected from the group of Hal, A, —(CY2)p—OY, —(CY2)p—NY2, COOY, COY, —CONY2, ═O and CN;
Hal denotes F, Cl, Br or I; and
m, n, p denote independently from one another 0, 1, 2, 3 or 4;
and/or a physiologically acceptable salt thereof, and
(b) contacting said system expressing said FSH receptor with said compound of formula (I) under conditions such that said FSH receptor is modulated.

### Claim 12 (depends on 11)

The method according to claim 11, wherein an effective amount of at least one compound and/or a physiologically acceptable salt thereof is administered to a mammal in need of treating fertility disorders.

### Claim 13 (depends on 11)

Process for manufacturing a compound of formula (I) comprising the steps of:
(a) reacting a compound of formula (II)
wherein
L, R3, R4, R5, R6, X3, X4, Y and n have the meaning according to claim 11,
with a compound of formula (III)
wherein
R8 denotes Hal or OH, and
R, R7, X1, X2, Y, Hal and m have the meaning according to claim 11,
to yield a compound of formula (I)
wherein
L, R, R3, R4, R5, R6, R7, X1, X2, X3, X4, Y, m and n have the meaning according to claim 11,
and optionally
(b) converting a base or an acid of the compound of formula (I) into a salt thereof.