# US 10,308,610 B2 · Inhibitor compounds of phosphodiesterase type 10A

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- Number: US 10,308,610 B2
- Document ID: US10308610B2
- Status: Granted
- Kind: B2
- Application number: 15/840,138
- Filed: 2017-12-13
- Published: 2018-04-12
- Granted: 2019-06-04
- Earliest claimed: 2011-11-09
- Assignees: AbbVie Deutschland GmbH & Co. KG; AbbVie Inc.
- Applicants: AbbVie Deutschland GmbH & Co. KG; AbbVie Inc.
- Inventors: Hervé Geneste; Michael Ochse; Karla Drescher; Jürgen Dinges; Clarissa Jakob
- Web page: https://patentgrep.com/patent/US10308610B2

## CPC

- C07D 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- A61K 31/47: Quinolines; Isoquinolines
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 217/24: Oxygen atoms
- C07D 237/32: with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
- 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 401/14: containing three or more hetero rings
- C07D 409/08: linked by a carbon chain containing alicyclic rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- 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 which are inhibitors of phosphodiesterase type 10A and to their use for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders. wherein X1 is CH or N, X2 is C—R5 or N, Y is O or S, R1 is inter alia C2-C8-alkyl, C2-C8-alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, C5-C8-cycloalkyl carrying a fused benzene ring, or a moiety Z1—Ar1; R2 is a radical of the formula CR21R22R23 or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Ra, R3 is inter alia hydrogen, C1-C8-alkyl, C2-C8-alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, etc, or R2 and R3 together with the nitrogen atom, to which they are bound form an optionally substituted saturated 5- to 7-membered heterocyclic ring which, in addition to the nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group of O, N, S, SO and SO2; R4 is inter alia C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl or Z4—Ar4; R5 is inter alia hydrogen, halogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy, C1-C4-fluoroalkoxy, —Z5—Ar5, —O—Z5—Ar5, etc; where Z1 to Z5, Ar1 to Ar5, Ra, R21, R22 and R23 are as defined in the claims.

## Claims

### Claim 1

A compound of formula (I)
where in formula (II)
X1 is CH or N;
Y is O or S;
R1 is selected from the group consisting of C2-C8-alkyl, C2-C8-alkenyl, C1-C4-fluoroalkyl, C5-C8-cycloalkyl carrying a fused benzene ring, fluorinated C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, fluorinated C3-C8-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc) and a moiety Z1—Ar1, and
X2 is C—R5 where R is —O—Z5—Ar5, or
R1 is a moiety Z1—Ar1, and
X2 is C—R5 or N;
R2 is a radical of the formula CR21R22R23 or phenyl or 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents W, where
R21 is selected from the group consisting of hydrogen, C1-C8-alkyl, trimethylsilyl, C2-C8-alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, fluorinated C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, fluorinated C3-C8-cycloalkyl-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), (CH2)mC(O)O—Rd, (CH2)mC(O)N(Re)(Rf) and Z2—Ar2,
R22 is selected from the group consisting of hydrogen, fluorine, C1-C8-alkyl, C2-C8-alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, fluorinated C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, fluorinated C3-C8-cycloalkyl-C1-C4-alkyl, hydroxy-C1-C4-alkyl and C1-C4-alkyl-N(Rb)(Rc), or
R21 and R22 together with the carbon atom, to which they are bound form a saturated 5- to 7-membered carbocyclic ring or a saturated 5- to 7-membered heterocyclic ring which has 1, 2 or 3 heteroatoms or heteroatom containing groups selected from the group consisting of O, N, 5, SO and SO2 as ring members, where the carbocyclic ring and the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents Rg, and where the carbocyclic ring and the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents Rh,
R23 is selected from the group consisting of hydrogen, fluorine, C1-C8-alkyl and C1-C4-fluoroalkyl;
R3 is selected from the group consisting of hydrogen, C1-C8-alkyl, C2-C8-alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), and trimethylsilyl, or
R2 and R3 together with the nitrogen atom, to which they are bound form a saturated 5- to 7-membered heterocyclic ring which, in addition to the nitrogen atom, may have 1 or 2 further heteroatoms or heteroatom containing groups selected from the group consisting of O, N, S, SO and SO2 as ring members, where the heterocyclic ring may be unsubstituted or may be substituted by 1, 2 or 3 identical or different substituents R31, and where the heterocyclic ring may carry a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring, where the fused rings themselves are unsubstituted or carry 1, 2 or 3 substituents R32, where
R31 is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, N(Rb)(Rc), C(O)O—Rd, C(O)N(Re)(Rf), where one radical R31 may also be a moiety —Z3—Ar3,
R32 is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, N(Rb)(Rc), C(O)O—Rd and C(O)N(Re)(Rf);
R4 is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl and —Z4—Ar4;
R5 is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy, C1-C4-fluoroalkoxy, —Z5—Ar5, —O—Z5—Ar5, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy and C3-C6-cycloalkyl-C1-C4-alkoxy, where the cyclic radical in the last four mentioned groups may be unsubstituted, partially or completely fluorinated or carries 1, 2, 3 or 4 methyl groups;
Ar1 is selected from the group consisting of phenyl, monocyclic 5- or 6-membered hetaryl and bicyclic 9- or 10-membered hetaryl, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N, where phenyl and hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh;
Ar2 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh;
Ar3 is phenyl or monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rh;
Ar4 and Ar5 are independently of each other selected from the group consisting of phenyl and monocyclic 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N, where phenyl and monocyclic hetaryl are unsubstituted or may carry 1, 2 or 3 identical or different substituents Rk;
Z1, Z4, Z5 are independently of each other C1-C4-alkylene;
Z2 is a single bond or C1-C4-alkylene;
Z3 is a single bond, C1-C4-alkylene, O, N, S, SO or SO2;
Ra is selected from the group consisting of halogen, CN, OH, NO2, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, (CH2)mN(Rb)(Rc), C(O)O—Rd, C(O)N(Re)(Rf), N(R)S(O)2(Rff) and S(O)2N(Re)(Rf);
Rb, Rc, independently of each other, are selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkylmethyl and benzyl or Rb and Rc form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group consisting of O, N, S, SO and SO2 as ring members and which may carry 1, 3, 4, 5 or 6 C1-C4-alkyl substituents;
Rd is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkylmethyl and benzyl;
Re, Rf, independently of each other, are selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkylmethyl and benzyl or Re and Rf form together with the N atom to which they are attached a 3- to 7-membered, nitrogen heterocycle which may have 1, 2 or 3 further different or identical heteroatoms or heteroatom containing groups selected from the group consisting of O, N, S, SO and SO2 as ring members and which may carry 1, 2, 3, 4, 5 or 6 C1-C4-alkyl substituents;
Rg is selected from the group consisting of halogen, CN, OH, C1-C6-alkyl, C2-C6-alkenyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, fluorinated C3-C6-cycloalkyl-C1-C4-alkyl, C1-C4-hydroxy-C1-C4-alkyl, C1-C4-alkyl-N(Rb)(Rc), C1-C4-alkoxy, and fluorinated C1-C4-alkoxy, or one Rg together with a carbon atom to which Rg is attached may also form a carbonyl group, or one Rg is phenyl or benzyl, where the phenyl ring in the last 2 mentioned radicals is unsubstituted or carries 1, 2 or 3 radicals Rh;
Rh is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C6-alkoxy, fluorinated C1-C4-alkoxy, C1-C4-alkylsulfanyl, C1-C4-alkoxy-C1-C4-alkoxy, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyi, C3-C6-cycloalkoxy, C3-C6-cycloalkyl-C1-C4-alkoxy, phenoxy, N(Rb)(Rc), C1-C4-alkyl-N(Rb)(Rc), C(O)O—Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff), S(O)2N(Re)(Rf), 3- to 7-membered heterocyclyloxy, and 3- to 7-membered heterocyclyl-C1-C4-alkoxy, where heterocyclyl in the two last mentioned radicals has 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of 0, S and N, and 5- to 6-membered hetaryl-C1-C4-alkoxy, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N;
Rk is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, N(Rb)(Rc), C(O)O—Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and S(O)2N(Re)(Rf), or two radicals Rk that are bound to adjacent carbon atoms together with said carbon atoms may form a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring having 1 or 2 ring members selected from the group consisting of O, N and S, where the fused benzene ring and the fused heteroaromatic ring are unsubstituted or may carry 1, 2 or 3 radicals Rh;
Ree is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C3-C6-cycloalkyl, C3-C6-cycloalkylmethyl and benzyl;
Rff is selected from the group consisting of C1-C4-alkyl, C1-C4-fluoroalkyl and phenyl, which is unsubstituted or carries 1, 2 or 3 radicals Rh; and
m is 0, 1, 2, 3.

### Claim 2 (depends on 1)

The compound of claim 1, where Rh is selected from the group consisting of halogen, CN, OH, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, fluorinated C1-C4-alkoxy, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, N(Rb)(Rc), C1-C4-alkyl-N(Rb)(Rc), C(O)O—Rd, C(O)N(Re)(Rf), N(Ree)S(O)2(Rff) and S(O)2N(Re)(Rf).

### Claim 3 (depends on 1)

The compound of claim 1, where X1 is C—H.

### Claim 4 (depends on 1)

The compound of claim 1, where X2 is C—R5.

### Claim 5 (depends on 1)

The compound of claim 1, here is O.

### Claim 6 (depends on 1)

The compound of claim 1, where R1 is C2-C8-alkyl, C3-C8-cycloalkyl or C3-C8-cycloalkylmethyl.

### Claim 7 (depends on 1)

The compound of claim 1, where R1 is a moiety Z1—Ar1.

### Claim 8 (depends on 1)

The compound of claim 1, where R2 is a radical of the formula CR21R22R23.

### Claim 9 (depends on 1, 8)

The compound of claim 8, where
R21 is selected from the group consisting of C1-C8-alkyl, trimethylsilyl, C2-C8-alkenyl, C1-C4-fluoroalkyl, C3-C8-cycloalkyl, fluorinated C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, fluorinated C3-C8-cycloalkyl-C1-C4-alkyl and Z2—Ar2, where Z2 and Ar2 are as defined in claim 1;
R22 is selected from the group consisting of hydrogen, fluorine, C1-C8-alkyl; and
R23 is hydrogen.

### Claim 10 (depends on 1)

The compound of claim 1, where R3 is hydrogen or C1-C4-alkyl.

### Claim 11 (depends on 1)

The compound of claim 1, where R4 is C1-C4-alkyl.

### Claim 12 (depends on 1)

The compound of claim 1, where X2 is C—R5 and R5 is hydrogen, fluorine, C1-C4-alkoxy or a radical O—Z5—Ar5.

### Claim 13 (depends on 12)

The compound of claim 12, where R4 is methyl and R5 is hydrogen, fluorine or methoxy.

### Claim 14 (depends on 1)

The compound of claim 1, which is a compound of the formula (Ia)

### Claim 15 (depends on 14)

The compound of claim 14, where
R1 is a moiety Z1—Ar1;
R2 is a radical of the formula CR21R22R23:
R3 is hydrogen or C1-C4-alkyl;
R4 is C1-C4-alkyl, and
R5 is hydrogen, fluorine or C1-C4-alkoxy.

### Claim 16 (depends on 14)

The compound of claim 14, where R4 is methyl and R5 is hydrogen, fluorine or methoxy.

### Claim 17 (depends on 14)

The compound of claim 14, where R4 is methyl and R5 is O—Z5—Ar5.

### Claim 18 (depends on 1)

The compound of claim 1, which is selected from the group consisting of
6,7-Dimethoxy-1-oxo-2-phenethyl-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide,
6,7-Dimethoxy-2-(2-methoxy-benzyl)-1oxo-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide,
2-Ethyl-7-methoxy-1-oxo-6-(2-quinolin-2-yl-ethoxy)-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide,
2-Ethyl-7-methoxy-1-oxo-6-(3-quinolin-2-yl-propoxy)-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide,
7-Methoxy-1oxo-2-(2quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylic acid butylamide, and
7-Methoxy-1oxo-2-(2quinolin-2-yl-ethyl)-1,2-dihydro-isoquinoline-4-carboxylic acid indan-1-ylamide.

### Claim 19 (depends on 1)

The compound of claim 1, which is selected from the group consisting of
N-Indan-1-yl-6,7-dimethoxy-2-[2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-carboxamide,
N-Butyl-6,7-dimethoxy-2- [2-(5-methyl-2-pyridyl)ethyl]-1-oxo-isoquinoline-4-carboxamide,
N-Butyl-6,7-dimethoxy-1-oxo-2-[2-(2-quino¬lyl)ethyl]isoquinoline-4-carboxamide, and
N-Indan-1-yl-6,7-dimethoxy-1oxo-2-[2-(2quino¬lyl)ethyl]iso¬quinoline-4-carboxamide.

### Claim 20 (depends on 1)

The compound of claim 1, wherein Ar5 is a monocyclic hetaryl substituted with two radicals Rk that are bound to adjacent carbon atoms and together with said carbon atoms form a fused benzene ring or a fused 5- or 6-membered heteroaromatic ring having 1 or 2 ring members selected from the group consisting of O, N and S, where the fused benzene ring and the fused heteroaromatic ring are unsubstituted or may carry 1, 2 or 3 radicals Rh.

### Claim 21 (depends on 20)

The compound of claim 20, where two radicals Rk that are bound to adjacent carbon atoms and together with said carbon atoms form an unsubstituted fused benzene ring.

### Claim 22 (depends on 1)

The compound of claim 1, where Ar1 is an unsubstituted bicyclic 9- or 10-membered hetaryl, where hetaryl has 1, 2 or 3 heteroatoms as ring members which are selected from the group consisting of O, S and N.