HK1142068A - Isoquinolinone derivatives as nk3 antagonists - Google Patents

Description

Isoquinolinone derivatives as NK3 antagonists

Technical Field

The present invention relates to compounds useful in therapy, in particular for the treatment of psychosis, compositions comprising said compounds, and methods of treating disease comprising administering said compounds.

Background

Currently approved antipsychotic drugs share a common feature of reducing dopamine signaling in the brain. This is achieved by the effect of dopamine D2 receptor antagonists or partial agonists. The first generation of antipsychotic drugs (also referred to as "typical") are often associated with extrapyramidal side effects, and thus the use of these drugs has been reduced. Second generation or "atypical" antipsychotics have, in addition to the affinity for the D2 receptor, the receptor for the 5-hydroxytryptamine 2A (5-HT)_2A) Also has affinity. In addition, some atypical antipsychotics also have a para-5-HT profile_2C、5-HT₆Or 5-HT₇The affinity of the receptor. Atypical antipsychotics cause fewer extrapyramidal side effects, but are still affected by the effects of weight gain and QTc. Atypical examples are clozapine, olanzapine and risperidone.

Recently, neurokinin receptors have been proposed and targeted in Central Nervous System (CNS) diseases [ Albert, Expert opin. ther. patents, 14, 1421-. Neurokinins (or tachykinins) are a family of neuropeptides that include Substance P (SP), neurokinin a (nka), and neurokinin b (nkb). The biological effects of these substances are mainly achieved by binding and activating three neurokinin receptors, NK1, NK2 and NK 3. Although there may be some cross-reactivity, SP has the highest affinity and is considered to be an endogenous ligand for NK1, NKA and NK2, and NKB and NK 3.

NK3 is expressed predominantly in regions that concentrate in the cortex, including areas of the cortex such as the frontal lobe, parietal lobe and cortex of the cingulate; amygdala such as the basal, central and lateral nuclei; sea horses; and midbrain structures such as the ventral tegmental area, substantia nigra pars compacta, and dorsal raphe nucleus [ Spooren et al, Naturereviews, 4, 967-]. The NK3 receptor is expressed on dopaminergic neurons and Spooren et al suggest that the antipsychotic effects of NK3 antagonists are through inhibition of dopamine states, especially at the D2 receptor, and 5-HT, especially_2AThe receptor is jointly mediated by a decrease in serotonin status.

Two structurally different NK3 antagonists, namely talnetant and osanetant, have been clinically tested for antipsychotic and especially anti-schizophrenia effects.

Oxosanetant talnetant

Osanetant proved superior to placebo [ am.j. psychiatry, 161, 2004, 975-. Similarly, talnetant was shown to improve cognitive performance in clinical trials in schizophrenia [ curr. opin. invest. drug, 6, 717. 721, 2005 ]. However, both compounds are limited by poor pharmacokinetic and pharmacodynamic properties, including poor solubility, poor bioavailability, relatively high clearance, and poor blood-brain barrier penetration [ Nature reviews, 4, 967-. These results support the notion that the NK3 receptor is a promising target for the treatment of e.g. psychosis, but underline the need to identify compounds with appropriate pharmacokinetic and pharmacodynamic properties.

WO95/32948 discloses a series of quinoline derivatives, including talnetant as NK3 antagonists.

More recently, WO 2006/130080 discloses compounds having the following core structure

These compounds are known as NK3 antagonists; WO 2006/050991 and WO2006/050992 disclose additional quinoline carboxamide derivatives, which are said to be NK3 antagonists.

WO 2005/014575 discloses compounds of the formula

Wherein R represents a N-containing heterocyclic ring, i.e. pyrazolyl, triazolyl and tetrazolyl.

Finally, Ind.J.chem.section B, 18B, 304-306, 1979 discloses synthetic studies of compounds having the following core structure

Summary of The Invention

The present inventors have surprisingly found that certain isoquinolinone (isoquinolone) derivatives are potent NK3 antagonists, which can be used as such for the treatment of e.g. psychosis. Thus, in one embodiment, the invention relates to compounds of formula I

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) -C_1-6Alkyl, -C (O) -C_2-6Alkenyl, -C (O) -C_2-6Alkynyl, -C (O) -O-C_1-6Alkyl, -C (O) -O-C_2-6Alkenyl, -C (O) -O-C_2-6Alkynyl or phenyl, wherein said phenyl, C_1-6Alkyl radical, C _2-6Alkenyl or C_2-6Alkynyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein X represents hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Or X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic, bicyclic or tricyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) — O₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -C_2-6Alkenyl, -C (O) -C_2-6Alkynyl, -C (O) -O-C_1-6Alkyl, -C (O) -O-C_2-6Alkenyl, -C (O) -O-C_2-6Alkynyl, -O-C (O) -C_1-6Alkyl, -O-C (O) -C_2-6Alkenyl, -O-C (O) -C_2-6Alkynyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O) ₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein each R⁴-R⁸、R⁹-R¹²And R¹³-R¹⁷Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, NR²R³Hydroxy, cyano, nitro, C_1-6Alkoxy, halo C_1-6Alkyl or hydroxy C_1-6An alkyl group;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

In one embodiment, the invention relates to compounds of formula I and pharmaceutically acceptable salts thereof for use in therapy.

In one embodiment, the present invention relates to pharmaceutical compositions comprising compounds of formula I and pharmaceutically acceptable salts thereof.

In one embodiment, the present invention relates to a method of treatment comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I and pharmaceutically acceptable salts thereof.

In one embodiment, the present invention relates to the use of compounds of formula I and pharmaceutically acceptable salts thereof for the manufacture of medicaments.

In one embodiment, the invention relates to compounds of formula I and pharmaceutically acceptable salts thereof for use in the treatment of diseases.

Definition of

In this context, "alkyl" is intended to mean straight, branched and/or cyclic saturated hydrocarbons. In particular, "C_1-6Alkyl "is intended to mean such hydrocarbons having 1, 2, 3, 4, 5, or 6 carbon atoms. C_1-6Examples of alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methyl-propyl, tert-butyl, and cyclopropylmethyl.

In this context, "alkenyl" is intended to mean straight, branched and/or cyclic hydrocarbons comprising at least one carbon-carbon double bond. In particular, "C_2-6Alkenyl "is intended to mean such hydrocarbons having 2, 3, 4, 5, or 6 carbon atoms. C_2-6Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, and cyclohexenyl.

In this context, "alkynyl" is intended to mean straight, branched and/or cyclic hydrocarbons comprising at least one carbon-carbon triple bond and optionally one or more carbon-carbon double bonds. In particular, "C _2-6Alkynyl "is intended to mean such hydrocarbons having 2, 3, 4, 5, or 6 carbon atoms. C_2-6Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 5-but-1-en-3-ynyl.

"halogen" herein is intended to mean a member of group 7 of the periodic system, such as fluorine, chlorine, bromine, and bromine.

As used herein, "alkoxy" is intended to mean a moiety of formula-OR ', wherein R' represents an alkyl group as defined above. In particular, "C_1-6Alkoxy "is intended to mean a moiety wherein the alkyl moiety has 1, 2, 3, 4, 5, or 6 carbon atoms.

In this context, haloalkyl is intended to mean an alkyl group as defined above substituted by one or more halogens. In particular, halo C_1-6Alkyl is intended to mean a moiety wherein the alkyl moiety has 1, 2, 3, 4, 5, or 6 carbon atoms. An example of haloalkyl is trifluoromethyl.

As used herein, pharmaceutically acceptable salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, sulfamic acid, nitric acid, and the like.

Examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, dimethylene salicylic (bismethylene salicylic), ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic, theophylline acetic, and 8-halotheophyllines such as 8-bromotheophylline and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in j.pharm.sci.1977, 66, 2, which are incorporated herein by reference.

Examples of the metal salt include lithium salt, sodium salt, potassium salt, magnesium salt and the like.

Examples of ammonium salts and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, and tetramethylammonium salts and the like.

Herein, "ring atom" is intended to mean an atom constituting a ring, and the ring atom is selected from C, N, O and S. As an example, benzene and toluene both have 6 carbons as ring atoms, while pyridine has 5 carbons and 1 nitrogen as ring atoms.

As used herein, "monocyclic moiety" is intended to mean a ring-forming structure comprising only one ring. Similarly, "two-ring portion" is intended to mean a structure of two connecting rings. The two rings may be connected at two adjacent ring atoms of each ring, in which case the bicyclic moiety is said to be fused. Naphthalene is an example of a fused bicyclic moiety. Alternatively, the two rings may be joined at a single ring atom, in which case the bicyclic moiety is said to be spirocyclic. 1, 4-dioxa-8-aza-spiro [4.5] decane is an example of a spiro bicyclic moiety. Alternatively, the two rings may be joined at two non-adjacent ring atoms of each ring, in which case the bicyclic moiety is referred to as caged. 3-aza-bicyclo [3.2.2] nonane is an example of a caged bicyclic moiety. "tricyclic moiety" is intended to mean a structure of three connecting rings. As discussed above for the bicyclic moieties, the tricyclic moieties may be fused, spiro or cage-like, or indeed a combination thereof.

As used herein, the term "therapeutically effective amount" of a compound refers to an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a particular disease and/or its complications in a therapeutic intervention that includes the administration of the compound. An amount sufficient to achieve these objectives is defined as a "therapeutically effective amount". The effective amount for each purpose will depend, for example, on the severity of the disease or injury and the weight and general condition of the subject. It will be appreciated that the appropriate dosage may be determined by constructing a valuable model and measuring various points in the model using routine experimentation, all within the routine skill of a trained physician.

Herein, the terms "treatment" and "treating" refer to the treatment and care of a patient for the purpose of combating a condition, such as a disease or disorder. The term is intended to encompass the full range of treatments for which a patient is suffering from a particular condition, such as the administration of the active compound to alleviate symptoms or complications, to delay the progression of a disease, disorder, or condition, to alleviate or slow symptoms and complications, and/or to cure or eliminate a disease, disorder, or condition and to prevent a condition, where prevention is to be understood as the treatment and care of a patient for the purpose of combating a disease, disorder, or condition, which includes the administration of the active compound to prevent the onset of symptoms or complications. Nevertheless, prophylactic (prevention) and therapeutic (cure) treatment are two separate aspects of the present invention. The patient to be treated is preferably a mammal, especially a human.

Detailed Description

The compounds of the present invention are defined by the following formula I

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) -C_1-6Alkyl, -C (O) -C_2-6Alkenyl, -C (O) -C_2-6Alkynyl, -C (O) -O-C_1-6Alkyl, -C (O) -O-C_2-6Alkenyl, -C (O) -O-C_2-6Alkynyl or phenyl, wherein said phenyl, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro radicals、C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein X represents hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Or X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic, bicyclic or tricyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) — O₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -C_2-6Alkenyl, -C (O) -C_2-6Alkynyl, -C (O) -O-C _1-6Alkyl, -C (O) -O-C_2-6Alkenyl, -C (O) -O-C_2-6Alkynyl, -O-C (O) -C_1-6Alkyl, -O-C (O) -C_2-6Alkenyl, -O-C (O) -C_2-6Alkynyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moietyIs optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein each R⁴-R⁸、R⁹-R¹²And R¹³-R¹⁷Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, NR²R³Hydroxy, cyano, nitro, C_1-6Alkoxy, halo C_1-6Alkyl or hydroxy C_1-6An alkyl group;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

In one embodiment, R⁴-R⁸Represents hydrogen.

In one embodiment, R⁹-R¹²Represents hydrogen.

In one embodiment, R¹³-R¹⁷Represents hydrogen.

In one embodiment, the compounds of the invention are prepared by the following formula I_aDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein X represents hydrogen, C_1-6Alkyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Or X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic, bicyclic or tricyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) — O₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH) ₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein each R⁴-R⁸、R⁹-R¹²And R¹³-R¹⁷Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, NR²R³Hydroxy, cyano, nitro, C_1-6Alkoxy, halo C_1-6Alkyl or hydroxy C_1-6An alkyl group;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A represents CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_aDefinitions in which X represents hydrogen, C _1-6Alkyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³-、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl. In particular, X represents hydrogen, methyl, or NR²R³Wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, or hydroxy C_1-6Alkyl, and especially R²And R³Independently represents hydrogen, cyclopropylmethyl, methyl, ethyl or cyclopropyl.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_aDefinitions, wherein X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three additional ring atoms may be a heteroatom selected from N, O and S, and wherein said monocyclic, bicyclic or tricyclic moiety may optionally be substituted with one or more substituents selected from the group consisting of alkyl, aryl, heteroarylMultiple substituents W, wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -O-C (O) -, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR ²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_aDefinitions wherein X represents a monocyclic moiety having 5 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), — O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro)、C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C _1-6Alkyl, -O-C (O) -, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl. Examples of such monocyclic moieties having 5 ring atoms include pyrrole, 2H-pyrrole, pyrazole, isothiazole, pyrrolidine, pyrroline, tetrazole, imidazolidine, imidazoline, pyrazolidine, and pyrazoline.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_aDefinitions wherein X represents a monocyclic moiety having 6 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), — O- (CH) ₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -O-C (O) -, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl. Examples of such monocyclic moieties having 6 ring atoms include pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, dihydropyridine, tetrahydropyridine, and morpholine.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I _aDefinitions wherein X represents a monocyclic moiety having 7 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), — O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_2-6Alkene(s)Base, C_2-6Alkynyl, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

Wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl. Examples of such monocyclic moieties having 7 ring atoms include azepane (azepane), [1, 4 ]]Diazepane (diazepane), and 2, 3, 4, 5-tetrahydro-1H- [1, 4]Diazepane.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_aDefinitions wherein X represents a monocyclic or bicyclic moiety having 8 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic (cyclic) or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) — O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or6 (spiro) and C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C _1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl. Examples of such monocyclic or bicyclic moieties having 8 ring atoms include quinuclidine (quinnunolidine), 8-aza-bicyclo [3.2.1]Octane and 2-aza-bicyclo [2.2.2]Octane.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_aDefinitions wherein X represents a monocyclic or bicyclic moiety having 9 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein said monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) ₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical、C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl. Examples of such monocyclic or bicyclic moieties having 9 ring atoms include indolizine, isoindole, 3H-indole, 1H-indazole, purine, indoline and isoindoline.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_aDefinitions wherein X represents a monocyclic or bicyclic moiety having 10 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein said monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl. Examples of such monocyclic or bicyclic moieties having 10 ring atoms include 4H-quinolizine, isoquinoline, quinoline, 2, 3-naphthyridine (phthalazine), naphthyridine (naphthyridine), quinoxaline, cinnoline, pteridine (pterridine), 1, 2, 3, 4-tetrahydro-isoquinolinone, 1, 4, 8-triaza-spiro [4.5 ] e]Decane and 1, 2, 3, 4-tetrahydro-quinoline.

In one embodiment, the compounds of the invention are prepared by the following formula I_bDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH) ₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A represents CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_bDefinition, wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C _1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl. In a further embodiment, Y represents a bond, C (O) or S (O)₂(ii) a Wherein a + b is O, 1, 2, 3, or 4; and wherein Z represents a monocyclic or fused bicyclic moiety comprising 5 to 12 carbon ring atoms and optionally one, two or three heteroatoms selected from N, O, and S, and wherein said monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl. Of particular mention are embodiments wherein Y represents a bond or c (O), and a + b is O, 1, 2, or 3. In particular, Z comprises 5 to 9 ring atoms, for example 5, 6, or 9 ring atoms. Examples of Z having 5 ring atoms include pyrolide (pyrrolidone) and a ring A pentyl group; examples of Z having 6 ring atoms include phenyl, pyrimidinyl, morpholinyl, and pyridinyl; examples of Z having 9 ring atoms include furo [3.2-c ]]A pyridyl group. Specific examples of Z are morpholinyl, which is attached to the rest of the W moiety, e.g. via nitrogen, and optionally substituted by one or more substituents, wherein said substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl. Another specific example of Z is piperidinyl, which is attached to the remainder of the W moiety, e.g. via nitrogen, and is optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl. Another specific example of Z is pyridyl, which is attached to the remainder of the W moiety, e.g., via nitrogen. Another specific example of Z is pyridinyl, which is attached to the remainder of the W moiety, e.g. at its 2, 3 or 4 position, and is optionally substituted by one or more substituents, wherein said substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl. Another specific example of Z is phenyl, optionally substituted with one or more substituents selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl. Another specific example of Z is pyrrolidinyl, optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl. Another specific example of Z is indolyl, for example attached at its 4, 5, 6, or 7 position to the rest of the W moiety, and optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl. Other specific examples of Z include cyclopentyl, furopyridinyl, and,Tetrahydrofuranyl, benzo [1.4 ]]Oxazinyl, benzo [1.4 ]]Dioxinyl, benzo [1.2.5 ]]Thiadiazoles, and quinazolinyl groups.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_bDefinitions, wherein Y represents a bond, C (O), -C (O) -O-, C (O) -NH-, -O-, or S (O)₂(ii) a a + b is O, 1, 2, 3, or 4; and wherein Z represents hydrogen, C_1-6Alkyl (e.g. methyl, isopropyl, isobutyl or tert-butyl), NR ²R³Or a cyano group.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_bDefinitions, wherein a represents CH; r¹Represents C_1-6Alkyl, such as ethyl or cyclopropyl, W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), - (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH.

In one embodiment, the compounds of the invention are prepared by the following formula I_cDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR ²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A represents CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_cWherein W independently represents hydrogen, hydroxy, phenyl, C_1-6Alkoxy-substituted phenyl, piperidinyl, pyridinyl, -O- (CH)₂)_C-O- (wherein c is 2 or 3 (spiro)), N (CH)₃)₂、C_1-6Alkyl, - (CH)₂)_a-C(O)-O-(CH₂)_b-H (wherein a + b is 1, 2, or 3), or

Wherein a represents 1, 2, or 3.

In one embodiment, the compounds of the invention are prepared by the following formula I_dDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R ¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; wherein R is⁹-R¹²Independently represents hydrogen or halogen; and pharmaceutically acceptable salts thereof. In particular, A is CH and R¹Represents C_1-6Alkyl, such as ethyl or cyclopropyl, and each R⁹-R¹²Independently represents hydrogen or halogen.

In one embodimentIn another embodiment, the compounds of the invention are prepared by the following formula I_eDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

Wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A is CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl. In particular, Z comprises 5 to 9 ring atoms, for example 5, 6, or 9 ring atoms. Examples of Z having 5 ring atoms include pyrrolide and cyclopentyl; examples of Z having 6 ring atoms include phenyl, pyrimidinyl, morpholinyl, and pyridinyl; examples of Z having 9 ring atoms include furo [3.2-c ] ]A pyridyl group.

In one embodiment, the compounds of the invention are prepared by the following formula I_fDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A is CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl. In particular, Z comprises 5 to 9 ring atoms, for example 5, 6, or 9 ring atoms. Examples of Z having 5 ring atoms include pyrrolide and cyclopentyl; examples of Z having 6 ring atoms include phenyl, pyrimidinyl, morpholinyl, and pyridinyl; examples of Z having 9 ring atoms include furo [3.2-c ]]A pyridyl group.

In one embodiment, the compounds of the invention are prepared by the following formula I_gDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,-C(O)-C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C _1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -N (R)²)-C(O)-R³-C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A is CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl. In particular, Z comprises 5 to 9 ring atoms, for example 5, 6, or 9 ring atoms. Having 5 ring atomsExamples of Z of the subgroups include pyrrolide and cyclopentyl; examples of Z having 6 ring atoms include phenyl, pyrimidinyl, morpholinyl, and pyridinyl; examples of Z having 9 ring atoms include furo [3.2-c ] ]A pyridyl group.

In one embodiment, the compounds of the invention are prepared by the following formula I_hDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or monocyclic or fused bicyclic ring containing 4 to 12 ring atomsWherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents selected from halo, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A is CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl. In particular, Z comprises 5 to 9 ring atoms, for example 5, 6, or 9 ring atoms. Examples of Z having 5 ring atoms include pyrrolide and cyclopentyl; examples of Z having 6 ring atoms include phenyl, pyrimidinyl, morpholinyl, and pyridinyl; examples of Z having 9 ring atoms include furo [3.2-c ]]A pyridyl group.

In one embodiment, the compounds of the invention are prepared by the following formula I_iDefinition of

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWhich isWherein d is 5 or 6 (spiro), C _1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein X represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A is CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl. In particular, Z comprises 5 to 9 ring atoms, for example 5, 6, or 9 ring atoms. Examples of Z having 5 ring atoms include pyrrolide and cyclopentyl; examples of Z having 6 ring atoms include phenyl, pyrimidinyl, morpholinyl, and pyridinyl; examples of Z having 9 ring atoms include furo [3.2-c ] ]A pyridyl group.

In one embodiment, the compounds of the present invention are defined by the following formula Ij

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein X represents hydrogen, C_1-6Alkyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Or X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic, bicyclic or tricyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) — O₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR ²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or containing 4 to 12 ring atomsA monocyclic or fused bicyclic moiety of a nucleus wherein optionally one, two or three ring atoms are heteroatoms selected from N, O, and S, and wherein said monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is⁴-R⁸One represents halogen and the others represent hydrogen; wherein R is¹³-R¹⁷One represents halogen and the others represent hydrogen;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl; and pharmaceutically acceptable salts thereof. In particular, A represents CH and R¹Represents C_1-6Alkyl groups such as ethyl or cyclopropyl; r¹⁴Represents halogen; and R⁵Or R⁸Represents halogen. In a particularly mentioned embodiment, wherein X represents piperazinyl or 1-piperidinyl substituted with one or two substituents W, wherein W is of the formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z; wherein a and b independently represent a group selected from O, 1, 2 and 3; y represents a bond, O, -NR²-c (o) -; and wherein Z represents hydrogen, C_1-6Alkyl, piperidinyl, morpholinyl, pyridinyl, phenyl, or C _1-6Alkoxy-substituted phenyl, or pyrrolidinyl.

In one embodiment, the compounds of the invention are prepared by the following formula I_kDefinition of

Wherein R is¹Represents hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

wherein X represents hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or NR²R³Or X represents a monocyclic or bicyclic moiety having 5 to 9 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, halogen, hydroxy, (═ O), C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, or wherein W represents a group of formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, and wherein Z represents a monocyclic moiety comprising 5 to 6 ring atoms, wherein optionally one, two or three ring atoms are heteroatoms selected from N, O, and S, and wherein the monocyclic moiety is optionally substituted by one or more substituents selected from halogen, C_1-6Alkyl, hydroxy, and C_1-6The substituent of the alkoxy group is substituted,

wherein each R⁴-R⁸Independently represents hydrogen or halogen;

wherein each R⁹-R¹²Independently represents hydrogen or halogen, provided that R ⁹-R¹²At least one of them represents halogen;

wherein each R¹³-R¹⁷Independently represents hydrogen or halogen;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6An alkynyl group; and pharmaceutically acceptable salts thereof. In particular, by the formula I_kThe defined compounds may be further defined by formula I_k' definition

Wherein R is¹Is selected from C_1-6An alkyl group;

wherein X represents hydrogen, C_1-6Alkyl, or NR²R³Or X represents a monocyclic or bicyclic moiety having 5 to 9 ring atoms, wherein one ring atom is nitrogen and wherein another ring atom may be a heteroatom selected from N, and wherein said monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, (═ O), C_1-6Alkyl or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, and wherein Z represents a monocyclic moiety comprising 5 to 6 ring atoms, wherein optionally one ring atom is a heteroatom selected from N, O, and S, and wherein the monocyclic moiety is optionally substituted by one or more substituents selected from halogen, C_1-6Alkyl, hydroxy, and C_1-6The substituent of the alkoxy group is substituted,

wherein R is¹²Represents halogen;

R¹³-R¹⁵each independently represents hydrogen or halogen;

and pharmaceutically acceptable salts thereof. In particular, R ¹Represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and X represents

-NR²R³Or hydrogen

Indicates the attachment site

In one embodiment, wherein the compounds of the invention are prepared by reacting a compound of formula I_k' Definitions and R¹Represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and X represents

And wherein W represents hydrogen, (═ O), C_1-6-alkyl, or- (CH)₂)_a-Y-(CH₂)_b-Z. In particular, W represents hydrogen, methyl, cyclopropylmethyl, isopropyl, isobutyl, tert-butyl, (═ O), or- (CH)₂)_a-Y-(CH₂)_a-Z, wherein a + b is 2 and Z is selected from 4-morpholinyl, phenyl, 1-piperidine or 1-pyrrolidinyl.

In one embodiment, wherein the compounds of the invention are prepared by reacting a compound of formula I_k' Definitions and R¹Represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and X represents

Wherein W represents hydrogen, hydroxy, C_1-6-alkyl, or- (CH)₂)_a-Y-(CH₂)_a-Z. In particular, W represents hydrogen, hydroxy, tert-butyl, or a + b is 0 or 2, and Z represents 4-morpholinyl, optionally substituted by C_1-6Alkoxy-substituted phenyl, or 4-piperidinyl.

In one embodiment, wherein the compounds of the invention are prepared by reacting a compound of formula I_k' Definitions and R¹Represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and X represents Watch (A)

And W represents (═ O), and in particular, X represents

In one embodiment, wherein the compounds of the invention are prepared by reacting a compound of formula I_k' Definitions and R¹Represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, X represents-NR²R³. In particular, R²And R³Independently represent hydrogen or C_1-6-alkyl, and the compounds specifically mentioned are those in which R is²Represents hydrogen, and R³Represents cyclopropyl, isobutyl or tert-butyl.

In one embodiment, wherein the compounds of the invention are prepared by reacting a compound of formula I_k' Definitions and R¹Represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and X is hydrogen.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_k"definition of

Wherein R is¹Represents ethyl, cyclopropyl or cyclobutyl;

wherein R is¹²Represents fluorine or chlorine; and

R¹³、R¹⁴and R¹⁵Each independently represents hydrogen, fluorine or chlorine, wherein R¹³、R¹⁴And R¹⁵Two of (a) represent hydrogen, and pharmaceutically acceptable salts thereof.

In particular, the compounds are substantially of formula I_k"the S enantiomer of

Wherein R is¹Represents ethyl or cyclopropyl;

wherein R is¹²Represents fluorine or chlorine; and

R¹³、R¹⁴and R¹⁵Each independently represents hydrogen, fluorine or chlorine, wherein R¹³、R¹⁴And R¹⁵Two of which represent hydrogen.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I _d' definition

Wherein R is¹Represents ethyl or cyclopropyl;

R¹²represents halogen;

R¹³、R¹⁴and R¹⁵Each independently represents hydrogen, or halogen;

and pharmaceutically acceptable salts thereof.

In one embodiment, the compounds of the invention are prepared by reacting a compound of formula I_d"definition of

Wherein R is¹Represents ethyl or cyclopropyl;

wherein R is¹²Represents chlorine or fluorine;

R¹²、R¹⁴and R¹⁵Each independently represents hydrogen, chlorine or fluorine, wherein R¹²、R¹⁴And R¹⁵Two of them represent hydrogen;

and pharmaceutically acceptable salts thereof. In particular, said compounds are essentially the S enantiomer described by the formula Id' ″

Wherein R is¹Represents ethyl or cyclopropyl;

wherein R is¹²Represents chlorine or fluorine;

R¹²、R¹⁴and R¹⁵Each independently represents hydrogen, chlorine or fluorine, wherein R¹²、R¹⁴And R¹⁵Two of them represent hydrogen;

and pharmaceutically acceptable salts thereof.

In one embodiment, the compounds of the present invention are selected from the following list. For convenience, the numbers designated in bold font before the compound name refer to the numbers of the corresponding examples.

1a 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1b 3, 6-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1c 7-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1d 7-bromo-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1e 6-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1f 3, 5-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1g 7-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1h 3, 7-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1i 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1r 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide

1S 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1j 3, 8-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1k 2- (2-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1l 3-methyl-1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1m 2- (2-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1n 2- (2, 6-difluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1o 2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1p 3-methyl-1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1q 2- (3-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1t 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2a 3-dimethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2b 3-methylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2c 3-Ethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2d 3-Cyclopropylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2e 3- [ (cyclopropylmethyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2f 3- (3, 6-dihydro-2H-pyridin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2g 3- [4- (2-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2h 3- [4- (4-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2i 3- (4-formyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2j 4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-carboxylic acid ethyl ester

2k 3- (4-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2l 1-oxo-2-phenyl-3- (1, 3, 4, 9-tetrahydro- β -carbolin-2-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2m 1-oxo-2-phenyl-3-piperazin-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2n 3- (3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2o 3- (3, 5-dimethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2p 3- (4-benzyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2q 1-oxo-3- [4- (2-oxo-2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2r 3-Morpholin-4-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2S 3- (2, 6-dimethyl-morpholin-4-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2t 1-oxo-phenyl-3-thiomorpholin-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2u 3- (1, 4-dioxa-8-aza-spiro [4.5] dec-8-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2v 1-oxo-2-phenyl-3-piperidin-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2w 3- (2-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2x 3- (2, 6-dimethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2y 3- (2-hydroxymethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2z 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine-3-carboxylic acid ethyl ester

2aa 3- (3-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ab 3- (4-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ac 1-oxo-2-phenyl-3- (4-phenyl-piperidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ad 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine-4-carboxylic acid ethyl ester

2ae 3- (4-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2af 1-oxo-2-phenyl-3- (4-pyridin-2-yl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ag 3- (octahydro-quinolin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ah 3-azepan-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ai 3- (3-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2aj 3- [4- (2, 4-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ak 3- [4- (3, 4-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2al 3- (4-dimethylamino-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2am 3- [4- (2, 5-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2an 3- [4- (2-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ao 3- [4- (3-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ap 1-oxo-2-phenyl-3- (4-m-tolyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2aq 3- [4- (4-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ar 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2as 1-oxo-2-phenyl-3- (4-pyrimidin-2-yl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2at 3- [4- (2-cyano-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2au 3- [4- (4-chloro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2av 3- ((1S, 3R, 5R) -3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2aw 3- (4-acetyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ax 3- (4-methyl- [1, 4] diazepan-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ay 3- (4-ethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2az 3- ((2S, 6R) -2, 6-dimethyl-morpholin-4-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ba 3- [4- (2, 4-difluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bb 3- [4- (3-dimethylamino-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bc 3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bd 3- (3-aza-bicyclo [3.2.2] non-3-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2be 3- (4-cyclopentyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bf 3- [1, 4 '] Bipiperidinyl (biperidinyl) -1' -ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bg 3- (3, 4-dihydro-1H-isoquinolin-2-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bh 3- [4- (2-dimethylamino-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bi 3- (4-hydroxymethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bj 1-oxo-2-phenyl-3- [4- (tetrahydro-furan-2-carbonyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bk 3- (4-isobutyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bl 3- [4- (2-methoxy-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bm 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bn 3- (1, 3-dihydro-isoindol-2-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bo 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bp 1-oxo-2-phenyl-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bq 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2br 3- (4-dimethylcarbamoylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bs 3- (octahydro-pyrido [1, 2-a ] pyrazin-2-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bt 3- (4-formyl- [1, 4] diazepan-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bu 3- [4- (4-cyano-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bv 1-oxo-2-phenyl-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bw 1-oxo-2-phenyl-3- [4- (3-pyrrolidin-1-yl-propyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bx 1-oxo-2-phenyl-3- (4-pyridin-2-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2by 3- (4-ethanesulfonyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bz 3- (4-sec-butyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ca 3- [4- (1-ethyl-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cb 3- [4- (2-cyano-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cc 3- (4-methanesulfonyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cd {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -acetic acid ethyl ester

2ce 3- [4- (3-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cf 1-oxo-2-phenyl-3- ((S) -3-phenyl-piperidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cg 1-oxo-2-phenyl-3- [4- (pyrrolidine-1-carbonyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ch 3- [4- (morpholine-4-carbonyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ci 3- (4-methoxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

cj 3- (4 '-hydroxy-3', 4 ', 5', 6 '-tetrahydro-2' H- [3, 4 '] bipyridinyl-1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ck 3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cl 3- (3H-spiro [ isobenzofuran-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cm 3- (4-hydroxy-4-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cn 3- (hexahydro-spiro [ benzo [1, 3] dioxol-2, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2co 1-oxo-2-phenyl-3- (3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cp 3- [4- (2-dimethylamino-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cq 3- (4-dimethylsulfamoyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cr 3- (1, 1-dioxo-thiomorpholin-4-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cs 1-oxo-2-phenyl-3- (2-pyridin-2-ylmethyl-piperidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ct 3- (2-morpholin-4-ylmethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cu 3- (4-furo [3, 2-c ] pyridin-4-yl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cv 3- (4-cyclopropylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cw 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cx 1-oxo-2-phenyl-3- (4-pyrimidin-2-yl- [1, 4] diazepan-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cy 3- (4-methyl-6, 7-dihydro-4H-thieno [3, 2-c ] pyridin-5-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cz 3- [1, 4] diazepan-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2da 3- ((2S, 5R) -2, 5-dimethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2db 3- ((S) -3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dc 3- ((R) -3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dd 3- [3- (3-chloro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2de 3- [4- (1H-indol-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2df 1-oxo-3- (3-oxo-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dg 3- [4- (1H-indol-5-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dh 3- (6, 9-diaza-spiro [4.5] decan-9-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dj 3- (1, 4-diaza-spiro [5.5] undec-4-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dj 3- (3-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dk 3- (3, 3-dimethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dl 3- [3- (4-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dm 1-oxo-2-phenyl-3- (3-p-tolyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dn 4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-carboxylic acid tert-butyl ester

2do 3- (4-methylcarbamoylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dp 8-chloro-3-dimethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dr 3-cyclopentylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ds 3-Cyclohexylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dt 3- { [ (2-hydroxy-ethyl) -methyl-amino ] -methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2du 3-imidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dv 3- (2-methyl-imidazol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dw 3- (4-methyl-imidazol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dx 3- (2, 5-dihydro-pyrrol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dy 3- (2, 5-dimethyl-2, 5-dihydro-pyrrol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dz 1-oxo-2-phenyl-3-pyrrolidin-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ea 1-oxo-2-phenyl-3- (thiazol-2-ylaminomethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eb 1-oxo-2-phenyl-3- (pyrimidin-4-ylaminomethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ec 3- (tert-butylamino-methyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ed 3- [ (2-hydroxy-1, 1-dimethyl-ethylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ee 3- (isopropylamino-methyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ef 3- [ (2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eg 3- [ (1-hydroxymethyl-propylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eh 3- [ (2, 2-dimethyl-propylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ei 1-oxo-2-phenyl-3-prop-2-ynylaminomethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ej 3-allylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ek 3- [ (methyl-prop-2-ynyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2el 3-Diallylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2em 3-diethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2en 3- [ (isopropyl-methyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eo 3- [ ((S) -2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ep 3- [ ((R) -2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eq 3- { [ (2-methoxy-ethyl) -methyl-amino ] -methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2er 3- ((R) -3-hydroxy-pyrrolidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2es 3- ((S) -3-hydroxy-pyrrolidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2et 3- [ (cyclopentyl-methyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eu 3- { [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ev 3- { [ ethyl- (2-hydroxy-ethyl) -amino ] -methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ew 3- [ (ethyl-methyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ex 3-Cyclobutylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ey 3-azetidin-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ez 3- (4-tert-butyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fa 3- [4- (2-hydroxy-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fb 3- {4- [2- (2-hydroxy-ethoxy) -ethyl ] -piperazin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fc 3- [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fd 3- [4- (3, 5-dichloro-pyridin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fe 4- [ 1-oxo-2-phenyl-4- ((S) -1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-carboxylic acid benzyl ester

2ff 3- [4- (3-morpholin-4-yl-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fg 1-oxo-2-phenyl-3- [4- (3-piperidin-1-yl-propyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fh 3- [4- (4, 6-dimethoxy-pyrimidin-2-ylmethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fi 3- [4- (3-hydroxy-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fj 3- [4- (2, 3-dihydroxy-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fk (2-oxo-2- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazin-1-yl } -ethyl) -carbamic acid tert-butyl ester

2fl 3- [4- (1H-indazol-5-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fm 1-oxo-2-phenyl-3- (4-quinolin-6-yl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fn 3- [4- (6, 7-dimethoxy-quinazolin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fo 4- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazin-1-yl } -piperidine-1-carboxylic acid tert-butyl ester

2fp 3- {4- [2- (4-chloro-phenoxy) -ethyl ] -piperazin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fq {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazin-1-yl } -acetic acid tert-butyl ester

2fr 1-oxo-2-phenyl-3- [4- (3, 3, 3-trifluoro-2-hydroxy-propyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fs 3- [4- (2-hydroxy-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fu 3- [4- (4-amino-6, 7-dimethoxy-quinazolin-2-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fv (2- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazin-1-yl } -ethyl) -carbamic acid tert-butyl ester

2fw 1-oxo-3- {4- [2- (2-oxo-imidazolidin-1-yl) -ethyl ] -piperazin-1-ylmethyl } -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fx 3- {4- [ (4, 6-dimethoxy-pyrimidin-2-yl) -phenyl-methyl ] -piperazin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fy 3- (4-benzo [1, 2, 5] thiadiazol-4-yl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fz 3- [4- (2, 3-dihydro-benzo [1, 4] dioxin-5-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ga 3- [4- (4-methyl-quinolin-2-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gb 1-oxo-2-phenyl-3- [4- (pyridin-2-ylcarbamoylmethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gc 3- [4- (6-chloro-3-oxo-3, 4-dihydro-2H-benzo [1, 4] oxazin-8-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gd 3- (4-carbamoylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ge 3- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gf 3- [4- (4-chloro-phenyl) -4-hydroxy-piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gg 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine-4-carboxylic acid

2gh 3- (4-cyano-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gi 3- (4-benzyl-4-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gj 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -4-phenyl-piperidine-4-carboxylic acid ethyl ester

2gk 1-oxo-2-phenyl-3- [4- (phenyl-propionyl-amino) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gl methyl- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -carbamic acid tert-butyl ester

2gm 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gn 3- {4- [5- (4-fluoro-phenyl) - [1, 3, 4] oxadiazol-2-yl ] -piperidin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2go 1-oxo-2-phenyl-3- [4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gp 1-oxo-2-phenyl-3- [4- (3-pyrazin-2-yl- [1, 2, 4] oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gq 1-oxo-2-phenyl-3- [4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gr 3- (4 '-hydroxy-3', 4 ', 5', 6 '-tetrahydro-2' H- [2, 4 '] bipyridinyl-1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gs of 3- (spiro [ isochroman-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gt 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gu 3- [4- (3-chloro-phenyl) -4-hydroxy-piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gv 3- (6-chloro-3H-spiro [ isobenzofuran-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gw 3- (4- { [ 4-chloro-3- (4-fluoro-phenyl) -indan-1-yl ] -methyl-amino } -piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gx 3- (1-acetyl-spiro [ indoline-3, 4 '-piperidine ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gy 3- (1-acetyl-5-fluoro-spiro [ indoline-3, 4' -piperidine ] -r-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gz 1-oxo-3- (4-oxo-1-phenyl-1, 3, 8-triaza-spiro [4.5] decan-8-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ha 3- (4-acetylamino-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hb 1-oxo-3- (1-oxo-2, 8-diaza-spiro [4.5] decan-8-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hc 3- [ 4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hd 1-oxo-2-phenyl-3- (4-trifluoromethyl-piperidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2he 3- [4- (4-methyl-piperazine-1-carbonyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hf 3- (5-isopropyl-3H-spiro [ isobenzofuran-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hg 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hh 4- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester

2hi (2- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -ethyl) -carbamic acid tert-butyl ester

2hj 3- (4-methylamino-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hk 3- (4-acetylamino-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hl 3- [ 4-acetylamino-4- (3-fluoro-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hm 1-oxo-3- [4- (4-oxo-piperidine-1-carbonyl) -piperidin-1-ylmethyl ] -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hn 3- [4, 4' ] bipiperidinyl-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ho {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -carbamic acid tert-butyl ester

2hp 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hq 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hr 3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hs 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ht 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hu 1-oxo-2-phenyl-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hv 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hw 1-oxo-2-phenyl-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hx 3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hy 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hz 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ia 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ib 2- (2-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ic 2- (2-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2id 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (2-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ie 2- (2-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2if 2- (2-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ig 2- (2-fluoro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ih 2- (2-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ii 2- (2-fluoro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ij 2- (2-fluoro-phenyl) -3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ik 2- (2-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2il 2- (2-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2im 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2in 1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2io 1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ip 2- (3-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iq 2- (3-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ir 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (3-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2is 2- (3-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2it 2- (3-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iu 2- (3-fluoro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iv 2- (3-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iw 2- (3-fluoro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ix 2- (3-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iy 2- (3-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iz 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -2- (3-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ja 2- (3-chloro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jb 2- (3-chloro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jc 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (3-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jd 2- (3-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2je 2- (3-chloro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jf 2- (3-chloro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jg 2- (3-chloro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jh 2- (3-chloro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ji 2- (3-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jj 2- (3-chloro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jk 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -2- (3-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jl 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jm 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jn 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jo 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jp 1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jq 1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jr 1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2js 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jt 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ju 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

3a 1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

3b 8-chloro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

4a 3-cyanomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

5a 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid N, N-diphenyl-hydrazide

5b N' - (3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carbonyl) -N-phenyl-hydrazinecarboxylic acid methyl ester

1aa 2- (3-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ab 2- (4-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ac 2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ad 2- (4-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ae 3-methyl-1-oxo-2-p-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1af 2- (3-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ag 2- (4-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ah 2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ai 2- (4-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1aj 3-methyl-1-oxo-2-p-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ak 2- (2-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1al 2- (2-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1am 3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1an 3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ao 8-methoxy-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ap 8-methoxy-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1aq 8-amino-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ar 8-cyano-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1as 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (4-chloro-phenyl) -propyl ] -amide

1at 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (4-fluoro-phenyl) -propyl ] -amide

1au 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (2-fluoro-phenyl) -propyl ] -amide

1av 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (3-chloro-phenyl) -propyl ] -amide

1aw 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) - (3-chloro-phenyl) -cyclopropyl-methyl ] -amide

1ax 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) - (4-chloro-phenyl) -cyclopropyl-methyl ] -amide

1ay 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (3-fluoro-phenyl) -propyl ] -amide

1az 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -2-methyl-1-phenyl-propyl) -amide

1ba 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (4-fluoro-phenyl) -methyl ] -amide

1bb 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (2-chloro-phenyl) -propyl ] -amide

1bc 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopentyl-phenyl-methyl) -amide

1bd 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) - (2-chloro-phenyl) -cyclopropyl-methyl ] -amide

1be 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (2-fluoro-phenyl) -methyl ] -amide

1bf 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclohexyl-phenyl-methyl) -amide

1bg 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide

1bh 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclobutyl- (3-fluoro-phenyl) -methyl ] -amide

1bi 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclobutyl- (4-fluoro-phenyl) -methyl ] -amide

1bl 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (R) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1bn 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) cyclobutyl-phenyl-methyl) -amide

1bo 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclobutyl- (2-fluoro-phenyl) -methyl ] -amide

2ka 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2kb 8-chloro-3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kc 8-chloro-3- (4-isobutyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kd 8-chloro-3- (octahydro-pyrido [1, 2-a ] pyrazin-2-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ke 8-chloro-3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kf 8-chloro-3- (4-cyclopropylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kg of 8-chloro-3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kh 8-chloro-3- [1, 4] diazepan-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ki 8-chloro-3- ((S) -3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kj delta-chloro-S-imidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kk 8-chloro-3- (4-methyl-imidazol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kl 3- (tert-butylamino-methyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2km 8-chloro-3- (isopropylamino-methyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kn 8-chloro-3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ko 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kp 3-benzimidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kq 1-oxo-2-phenyl-3-pyrazol-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kr 3- (4-methyl-pyrazol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ks 1-oxo-2-phenyl-3- [1, 2, 3] triazol-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kt 2- (3-methoxy-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ku 2- (4-methoxy-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kv 2- (4-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kw 2- (4-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kx 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (4-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ky 2- (4-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kz 2- (4-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21a 2- (4-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21b 2- (4-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21c 2- (4-chloro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21d 2- (4-chloro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21e 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (4-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21f 2- (4-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21g 2- (4-chloro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21h 2- (4-chloro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21i 2- (4-chloro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21j 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-fluoro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21k 8-chloro-3-cyclopropylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21l 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-fluoro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

21m 8-fluoro-1-oxo-2-phenyl-3-piperazin-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

21n 8-fluoro-1-oxo-3- (3-oxo-pyrazolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

21o 8-fluoro-1-oxo-3- (3-oxo-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3c 1-oxo-2-phenyl-3- (1H- [1, 2, 4] triazol-3-ylthiomethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

3d 8-chloro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3e 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

3f 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3g 8-fluoro-1-oxo-3- (5-oxo-pyrazolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3h 8-fluoro-1-oxo-3- (2-oxo-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3i 8-fluoro-1-oxo-3- (2-oxo-piperidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

4b 8-chloro-3-cyanomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

6a 2- (3, 4-dichloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

6b 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide

6c 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide

7a 3-Ethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

7b 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

7c 8-fluoro-2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

7d 8-fluoro-2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

7e 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7f 8-fluoro-2- (3-fluoro-phenyl) -1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7g 8-fluoro-2- (4-fluoro-phenyl) -1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7h 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclobutyl- (3-fluoro-phenyl) -methyl ] -amide

7i 8-fluoro-2- (2-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7j 8-fluoro-2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7k 8-fluoro-2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7l 6, 8-difluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7m 5, 8-difluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7n 3-methyl-1-oxo-2-phenyl-8-trifluoromethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

8a 3- (1-tert-butyl-piperidin-4-ylmethyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

And pharmaceutically acceptable salts thereof.

Further, the compounds of the present invention may exist in unsolvated forms as well as solvated forms containing pharmaceutically acceptable solvents such as water, ethanol, and the like. For the purposes of the present invention, the solvated forms are generally considered equivalent to unsolvated forms.

The compounds of the present invention may have one or more asymmetric centers, which is meant to include within the scope of the present invention any optical isomer (i.e., enantiomer or diastereomer) thereof, such as an isolated, purified or partially purified optical isomer and any mixture thereof including racemic mixtures, i.e., mixtures of stereoisomers. In particular, when A represents CH or CR¹When A can be the optical center, two optical isomers are produced: r-form and S-form. In one embodiment, the compounds of the present invention have the S configuration.

In a particular embodiment, the compounds of the invention have the following absolute configuration around A (A is CH)

For example

In this context, it is to be understood that when designated as enantiomeric forms, the compounds are in enantiomeric excess, e.g., in substantially pure form. Accordingly, one embodiment of the present invention relates to compounds of the present invention having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.

The racemic form can be resolved into the optical antipodes by known methods, for example by separation of the diastereomeric salts by optically active acids and treatment with a base to liberate the optically active amine compound. Another method for resolving racemates into the optical antipodes is chromatography on an optically active matrix. The compounds of the present invention may also be resolved by formation of diastereomeric derivatives. Additional methods for resolving optical isomers known to those skilled in the art may be used. Such methods include those described by j.jaques, a.collet and s.wilen in "enertiomers, racemes, and solutions", John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials.

In addition, geometric isomers may be formed when double bonds or fully or partially saturated cyclic systems are present in the molecule. This is meant to include within the scope of the present invention any geometric isomer, such as an isolated, purified, or partially purified geometric isomer or a mixture thereof. Likewise, molecules with rotationally constrained bonds may form geometric isomers. These are also intended to be included within the scope of the present invention.

In addition, some of the compounds of the present invention may exist in different tautomeric forms, and any tautomeric form that can be formed from the compounds is intended to be included within the scope of the present invention.

In addition to the above discussed psychosis and schizophrenia, NK3 receptor antagonists have been implicated in a variety of diseases. Langlois et al J.pharm.Exp.Ther.299, 712-717, 2001 conclude that NK3 antagonists may be useful in CNS disorders in general, and in particular in anxiety and depression. Yip et al, br.j.phar., 122, 715-722, 1997, further suggest that NK3 antagonists are involved in various brain functions such as cortical processing, learning and memory, neuroendocrine and behavioral regulation. Additional studies have shown that NKB and NK3 receptors are involved in pain, and that NK3 antagonists have analgesic and analgesic effects [ Fioramti, Neurogastroentol. motil., 15, 363-369, 2003 ]. Mazelin et al, Life Sci, 63, 293-304, 1998, have shown a role for NK3 antagonists in intestinal inflammation and conclude that such antagonists are useful in the treatment of Irritable Bowel Syndrome (IBS). Furthermore, NK3 antagonists have been demonstrated in vivo models to be useful in the treatment of airway-related diseases such as asthma, airway hyperresponsiveness, cough, and bronchoconstriction [ Daoui, am.j.respir.crit.care med., 158, 42-48, 1998 ]. Maubach et al in neurosci, 83, 1047-one 1062, 1998 showed that the NKB and NK3 agonists senktide increase the frequency and duration of epileptiform discharges and therefore concluded that NK3 antagonists have anticonvulsant potential. Finally, Kemel et al J.Neurosci, 22, 1929-1936, 2002 propose the use of NK3 antagonists in the treatment of Parkinson's disease.

Thus, clinical, preclinical, in vivo and in vitro studies support that NK3 receptor antagonists are suitable for use in the treatment or prevention of a variety of disorders, including psychosis, schizophrenia, depression, anxiety, cognitive impairment, obesity, alzheimer's disease, parkinson's disease, pain, convulsions, cough, asthma, airway hyperresponsiveness, microvascular hypersensitivity, bronchoconstriction, intestinal inflammation, and inflammatory bowel syndrome (inflammatory bowel syndrome).

Schizophrenia is divided into various subtypes. Paranoid types are characterized by delusions and hallucinations and thought deficit disorders, behavioral disturbances, and affective flattening. Schizotypy is also known as 'adolescent schizophrenia' in ICD, in which thought disorder and poverty of emotion coexist. Catatonic, where prominent psychomotor disturbances are evident, and symptoms may include catatonic stupor and waxy flexing. Undifferentiated type, in which there are psychotic symptoms, does not meet the criteria of paranoid, schizotypal, catatonic type. Symptoms of schizophrenia are generally characterized in three major groups, positive, negative and cognitive symptoms. Positive symptoms are those normal sensations that represent "excess", such as hallucinations and delusions. Negative symptoms are those in which the patient suffers from a normal feeling of deficiency, such as anhedonia and lack of social relevance. Cognitive symptoms are related to cognitive impairment in schizophrenia, such as sustained attention deficit and decision making deficits. Current antipsychotic drugs are quite successful in treating positive symptoms, but are quite inadequate for negative and cognitive symptoms. In contrast, NK3 antagonists have been shown clinically to improve the negative and negative symptoms in patients with schizophrenia [ am.J. Psychiatry, 161, 975-984, 204], and it is expected that they will also provide efficacy in cognitive symptoms in light of the above discussion.

Cognitive impairment includes deterioration in cognitive function and cognitive domains, such as working memory, attention and alertness, verbal learning and memory, visual learning and memory, reasoning and problem solving such as speed of executive function, processing and/or social cognition. In particular, cognitive impairment may indicate lack of attention, disturbed thinking, slow thinking, difficulty in understanding, poor concentration, impaired problem solving, poor memory, difficulty in expressing ideas and/or difficulty in integrating ideas, emotions and behaviors, or difficulty in disappearing unrelated ideas.

In one embodiment, the invention relates to a compound of the invention for use in therapy.

In one embodiment, the invention relates to a method of treating a disease selected from the group consisting of treating a psychotic disorder; schizophrenia; schizophreniform (schizophoreno) disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; sensory psychiatric disorders (shared psychiatric disorders); psychiatric disorders due to general medical conditions; substance or drug induced psychotic disorders (cocaine, alcohol, amphetamine, etc.); schizoid personality disorder; personality disorder of the schizophrenic type (schizotypal); psychosis or schizophrenia associated with major depression, bipolar disorder, alzheimer's disease, or parkinson's disease; major depression; generalized anxiety disorder; bipolar disorder (maintenance therapy, relapse prevention and stabilization); mania; hypomania; cognitive impairment; ADHD; obesity; a decline in appetite; alzheimer's disease; parkinson's disease; pain; convulsions; cough; asthma; airway hyperresponsiveness; microvascular hypersensitivity; bronchoconstriction; chronic obstructive pulmonary disease; urinary incontinence; intestinal inflammation; and inflammatory bowel syndrome. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.

In one embodiment, the present invention relates to a method of treating schizophrenia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention. In particular, the treatment includes the treatment of positive, negative and/or cognitive symptoms of schizophrenia.

In one embodiment, the present invention relates to a method of treating cognitive impairment comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention. In particular, the cognitive impairment is characterized by a decline in the speed of working memory, attention and alertness, verbal learning and memory, visual learning and memory, reasoning and problem solving such as executive function, processing and/or social cognition.

The antipsychotic effect of typical and atypical antipsychotics, particularly D2 antagonists, is exerted by inhibition of the postsynaptic D2 receptor. However, presynaptic D2 autoreceptors are also affected by the administration of these compounds, causing an increase in the dopamine neuron firing rate, which in fact hinders the antipsychotic effect. The increased rate of firing continues until the presynaptic D2 autoreceptor blocking (depolarization block) effect occurs, typically after about 3 weeks of chronic treatment with typical or atypical antipsychotics. This model explains that clinical effects are generally observed with a delay of up to 3 weeks after initiation of D2 antagonist treatment. The NK3 antagonist appears to inhibit the increase in presynaptic D2 autoreceptor-mediated dopamine neuron release brought about by the D2 antagonist, and thus the combined administration of the NK3 antagonist and the D2 antagonist is expected to cause a more rapid onset of clinical effect. In addition, D2 antagonists are known to increase prolactin levels, which may cause serious side effects such as osteoporosis. It is known that NK3 agonists cause an increase in prolactin, and it can be concluded that NK3 antagonists reduce this increase even if prolactin levels are normalized. The combined use of NK3 antagonist and D2 antagonist may thus address some of the safety aspects associated with D2 antagonist administration. Likewise, NK3 antagonists may interact with one or more of the targets dopamine D2 receptor, dopamine D3 receptor, dopamine D4 receptor, phosphodiesterase PDElO, serotonin 5-HT _1AA receptor,Serotonin 5-HT_2AReceptor, serotonin 5-HT₆Antagonists/inverse agonists/negative modulators (negative modulators)/partial agonists of the receptor, adrenergic alpha 2 receptor, cannabinoid type 1 receptor, histamine H3 receptor, cyclooxygenase, sodium channel or glycine transporter GlyTl; or with one or more of the target serotonin 5-HT_2CAgonists/positive modulators (positive modulators)/partial agonists of the receptor, KCNQ channel, NMDA receptor, AMPA receptor, nicotinic α -7 receptor, muscarinic M1 receptor, muscarinic M4 receptor, metabotropic glutamate receptor mGluR2, metabotropic glutamate receptor mGluR5, dopamine D1 receptor or dopamine D5 receptor are administered together.

The compounds of the invention and other antipsychotic compounds such as D2 antagonists, D2 partial agonists, PDElO antagonists, 5-HT_2AAntagonists, 5-HT₆Such combined administration of the antagonist or KCNQ4 antagonist may be sequential or simultaneous. Examples of D2 antagonists or partial agonists include haloperidol, chlorpromazine, sulpiride, risperidone, ziprasidone, olanzapine, quetiapine, and clozapine.

In one embodiment, the compounds of the present invention are administered in an amount of about 0.001mg/kg body weight to about 100mg/kg body weight per day. In particular, the daily dose may be from 0.01mg/kg body weight to about 50mg/kg body weight per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight, and general condition of the subject to be treated, the nature and severity of the condition to be treated, any co-morbidities to be treated, the desired therapeutic effect, and other factors known to those skilled in the art.

Typical oral dosages of the compounds of the invention for adults are in the range of 1 to 1000 mg/day, for example 1 to 500 mg/day.

In one embodiment, the present invention relates to the use of a compound of the present invention for the preparation of a medicament for the treatment of a disease, wherein the disease is selected from psychosis; schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; an induced psychotic disorder; psychiatric disorders due to general medical conditions; substance or drug induced psychotic disorders (cocaine, alcohol, amphetamine, etc.); schizoid personality disorder; personality disorder of the schizophrenic type; psychosis or schizophrenia associated with major depression, bipolar disorder, alzheimer's disease, or parkinson's disease; major depression; generalized anxiety disorder; bipolar disorder (maintenance therapy, relapse prevention and stabilization); mania; hypomania; cognitive impairment; ADHD; obesity; a decline in appetite; alzheimer's disease; parkinson's disease; pain; convulsions; cough; asthma; airway hyperresponsiveness; microvascular hypersensitivity; bronchoconstriction; chronic obstructive pulmonary disease; urinary incontinence; intestinal inflammation; and inflammatory bowel syndrome.

In one embodiment, the invention relates to the use of a compound of the invention for the preparation of a medicament for the treatment of schizophrenia. In particular, the treatment includes the treatment of positive, negative and/or cognitive symptoms of schizophrenia.

In one embodiment, the present invention relates to the use of a compound of the present invention for the manufacture of a medicament for the treatment of cognitive impairment. In particular, the cognitive impairment is characterized by a decline in the speed of working memory, attention and alertness, verbal learning and memory, visual learning and memory, reasoning and problem solving such as executive function, processing and/or social cognition.

In one embodiment, the present invention relates to a compound of the present invention for use in the treatment of a disease, wherein said disease is selected from psychosis; schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; an induced psychotic disorder; psychiatric disorders due to general medical conditions; substance or drug induced psychotic disorders (cocaine, alcohol, amphetamine, etc.); schizoid personality disorder; personality disorder of the schizophrenic type; psychosis or schizophrenia associated with major depression, bipolar disorder, alzheimer's disease, or parkinson's disease; major depression; generalized anxiety disorder; bipolar disorder (maintenance therapy, relapse prevention and stabilization); mania; hypomania; cognitive impairment; ADHD; obesity; a decline in appetite; alzheimer's disease; parkinson's disease; pain; convulsions; cough; asthma; airway hyperresponsiveness; microvascular hypersensitivity; bronchoconstriction; chronic obstructive pulmonary disease; urinary incontinence; intestinal inflammation; and inflammatory bowel syndrome.

In one embodiment, the present invention relates to compounds of the present invention for use in the treatment of schizophrenia. In particular, the treatment includes the treatment of positive, negative and/or cognitive symptoms of schizophrenia.

In one embodiment, the present invention relates to compounds of the present invention for use in the treatment of cognitive impairment. In particular, the cognitive impairment is characterized by a decline in the speed of working memory, attention and alertness, verbal learning and memory, visual learning and memory, reasoning and problem solving such as executive function, processing and/or social cognition.

The compounds of the present invention may be administered alone as the pure compound or in combination with pharmaceutically acceptable carriers or excipients in single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents and other known adjuvants and excipients according to, for example, Remington: the Science and Practice of Pharmacy, 19 th edition, Gennaro, eds., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal), preferably oral routes. It will be appreciated that the preferred route will depend upon the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient selected.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. They may be coated, where appropriate.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution in sterile injectable solutions or dispersions prior to use.

Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants and the like.

Suitably, the compounds of the invention are administered in unit dosage form containing an amount of about 0.01 to 500mg of the compound, for example 10mg, 50mg, 100mg, 150mg, 200mg or 250mg of the compound of the invention.

For parenteral routes such as intravenous, intrathecal, intramuscular and the like, they are usually administered in doses on the order of about half the dose used for oral administration.

For parenteral administration, solutions of the compounds of the present invention in sterile aqueous solutions, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent first rendered isotonic with sufficient salt or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium employed can be readily obtained by standard techniques well known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical compositions formed by combining the compounds of the present invention and a pharmaceutically acceptable carrier can then be readily administered in a variety of dosage forms appropriate to the route of administration.

Formulations of the invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include suitable excipients. In addition, orally available formulations may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or in the form of oil-in-water or water-in-oil liquid emulsions.

If solid carriers are used for oral administration, the formulations may be presented as tablets, for example, in the form of powders or tablets, placed in hard gelatin capsules, or as lozenges or pastilles. The amount of solid carrier can vary, but is generally from about 25 mg to about 1 g.

If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.

Tablets may be prepared by mixing the active ingredient with conventional adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually employed for this purpose may be used, such as colorants, flavors, preservatives, and the like, provided they are compatible with the active ingredient.

In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a second antipsychotic agent. In one embodiment, the second antipsychotic agent is selected from the group consisting of the targeted dopamine D2 receptor, dopamine D3 receptor, dopamine D4 receptor, phosphodiesterase PDElO, serotonin 5-HT_1AReceptor, serotonin 5-HT_2AReceptor, serotonin 5-HT₆Receptors, adrenergic alpha 2 receptors, cannabinoid type 1 receptors, histamine H3 receptors, cyclooxygenase, sodium channels or glycerolsAntagonists/inverse agonists/negative modulators/partial agonists of the amino acid transporter GlyTl; or the target serotonin 5-HT _2CAgonists/positive modulators/partial agonists of the receptor, KCNQ channel, NMDA receptor, AMPA receptor, nicotinic α -7 receptor, muscarinic M1 receptor, muscarinic M4 receptor, metabotropic glutamate receptor mGluR2, metabotropic glutamate receptor mGluR5, dopamine D1 receptor or dopamine D5 receptor. In one embodiment, the second antipsychotic agent is selected from the group consisting of a typical antipsychotic agent, an atypical antipsychotic agent, a D2 antagonist, a partial D2 agonist, a PDElO antagonist, 5-HT_2AAntagonists, 5-HT₆Antagonists and KCNQ4 antagonists, and in particular atypical antipsychotics, D2 antagonists, partial D2 agonists. Specific examples of such antipsychotics include haloperidol, chlorpromazine, sulpiride, risperidone, ziprasidone, olanzapine, quetiapine, and clozapine.

In one embodiment, the present invention relates to a pharmaceutical kit comprising a compound of the present invention and a separate container comprising a second antipsychotic agent. Typical antipsychotics, atypical antipsychotics, D2 antagonists, partial D2 agonists, PDElO antagonists, 5-HT_2AAntagonists, 5-HT₆Antagonists and KCNQ4 antagonists, and in particular atypical antipsychotics, D2 antagonists, partial D2 agonists. Specific examples of such antipsychotics include haloperidol, chlorpromazine, sulpiride, risperidone, ziprasidone, olanzapine, quetiapine, and clozapine.

All documents, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety to the same extent as if each document were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent allowed by law) regardless of the incorporation of any individually provided specific documents mentioned elsewhere herein.

In the context of describing the invention, the terms "a" and "an" and "the" and similar referents are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Unless otherwise indicated, for example, the phrase "compound" is understood to mean various "compounds" of the invention or of the particular described aspects.

Unless otherwise indicated, all exact values provided herein are expressed as corresponding approximate values (e.g., all exact exemplary values provided for a particular factor or measurement can be considered to also provide a corresponding approximate measurement, limited by "about" where appropriate).

Terms such as "comprising," having, "" including, "or" containing, "when used herein to describe an element or elements of any aspect or inventive aspect, are intended to provide support for a similar aspect or inventive aspect to be" consisting of, "" consisting essentially of, "or" consisting essentially of a particular element or elements, unless otherwise indicated herein, or otherwise clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise indicated herein, or clearly contradicted by context).

Synthetic route

In the general formula I of the invention, R¹-R¹⁷Compounds in which a, and X are as defined above may be prepared by the methods outlined in the reaction schemes and examples below. In the methods described, variations or modifications may be employed which are known per se to the chemist skilled in the art or which would be apparent to a person of ordinary skill in the art. In addition, other methods of preparing the compounds of the present invention will be readily apparent to those of ordinary skill in the art from the following reaction schemes and examples.

Intermediate compounds of the general formulae I-XX, wherein R1-R17, A, and X are defined under formula I.

As for the compounds, they may exist in a mixture or equilibrium of two or more tautomers, of which only one is shown in these schemes, although it may not be the most stable tautomer. As regards the compounds, they may exist in the form of enantiomers, stereoisomers or geometric isomers, the geometric configurations of which are specified; otherwise the structure represents a mixture of stereoisomers. Such compounds include, but are not limited to, 1, 3-ketoesters or enamines of the general formulae IV and VII, which may exist in equilibrium keto or enol forms, which may also exist in Z-and E-isomeric forms well known to chemists skilled in the art. The compounds of the general formula I according to the invention also include those which, owing to the restricted rotation around the carbon-carbon single bond, can exist as a mixture of atropisomers, which is analogous to the atropisomeric phenomena in ortho-, ortho' -disubstituted biaryls, which are also well known to the person skilled in the art.

The starting materials of formulae III, VI, and XI are either obtained from commercial sources as outlined in table 2 or they are readily prepared by standard methods described in the literature or modifications thereof.

Coupling of 2-bromobenzoic acid of formula II with a keto-ester of formula III in the presence of a strong base such as sodium hydride and a copper or copper salt such as copper (I) bromide in a suitable solvent such as 1, 4-dioxane, acetonitrile or with an excess of the above keto-ester at a suitable temperature such as reflux or at 70 ℃ forms the compound of formula IV. Such arylation reactions are well known and are commonly referred to as copper-catalyzed Ullmann-type coupling reactions (reviewed in: s.v. ley, a.w. thomas angelw.chem.int.ed.2003, 42, 5400). Also, in this particular case, when the coupling reaction involves an activated methylene compound such as a compound of formula IV in the presence of copper or a copper salt, the reaction is referred to as a Hurtley reaction (w.r.h.hurtley j.chem.soc.1929, 1870).

The resulting compound of formula IV is then reacted with a aniline of formula VI with or without the addition of suitable solvents under heating to form an intermediate of enamine of formula VII, which is generally not isolated from the reaction mixture, to form isoquinolinone of formula VIII. Alternatively, the enamine of formula VII may be obtained from an aniline of formula VI in the presence of a suitable dehydrating agent such as tetraethoxysilane, under heated conditions or in the presence of a catalytic amount of an acid such as acetic acid at ambient temperature. The cyclization reaction to form isoquinolinones of general formula VIII can then be carried out under the heated conditions as mentioned above or in the presence of an appropriate coupling reagent such as EDC/HOBT at ambient temperature.

Furthermore, in a modified one-pot process involving a Hurtley reaction, starting from 2-bromobenzoic acid of formula II and a deprotonated enamine of formula V, the reaction proceeds at 70 ℃ to form the compound of formula VII, which is subsequently cyclized at a higher temperature, to give the isoquinolinone of formula VIII directly. Enamines of the formula V are readily obtained from ketoesters III and anilines VI under the conditions described above for the preparation of enamines of the formula VII.

The compound of formula VIII is readily hydrolyzed to the acid of formula IX under ester hydrolysis conditions well known to the chemist skilled in the art. Finally, subsequent coupling with amines of the general formula XI (a ═ C) or hydrazines (a ═ N) leads to the formation of the compounds of the general formula I according to the invention. Such coupling reactions are typically carried out via activation of an acid with a suitable coupling or activating reagent such as, but not limited to, thionyl chloride to form the corresponding acid chloride. Hydrazines of formula I wherein R1 ═ H can be converted to disubstituted hydrazides of the same formula wherein R1 is not hydrogen, by acylation, alkylation or arylation reactions using a suitable acylating or alkylating reagent such as, but not limited to, an acid chloride, carbamoyl chloride, chloroformate or alkyl halide (alkylhalogenide).

Compounds of formula I wherein X is hydrogen can be converted to compounds of formula XII by regioselective bromination in the presence of a brominating agent such as bromine. The bromine atom may then be substituted by a group of the general formula X-H or X ^-To form the compounds of formula I of the present invention. One skilled in the art will readily appreciate that many nitrogen, carbon and sulfur nucleophiles such as, but not limited to, amines, aromatic amines, amides, heterocycles, alcohols, phenols, cyanides or thiols, in neutral or in deprotonated anionic form, necessary for such conversion, are commercially available or readily available.

Further derivatization or transformation of substituents R4-R12 and X may be carried out if desired, using standard methods of organic synthesis known to those of ordinary skill in the art.

Scheme 1

Scheme 2

Scheme 3 Synthesis of Homophthalic anhydride

Scheme 4

Alternatively, the compounds of formula I can be prepared as shown in scheme 4 starting from substituted homophthalic anhydrides of formula XVIII. High phthalic anhydrides are commercially available or can be prepared as shown in scheme 3 starting from the corresponding fluorobenzonitrile or fluorobenzoate esters of the general formulae XIII and XVII, respectively. They are subjected to aromatic nucleophilic substitution reaction with ethyl cyanoacetate XIV in the presence of a base such as potassium carbonate or cesium carbonate under heating in a suitable solvent such as dimethyl sulfoxide. The coupled product is hydrolyzed in the presence of a strong acid, such as sulfuric acid or hydrochloric acid, in water under heating to form the dibasic acid of formula XVI. Finally, the dibasic acid is converted to the homophthalic anhydride of formula XVIII in the presence of a dehydrating agent such as, but not limited to, acetyl chloride, either neat or in a suitable solvent such as toluene, under heating conditions such as reflux.

The highly phthalic anhydrides of the formula XVIII are regioselectively converted to the acid-amides of the formula XIX at room temperature or with heating in a suitable solvent such as acetonitrile. Then, it is treated with the appropriate anhydride or acid chloride of the general formulae XX and XXI, respectively, in the absence or presence of a base such as triethylamine and DMAP, in a suitable solvent, usually acetonitrile, at room temperature or under mild heating conditions (T < +100 ℃). This conversion first provides an intermediate ketene-aminal of formula XXII, which is further subjected to an acylation reaction to form a compound of formula XXIII. Further heating at higher temperatures, for example at +150 ℃, results in rearrangement to form the amide of formula XIV. Both compounds of formula XXIII and XXIV can be easily hydrolyzed at ambient temperature in aqueous methanol or aqueous tetrahydrofuran as solvent with a suitable base such as sodium hydroxide. The resulting keto-acid of the formula XXV or the ketene-aminal of the formula XXIII is converted into the final compound of the formula I according to the invention by condensation with an aniline of the formula VI under the same conditions as described above for the keto-acid condensation of the formula IV.

Alternatively, acid-amides of formula XIX can be converted directly to compounds of formula I of the present invention by condensation with the appropriate imido chloride of formula XXVII, which is readily obtained from formula XXVI of the corresponding amide, formula XXVI being readily obtained by the well-known coupling between anilines of formula VI and the corresponding carboxylic acids of formulae XX and XXI, or the anhydrides or acid chlorides thereof, respectively.

Examples

LC-MS analyzed, method a (used in most cases, unless otherwise specified): LC/MS System data obtained from Sciex API150EX analysis, equipped with a single quadrupole mass spectrometer of Applied biosystems API150EX and an ion source for Atmospheric Pressure Photoionization (APPI), Shimadzu LClOADvp LC Pump (3X), Shimadzu SPD-M20A photodiode array Detector, SEDERE Sedex 85-Low temperature Evaporative Light Scattering Detector (ELSD), Shimadzu CBM-20A System controller, Gilson 215 autosampler and Gilson 864 degasser, fromThe analysis software performs the control. Column: 30X 4.6mm Waters symmetry C18 column of 3.5 μm particle size; sample introduction amount: 15 mu L of the solution; column temperature: 60 ℃; solvent system: a ═ water/trifluoroacetic acid (100: 0.05) and B ═ water/acetonitrile/trifluoroacetic acid (5: 95: 0.035); the method comprises the following steps: linear gradient elution, 10% B to 100% B in 2.4 min, then 10% B in 0.4 min, flow rate 3.3 mL/min. UV-scanning based on 254nm indicates the retention time (t) in minutes_R)。

Analytical LC-MS, method B: data obtained from the Sciex API300 analyzed LC/MS system equipped with an Applied biosystems API300 three-stage quadrupole mass spectrometer carrying an Atmospheric Pressure Photoionization (APPI) ion source, a Shimadzu LClOADvp LC pump (3X), a Shimadzu SPD-M20A photodiode array detector, Polymer Labs PL-ELS 2100-Low temperature Evaporative Light Scattering Detector (ELSD), Shimadzu SCLLOA VP System controller, Gilson 215 autosampler, and Gilson 864 degasser, controlled by the analysis software. Column: symmetryc183.5 μm, 4.6 × 30mm, 30 × 4.6 mm; sample introduction amount: 5 mu L of the solution; column temperature: 60 ℃; solvent system: a ═ water/trifluoroacetic acid (100: 0.05) and B ═ water/acetonitrile/trifluoroacetic acid (5: 95: 0.035); the method comprises the following steps: linear gradient elution, 10% B to 100% B in 1.45 min, then 10% B in 0.55 min, flow rate 5.5 mL/min:

Time, min% B

0.00 10.0

1.45 100.0

1.55 10.0

2.0 10.0

UV-scanning based on 254nm indicates the retention time (t) in minutes_R)。

The LC-MS purification of the preparations was carried out on the same Sciex API 150EX system equipped with Gilson 333 and 334 pumps, Shimadzu LClOADvp pump, Gilson UV/VIS 155UV detector, Gilson 233XL autosampler, Gilson FC204 knockout (fraction), Gilson 506C system interface, Gilson 864 degasser, DIY splitter (approximately 1: 1000) and LC Packings Accurate splitter (1: 10.000@140 ml/min). The MS and flow collector were controlled by massschrom software (Macintosh PC) and the LC system by Unipoint software. For small scale (< 20mg) purified fractions collected in 4ml vials, Symmetry Cl 85 μm, 10X 50mm column, 0-300 μ L sample size, flow rate of 5.7ml/min and duration of 8 min were applied.

Gradient:

time, min% B

0.0010.0-50.0 (variable, depending on the sample)

7.00 100.0

7.10 10.0-50.0

8.00 10.0-50.0

T303.3K recorded on a Bruker Avance DRX-500 instrument at 500.13MHz¹H NMR spectrum. Temperature changes were recorded on a 250MHz Bruker Avance DPX-250 instrument¹H NMR spectrum. Unless otherwise stated, deuterated dimethyl sulfoxide (DMSO-d) was used ₆99.8% D) as solvent. Tetramethylsilane was used as an internal reference standard. The chemical shift values are expressed in ppm-value relative to tetramethylsilane. The following abbreviations or combinations thereof are used to represent multiple states of the NMR signal: s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, qui ═ quintet, h ═ heptat, dd ═ doublet, ddd ═ doublet (double double double doublet), dt ═ doublet, dq ═ doublet, tt ═ triplet (triplet), m ═ multiplet and br ═ broad or broad singlet.

Microwave experiments were performed in sealed process bottles or reactors using the Emrys Synthesizer of Personal Chemistry or the Emrys OptimizereXP or the Milestone Microsynth instrument of Milestone. Before the treatment bottle was sealed, it was flushed with argon. The reaction was heated in a microwave apparatus, cooled to 25 ℃ and then subjected to the next step.

Preparation of intermediates

2- (1-ethoxycarbonyl-2-oxo-propyl) -benzoic acid.

To a stirred cold (ice/water bath) mixture of 2-bromobenzoic acid (20.1g, 0.1mol) and ethyl acetoacetate (13.01g, 0.1mol) in 1, 4-dioxane (200ml) was added sodium hydride (8g, 0.2mol, 60% dispersed in mineral oil in small portions. After addition was complete, the cold bath was removed and the reaction mixture was stirred at ambient temperature for 10 minutes. Copper (I) bromide (15.2g, 0.106mol) was added in portions, and the resulting mixture was heated under reflux for 1 hour. It was allowed to cool and stirred at ambient temperature overnight. The resulting green suspension was quenched with ethyl acetate (200ml) and ice (300g) and acidified with concentrated HCl (50 ml). The organic phase was washed with 2M aqueous HCl (2X 100ml) and brine and dried (Na) ₂SO₄) And evaporated in vacuo. The remaining mineral oil was removed by decanting and evaporation after shaking with heptane (3X 100 ml). Yield about 2Og, pale yellow oil. The crude product was used in the next step without further purification. LC-MS (M/z)205([ M-CO)₂]⁺)；t_R＝0.91。¹H NMR(500MHz，DMSO-d₆): a mixture of at least 3 tautomers.

Unless otherwise indicated, the following compounds were prepared analogously from the corresponding 2-bromobenzoic acid and used in the next step without further purification and identification:

2- (1-ethoxycarbonyl-2-oxo-propyl) -4-methyl-benzoic acid.

LC-MS(m/z)247.2([MH-H₂O]⁺)；t_R＝1.05。

2- (1-ethoxycarbonyl-2-oxo-propyl) -4-fluoro-benzoic acid.

5-chloro-2- (1-ethoxycarbonyl-2-oxo-propyl) -benzoic acid.

5-bromo-2- (1-ethoxycarbonyl-2-oxo-propyl) -benzoic acid.

2- (1-ethoxycarbonyl-2-oxo-propyl) -5-methyl-benzoic acid.

2- (1-ethoxycarbonyl-2-oxo-propyl) -5-fluoro-benzoic acid.

2- (1-ethoxycarbonyl-2-oxo-propyl) -3-methyl-benzoic acid.

2-chloro-6- (1-ethoxycarbonyl-2-oxo-propyl) -benzoic acid.

2-chloro-6- (1-methoxycarbonyl-2-oxo-propyl) -benzoic acid.

To a stirred mixture of 2-bromo-6-chlorobenzoic acid (20g, 85mmol), methyl acetoacetate (310ml, excess), and copper (I) bromide (12.2g, 85mmol) was added sodium hydride (8.5g, 212mmol, 60% in oil) in portions, followed by heating at 70 ℃ for 16 h. The resulting mixture was diluted with water (600ml) and extracted with diethyl ether (3X 500 ml). The aqueous phase was acidified with 2M HCl and extracted with ethyl acetate (2X 800 ml). The combined organic solutions were washed with brine (100ml) and dried (Na) ₂SO₄) And evaporation. The resulting oil was treated with a hot mixture of ethyl acetate (20ml) and heptane (200ml), decanted 2 times, and dried in vacuo to give 8g of a tan solid in 34% yield.¹H NMR(500MHz，DMSO-d₆): 1.73(s, 3H), 3.6(s, 3H), 7.24(d, 1H), 7.44(t, 2H), 7.5(d, 1H), 12.85(s, 1H, OH in enol form), 13.4(br, 1H, CO₂H)。

2- (1-methoxycarbonyl-2-oxo-propyl) -6-nitro-benzoic acid.

2-methoxy-6- (1-methoxycarbonyl-2-oxo-propyl) -benzoic acid.

3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

A mixture of 2- (1-ethoxycarbonyl-2-oxo-propyl) -benzoic acid (7.6g, 30.4mmol) and aniline (10ml, 108mmol) was flushed with argon, sealed in an Emrys treatment flask, and heated under microwave radiation at 150 ℃ for 15 minutes. The volatiles were removed in vacuo and the resulting residue partitioned between ethyl acetate (100ml) and 2M HCl (100 ml). The organic layer was washed with brine (2X 20ml) and dried (Na)₂SO₄) And evaporated to give 8.7g of a solidified brown oil. The crude product obtained is according to¹H NMR was about 90% pure and was used in the next step without further purification. Alternatively, the crude product was dissolved in hot ethyl acetate (20ml), precipitated with heptane (60ml), allowed to cool, filtered and washed with diethyl ether to give 4.2g of a light brown crystalline solid in 45% yield. LC-MS (m/z)308.2 (MH) ⁺)；t_R＝1.43。¹H NMR(500MHz，DMSO-d₆): 1.34(t, 3H), 1.97(s, 3H), 4.41(q, 2H), 7.38(d, 2H), 7.51(t, 1H), 7.56(t (overlapping m), 3H), 7.62(d, 1H), 7.8(t, 1H), 8.22(d, 1H).

The following compounds were prepared analogously from the corresponding crude 2- (1-ethoxycarbonyl-2-oxo-propyl) -4-methylbenzoic acid and the corresponding aniline.

3, 6-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without crystallization. LC-MS (m/z)322.1 (MH)⁺)；t_R＝1.53。¹H NMR(500MHz，DMSO-d₆)：1.34(t，3H)，1.96(s，3H)，2.47(s，3H)，4.41(q，2H)，7.28(t，1H)，7.37(m，3H)，7.50(d，1H)，7.56(m，2H)，8.11(d，1H)。

6-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without crystallization. LC-MS (m/z)326.3 (MH)⁺)；t_R＝1.54。¹H NMR(500MHz，DMSO-d₆)：1.33(t，3H)，2.0(s，3H)，4.41(q，2H)，7.28(t，1H)，7.39(d，2H)，7.42(m，1H)，7.51(t，1H)，7.57(t，2H)，8.29(dd，1H)。

7-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without crystallization. LC-MS (m/z)342.0 (MH)⁺)；t_R＝1.67.¹H NMR(500MHz，DMSO-d₆)：1.33(t，3H)，1.98(s，3H)，4.41(q，2H)，7.4(d，2H)，7.51(t，1H)，7.57(t，2H)，7.7(d，1H)，7.85(dd，1H)，8.15(d，1H)。

7-bromo-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without crystallization. LC-MS (m/z)386.1 (MH)⁺，⁷⁹Br)；t_R＝1.71。¹H NMR(500MHz，DMSO-d₆)：1.33(t，3H)，1.98(s，3H)，4.4(q，2H)，7.39(d，2H)，7.51(t，1H)，7.57(t，2H)，7.62(d，1H)，7.96(dd，1H)，8.29(d，1H)。

3, 7-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was a brown oil, which was used in the next step without purification. LC-MS (m/z)322.2 (MH)⁺)；t_R＝1.59。

7-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was a brown oil, which was used in the next step without purification. LC-MS (m/z)326.1 (MH)⁺)；t_R0.79 (method B).

3, 5-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without purification. LC-MS (m/z)322.1 (MH)⁺)；t_R＝1.63。

8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without purification. LC-MS (m/z)342.0 (MH)⁺)；t_R＝1.55。

2- (2-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

LC-MS(m/z)326.5(MH⁺)；t_R＝1.46。

2- (2, 6-difluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without further purification and characterization.

2- (2-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without further purification and characterization.

3-methyl-1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The crude product was used in the next step without further purification and characterization.

2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

LC-MS(m/z)326.3(MH⁺)；t_R＝1.47。

2- (3-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

LC-MS(m/z)342.1(MH⁺)；t_R＝1.61。

3-methyl-1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

LC-MS(m/z)322.1(MH⁺)；t_R＝1.57。

8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid methyl ester.

A mixture of 2-chloro-6- (1-methoxycarbonyl-2-oxo-propyl) -benzoic acid (4g, 15mmol), aniline (1.369ml, 15mmol) and tetraethoxysilane (6.65ml, 30mmol) in methanol (20ml) was sealed and heated under microwave radiation at +150 ℃ for 20 min. The resulting solution was diluted with water (150ml) and extracted with ethyl acetate (2X 300 ml). The combined organic solutions were dried (MgSO)₄) And evaporation. The resulting crude enamine (2-chloro-6- (1-methoxycarbonyl-2-phenylamino-propenyl) -benzoic acid) was dissolved in dimethylformamide (80ml), followed by addition of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, 4.3g, 22.5mmol) and 1-hydroxybenzotriazole (HOBT, 3.04g, 22.5 mmol). It was stirred for 16 h and partitioned between water (250ml), diethyl ether (250ml) and ethyl acetate (150 ml). The organic phase was washed with 0.5M NaOH (2X 100ml), brine (2X 200ml) and dried (MgSO)₄) And evaporated to give 4.25g of a brown oil which was used in the next step without further purification. The yield was 87%. LC-MS (m/z)328.0 (MH) ⁺)；t_R＝1.36。¹H NMR(500MHz，CDCl₃)：2.02(s，3H)，3.98(s，3H)，7.23(d，2H)，7.44-7.55(m，6H)。

2- (2-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The title compound was used in the next step without purification. LC-MS (m/z)338.3(MH⁺)；t_R＝1.38。

2- (3-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The title compound was used in the next step without purification. LC-MS (m/z)338.5 (MH)⁺)；t_R＝1.41。

2- (4-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The title compound was used in the next step without purification. LC-MS (m/z)338.5 (MH)⁺)；t_R＝1.4。

2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The title compound was used in the next step without purification. LC-MS (m/z)326.2 (MH)⁺)；t_R＝1.41。

2- (4-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The title compound was used in the next step without purification.

LC-MS(m/z)342.2(MH⁺)；t_R＝1.53。

3-methyl-1-oxo-2-p-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The title compound was used in the next step without purification. LC-MS (m/z)321.7 (MH)⁺)；t_R＝1.51。

2- (3-cyano-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

The title compound was used in the next step without purification. LC-MS (m/z)333.0 (MH)⁺)；t_R＝1.3。

3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid methyl ester.

The title compound was used in the next step without purification. LC-MS (m/z)339.3 (MH)⁺)；t_R＝1.26。

8-methoxy-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid methyl ester.

The title compound was used in the next step without purification. LC-MS (m/z)324.3 (MH)⁺)；t_R＝1.12。

8-cyano-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid methyl ester.

A suspension of methyl 3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylate (320mg, 0.95mmol) and Zn (898mg, 13.8mmol) in THF (4.5ml) and 2M aqueous HCl (4.5ml) was stirred for 10 min, filtered, and partitioned between ethyl acetate (3X 150ml) and NaHCO₃Saturated aqueous solution (100 ml). The combined organic solutions were dried (MgSO)₄) And evaporated to give 8-amino-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid methyl ester as a black oil (200mg, 0.645mmol, 69% yield. LC-MS (m/z)309.4 (MH)⁺)；t_R12. It was dissolved in aqueous concentrated HCl (0.4ml) and H₂O (3.25 ml). To the obtained solution, NaNO was added dropwise at 0 deg.C₂(46.3mg, 0.645mmol in 0.12ml H₂In O). After 15 minutes, it was treated with NaHCO₃The saturated aqueous solution was neutralized (pH 6-7) to obtain a diazonium salt solution. To a solution of KCN (202mg, 3mmol) in water (0.4ml) was added dropwise CuSO at 0 deg.C ₄x5H₂O (197mg, 0.774mmol) in water (0.8 ml). After the addition was complete, benzene (2ml) was added and the mixture was heated to +60 ℃. To this mixture, a diazonium salt solution was added dropwise over 15 minutes, followed by holding at 70 ℃ for 85 minutes. It was cooled to room temperature, diluted with ethyl acetate (10ml) and filtered through a plug of celite. The organic layer was washed with brine (10ml) and dried (MgSO)₄) And evaporated to give 97.9mg of the title compound (48% yield). LC-MS (m/z)319.2 (MH)⁺)；t_R＝1.15。

3-phenylamino-but-2-enoic acid ethyl ester.

This compound was prepared according to the procedure described (q.dai, w.yang, and x.zhang org.letters2005, 5343).

¹H NMR(500MHz，DMSO-d₆): 1.19(t, 3H), 2.01(s, 3H), 4.06(q, 2H), 4.7(s, 1H), 7.17 (overlapping t, 1H), 7.18 (overlapping d, 2H), 7.36(t, 2H), 10.36(s, 1H).

3, 8-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester.

To a cold (ice/water bath) solution of 2-bromo-6-methyl-benzoic acid (650mg, 3.023mmol) and ethyl 3-phenylamino-but-2-enoate (750mg, 3.65mmol) in acetonitrile (10ml) was added sodium hydride (267mg, 6.67mmol, 60% dispersed in mineral oil) in portions. The cooling bath was removed and the mixture was sonicated at ambient temperature until the gas evolution ceased (10 minutes). Copper (I) bromide (957mg, 6.67mmol) was added and the resulting suspension flushed with argon, sealed and heated under microwave radiation at +80 ℃ for 30 min. LC-MS showed total conversion to 2- (1-ethoxycarbonyl-2-phenylamino-propenyl) -6-methyl-benzoic acid (LC-MS (m/z)340.4 (MH) ⁺)；t_R1.59. The resulting suspension was heated for 30 minutes under microwave irradiation at +160 ℃. It was diluted with ethyl acetate (50ml) and filtered. The organic solution obtained was washed with 1M HCl (3X 50ml), water (2X 10ml) and NaHCO₃Washed with saturated aqueous solution (30ml) and with SiO₂(3g) Absorption through SiO₂Flash chromatography (50g, heptane)Gradient of-30% ethyl acetate in heptane) to yield 217mg of a yellow oil. The yield was 22%. LC-MS (m/z)322.2 (MH)⁺)；t_R＝1.62。¹H NMR(500MHz，DMSO-d₆): 1.32(t, 3H), 1.91(s, 3H), 2.74(s, 3H), 4.39(q, 2H), 7.3(d, 1H), 7.36 (m, 3H with overlap), 7.49(m, 1H), 7.55(t, 2H), 7.61(t, 1H).

3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ethyl ester (4.2g, 13.7mmol) is dissolved in 100ml of hot methanol and NaOH (6g) in water (20ml) is added. The reaction mixture was heated at reflux for 2h, diluted with water (200ml) and stirred at ambient temperature overnight. The organic volatiles were removed under reduced pressure and the resulting aqueous solution was extracted with ethyl acetate (2X 50 ml). The aqueous solution was poured into ice/2M HCl (150 ml). The resulting suspension was sonicated, the product was isolated by filtration, washed with water and dried under vacuum to give 2.9g of a colourless solid in 76% yield. LC-MS (m/z)280.2 (MH) ⁺)；t_R＝0.9。¹H NMR(500MHz，DMSO-d₆): 2.01(s, 3H), 7.36(d, 2H), 7.50(t, 1H), 7.56(q (overlapping m), 3H), 7.72(d, 1H), 7.81(t, 1H), 8.22(d, 1H), 13.5(br, 1H).

The following acids were prepared analogously from the corresponding ethyl esters:

3, 6-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)293.9(MH⁺)；t_R＝0.99。¹H NMR(500MHz，DMSO-d₆)：2.0(s，3H)，2.47(s，3H)，7.34(d，2H)，7.38(d，1H)，7.47(s，1H)，7.50(d，1H)，7.56(t，2H)，8.11(d，1H)，13.4(br，1H)。

6-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)298.4(MH⁺)；t_R＝0.99。¹H NMR(500MHz，DMSO-d₆)：2.05(s，3H)，7.37(d，2H)，7.41(dt，1H)，7.48(dd，1H)，7.51(t，1H)，7.57(t，2H)，8.28(dd，1H)，13.6(b，1H)。

7-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The crude product was used in the next step without crystallization. LC-MS (m/z)314.2 (MH)⁺)；t_R＝1.13。¹H NMR(500MHz，DMSO-d₆)：¹H NMR(500MHz，DMSO-d₆)：2.03(s，3H)，7.38(d，2H)，7.51(t，1H)，7.57(t，2H)，7.79(d，1H)，7.86(dd，1H)，8.15(d，1H)，13.55(b，1H)。

7-bromo-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)358.1(MH⁺，⁷⁹Br)；t_R＝1.2。¹H NMR(500MHz，DMSO-d₆)：2.02(s，3H)，7.38(d，2H)，7.51(t，1H)，7.57(t，2H)，7.72(d，1H)，7.97(dd，1H)，8.29(d，1H)，13.55(b，1H)。

3, 7-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)293.9(MH⁺)；t_R＝1.02。¹H NMR(500MHz，DMSO-d₆)：2.0(s，3H)，2.45(s，3H)，7.34(d，2H)，7.5(t，1H)，7.56(t，2H)，7.63(m，2H)，8.02(s，1H)，13.38(br，1H)。

7-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)298.2(MH⁺)；t_R＝1.01。¹H NMR(500MHz，DMSO-d₆)：2.02(s，3H)，7.37(d，2H)，7.51(t，1H)，7.57(t，2H)，7.71(dt，1H)，7.83(dd，1H)，7.88(dd，1H)，13.54(br，1H)。

3, 5-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)294.1(MH⁺)；t_R＝1.09。¹H NMR(500MHz，DMSO-d₆)：1.95(s，3H)，2.74(s，3H)，7.27-7.64(m，8H)，13.35(b，1H)。

2- (2-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)298.4(MH⁺)；t_R＝0.83。

2- (2, 6-difluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)316.2(MH⁺)；t_R＝1.03。

2- (2-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)314.2(MH⁺)；t_R＝1.0。

3-methyl-1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)294.1(MH⁺)；t_R＝0.99。

2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)298.4(MH⁺)；t_R＝0.96。¹H NMR(250MHz，DMSO-d₆)：2.02(s，3H)，7.24(d，1H)，7.32-7.42(m，2H)，7.5-7.65(m，2H)，7.71(d，1H)，7.81(m，1H)，8.21(d，1H)，13.49(br，1H)。

2- (3-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)314.2(MH⁺)；t_R＝1.09。¹H NMR(500MHz，DMSO-d₆)：2.04(s，3H)，7.39(t，1H)，7.56(t，1H)，7.58-7.62(m，3H)，7.72(d，1H)，7.81(t，1H)，8.21(d，1H)，13.5(br，1H)。

3-methyl-1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)293.9(MH⁺)；t_R＝1.03。¹H NMR(250MHz，DMSO-d₆): 2.02(s, 3H), 2.38(s, 3H), 7.14 (overlapping d, 1H), 7.16 (overlapping s, 1H), 7.31(d, 1H), 7.44(t, 1H), 7.54(t, 1H), 7.71(d, 1H), 7.8(t, 1H), 8.21(d, 1H), 13.46(br, 1H).

3, 8-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

A solution of ethyl 3, 8-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylate (200mg, 0.62mmol) in DMSO (3ml) and 1N aqueous NaOH (2ml, 2mmol) was heated under microwave irradiation at +120 ℃ for 20 minutes and diluted with water (30 ml). The uncharged impurities were extracted with diethyl ether (30ml) and the aqueous solution was poured into ice (50g) containing 2M aqueous HCl (10 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give 75mg of a yellow solid. The yield was 41%. LC-MS (m/z)293.9 (MH)⁺)；t_R＝1.09。¹H NMR(500MHz，DMSO-d₆): 1.95(s, 3H), 2.74(s, 3H), 7.3(d, 1H), 7.32(d, 2H), 7.48 (two overlapping m, 2H), 7.55(t, 2H), 7.62(t, 1H), 13.42(b, 1H).

8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was prepared analogously by hydrolysis of the corresponding methyl or ethyl ester at 100 ℃. LC-MS (m/z)314.1 (MH)⁺)；t_R＝1.03。

2- (2-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was used in the next step without purification. LC-MS (m/z)310.3 (MH)⁺)；t_R＝0.87。

2- (3-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was used in the next step without purification. LC-MS (m/z)310.4 (MH)⁺)；t_R＝0.9。

2- (4-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was used in the next step without purification. LC-MS (m/z)310.4 (MH)⁺)；t_R＝0.89。

2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was used in the next step without purification. LC-MS (m/z)298.2 (MH)⁺)；t_R＝0.9。

2- (4-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was used in the next step without purification. LC-MS (m/z)314.2(MH⁺)；t_R＝1.53。

3-methyl-1-oxo-2-p-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was used in the next step without purification. LC-MS (m/z)293.9 (MH)⁺)；t_R＝0.99。

3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was used in the next step without purification. LC-MS (m/z)325.5 (MH)⁺)；t_R＝0.94。

8-methoxy-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

The title compound was used in the next step without purification. LC-MS (m/z)310.6 (MH)⁺)；t_R＝0.73。

8-cyano-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid.

LC-MS(m/z)305.0(MH⁺)；t_R＝0.82。

Synthesis of homophthalic anhydride of general formula XVIII:

cyano- (2-cyano-3-fluoro-phenyl) -acetic acid ethyl ester.

A mixture of ethyl cyanoacetate (26.7mL, 251mmol), 2, 6-difluorobenzonitrile (33.2g, 239mmol) and potassium carbonate (82.5g, 597mmol) in dimethyl sulfoxide (120mL) was stirred at +55 ℃ for 16 h and poured into a mixture of ice and water (ca. 400 mL). It is acidified carefully with aqueous concentrated HCl (evolution of CO)₂) Then, the mixture was extracted with ethyl acetate (600 ml). The organic phase was washed with brine (100mL) and evaporated to give 55.1g of a pale yellow solid which was used in the next step without further purification.¹H NMR(500MHz，CDCl₃)：1.35(t，J＝7.0Hz，3H)，4.34(m，2H)，5.13(s，1H)，7.33(t，J＝8.4Hz，1H)，7.57(d，J＝7.9Hz，1H)，7.33(dd，J＝7.9Hz，J＝13.9Hz，1H)。

2-carboxymethyl-6-fluoro-benzoic acid.

A mixture of 62% sulfuric acid (2: 1 concentrated sulfuric acid/water, 400ml) and cyano- (2-cyano-3-fluoro-phenyl) -acetic acid ethyl ester (52.0g, 224mmol) was stirred overnight (16 h) at +150 ℃. The reaction mixture was poured into ice (about 500g), neutralized with 10.8N aqueous NaOH (500mL), and cooled. The mixture was extracted with ethyl acetate (3X 50OmL), and the combined organic solutions were washed with brine, over MgSO ₄Drying and evaporation gave 40.28g of crude product which was used in the next step without further purification. The sample analyzed was prepared by recrystallization from toluene-ethyl acetate.¹H NMR(500MHz，DMSO-d₆)：3.4(br，CO₂H+H₂O), 3.77(s, 2H), 7.17(d, J ═ 7.9Hz, 1H), 7.2 (overlapping t (unseparated) dd), 1H), 7.45(dd, J ═ 7.9Hz, J ═ 13.9Hz, 1H), 12.95(br, CO ═ 7.9Hz, 1H), and so on₂H)。

8-fluoro-isochroman-1, 3-dione.

2-carboxymethyl-6-fluoro-benzoic acid (130mg, 0.65mmol) was heated under microwave irradiation in acetyl chloride (2ml) for 10 minutes at 150 ℃ and then concentrated in vacuo to give the title product (120mg, 100% yield). The compound absorbs water in a wet solvent (wet solvent) or in a humid atmosphere and slowly decomposes back to the starting diacid.¹H NMR(500MHz，DMSO-d₆)：4.29(s，2H)，7.27(d，J＝7.8Hz，1H)，7.34(dd，J＝8.5Hz，J＝I 1Hz，1H)，7.76(dt，J＝5.3Hz，J＝8Hz，1H)。

The following high phthalic anhydride was obtained analogously from the corresponding fluorobenzonitrile and ethyl cyanoacetate by the 3-step procedure described above:

8-chloro-isochroman-1, 3-dione.

8-trifluoromethyl-isochroman-1, 3-dione.

6, 8-difluoro-isochroman-1, 3-dione.

5, 8-difluoro-isochroman-1, 3-dione.

Synthesis of chiral and racemic amines of formula XI:

(S) - (-) -2-methyl-2-propylsulfinamide.

The title chiral auxiliary was prepared according to the method described for the (R) - (+) -enantiomer in d.j.weix and j.a.ellman Organic Syntheses2005, 82, 157.

(S) -2-methyl-2-propylsulfinic acid 1-cyclopropylmethylene-amide.

The title compound was prepared according to the general methods described in g.liu, d.a.cogan, t.d.owens, t.p.tang, and j.a.ellman j.org.chem.1999, 64, 1278: cyclopropanecarboxaldehyde (35.0g, 0.5mol), 2-methyl-2-propylsulfinic acid 1-cyclopropyl-methyleneamide (30g, 0.25mol) and anhydrous CuSO₄(120g, 0.75mol) in CH₂Cl₂The mixture in (1500mL) was stirred at room temperature overnight. The reaction mixture was filtered and evaporated to give the title compound (39g, 95% yield) which was used in the next step without further purificationAnd (5) carrying out a step.

(S) -2-methyl-2-propylsulfinic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide and (S) -2-methyl-2-propylsulfinic acid [ (R) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

The title compound was obtained following the procedure for 1, 2-stereoselective addition of organometallic reagents to sulfinimides as generally described in d.a.cogan, g.liu, j.a.ellman, Tetrahedron 1999, 55, 8883.

The method A comprises the following steps: to anhydrous lithium chloride (1.7g, 40mmol) under nitrogen was added THF (20mL) followed by slow addition of isopropyl magnesium chloride (i-PrMgCl) (22mL, 2M in THF) and the resulting mixture was stirred at room temperature overnight. The resulting solution of i-PrMgCl. LiCl was added dropwise to a stirred solution of 1-bromo-3-fluorobenzene (5.6g, 33mmol) in THF (25ml) at 0 deg.C and stirring was continued for 2 h. The Grignard (Grignard) reagent obtained was added to CH of (S) -2-methyl-2-propylsulfinic acid 1-cyclopropyl-methyleneamide (2.5g, 14mmol) at-48 deg.C ₂Cl₂(60mL) in solution. The mixture was stirred at-48 ℃ for 5 hours and then at room temperature overnight. The reaction mixture is reacted by adding NH₄Quenching with saturated aqueous Cl (50mL) and CH₂Cl₂(3X 100 mL). The combined organic solution was dried (Na)₂SO₄) And evaporation to give a crude mixture which was purified by silica gel column chromatography (EtOAc/petroleum ether ═ 1/10). The obtained mixture diastereomer was resolved by SFC to obtain the title (S, S) -isomer (1.5g, yield 37.5%) and the title (S, R) -isomer (0.16g, yield: 4.0%) of the main product.

The method B comprises the following steps: alternatively, a solution of 1-bromo-3-fluorobenzene (89.0g, 0.50mol) is added dropwise at 5O ℃ to a suspension of Mg (13.4g, 0.55mol) in 50mL anhydrous THF. The mixture was stirred at +50 ℃ for 2 hours and then at 50-60 ℃To a solution of (S) -2-methyl-2-propylsulfinic acid 1-cyclopropyl-methyleneamide (78.0g, 0.46mol) in 100mL THF was added dropwise and stirred for 2 hours. Subjecting it to NH treatment₄Saturated aqueous Cl (100mL), water (300mL) were quenched, filtered, and the solid and filtrate were extracted with hot ethyl acetate (600mL) and evaporated in vacuo. The residue was crystallized from a mixture of ethyl acetate and petroleum ether (1: 1, 200mL) at-2O ℃ to give 80g of the title (S, S) -isomer as a white powder in 66% yield as determined by chiral HPLC as 100% de. ¹H NMR(CDCl₃，400MHz，TMS＝O ppm)：7.34-7.28(m，1H)，7.16-7.12(m，2H)，7.00-6.96(m，1H)，3.68(dd，J＝8.8Hz，3.2Hz，1H)，3.52(s，1H)，1.42(s，9H)，1.15-1.08(m，1H)，0.84-0.75(m，1H)，0.69-0.61(m，1H)，0.55-0.46(m，1H)，0.28-0.21(m，1H)。

(S) - (+) -C- [ C-cyclopropyl-C- (3-fluoro-phenyl) ] -methylamine hydrochloride

To a saturated solution of HCl in anhydrous dioxane (400ml) at 0 ℃ was added (S) -2-methyl-2-propylsulfinic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl]Amide (80g, 0.3 mol). After stirring at room temperature for 1 hour, the reaction mixture was evaporated in vacuo. The residue was washed with dry ether (2X 100ml) and dried in vacuo to give 56g of the title compound as a white solid in 93% yield and 100% ee as determined by chiral HPLC. [ alpha ] to]²⁰ _，D＝+52.69(c＝10mg/mL，CH₃OH)。¹H NMR(CD₃OD，400MHz，TMS＝O)：7.44-7.39(m，1H)，7.25-7.19(m，2H)，7.12-7.07(m，1H)，3.56(d，J＝10.0Hz，1H)，1.37-1.28(m，1H)，0.78-0.75(m，1H)，0.61-0.55(m，2H)，0.39-0.36(m，1H)。

(R) - (-) -C- [ C-cyclopropyl-C- (3-fluoro-phenyl) ] -methylamine hydrochloride.

The title compound was prepared from (S) -2-methyl-2-propylsulfinic acid [ (R) -cyclopropyl- (3-fluoro-phenyl) -methyl ] according to the same method as above]Preparation of-amide (0.16g, 0.6mmol) to give 0.116g of the title compound as a white solid. [ alpha ] to]²⁰ _，D＝-49.18(c＝10mg/mL，CH₃OH)，ee100％。¹H NMR(CD₃OD, 400MHz, TMS ═ O): the same as the (S) -enantiomer.

Starting from the condensation of the corresponding aldehyde with a chiral auxiliary in a three-step process, the following enantiomerically pure amine hydrochloride is obtained analogously via stereoselective Grignard addition, in which a mixture of diastereomers is resolved by recrystallization or by chromatography (SFC or column), and finally the predominant (S, S) -diastereomer is converted into the chiral amine with HCl.

C-cyclobutyl-C- (2-fluoro-phenyl) -methylamine.

One third of the cyclobutylbromide is addedA solution of (5.0g, 41.3mmol) in dry tetrahydrofuran (24mL) was stirred with magnesium (1.11g, 46.3mmol) at reflux. The remaining solution was added dropwise over 15 minutes and stirring was continued at reflux for 30 minutes. To the obtained solution was added dropwise 2-fluorobenzonitrile (1.2g) in THF (15ml) at 0 ℃. The mixture was stirred at O ℃ for 5.5 hours, followed by addition of methanol (30ml) and sodium borohydride (1.13 g). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated. The residue was partitioned between chloroform (3X 100ml) and water and the pH was adjusted to 1. The mixture was extracted with chloroform. The aqueous phase was adjusted to pH 10 and extracted with chloroform (3 × 100 ml). The combined organic layers were dried, evaporated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 1/1) to give the title amine (0.45g, yield: 7.9%)¹H NMR(CD₃OD，400MHz)7.49-7.38(m，2H)，7.30-7.15(m，2H)，4.50(d，J＝10.4Hz，1H)，3.00-2.90(m，1H)，2.29-2.21(m，1H)，2.09-1.71(m，5H)。

Synthesis of acid-amides of general formula XIX:

2- [ ((S) -1-phenyl-propylcarbamoyl) -methyl ] -benzoic acid.

A mixture of high phthalic anhydride (810mg, 5mmol) and (S) - (-) -1-phenylpropylamine (676mg, 5mmol) in acetonitrile (15ml) was heated for 15 minutes under microwave irradiation at +150 ℃. The white precipitate was collected by filtration, washed with heptane and dried in vacuo to give the pure title compound in 72% yield (1.065 g). Alternatively, (S) - (-) -1-phenylpropylamine (13.83g, 0.102mol) was added dropwise to a stirred solution of high phthalic anhydride (16.214g, 0.1mol) in acetonitrile (100ml) (exothermic reaction), and the resulting reaction mixture was refluxed for 5 minutes. It was allowed to cool and the product isolated by filtration as above to give 23.4g of a colourless solid in 79% yield. LC-MS (m/z)298.5 (MH) ⁺)；t_R＝1.11。¹H NMR(500MHz，DMSO-d₆)：0.84(t, J ═ 7.3Hz, 3H), 1.67 (quintuple, J ═ 7.3Hz, 2H), 3.85 (d of AB system, J ═ 15.1Hz, 1H), 3.95 (d of AB system, J ═ 15.1Hz, 1H), 4.66(q, J ═ 7.6Hz, 1H), 7.2 (nonres.m, 1H), 7.25-7.34(m, 5H), 7.45(t, J ═ 7.3Hz, 1H), 7.8(d, J ═ 7.8Hz, 1H), 8.39(br.d, J ═ 7.7Hz, 1H, NH).

The following compounds are obtained analogously from the reaction of the corresponding homophthalic anhydrides of the general formula with amines of the general formulae XVIII and XI, respectively. These reactions are usually carried out at room temperature and the product is isolated by extraction or filtration and used in the next step without further purification.

2- ({ [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -methyl) -6-fluoro-benzoic acid.

LC-MS(m/z)346.2(MH⁺)；t_R＝1.14。¹H NMR(500MHz，DMSO-d₆)：0.35(m，1H)，0.39(m，1H)，0.5(m，2H)，1.12(m，1H)，3.68&3.74 (two of the AB systems d, J ═ 15.2Hz, 2H, CH₂)，4.25(t，J＝8.5Hz，1H)，7.05(dt，J＝2.2，8.05Hz，1H)，7.13(d，J＝8.1Hz，1H)，7.16-7.21(m，2H)，7.35(m，1H)，7.42(m，1H)，8.66(d，J＝8.2Hz，1H，NH)，13.44(br.，CO₂H)。

2-chloro-6- [ ((S) -1-phenyl-propylcarbamoyl) -methyl ] -benzoic acid.

LC-MS(m/z)332.2(MH⁺)；t_R＝1.19。¹H NMR(500MHz，DMSO-d₆): 0.84(t, J ═ 7.3Hz, 3H), 1.68 (quintuple, J ═ 7.3Hz, 2H), 3.54&3.61 (two of the AB systems d, J ═ 15.3Hz, 2H, CH)₂)，4.67(q，J＝7.5Hz，1H)，7.19-7.4(m，8H)，8.48(d，J＝8.3Hz，1H，NH)，13.64(br.，CO₂H)。

2-fluoro-6- [ ((S) -1-phenyl-propylcarbamoyl) -methyl ] -benzoic acid.

LC-MS(m/z)316.3(MH⁺)；t_R＝1.13。¹H NMR(500MHz，CDCl₃): 0.79(t, J ═ 7.4Hz, 3H), 1.76 (quintuple doublet, diastereomeric CH of 2H, Et₂)，3.64(s，2H，CH₂) 4.75(q, J ═ 7.7Hz, 1H), 7.04(t, J ═ 8.5Hz, 1H), 7.08(d, J ═ 7.7Hz, 1H), 7.17-7.23 (overlapping m, 3H), 7.24-7.28 (overlapping m, 2H), 7.32(m, 1H), 7.45(br d, J ═ 8.1Hz, 1H, NH). 8.48(d, J ═ 8.3Hz, 1H, NH), 11.14(br., CO) ₂H)。

2-chloro-6- ({ [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -methyl) -benzoic acid.

2- { [ ((S) -cyclopropyl-phenyl-methyl) -carbamoyl ] -methyl } -6-fluoro-benzoic acid.

LC-MS(m/z)328.4(MH⁺)；t_R＝1.12。

2- ({ [ (S) -cyclobutyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -methyl) -6-fluoro-benzoic acid.

LC-MS(m/z)360.2(MH⁺)；t_R＝1.31。

2- ({ [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -methyl) -4, 6-difluoro-benzoic acid.

2- ({ [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -methyl) -3, 6-difluoro-benzoic acid.

2- [ ((S) -1-phenyl-propylcarbamoyl) -methyl ] -6-trifluoromethyl-benzoic acid.

LC-MS(m/z)366.4(MH⁺)；t_R＝1.24。

Synthesis of compounds of general formula XXIII:

4-acetyl-3- ((S) -1-phenyl-propylamino) -isochromen-1-one.

2- [ ((S) -1-phenyl-propylcarbamoyl) -methyl]-a mixture of benzoic acid (10g), acetic anhydride (50ml), and N, N-dimethylaminopyridine (100mg) was heated at mild reflux (T)_max7 min at +124 c) and evaporated in vacuo at +50 c to give the title compound as a tan solid (11.1g, 98% purity by NMR). LC-MS (m/z)322.3 (MH)⁺)；t_R＝1.72。¹H NMR(500MHz，DMSO-d₆)：0.89(t，J＝7.2Hz，3H)，1.86-1.97(m，2H)，2.56(s，3H)，4.95(q，J＝7.1Hz，1H，CH-NH)，7.26(t，J＝7.5Hz，1H)，7.29(unres.m，1H)，7.36-7.41(unres m.，3H)，7.71(t，J＝7.5Hz，1H)，7.75(d，J＝8.3Hz，1H)，7.98(d，J＝7.8Hz，1H)，11.53(d，J＝7.6Hz，1H，NH)。¹³CAPT NMR(125MHz，DMSO-d₆，δ(DMSO-d₆)＝39.87ppm)：10.68(CH₃)，30.0(CH₂)，31.57(CH₃)，57.01(CH)，92.44(C)，114.88(C)，124.2(CH)，(CH)，124.26(CH)，126.65(CH)，127.8(CH)，129.05(CH)，129.93(CH)，135.71(CH)，138.68(C)，141.86(C)，158.51(C)，160.55(C)，194.82(C，MeCO)。

4-acetyl-8-chloro-3- ((S) -1-phenyl-propylamino) -isochromen-1-one.

2-chloro-6- [ ((S) -1-phenyl-propylcarbamoyl) -methyl]Benzoic acid (11.4g) and acetic anhydride (50ml) were heated at 103 ℃ for 60 minutes and evaporated to give 12.45g of a brown oil (purity about 95%, according to ¹H NMR)。LC-MS(m/z)355.2(MH⁺)；t_R1.82. A pure sample for analysis was prepared by recrystallization (9g from 30ml hot MeCN), cooled (dry ice-EtOH bath) and filtered to give the title compound as a pale yellow solid (4.41 g). LC-MS (m/z)355.2 (MH)⁺)；t_R＝1.82。¹H NMR(500MHz，DMSO-d₆)：0.88(t，J＝7.4Hz，3H)，1.92(m，2H)，2.5(s，3H)，4.92(q，J＝7.3Hz，1H，CH-NH)，7.27-7.33(m，2H)，7.39(d(unres.m)，J＝4.3Hz，4H)，7.59-7.66(m，2H)，11.11(d，J＝7.8Hz，1H，NH)。

4-acetyl-3- { [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amino } -8-fluoro-isochromen-1-one.

Reacting 2- ({ [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl]A mixture of-carbamoyl } -methyl) -6-fluoro-benzoic acid (12.92g, 37.41mmol) and acetic anhydride (100mL, 1mol) was stirred at +65 ℃ for 20 h, evaporated in vacuo (65 ℃, 10mbar, 2 h) to give the title compound as a thick brown oil, which was used in the next step without purification (14.30g, 103.5% yield, according to¹HNMR purity 95%). LC-MS (m/z)370.1 (MH)⁺)；t_R＝1.65。¹H NMR(500MHz，DMSO-d₆)：0.45-0.59(m，3H)，0.64(m，1H)，1.41(m，1H)，2.53(s，3H)，4.36(t(unres.dd)，1H)，7.03(dd，J＝8.3，10.7Hz，1H)，7.12(dt，J＝1.9，8.5Hz，1H)，7.27(d，J＝10.2Hz，1H)，7.3(d，J＝7.8Hz，1H)，7.42(q，J＝7.8Hz，1H)，7.53(d，8.5Hz，1H)，7.7(m，1H)，11.3(d，J＝7.3Hz，1H，NH)。

4-acetyl-3- { [ (S) -cyclobutyl- (3-fluoro-phenyl) -methyl ] -amino } -8-fluoro-isochromen-1-one.

LC-MS(m/z)384.4(MH⁺)；t_R＝1.82。

(2-oxo-pyrrolidin-1-yl) -acetic acid.

A mixture of 2-pyrrolidone (2.66ml, 34mmol) and NaH (60% in oil, 1.25g, 31.3mmol) in THF (75ml) was stirred until the evolution of gas ceased (30 min). Tert-butyl 2-bromoacetate (4.45ml, 30mmol) was added and stirred at room temperature overnight, then partitioned between water (200ml) and ethyl acetate (200ml) to give intermediate 2- (oxo-pyrrolidin-1-yl) -acetic acid tert-butyl ester (5.8 g). This was dissolved in acetic acid (40ml) and aqueous concentrated HCl (6ml) and gas evolution was observed. After stirring at room temperature for 2 hours, it was evaporated and recrystallized from toluene/ethanol to give 2.58g of the title compound (60% yield). ¹H NMR(500MHz，DMSO-d₆): 1.95 (quintuple, J ═ 7.7Hz, 2H), 2.24(t, J ═ 8.1Hz, 2H), 3.38(m, and H)₂O-overlapped (3.35ppm), 2H), 3.91(s, 2H), 12.77(br., 1H).

1- {2- [ 8-fluoro-1-oxo-3- ((S) -1-phenyl-propylamino) -1H-isochromen-4-yl ] -2-oxo-ethyl } -pyrrolidin-2-one.

To a solution of 2-oxo-pyrrolidin-1-yl-acetic acid (1.56g, 10.9mmol) in 1, 2-dichloroethane (40ml) was added oxalyl chloride (0.95ml, 10.9mmol) and DMF (1 drop) and gas evolution was observed. After stirring at room temperature for 1 hour, 2-fluoro-6- [ ((S) -1-phenyl-propylcarbamoyl) -methyl ] -benzoic acid (1.56g, 4.95mmol), triethylamine (2.1ml, 14.9mmol) and DMAP (85mg, 0.1 equiv.) were added and stirred at room temperature overnight. It was partitioned between 0.2M aqueous HCl (100ml) -brine (100ml) mixture and ethyl acetate (250ml), washed with water and evaporated to give 1.89g of crude title compound which was used in the next step without further purification.

¹H NMR(500MHz，DMSO-d₆Selective resonance): 4.51&4.58 (two of the AB systems d, J ═ 16.3Hz, N-CH)₂-CO)，4.99(q，J＝7.5Hz，1H，CH-NH)，11.31(d，J＝7.9Hz，1H，NH)。

1- [2- (3- { [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amino } -8-fluoro-1-oxo-1H-isochromen-4-yl) -2-oxo-ethyl ] -pyrrolidin-2-one.

The title compound is prepared analogously and via SiO ₂And (4) purifying by flash chromatography. LC-MS (m/z)453.3 (MH)⁺)；t_R＝1.48。

1- (2- {3- [ ((S) -cyclopropyl-phenyl-methyl) -amino ] -8-fluoro-1-oxo-1H-isochromen-4-yl } -2-oxo-ethyl) -pyrrolidin-2-one.

The title compound was prepared analogously. LC-MS (m/z)435.3 (MH)⁺)；t_R＝1.43。

4-acetyl-3- [ ((S) -cyclopropyl-phenyl-methyl) -amino ] -8-fluoro-isochromen-1-one.

LC-MS(m/z)352.6(MH⁺)；t_R＝1.62。¹H NMR(500MHz，DMSO-d₆)：0.48(m，2H)，0.54(m，1H)，0.64(m，1H)，1.39(m，1H)，2.53(s，3H)，4.39(t(unres.dd)，1H)，7.04(dd，J＝8.2，10.8Hz，1H)，7.3(t，J＝7.3Hz，1H)，7.39(t，J＝7.6Hz，2H)，7.43(d，J＝7.3Hz，2H)，7.53(d，8.5Hz，1H)，7.7(m，1H)，11.39(d，J＝7.5Hz，1H，NH)。

Hydrolysis of a compound of formula XXIII to a compound of formula XXV:

2- (1- { [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -2-oxo-propyl) -6-fluoro-benzoic acid.

Reacting 4-acetyl-3- { [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl]-amino } -8-fluoro-2-benzopyran-1-one (14.30g, 38.72mmol) was dissolved in a mixture of tetrahydrofuran (50mL) and methanol (50mL) and placed under stirring on an ice/water bath. NaOH (1M in H) was added₂O, 100ml), stirring was continued for 1 hour. The cold bath was removed and the mixture was allowed to warm to room temperature (20 ℃) over 1 hour. The reaction mixture was poured into an ice-water mixture (200g +200mL), followed by slow addition of 2M aqueous Cl (200mL), extraction with ethyl acetate (200mL), washing with saturated aqueous NaCl solution, and drying (Na)₂SO₄) Filtration and evaporation gave the title compound as a light brown foam (14.65g, 97.7% yield). The crude product was used in the next step without further purification. LC-MS (m/z)388.3 (MH) ⁺)；t_R＝1.2。¹H NMR(500MHz，DMSO-d₆): tautomers and mixtures of diastereomers.

The following compounds were prepared analogously:

2-fluoro-6- [ 2-oxo-3- (2-oxo-pyrrolidin-1-yl) -1- ((S) -1-phenyl-propylcarbamoyl) -propyl ] -benzoic acid.

2- [1- { [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -2-oxo-3- (2-oxo-pyrrolidin-1-yl) -propyl ] -6-fluoro-benzoic acid.

LC-MS(m/z)471.4(MH⁺)；t_R＝1.17。

2- (1- { [ (S) -cyclobutyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -2-oxo-propyl) -6-fluoro-benzoic acid.

LC-MS(m/z)402.2(MH⁺)；t_R＝1.36。

Preparation of compounds of formulae XXIV and XXV: the compounds of formula XXIV are obtained analogously as described for the compounds of formula XXIII above but at higher temperatures (150 ℃, 15 minutes) and are generally hydrolyzed to compounds of formula XXV without isolation and identification, so only two examples of compounds of formula XXIV are given below.

3-methyl-1-oxo-1H-isochromene-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

Through SiO₂Flash chromatography purified the title compound. LC-MS (m/z)322.1 (MH)⁺)；t_R＝1.27。¹H NMR(500MHz，CDCl₃): 1.03(t, J ═ i.3hz, 3H), 1.91-2.06 (complex m, 2H, CH)₂)，2.19(s，3H)，5.11(q，J＝7.8Hz，1H)，7.06(br.d，J＝8.3Hz，1H，NH)，7.22-7.33(m，3H)，7.36-7.43(m，4H)，7.54(t，J＝7.6Hz，1H)，7.95(d，J＝7.8Hz，1H)。¹H NMR(500MHz，DMSO-d₆)：0.92(t，J＝7.3Hz，3H)，1.76(m，2H)，2.18(s，3H)，4.93(q，J＝8.3Hz，1H)，7.21-7.41(m，6H)，7.59(t，J＝7.7Hz，1H)，7.82(t，J＝7.2Hz，1H)，8.17(d，J＝7.8Hz，1H)，9.1(br.d，J＝8.4Hz，1H，NH)。

6, 8-difluoro-3-methyl-1-oxo-1H-isochromene-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

Through SiO₂Flash chromatography purified the title compound. LC-MS (m/z)388.4 (MH) ⁺)；t_R＝1.39。

2- [ 2-oxo-1- ((S) -1-phenyl-propylcarbamoyl) -butyl ] -benzoic acid.

Sealing 2- [ ((S) -1-phenyl-propylcarbamoyl) -methyl]A mixture of benzoic acid (409mg, 1.38mmol), propionic anhydride (10ml) and 4-N, N-dimethylaminopyridine (15mg) was heated under microwave radiation at 150 ℃ for 20 minutes and partitioned between 1M HCl (50ml) and ethyl acetate (100 ml). NaHCO for organic layer₃The saturated aqueous solution (2X 50ml) was washed with brine and concentrated in vacuo. To the obtained residue, methanol (25ml), tetrahydrofuran (25ml) and 2M aqueous NaOH solution (50ml) were added, and stirred at room temperature for 1 hour. The organic volatiles were removed in vacuo and the pH was adjusted to 1 with 3MHCl aqueous solution. The crude titled product (495mg) was isolated by extraction with ethyl acetate (150ml) and used in the next step without further purification.¹H NMR(500MHz，DMSO-d₆): tautomers and mixtures of diastereomers.

The following compounds were obtained analogously:

2-fluoro-6- [ 2-oxo-1- ((S) -1-phenyl-propylcarbamoyl) -propyl ] -benzoic acid.

LC-MS(m/z)358.4(MH⁺)；t_R＝1.17。

2- (1- { [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -2-oxo-propyl) -4, 6-difluoro-benzoic acid.

LC-MS(m/z)406.7(MH⁺)；t_R＝1.3。

2- (1- { [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -carbamoyl } -2-oxo-propyl) -3, 6-difluoro-benzoic acid.

LC-MS(m/z)406.0(MH⁺)；t_R0.72 (method B).

2- [ 2-oxo-1- ((S) -1-phenyl-propylcarbamoyl) -propyl ] -6-trifluoromethyl-benzoic acid.

The title compound was used directly in the next step.

1-tert-butyl-piperidin-4-one.

The title compound was prepared according to the procedure described in j.s.amato, j.y.l.chung, rj.cvetovich, x.gong, m.mclaughlin, r.a.Reamer j.org.chem.2005, 70, 1930.

(1-tert-butyl-piperidin-4-ylidene) -acetic acid ethyl ester.

A mixture of 1-tert-butyl-piperidin-4-one (4.59g, 23.6mmol) and ethoxycarbonylmethylenetriphenylphosphine (ethyl (triphenylphosphonylidene) acetate) (10.3g, 23.6mmol) in toluene (100mL) was stirred under nitrogen at reflux for 24 h and evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/triethylamine ═ 100/1) to give 5.1g of the title compound as a pale yellow oil in 76.5% yield.

(1-tert-butyl-piperidin-4-yl) -acetic acid ethyl ester.

To a solution of (1-tert-butyl-piperidin-4-ylidene) -acetic acid ethyl ester (5.1g, 22.7mmol) in ethanol (50mL) was added 10% Pd/C (0.6g), and the mixture was stirred at ambient temperature under a hydrogen atmosphere (42psi) for 14 hours. The catalyst was removed by filtration and the filtrate was concentrated to give the title material (4.03g, 78% yield), which was used directly in the next step.

(1-tert-butyl-piperidin-4-yl) -acetic acid.

To a solution of NaOH in water/ethanol (v/v ═ 40/10, 50mL) was added (1-tert-butyl-piperidin-4-yl) -acetic acid ethyl ester (4.03g, 17.8mmol), and the mixture was stirred at room temperature overnight. 1N aqueous HCl was added to adjust the pH to 5. The volatiles were evaporated in vacuo and the residue was diluted with methanol (30mL) and the insoluble inorganic salts were removed by filtration. Concentrating the filtrate, and performing silica gel column Chromatography (CH)₂Cl₂MeOH 20/1-5/1) to yield 0.7g of the title compound as a pale gray powder.¹H NMR(400MHz，DMSO-d₆)：3.15-3.08(br m，2H)，2.30(brt，J＝11.2Hz，2H)，2.05(d，J＝6.4Hz，2H)，1.71-1.68(m，3H)，1.30-1.27(m，2H)，1.10(s，9H)。

2- (1-tert-butyl-piperidin-4-yl) -N-phenyl-acetamide.

To a mixture of (1-tert-butyl-piperidin-4-yl) -acetic acid (672mg, 3.37mmol), aniline (0.32ml, 3.5mmol), and HOBt (568mg, 4.2mmol) in DMF (20ml) was added EDC (805mg, 4.2 mmol). It was stirred at room temperature for 2 hours and partitioned between water (200ml) and ethyl acetate (200 ml). The organic phase was washed with 0.5N aqueous NaOH (2X 50ml) and brine (3X 50ml) and dried (MgSO 4)₄) And concentrated in vacuo. The residue was purified by flash chromatography (SiO)₂A gradient of heptane-ethyl acetate) to yield 250mg of the title compound.¹HNMR(500MHz，DMSO-d₆)：1.07(s，9H)，1.32(br.m，2H)，1.81(br.d，2H)，1.89(m，1H)，2.11(br.t，2H)，2.25(d，2H)，3.03(br.d，2H)，7.1(t，1H)，7.24(br.，1H)，7.31(t，2H)，7.52(d，2H)。

Compounds of the invention

Example 1

1a 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid (212mg, 0.76mmol) in SOCl₂The solution in (15ml) and dimethylformamide (ca. 5. mu.L) was heated at reflux for 5 minutes. The volatiles were removed in vacuo to give 228mg of the corresponding acid chloride as a light brown solid. A portion of the acid chloride (110mg, 0.37mmol) was dissolved in 1, 2-dichloroethane (2ml) and (S) - (-) -1-amphetamine (150. mu.L, 1.1mmol) was added. The resulting suspension was shaken for 5 minutes, diluted with 1, 2-dichloroethane (10ml) and washed with 1M aqueous HCl (3X 5ml) and water (5 ml). The organic phase is poured onto SiO₂(5g) The product was eluted with 1, 2-dichloroethane (50ml) and 1: 1 ethyl acetate-heptane to give 140mg of a colorless crystalline solid. The yield was 95%. Alternatively, in another run, the reaction mixture was partitioned between 2M HCl and heptane (10ml) and the product isolated by filtration from the resulting two phase system. LC-MS (m/z)397.1 (MH)⁺)；t_R＝1.44。¹H NMR(500MHz，CDCl₃)：1.0(t，3H)，1.93(m，5H)，5.16(q，1H)，6.7(d，1H)，7.07(d，2H)，7.31(m，1H)，7.36(d，4H)，7.4-7.5(m，5H)，7.63(unres.t，1H)，8.31(d，1H)。

The following compounds were obtained analogously from the corresponding acids and amines and purified by preparative LC-MS:

1b 3, 6-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)411.3(MH⁺)；t_R0.8 (method B).

1c 7-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)431.3(MH⁺)；t_R0.86 (method B).

1d 7-bromo-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)475.1(MH⁺，⁷⁹Br)；t_R0.87 (method B).

1e 6-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)415.5(MH⁺)；t_R0.80 (method B).

1f 3, 5-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)411.3(MH⁺)；t_R0.84 (method B).

1g of 7-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)415.4(MH⁺)；t_R＝1.49。

1h 3, 7-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)411.4(MH⁺)；t_R＝1.5。

1i 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)431.4(MH⁺)；t_R＝1.54。

1j 3, 8-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)411.4(MH⁺)；t_R＝1.5。¹H NMR(250MHz，DMSO-d₆T ═ 343K): 0.91(t, 3H), 1.78 (overlapping s, 3H), 1.79 (overlapping m, 1H), 2.75(s, 3H), 4.94(q, 1H), 7.15-7.27(m, 5H), 7.27-7.39(m, 4H), 7.41-7.58(m, 4H), 8.67(d, 1H).

1k 2- (2-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)415.5(MH⁺)；t_R＝1.49。

1l 3-methyl-1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)411.5(MH⁺)；t_R＝1.5。

1m 2- (2-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)431.2(MH⁺)；t_R＝1.51。

1n 2- (2, 6-difluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)433.4(MH⁺)；t_R＝1.54。

1o 2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)415.1(MH⁺)；t_R＝1.48。

1p 3-methyl-1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)411.5(MH⁺)；t_R＝1.53。

1q 2- (3-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)431.2(MH⁺)；t_R＝1.57。

1r 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide.

LC-MS(m/z)409.4(MH⁺)；t_R＝1.43。¹H NMR(250MHz，DMSO-d₆，T＝343K)：0.45(m，2H)，0.56(m，2H)，1.25(m，1H)，1.88(s，3H)，4.51(t，1H)，7.21-7.37(m，5H)，7.42-7.59(m，7H)，7.7(dt，1H)，8.21(dd，1H)，8.89(d，1H)。

1S 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)427.1(MH⁺)；t_R＝1.48。¹H NMR(250MHz，DMSO-d₆，T＝343K)：0.48(m，2H)，0.57(m，2H)，1.24(m，1H)，1.89(s，3H)，4.51(t，1H)，7.05(m，1H)，7.21-7.31(m，4H)，7.33-7.6(m，6H)，7.7(dt，1H)，8.21(dd，1H)，8.94(d，1H)。

1t 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)461.6(MH⁺)；t_R＝1.51。¹H NMR(250MHz，DMSO-d₆，T＝343K)：0.48(m，2H)，0.58(m，2H)，1.27(m，1H)，1.87(s，3H)，4.5(t，1H)，7.06(m，1H)，7.21-7.32(m，4H)，7.32-7.45(m，2H)，7.45-7.66(m，5H)，8.95(d，1H)。

1aa 2- (3-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)426.7(MH⁺)；t_R＝1.43。

1ab 2- (4-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)427.0(MH⁺)；t_R＝1.43。

1ac 2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)415.0(MH⁺)；t_R＝1.43。

1ad 2- (4-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)431.1(MH⁺)；t_R＝1.54。

1ae 3-methyl-1-oxo-2-p-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)411.2(MH⁺)；t_R＝1.51。

1af 2- (3-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)457.0(MH⁺)；t_R＝1.47。

1ag 2- (4-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)457.1(MH⁺)；t_R＝1.46。

1ah 2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)445.6(MH⁺)；t_R＝1.48。

1ai 2- (4-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)461.3(MH⁺)；t_R＝1.57。

1aj 3-methyl-1-oxo-2-p-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)440.9(MH⁺)；t_R＝1.54。

1ak 2- (2-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)427.0(MH⁺)；t_R＝1.39。

1al 2- (2-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)457.4(MH⁺)；t_R＝1.43。

1am 3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)442.4(MH⁺)；t_R＝1.46。

1an 3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)442.4(MH⁺)；t_R＝1.46。

1ao 8-methoxy-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)427.1(MH⁺)；t_R＝1.32。

1ap 8-methoxy-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)457.4(MH⁺)；t_R＝1.36。

1aq 8-amino-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

To a stirred solution of ((S) -1-phenyl-propyl) -amide ((S) -1-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid) (1am, 10mg, 0.023mmol) in tetrahydrofuran (0.15ml) was added 2M aqueous HCl (0.12ml, 0.25mmol) and Zn powder (45mg, 0.69 mmol). After 30 min, the mixture was filtered and partitioned between ethyl acetate (4ml) and NaHCO₃Saturated aqueous solution (2ml) then brine (3 ml). The organic solution was dried (MgSO ₄) And evaporated to give 5.9mg of the title compound (70% yield). LC-MS (m/z)412.4 (MH)⁺)；t_R＝1.37。

1ar 8-cyano-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)422.1(MH⁺)；t_R＝1.37。

The following compounds were obtained according to the general method: in Et₃N (3 equivalents), EDC (1.5 equivalents), and HOBT (1.5 equivalents),the corresponding acid of the formula IX (0.04mmol) and the amine of the formula XI (0.06mmol) were stirred overnight at room temperature in DMF (0.5ml), then partitioned between ethyl acetate (2ml) and 0.5M NaOH (1ml), and SiO was performed₂Flash chromatography.

3-bromomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

To CaCO₃(500mg, 5mmol) and a suspension of 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (115mg, 0.29mmol) in 1, 2-dichloroethane (5ml) was added bromine (600mg, 3.75 mmol). The resulting mixture was sonicated at +33 ℃ for 2 h, diluted with 1, 2-dichloroethane (20ml) and poured onto a silica gel column (5 g). The excess bromine was eluted with 1, 2-dichloroethane and the product was eluted with 1: 1 ethyl acetate-heptane to give 135mg of a brown solid. This was dissolved in ethyl acetate (0.5ml) and precipitated with heptane (20ml) to give 100mg of a tan solid. The yield was 72%. LC-MS (m/z)475.2 (MH) ⁺，⁷⁹Br)；t_R＝1.59。¹HNMR(500MHz，DMSO-d₆A mixture of two tautomeric rotamers): 0.95(br，3H，CH₃) 1.74 and 1.82 (two nonres. m, 2x 1H, CH)₂)，4.0(unres.m，1H，CH₂Br), 4.21 and 4.35 (two nonres. m, 2x 0.5H, CH)₂Br)，4.97(q，1H，CH)，7.1(br，0.5H)，7.24(br，0.5H)，7.28-7.21(br m，11.5H)，7.89(br，0.5H)，8.25(br，1H)，9.28(d，1H，NH)。

The following compounds were obtained analogously:

3-bromomethyl-8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

The crude product was used in the next step without further purification. LC-MS (m/z)511.3 (MH)⁺，⁷⁹Br)；t_R＝1.68。

3-bromomethyl-2- (2-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

The crude product was used in the next step without further purification. LC-MS (m/z)493.3 (MH)⁺，⁷⁹Br)；t_R＝1.62。

3-bromomethyl-1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

The crude product is not further processedStep (5), purifying and using in the next step. LC-MS (m/z)489.3 (MH)⁺，⁷⁹Br)；t_R＝1.65。

3-bromomethyl-2- (3-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)493.5(MH⁺，⁷⁹Br)；t_R0.80 (method B).

3-bromomethyl-2- (3-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)511.5(MH⁺，⁸¹Br)；t_R0.84 (method B).

3-bromomethyl-1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)489.2(MH⁺，⁷⁹Br)；t_R0.86 (method B).

3-bromomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)505.1(MH⁺)；t_R＝1.62。

3-bromomethyl-2- (3-methoxy-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

The product is processed by SiO₂Flash chromatography (heptane-ethyl acetate gradient) purification was used directly in the next step.

3-bromomethyl-2- (4-methoxy-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

Through SiO₂The product was purified by flash chromatography (heptane-ethyl acetate gradient). LC-MS (m/z)505.1&507.2(MH⁺)；t_R＝1.52。

3-bromomethyl-2- (4-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

Through SiO₂The product was purified by flash chromatography (heptane-ethyl acetate gradient). LC-MS (m/z)493.3&495.3(MH⁺)；t_R＝1.54。

3-bromomethyl-2- (4-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)509.2&511.1(MH⁺)；t_R＝1.63。

3-bromomethyl-8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)539.1&541.4(MH⁺)；t_R＝1.69。

3-bromomethyl-8-fluoro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)493.3&495.2(MH⁺)；t_R＝1.52。

3-bromomethyl-8-fluoro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)523.5&525.6(MH⁺)；t_R＝1.56。

Compounds of the invention

2a 3-dimethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

A mixture of 3-bromomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (70mg, 0.147mmol) and dimethylamine (1ml, 33% absolute ethanol solution, excess) was kept at 50 ℃ for 10 min and then evaporated in vacuo. The residue was dissolved in methanol and passed through an SCX cation exchange column (1g, RSO)₃H form). Eluting the uncharged impurities with methanol, and eluting the product with 4M NH₃Methanol solution elution gave 53mg of a colorless glassy solid. Passing it through SiO₂Further purification by flash chromatography (5g, gradient of 1, 2-dichloroethane-10% ethyl acetate/1, 2-dichloroethane) afforded 45mg of a colorless solid. The yield was 70%. LC-MS (m/z)440.1 (MH)⁺)；t_R＝0.88。¹H NMR(250MHz，DMSO-d₆T333K): 0.92(t, 2H), 1.83 (two overlapping m, 2H), 1.66(s, 6H), 2.96 and 3.08 (CH)_AH_BTwo of N, d, 2H), 4.96(q, 1H), 7.19-7.56(m, 12H), 7.68(t, 1H), 8.21(d, 1H), 8.75(d, 1H).

2b 3-methylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

A mixture of 3-bromomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (4.7mg, 0.01mmol) and methylamine (1ml, 2M in tetrahydrofuran, excess) was kept at ambient temperature for 20 minutes, then evaporated in vacuoAnd (4) sending. The product was used in biological tests without further purification. LC-MS (m/z)426.3 (MH)⁺)；t_R＝0.85。

The following 3-aminomethyl derivatives are prepared analogously from the corresponding 3-bromomethyl derivatives and from 1.2 to 5 molar equivalents of the appropriate aliphatic or aromatic primary or secondary amine in tetrahydrofuran as solvent at ambient temperature. These reactions were monitored by LC-MS. In several cases, longer reaction times were applied or the reaction mixture was heated to 50 ℃ and/or diisopropylethylamine (2 equivalents) was added as base. After evaporation of the reaction mixture, the compound was of sufficient purity as determined by analytical LC-MS; otherwise the compound is further purified by SCX column or by preparative LC-MS.

List of compounds of example 2

Chemical name t_R(min) MW m/z

(MH+)

2c 3-Ethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-iso-0.45439.6440.6

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (method B)

2d 3-Cyclopropylaminomethyl-1-oxo-2-phenyl-1, 2-bis 0.49451.6452.1

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (method B)

2e 3- [ (cyclopropylmethyl-amino) -methyl ] -1-oxo-2-benzene 0.51465.6466.4

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) (method B)

Amides)

2f 3- (3, 6-dihydro-2H-pyridin-1-ylmethyl) -1-oxo-2-0.99477.6478.1

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane

Acyl) -amides

2g 3- [4- (2-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo 1.14586.7587.5

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2h 3- [4- (4-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo 1.35574.7575.6

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2i 3- (4-formyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 1.12508.6509.3

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2j 4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) 1.33552.7553.7

1, 2-dihydro-isoquinolin-3-ylmethyl-piperazine-1-carboxylic acid

Acid ethyl ester

2k 3- (4-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 0.87494.6495.7

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2l 1-oxo-2-phenyl-3- (1, 3, 4, 9-tetrahydro-beta-carbolin-2-yl 1.27566.7567.7

Methyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-

Propyl) -amides

2m 1-oxo-2-phenyl-3-piperazin-1-ylmethyl-1, 2-dihydro-iso-0.86480.6481.2

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2n 3- (3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 0.88494.6495.7

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2o 3- (3, 5-dimethyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 0.9508.7509.3

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2p 3- (4-benzyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 1.02570.7571.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2q 1-oxo-3- [4- (2-oxo-2-pyrrolidin-1-yl-ethyl) -0.92591.8592.4

Piperazin-1-ylmethyl ] -2-phenyl-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2r 3-Morpholin-4-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-1.08481.6482.2

Isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2s 3- (2, 6-dimethyl-morpholin-4-ylmethyl) -1-oxo-2-benzene 1.21509.6510.2

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2t 1-oxo-2-phenyl-3-thiomorpholin-4-ylmethyl-1, 2-di 1.22497.7498.8

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2u 3- (1, 4-dioxa-8-aza-spiro [45] dec-8-ylmethyl 1.01537.7538.4

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2v 1-oxo-2-phenyl-3-piperidin-1-ylmethyl-1, 2-dihydro-iso-1479.6480.3

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2w 3- (2-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl 1.07493.6494.4

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2x 3- (2, 6-dimethyl-piperidin-1-ylmethyl) -1-oxo-2-benzene 1.09507.7508.4

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2y 3- (2-hydroxymethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl 0.93509.6510.3

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2z 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) 1.14551.7552.4

1, 2-dihydro-isoquinolin-3-ylmethyl-piperidine-3-carboxylic acid

Acid ethyl ester

2aa 3- (3-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl 1.09493.6494.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2ab 3- (4-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl 0.83495.6496.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2ac 1-oxo-2-phenyl-3- (4-phenyl-piperidin-1-ylmethyl 1.27555.7556.5

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2ad 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) 1.11551.7552.5

1, 2-dihydro-isoquinolin-3-ylmethyl-piperidine-4-carboxylic acid

Acid ethyl ester

2ae 3- (4-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl 1.1493.6494.6

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2af 1-oxo-2-phenyl-3- (4-pyridin-2-yl-piperazin-1-ylmethyl 0.97557.7558.4

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2ag 3- (octahydro-quinolin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-1.18533.7534.4

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ah 3-azepan-1-ylmethyl-1-oxo-2-phenyl-1, 2-1.08493.6494.6

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ai 3- (3-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl 0.88495.6496.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2aj 3- [4- (2, 4-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-1.45584.8585.5

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2ak 3- [4- (3, 4-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-1.29584.8585.6

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2al 3- (4-dimethylamino-piperidin-1-ylmethyl) -1-oxo-2-benzene 0.81522.7523.5

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2am 3- [4- (2, 5-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-1.47584.8585.6

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2an 3- [4- (2-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-1.42574.7575.4

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2ao 3- [4- (3-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo 1.32586.7587.3

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2ap 1-oxo-2-phenyl-3- (4-m-tolyl-piperazin-1-ylmethyl 1.33570.7571.7

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2aq 3- [4- (4-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo 1.11586.7587.6

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2ar 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-phenyl 1.09584.8585.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2as 1-oxo-2-phenyl-3- (4-pyrimidin-2-yl-piperazin-1-ylmethyl 1.18558.7559.3

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2at 3- [4- (2-cyano-phenyl) -piperazin-1-ylmethyl ] -1-oxo 1.43581.7582.7

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2au 3- [4- (4-chloro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-1.54591.2591.3

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2av 3- ((1S, 3R, 5R) -3-hydroxy-8-aza-bicyclo [3.2.1] octan 0.88521.7522.7

-8-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2aw 3- (4-acetyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 1.07522.6523.5

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2ax 3- (4-methyl- [1, 4] diazepan-1-ylmethyl) -1-0.89508.7509.2

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2ay 3- (4-ethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 0.89508.7509.2

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2az 3- ((2S, 6R) -2, 6-dimethyl-morpholin-4-ylmethyl) -1-oxo 1.21509.6510.2

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2ba 3- [4- (2, 4-difluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo 1.48592.7593.6

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2bb 3- [4- (3-dimethylamino-propyl) -piperazin-1-ylmethyl ] -1-0.76565.8566.7

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2bc 3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 0.91522.7523.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2bd 3- (3-aza-bicyclo [3.2.2] non-3-ylmethyl) -1-oxo 1.21519.7520.4

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl)

-propyl) -amide

2be 3- (4-cyclopentyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 0.98548.7549.6

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2bf 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-1-oxo-2-phenyl 0.86562.8563.2

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2bg 3- (3, 4-dihydro-1H-isoquinolin-2-ylmethyl) -1-oxo-2-1.22527.7528.7

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2bh 3- [4- (2-dimethylamino-ethyl) -piperazin-1-ylmethyl ] -1-0.74551.7552.5

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2bi 3- (4-hydroxymethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl 0.86509.6510.3

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2bj 1-oxo-2-phenyl-3- [4- (tetrahydro-furan-2-carbonyl) -piperazine 1.16578.7579.9

Oxazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2bk 3- (4-isobutyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 0.98536.7537.4

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2bl 3- [4- (2-methoxy-ethyl) -piperazin-1-ylmethyl ] -1-oxo 0.91538.7539.6

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2bm 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-0.75593.8594.7

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2bn 3- (1, 3-dihydro-isoindol-2-ylmethyl) -1-oxo-2-benzene 1.16513.6514.8

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2bo 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-0.72577.8578.5

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2bp 1-oxo-2-phenyl-3- [4- (2-piperidin-1-yl-ethyl) -piperazines 0.75591.8592.5

Oxazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2bq 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -0.74577.8578.4

Piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2br 3- (4-dimethylcarbamoylmethyl-piperazin-1-ylmethyl 0.89565.7566.6

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2bs 3- (octahydro-pyrido [1, 2-a ] pyrazin-2-ylmethyl) -1-oxo 0.93534.7535.4

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2bt 3- (4-formyl- [1, 4] diazepan-1-ylmethyl) -1-0.94522.6523.6

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2bu 3- [4- (4-cyano-phenyl) -piperazin-1-ylmethyl ] -1-oxo 1.46581.7582.6

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2bv 1-oxo-2-phenyl-3- (4-pyridin-4-ylmethyl-piperazine-1-0.77571.7572.4

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2bw 1-oxo-2-phenyl-3- [4- (3-pyrrolidin-1-yl-propyl) -0.75591.8592.6

Piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2bx 1-oxo-2-phenyl-3- (4-pyridin-2-ylmethyl-piperazine-1-0.93571.7572.5

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2by 3- (4-ethanesulfonyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 1.38572.7573.7

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2bz 3- (4-sec-butyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 0.96536.7537.4

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2ca 3- [4- (1-ethyl-propyl) -piperazin-1-ylmethyl ] -1-oxo 1.01550.7551.8

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2cb 3- [4- (2-cyano-ethyl) -piperazin-1-ylmethyl ] -1-oxo 0.9533.7534.4

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2cc 3- (4-Methylsulfonyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 1.31558.7559.2

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2cd {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) 1.12565.7566.7

1, 2-dihydro-isoquinolin-3-ylmethyl-piperidine-4-carboxylic acid

Methyl } -acetic acid ethyl ester

2ce 3- [4- (3-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo 1.48574.7575.5

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2cf 1-oxo-2-phenyl-3- ((S) -3-phenyl-piperidin-1-ylmethyl 1.27555.7556.5

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2cg 1-oxo-2-phenyl-3- [4- (pyrrolidine-1-carbonyl) -piperazine-1-1.11577.7578.6

Ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2ch 3- [4- (morpholine-4-carbonyl) -piperazin-1-ylmethyl ] -1-oxo 1.04593.7594.7

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2ci 3- (4-methoxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl 0.98509.6510.2

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2cj 3- (4 ' -hydroxy-3 ', 4 ', 5 ', 6 ' -tetrahydro-2 ' H- [3, 4 ' ] bipyridinyl 0.71572.7573.8

1-oxo-2-phenyl-1, 2-dihydro-isoquine-1' -ylmethyl-1-methyl-phenyl

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ck 3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl 0.71572.7573.8

-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cl 3- (3H-spiro [ isobenzofuran-1, 4 '-piperidin ] -1' -ylmethyl 1.25583.7584.5

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2cm 3- (4-hydroxy-4-methyl-piperidin-1-ylmethyl) -1-oxo 0.91509.6510.1

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2cn 3- (hexahydro-spiro [ benzo [1, 3] dioxol-2, 4' -1.27591.7592.5

Piperidin-1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-

Isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2co 1-oxo-2-phenyl-3- (3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bi-0.71556.7557.4

Pyridinyl-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2cp 3- [4- (2-dimethylamino-ethyl) -piperidin-1-ylmethyl ] -1-0.68550.7551.4

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2cq 3- (4-dimethylsulfamoyl-piperazin-1-ylmethyl) -1-oxo 1.43587.7588.3

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2cr 3- (1, 1-dioxo-thiomorpholin-4-ylmethyl) -1-oxo 1.29529.7530.3

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl)

-propyl) -amide

2cs 1-oxo-2-phenyl-3- (2-pyridin-2-ylmethyl-piperidine-1-1.05570.7571.6

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2ct 3- (2-morpholin-4-ylmethyl-piperidin-1-ylmethyl) -1-oxo 1.08578.8579.8

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2cu 3- (4-furo [3, 2-c ] pyridin-4-yl-piperazin-1-ylmethyl 1.01597.7598.5

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2cv 3- (4-cyclopropylmethyl-piperazin-1-ylmethyl) -1-oxo-2-0.95534.7535.3

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2cw 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-0.69592.8593.5

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2cx 1-oxo-2-phenyl-3- (4-pyrimidin-2-yl- [1, 4] diaza 1.05572.7573.5

Cycloheptan-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2cy 3- (4-methyl-6, 7-dihydro-4H-thieno [3, 2-c ] pyridine 1.23547.7548.5

-5-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cz 3- [1, 4] diazepan-1-ylmethyl-1-oxo-2-benzene 0.89494.6495.7

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2da 3- ((2S, 5R) -2, 5-dimethyl-piperazin-1-ylmethyl) -1-0.92508.7509.2

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2db 3- ((S) -3-methyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 0.88494.6495.7

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2dc 3- ((R) -3-methyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 0.88494.6495.7

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2dd 3- [3- (3-chloro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-1.11591.2591.4

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2de 3- [4- (1H-indol-4-yl) -piperazin-1-ylmethyl ] -1-oxo 1.1595.7596.6

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2df 1-oxo-3- (3-oxo-piperazin-1-ylmethyl) -2-phenyl 1.09494.6495.7

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2dg 3- [4- (1H-indol-5-yl) -piperazin-1-ylmethyl ] -1-oxo 1.04595.7596.7

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2dh 3- (6, 9-diaza-spiro [4.5] decan-9-ylmethyl) -1-oxo 0.97534.7535.3

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl)

-propyl) -amide

2di 3- (1, 4-diaza-spiro [5.5] undec-4-ylmethyl) -1-oxo 1.01548.7549.7

O-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2dj 3- (3-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 0.96522.7523.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2dk 3- (3, 3-dimethyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 0.9508.7509.2

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2dl 3- [3- (4-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-1.05574.7575.4

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2dm 1-oxo-2-phenyl-3- (3-p-tolyl-piperazin-1-ylmethyl 1.08570.7571.7

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2dn 4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) 1.49580.7581.9

1, 2-dihydro-isoquinolin-3-ylmethyl-piperazine-1-carboxylic acid

Tert-butyl ester

2do 3- (4-methylcarbamoylmethyl-piperazin-1-ylmethyl 0.86551.7552.9

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2dp 8-chloro-3-dimethylaminomethyl-1-oxo-2-phenyl-1, 2-0.95474.0474.6

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dr 3-cyclopentylaminomethyl-1-oxo-2-phenyl-1, 2-bis 1.03479.6480.4

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ds 3-Cyclohexylaminomethyl-1-oxo-2-phenyl-1, 2-bis 1.1493.6494.4

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dt 3- { [ (2-hydroxy-ethyl) -methyl-amino ] -methyl } -1-oxo 0.84469.6470.6

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2du 3-imidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-0.86462.6463.4

Isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dv 3- (2-methyl-imidazol-1-ylmethyl) -1-oxo-2-phenyl 0.88476.6477.3

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2dw 3- (4-methyl-imidazol-1-ylmethyl) -1-oxo-2-phenyl 0.89476.6477.3

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2dx 3- (2, 5-dihydro-pyrrol-1-ylmethyl) -1-oxo-2-phenyl 0.92463.6464.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2dy 3- (2, 5-dimethyl-2, 5-dihydro-pyrrol-1-ylmethyl) -1-1.06491.6492.4

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2dz 1-oxo-2-phenyl-3-pyrrolidin-1-ylmethyl-1, 2-dihydro-0.92465.6466.3

Isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ea 1-oxo-2-phenyl-3- (thiazol-2-ylaminomethyl) -1, 2-0.88494.6495.6

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eb 1-oxo-2-phenyl-3- (pyrimidin-4-ylaminomethyl) -1, 2-0.85489.6490.4

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ec 3- (tert-butylamino-methyl) -1-oxo-2-phenyl-1, 2-bis 1467.6468.7

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ed 3- [ (2-hydroxy-1, 1-dimethyl-ethylamino) -methyl ] -1-oxo 0.91483.6484.3

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2ee 3- (isopropylamino-methyl) -1-oxo-2-phenyl-1, 2-bis 0.93453.6454.3

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ef 3- [ (2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo-2-0.86469.6470.5

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2eg 3- [ (1-hydroxymethyl-propylamino) -methyl ] -1-oxo-2-benzene 0.92483.6484.4

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2eh 3- [ (2, 2-dimethyl-propylamino) -methyl ] -1-oxo-2-1.13481.6482.2

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane

Acyl) -amides

2ei 1-oxo-2-phenyl-3-prop-2-ynylaminomethyl-1, 2-bis 0.95449.6450.2

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ej 3-allylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-0.94451.6452.4

Isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ek 3- [ (methyl-prop-2-ynyl-amino) -methyl ] -1-oxo-2-1.22463.6464.5

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane

Acyl) -amides

2el 3-Diallylaminomethyl-1-oxo-2-phenyl-1, 2-bis 1.19491.6492.4

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2em 3-diethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-0.98467.6468.5

Isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2en 3- [ (isopropyl-methyl-amino) -methyl ] -1-oxo-2-benzene 0.96467.6468.7

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2eo 3- [ ((S) -2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo 0.86469.6470.5

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2ep 3- [ ((R) -2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo 0.87469.6470.5

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2eq 3- { [ (2-methoxy-ethyl) -methyl-amino ] -methyl } -1-0.96483.6484.4

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2er 3- ((R) -3-hydroxy-pyrrolidin-1-ylmethyl) -1-oxo-2-0.85481.6482.3

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane

Acyl) -amides

2es 3- ((S) -3-hydroxy-pyrrolidin-1-ylmethyl) -1-oxo-2-0.84481.6482.3

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane

Acyl) -amides

2et 3- [ (cyclopentyl-methyl-amino) -methyl ] -1-oxo-2-benzene 1.09493.6494.5

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2eu 3- { [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -methyl 0.89483.6484.4

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2ev 3- { [ ethyl- (2-hydroxy-ethyl) -amino ] -methyl } -1-oxo 0.89483.6484.4

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2ew 3- [ (ethyl-methyl-amino) -methyl ] -1-oxo-2-phenyl 0.92453.6454.4

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2ex 3-Cyclobutylaminomethyl-1-oxo-2-phenyl-1, 2-bis 0.98465.6466.4

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ey 3-azetidin-1-ylmethyl-1-oxo-2-phenyl-1, 2-0.86451.6452.3

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ez 3- (4-tert-butyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl 0.91536.7537.3

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2fa 3- [4- (2-hydroxy-ethyl) -piperazin-1-ylmethyl ] -1-oxo 0.86524.7525.6

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2fb 3- {4- [2- (2-hydroxy-ethoxy) -ethyl ] -piperazin-1-yl 0.86568.7569.6

Methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2fc 3- [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazine-1-1.77660.1660.8

Ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fd 3- [4- (3, 5-dichloro-pyridin-4-yl) -piperazin-1-ylmethyl 1.45626.6626.5

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2fe 4- [ 1-oxo-2-phenyl-4- ((S) -1-phenyl-propylaminomethane 1.57614.7615.4

Acyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-

Carboxylic acid benzyl ester

2ff 3- [4- (3-morpholin-4-yl-propyl) -piperazin-1-ylmethyl 0.74607.8609.0

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2fg 1-oxo-2-phenyl-3- [4- (3-piperidin-1-yl-propyl) -piperazino 0.76605.8607.1

Oxazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2fh 3- [4- (4, 6-dimethoxy-pyrimidin-2-ylmethyl) -piperazine-1-1.05632.8633.9

Ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fi 3- [4- (3-hydroxy-propyl) -piperazin-1-ylmethyl ] -1-oxo 0.86538.7539.4

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2fj 3- [4- (2, 3-dihydroxy-propyl) -piperazin-1-ylmethyl ] -1-0.84554.7555.7

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2fk (2-oxo-2- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propan-1.39637.8638.5)

Hydroxycarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethanes

Yl ] -piperazin-1-yl } -ethyl) -carbamic acid tert-butyl ester

2fl 3- [4- (1H-indazol-5-yl) -piperazin-1-ylmethyl ] -1-oxo 0.99596.7597.7

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2fm 1-oxo-2-phenyl-3- (4-quinolin-6-yl-piperazin-1-ylmethyl 0.95607.8608.7

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2fn 3- [4- (6, 7-dimethoxy-quinazolin-4-yl) -piperazin-1-yl 1.06668.8669.3

Methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2fo 4- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylaminomethyl 1.09663.9664.8

Acyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-

Butyl ester of yl } -piperidine-1-carboxylic acid

2fp 3- {4- [2- (4-chloro-phenoxy) -ethyl ] -piperazin-1-ylmethyl 1.19635.2635.9

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2fq {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl 1.08594.8595.9

1, 2-dihydro-isoquinolin-3-ylmethyl-piperazine-1-

Butyl-acetic acid tert-butyl ester

2fr 1-oxo-2-phenyl-3- [4- (3, 3, 3-trifluoro-2-hydroxy-propan 0.96592.7593.6

1, 2-dihydro-4-quinolinyl-piperazin-1-ylmethyl ] -piperazine

Acid ((S) -1-phenyl-propyl) -amide

2fs 3- [4- (2-hydroxy-propyl) -piperazin-1-ylmethyl ] -1-oxo 0.86538.7539.5

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2fu 3- [4- (4-amino-6, 7-dimethoxy-quinazolin-2-yl) -1.03683.8684.7

Piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-

Isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fv (2- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylaminomethyl 1.06623.8624.5)

Acyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-

Methyl ethyl carbamic acid tert-butyl ester

2fw 1-oxo-3- {4- [2- (2-oxo-imidazolidin-1-yl) -ethyl ] -0.85592.7593.7

Piperazin-1-ylmethyl } -2-phenyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fx 3- {4- [ (4, 6-dimethoxy-pyrimidin-2-yl) -phenyl-methano 1.21708.9709.4

1-oxo-2-phenyl-1, 2-bis (piperazinyl) -1-ylmethyl

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fy 3- (4-benzo [1, 2, 5] thiadiazol-4-yl-piperazin-1-ylmethyl 1.48614.8615.4

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2fz 3- [4- (2, 3-dihydro-benzo [1, 4] dioxin-5-1.2614.7615.3

1-oxo-2-phenyl-1, 2-bis-piperazin-1-ylmethyl

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ga 3- [4- (4-methyl-quinolin-2-yl) -piperazin-1-ylmethyl 1.15621.8622.7

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2gb 1-oxo-2-phenyl-3- [4- (pyridin-2-ylcarbamoyl 0.93614.7615.4

Methyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2gc 3- [4- (6-chloro-3-oxo-3, 4-dihydro-2H-benzo 1.21662.2662.8

[1, 4] oxazin-8-yl) -piperazin-1-ylmethyl ] -1-oxo-2-

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2gd 3- (4-carbamoylmethyl-piperazin-1-ylmethyl) -1-oxo 0.85537.7538.5

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2ge 3- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -1-oxo 1.12571.7572.6

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2gf 3- [4- (4-chloro-phenyl) -4-hydroxy-piperidin-1-ylmethyl 1.23606.2606.8

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2gg 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) 0.9523.6524.5

1, 2-dihydro-isoquinolin-3-ylmethyl-piperidine-4-carboxylic acid

Acid(s)

2gh 3- (4-cyano-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-1.59580.7581.9

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2gi 3- (4-benzyl-4-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-1.16585.7586.0

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2gj 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) 1.35627.8628.5

1, 2-dihydro-isoquinolin-3-ylmethyl-4-phenyl-piperazines

Pyridine-4-carboxylic acid ethyl ester

2gk 1-oxo-2-phenyl-3- [4- (phenyl-propionyl-amino) -piperidine 1.17626.8627.6

-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2gl methyl- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylamino 1.25608.8609.8

Formyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine

-4-yl } -carbamic acid tert-butyl ester

2gm 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -0.72576.8577.5

Piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2gn 3- {4- [5- (4-fluoro-phenyl) - [1, 3, 4] oxadiazol-2-yl ] -piperazine 1.22641.7642.3

Pyridin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-iso-isomer

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2go 1-oxo-2-phenyl-3- [4- (3-pyridin-4-yl- [1, 2, 4] oxa 0.96624.7625.5

Oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gp 1-oxo-2-phenyl-3- [4- (3-pyrazin-2-yl- [1, 2, 4] oxa 1.04625.7626.5

Oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gq 1-oxo-2-phenyl-3- [4- (3-pyridin-4-yl- [1, 2, 4] oxa 1.04624.7625.5

Oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gr 3- (4 ' -hydroxy-3 ', 4 ', 5 ', 6 ' -tetrahydro-2 ' H- [2, 4 ' ] bipyridinyl 0.83572.7573.5

1-oxo-2-phenyl-1, 2-dihydro-isoquine-1' -ylmethyl-1-methyl-phenyl

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gs of 3- (spiro [ isochroman-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo 1.24597.8598.6

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2gt 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl 1.13601.7602.4

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2gu 3- [4- (3-chloro-phenyl) -4-hydroxy-piperidin-1-ylmethyl 1.23606.2606.8

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2gv 3- (6-chloro-3H-spiro [ isobenzofuran-1, 4 '-piperidin ] -1' -yl 1.36618.2618.4

Methyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2gw 3- (4- { [ 4-chloro-3- (4-fluoro-phenyl) -indan-1-yl ] -methyl-1.36753.4753.4

Amino } -piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gX 3- (1-acetyl-spiro [ indoline-3, 4 '-piperidine ] -1' -ylmethyl 1.15624.8625.6

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2gy 3- (1-acetyl-5-fluoro-spiro [ indoline-3, 4' -piperazine 1.2642.8643.4

Pyridin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-iso-isomer

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gz 1-oxo-3- (4-oxo-1-phenyl-1, 3, 8-triaza-spiro 1.15625.8626.6

[4.5] decan-8-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ha 3- (4-acetylamino-piperidin-1-ylmethyl) -1-oxo-2-0.83536.7537.4

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane

Acyl) -amides

2hb 1-oxo-3- (1-oxo-2, 8-diaza-spiro [45] decane-8-0.85548.7549.7

Ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2hc 3- [ 4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidin-1-yl 1.29639.7640.3

Methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2hd 1-oxo-2-phenyl-3- (4-trifluoromethyl-piperidin-1-ylmethyl 1.3547.6548.4

1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane)

Acyl) -amides

2he 3- [4- (4-methyl-piperazine-1-carbonyl) -piperidin-1-ylmethyl 0.7605.8607.0

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2hf 3- (5-isopropyl-3H-spiro [ isobenzofuran-1, 4' -piperazine 1.48625.8626.6

Pyridin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-iso-isomer

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hg 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-yl 1.13626.8627.7

Methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2hh 4- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylaminomethyl 1.03663.9664.7

Acyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine-4-carboxylic acid

Radical } -piperazine-1-carboxylic acid tert-butyl ester

2hi (2- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylaminomethyl 1.19622.8623.5)

Acyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine-4-carboxylic acid

Methyl ethyl carbamic acid tert-butyl ester

2hj 3- (4-methylamino-4-phenyl-piperidin-1-ylmethyl) -1-oxo 1.01584.8585.5

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2hk 3- (4-acetylamino-4-phenyl-piperidin-1-ylmethyl) -1-1.06612.8613.3

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2hl 3- [ 4-acetylamino-4- (3-fluoro-phenyl) -piperidin-1-ylmethyl 1.06630.8631.5

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2hm 1-oxo-3- [4- (4-oxo-piperidine-1-carbonyl) -piperidin-1-yl 0.89604.7605.3

Methyl ] -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2hn 3- [4, 4' ] bipiperidinyl-1-ylmethyl-1-oxo-2-phenyl 0.7562.8563.2

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2ho {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl 1.15594.8595.8

1, 2-dihydro-isoquinolin-3-ylmethyl-piperidine-4-carboxylic acid

Methyl-carbamic acid tert-butyl ester

2hp 3- [4, 4 '] bipiperidinyl-1' -ylmethyl-1-oxo-2-phenyl 0.95592.8593.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-benzene)

Methyl-amide

2hq 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-phenyl 1.15614.8615.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-benzene)

Methyl-amide

2hr 3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-benzene 0.97552.7553.8

1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-

Phenyl) -methyl ] -amides

2hs 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl 0.81623.8624.6

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ht 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-0.78607.8608.9

Oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl ] -

Yl- (3-fluoro-phenyl) -methyl ] -amide

2hu 1-oxo-2-phenyl-3- [4- (2-piperidin-1-yl-ethyl) -piperazines 0.82621.8622.6

Oxazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl ] -ester

Yl- (3-fluoro-phenyl) -methyl ] -amide

2hv 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -0.8607.8608.8

Piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid [ ring

Propyl- (3-fluoro-phenyl) -methyl ] -amide

2hw 1-oxo-2-phenyl-3- (4-pyridin-4-ylmethyl-piperazine-1-0.84601.7602.6

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl ]

- (3-fluoro-phenyl) -methyl ] -amide

2hx 3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl 0.77602.7603.7

-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hy 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl 0.75622.8623.7

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hz 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl 1.17631.7632.6

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ia 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-yl 1.18656.8657.8

Methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-

Carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ib 2- (2-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazine-1-1.12602.8603.8

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2ic 2- (2-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl 0.96540.7541.7

1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-)

Phenyl-propyl) -amides

2id 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (2-fluoro-phenyl) -1-1580.7581.7

Oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2ie 2- (2-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazines 0.82611.8612.5

Oxazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2if 2- (2-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazi ne 0.76595.8596.8

Oxazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2ig 2- (2-fluoro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-eth-yl 0.81609.8610.5

1, 2-dihydro-4-quinolinyl-piperazin-1-ylmethyl ] -piperazine

Acid ((S) -1-phenyl-propyl) -amide

2ih 2- (2-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-0.8595.8596.7

Ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2ii 2- (2-fluoro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-0.84589.7590.4

Piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2ij 2- (2-fluoro-phenyl) -3- (4-hydroxy-3, 4, 5, 6-tetrahydro 0.85590.7591.3

-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-1, 2-

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ik 2- (2-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazines 0.76610.8611.7

Pyridin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2il 2- (2-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-benzene 1.21619.7620.3

1-oxo-1, 2-dihydro-isoquinolin-1-yl-piperidin-1-ylmethyl ] -piperidine

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2im 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl 0.82607.8608.8

1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2in 1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-yl 0.81605.8606.9

Methyl ] -2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2io 1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl 0.84585.7586.4

Yl) -2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2ip 2- (3-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazine-1-1.13602.8603.8

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2iq 2- (3-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl 0.96540.7541.3

1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-)

Phenyl-propyl) -amides

2ir 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (3-fluoro-phenyl) -1-0.98580.7581.8

Oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2is 2- (3-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazino 0.81611.8612.6

Oxazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2it 2- (3-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazines 0.75595.8596.8

Oxazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2iu 2- (3-fluoro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-eth-yl 0.8609.8610.7

1, 2-dihydro-4-quinolinyl-piperazin-1-ylmethyl ] -piperazine

Acid ((S) -1-phenyl-propyl) -amide

2iv 2- (3-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-0.79595.8596.8

Ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2iw 2- (3-fluoro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-0.83589.7590.2

Piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2ix 2- (3-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazino 0.73610.8611.6

Pyridin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2iy 2- (3-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-benzene 1.18619.7620.7

1-oxo-1, 2-dihydro-isoquinolin-1-yl-piperidin-1-ylmethyl ] -piperidine

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iz 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-yl 1.2644.8645.7

Methyl ] -2- (3-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ja 2- (3-chloro-phenyl) -1-oxo-3- (4-phenethyl-piperazine-1-1.17619.2619.4

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2jb 2- (3-chloro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl 1557.1557.5

1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-)

Phenyl-propyl) -amides

2jc 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (3-chloro-phenyl) -1-1.04597.2597.8

Oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2jd 2- (3-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazines 0.86628.2628.6

Oxazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2je 2- (3-chloro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazine 0.79612.2612.2

Oxazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2jf 2- (3-chloro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-eth-yl 0.84626.2626.7

1, 2-dihydro-4-quinolinyl-piperazin-1-ylmethyl ] -piperazine

Acid ((S) -1-phenyl-propyl) -amide

2jg 2- (3-chloro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-0.83612.2612.4

Ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2jh 2- (3-chloro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-0.88606.2606.1

Piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2ji 2- (3-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazines 0.78627.2627.4

Pyridin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2jj 2- (3-chloro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-benzene 1.23636.2636.7

1-oxo-1, 2-dihydro-isoquinolin-1-yl-piperidin-1-ylmethyl ] -piperidine

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jk 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-yl 1.26661.2662.0

Methyl ] -2- (3-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jl 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-m-methyl 1.15598.8599.6

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane

Acyl) -amides

2jm 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-1-oxo-2-m-methyl 0.96576.8577.5

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propane

Acyl) -amides

2jn 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl 0.83607.8609.0

1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jo 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-0.78591.8592.6

Oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2jp 1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-yl 0.83605.8607.1

Methyl ] -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2jq 1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-yl 0.81591.8592.6

Methyl ] -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2jr 1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl 0.85585.7586.0

2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2js 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl 0.73606.8608.1

1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jt 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl 1.18615.8616.3

1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline

-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ju 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-yl 1.19640.8641.7

Methyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

Example 2 list of compounds, proceed

Chemical name t_R(min) MW m/z

(MH+)

2ka 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-chloro-1-oxo-2-1.06601.2601.5

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl

- (3-fluoro-phenyl) -methyl ] -amide

2kb 8-chloro-3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo 1.01557.1557.5

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl)

-propyl) -amide

2kc 8-chloro-3- (4-isobutyl-piperazin-1-ylmethyl) -1-oxo 1.07571.2571.7

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl)

-propyl) -amide

2kd 8-chloro-3- (octahydro-pyrido [1, 2-a ] pyrazin-2-ylmethyl 1.03569.1569.6

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2ke 8-chloro-3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl 0.8607.2607.9

Pyridin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-iso-phenyl

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kf 8-chloro-3- (4-cyclopropylmethyl-piperazin-1-ylmethyl) -1-oxo 1.04569.1569.8

Sub-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-

Phenyl-propyl) -amides

2kg of 8-chloro-3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl 0.75627.2627.4

1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2kh 8-chloro-3- [1, 4] diazepan-1-ylmethyl-1-oxo 0.98529.1529.3

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl)

-propyl) -amide

2ki 8-chloro-3- ((S) -3-methyl-piperazin-1-ylmethyl) -1-oxo 0.98529.1529.2

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl)

-propyl) -amide

2kj 8-chloro-3-imidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-0.92497.0497.4

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kk 8-chloro-3- (4-methyl-imidazol-1-ylmethyl) -1-oxo-2-0.97511.0511.3

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2kl 3- (tert-butylamino-methyl) -8-chloro-1-oxo-2-phenyl 1.06502.1502.5

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2km 8-chloro-3- (isopropylamino-methyl) -1-oxo-2-phenyl 1488.0488.6

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2kn 8-chloro-3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidine-1-1.2636.2636.8

Ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2ko 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-chloro-1-oxo-2-1.03571.2571.4

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2kp 3-benzimidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-1.02512.6513.3

Dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kq 1-oxo-2-phenyl-3-pyrazol-1-ylmethyl-1, 2-dihydro-1.54462.6463.4

Isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kr 3- (4-methyl-pyrazol-1-ylmethyl) -1-oxo-2-phenyl 1.65476.6477.3

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -

Amides of carboxylic acids

2ks 1-oxo-2-phenyl-3- [1, 2, 3] triazol-1-ylmethyl-1, 2-di 1.23463.5464.4

Hydrogen-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kt 2- (3-methoxy-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl 0.82601.7602.7

1, 2-dihydro-1-piperazin-1-ylmethyl-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2ku 2- (4-methoxy-phenyl) -3- [4- (2-morpholin-4-yl-ethan 0.8623.8624.5

1-oxo-1, 2-dihydro-isoquinolin-1-yl-piperazin-1-ylmethyl ] -piperazine

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kv 2- (4-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazine-1-1.13602.8603.8

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2kw 2- (4-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl 0.95540.7541.7

1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2kx 3- [1, 4 '] bipiperidinyl-1' ylmethyl-2- (4-fluoro-phenyl) -1-0.98580.7581.9

Oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2ky 2- (4-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazines 0.79611.8612.6

Oxazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2kz 2- (4-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazine 0.74595.8596.8

-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2la 2- (4-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-0.78595.8596.7

Ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2lb 2- (4-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-benzene 1.18619.7620.4

1-oxo-1, 2-dihydro-isoquinolin-1-yl-piperidin-1-ylmethyl ] -piperidine

Quinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2lc 2- (4-chloro-phenyl) -1-oxo-3- (4-phenethyl-piperazine-1-1.17619.2619.3

Ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2ld 2- (4-chloro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl 0.99557.1557.4

1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-benzene)

Yl-propyl) -amides

2le 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (4-chloro-phenyl) -1-1.04597.2597.8

Oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2lf 2- (4-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazines 0.85628.2628.6

Oxazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

Acid ((S) -1-phenyl-propyl) -amide

2lg 2- (4-chloro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazine 0.77612.2612.3

-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid

((S) -1-phenyl-propyl) -amide

2lh 2- (4-chloro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-eth-yl 0.84626.2626.8

1, 2-dihydro-4-quinolinyl-piperazin-1-ylmethyl ] -piperazine

Acid ((S) -1-phenyl-propyl) -amide

21i 2- (4-chloro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-0.81612.2612.6

Ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-

Carboxylic acid ((S) -1-phenyl-propyl) -amide

2lj 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-fluoro-1-oxo-2-0.96554.7555.7

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-)

Propyl) -amides

2lk 8-chloro-3-cyclopropylaminomethyl-1-oxo-2-phenyl 0.61486.0486.4

-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) - (method B)

Amides of carboxylic acids

2ll 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-fluoro-1-oxo 0.98584.7585.5

-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropane

Yl- (3-fluoro-phenyl) -methyl ] -amide

2lm 8-fluoro-1-oxo-2-phenyl-3-piperazin-1-ylmethyl-1, 2-bis 0.89528.6529.4

Hydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -

Methyl radical]-amides (a)^*)

2ln 8-fluoro-1-oxo-3- (3-oxo-pyrazolidin-1-ylmethyl) -2-1.14528.6528.8

Phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl

- (3-fluoro-phenyl) -methyl ] -amide

2lo 8-fluoro-1-oxo-3- (3-oxo-piperazin-1-ylmethyl) -2-benzene 1.13542.6543.5

1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-

Fluoro-phenyl) -methyl ] -amides

(^*): 1- (tert-Butoxycarbonyl) piperazine was used as amine and the BOC-group was removed in the next step by 2M HCl in diethyl ether and methanol (1: 1) at room temperature.

Example 3

3a 1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

To a solution of 2-pyrrolidone (0.1ml) in tetrahydrofuran (2ml) was added sodium hydride (20mg, 60% dispersed in mineral oil). The reaction mixture was stirred at ambient temperature until evolution of gas ceased, then-bromomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (30mg) was added. After 30 minutes, acetic acid (0.05ml) was added and the volatiles were removed in vacuo. The product is processed by SiO ₂Purification by flash chromatography (5g, 1, 2-dichloroethane followed by a gradient of 50% to 100% ethyl acetate in heptane) to yield 17mg of whiteAnd (3) a solid. The yield was 56%. LC-MS (m/z)480.5 (MH)⁺)；t_R＝1.21。

Similarly, the following compounds were obtained:

3b 8-chloro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)514.7(MH⁺)；t_R＝1.33。

And (3) synthesis of an intermediate:

3-oxo-pyrazolidine-1-carboxylic acid tert-butyl ester.

To the solution were added 3-pyrazolidinone hydrochloride (55.3mg, 0.45mmol), Na₂CO₃To a mixture of (133mg, 1.24mol), water (0.5ml) and dioxane (0.054ml) was added BOC-anhydride (101mg, 0.46mmol) in dioxane (0.16ml) and stirred at room temperature overnight. It was filtered, evaporated, and used in the next step without further purification.¹H NMR(500MHz，DMSO-d₆)：1.4(s，9H)，2.32(t，J＝9Hz，2H)，3.6(t，J＝9Hz，2H)。

3c 1-oxo-2-phenyl-3- (1H- [1, 2, 4] triazol-3-ylthiomethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)496.6(MH⁺)；t_R0.64 (method B).

3d 8-chloro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)544.3(MH⁺)；t_R＝1.39。¹H NMR(250MHz，70℃，DMSO-d₆)：0.4-0.64(m，4H)，1.28(m，1H)，1.74(m，2H)，1.97(m，2H)，2.89(br，1H)，3.06(H₂O)，4.02-4.14(br，2H)，4.51(t，J＝8.6Hz，1H)，7.08(dt，1H)，7.2-7.3(m，4H)，7.37-7.7(m，7H)，9.07(d，J＝8.1Hz，1H，NH)。

3e 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)498.8(MH⁺)；t_R＝1.23，t_R0.68 (method B).¹H NMR(250MHz，70℃，DMSO-d₆): 0.93(t, J ═ i.3hz, 3H), 1.66-2.0(m, 6H), 2.84(brt, 1H), 3.01 (overlapping H)₂O signal), 3.98-4.08(br, 2H), 4.97(t, J ═ 7.6Hz, 1H), 7.2-7.54(m, 12H), 7.69(m, 1H), 8.77(d, J ═ 7.9Hz, 1H, NH).

3f 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)528.7(MH⁺)；t_R＝1.29，t_R0.7 (method B).¹H NMR(250MHz，80℃，DMSO-d₆): 0.37-0.62(m, 4H), 1.25(m, 1H), 1.71 (quintuple, J ═ 7.5Hz, 2H), 1.94(t, J ═ 7.9Hz, 2H), 2.85(br, 2H), 2.94(H₂O)，4.05(br，2H)，4.5(t，J＝8.6Hz，1H)，7.04(m，1H)，7.17-7.32(m，5H)，7.32-7.52(m，5H)，7.7(m，1H)，8.97(d，J＝8.1Hz，1H，NH)。

3g 8-fluoro-1-oxo-3- (5-oxo-pyrazolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

3-oxo-pyrazolidine-1-carboxylic acid tert-butyl ester was used in the coupling reaction accelerated by NaH. Intermediate 2- (4- { [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl at RT]The BOC-group of-carbamoyl } -8-fluoro-1-oxo-2-phenyl-1, 2-dihydro-isoquinolin-3-ylmethyl) -3-oxo-pyrazolidine-1-carboxylic acid tert-butyl ester was removed with a solution of 2M HCl ether-methanol (1: 1) for 30 minutes and the title compound was purified by LC-MS of preparation. LC-MS (m/z)529.3 (MH) ⁺)；t_R＝1.15。

3h 8-fluoro-1-oxo-3- (2-oxo-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

HeadlineingThe compound is prepared analogously starting from 2-oxo-4- (tert-butoxycarbonyl) piperazine and subsequently removing the BOC group. LC-MS (m/z)543.6 (MH)⁺)；t_R＝0.84。

3i 8-fluoro-1-oxo-3- (2-oxo-piperidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

The title compound was prepared analogously from 2-piperidone. LC-MS (m/z)542.5 (MH)⁺)；t_R＝1.35。

Example 4

4a 3-cyanomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

To a solution of 3-bromomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (83mg, 0.174mmol) in THF (1.5ml, anhydrous) and DMF (1.5ml, anhydrous) was added sodium cyanide (83mg, excess). After 5 minutes, the resulting suspension was poured into water (50ml) followed by heptane (20 ml). The crude product is separated off by filtration and passed through SiO₂Flash chromatography (5g, 1: 1 EA-heptane) afforded 50mg of a colorless solid in 68% yield. LC-MS (m/z)422.4 (MH)⁺)；t_R＝1.39。¹H NMR(250MHz，DMSO-d₆T ═ 343K): 0.94(t, 3H), 1.78 and 1.85 (ABX) ₄Two overlapping quintet, CH of 2H, Et₂) 3.45 and 3.54 (two doublets of AB, 2H, CH)₂CN)，4.98(q，1H)，7.22-7.44(m，8H)，7.53-7.64(m，4H)，7.72(dt，1H)，8.25(dd，1H)，9.05(d，1H)。

4b 8-chloro-3-cyanomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)486.5(MH⁺)；t_R＝1.81。

Example 5

5a 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid N ', N' -diphenyl-hydrazide.

A mixture of 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carbonyl chloride, the synthesis of which is described in example 1a above, (25mg, 0.08mmol) and 1, 1-diphenylhydrazine hydrochloride (56mg, 0.25mmol) in 1, 2-dichloroethane (1ml) was heated under microwave irradiation at 140 ℃ for 20 minutes. The volatiles were removed in vacuo and the product was purified by preparative LC-MS to give 14mg of a colorless solid. LC-MS (m/z)446.7 (MH)⁺)；t_R＝1.58。

3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid N' -phenyl-hydrazide. [740-170]

The title compound was prepared analogously. LC-MS (m/z)370.2 (MH)⁺)；t_R＝1.15。¹HNMR(500MHz，DMSO-d₆)：2.01(s，3H)，6.76(t，1H)，6.83(d，2H)，7.2(t，2H)，7.33(br，2H)，7.5-7.62(m，5H)，7.83(t，1H)，8.11(br，1H)，8.24(d，1H)，10.33(s，1H)。

5b N' - (3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carbonyl) -N-phenyl-hydrazinecarboxylic acid methyl ester.

A mixture of 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid N' -phenyl-hydrazide (5a, 490mg, 1.3mmol) and methyl chloroformate (0.6ml, 8mmol) in 1, 2-dichloroethane (10ml) was heated under microwave irradiation at 100 ℃ for 10 minutes. The volatiles were removed in vacuo and the product was flash chromatographed (SiO) ₂Heptane-1: 1 ethyl acetate/heptane gradient) to yield 190mg of a solid. LC-MS (m/z)428.8 (MH)⁺)；t_R＝1.22。

Example 6

6a 2- (3, 4-dichloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

A mixture of 4-acetyl-3- ((S) -1-phenyl-propylamino) -isochromen-1-one (60mg) and 3, 4-dichloroaniline (250mg) in acetonitrile (0.5ml) was heated for 15 minutes under microwave irradiation at 160 ℃. The reaction mixture was partitioned between 2M HCl (3ml) and ethyl acetate (3 ml). Using SiO for organic solution₂(600mg) absorption over a heptane-ethyl acetate gradient of SiO₂(2Og) flash chromatography gave 22mg of the title compound as a white solid. LC-MS (m/z)465.4&467.4(MH⁺)；t_R＝1.63。

The following compounds are obtained analogously from the corresponding compounds of the formula XXIII and the appropriate anilines of the formula VI:

8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (1 i).

The title compound and an alternative preparation thereof are described in example 1 i.

6b 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide.

LC-MS(m/z)510.3(MH⁺)；t_R＝1.25。

6c 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide.

LC-MS(m/z)427.3(MH⁺)；t_R＝1.39。

Example 7

7a 3-ethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

2- [ 2-oxo-1- ((S) -1-phenyl-propylcarbamoyl) -butyl sealed in acetonitrile (0.3ml)]A mixture of benzoic acid (82mg, 0.2mmol) and aniline (0.3ml, 3.3mmol) was heated under microwave radiation at 160 ℃ for 10 minutes. The mixture was partitioned between ethyl acetate (20ml) and 3M aqueous HCl (2X 8ml), NaHCO₃Between saturated aqueous solution (2X 10ml) and brine, dried (MgSO)₄) And evaporation. Flash chromatography of the residue (SiO)₂A gradient of heptane-ethyl acetate) to yield 32mg of the title compound. LC-MS (m/z)411.5 (MH)⁺)；t_R＝1.48。¹HNMR(500MHz，DMSO-d₆): a mixture of two atropisomers.

The following compounds are obtained analogously by condensation of compounds of the formula XXV with the appropriate anilines of the formula VI:

7b 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)415.5(MH⁺)；t_R＝1.39。

7c 8-fluoro-2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)433.5(MH⁺)；t_R＝1.41。

7d 8-fluoro-2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)433.6(MH⁺)；t_R＝1.4。

8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide (3 e).

The title compound and an alternative method of preparation thereof are described above in example 3.

7e 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)445.6(MH⁺)；t_R＝1.44。¹H NMR(250MHz，70℃，DMSO-d₆)：0.41-0.61(m，4H)，1.25(m，1H)，1.86(s，3H)，4.49(t，J＝8.9Hz，1H)，7.04(m，1H)，7.13-7.31(m，6H)，7.37(m，1H)，7.42-7.6(m，3H)，7.67(m，1H)，8.93(br d，J＝8.5Hz，1H，NH)。

7f 8-fluoro-2- (3-fluoro-phenyl) -1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

The title product was isolated by TLC prepared on silica gel. LC-MS (m/z)546.4 (MH)⁺)；t_R0.71 (method B).

7g 8-fluoro-2- (4-fluoro-phenyl) -1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

The title product was isolated by TLC prepared on silica gel. LC-MS (m/z)546.3 (MH)⁺)；t_R0.71 (method B).

7h 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclobutyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)459.4(MH⁺)；t_R＝1.54。

7i 8-fluoro-2- (2-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)463.3(MH⁺)；t_R＝1.46。

7j 8-fluoro-2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)463.3(MH⁺)；t_R＝1.46。

7k 8-fluoro-2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)463.4(MH⁺)；t_R＝1.45。

7l 6, 8-difluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)463.2(MH⁺)；t_R0.82 (method B).

7m 5, 8-difluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

LC-MS(m/z)463.4(MH⁺)；t_R＝1.39。

7n 3-methyl-1-oxo-2-phenyl-8-trifluoromethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide.

LC-MS(m/z)465.3(MH⁺)；t_R＝1.57。

Example 8

8a 3- (1-tert-butyl-piperidin-4-ylmethyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide.

To a cold (ice bath) mixture of 2- (1-tert-butyl-piperidin-4-yl) -N-phenyl-acetamide (250mg, 0.91mmol) and 2, 6-lutidine (0.139ml, 1.2mmol) in 1, 2-dichloroethane (8ml) was added oxalyl chloride (0.07ml, 0.8mmol) and stirred at 0 ℃ for 15 min. Adding 2-chloro-6- ({ [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl]-carbamoyl } -methyl) -benzoic acid (70mg, 0.2mmol) and the reaction mixture was stirred in a closed vessel at 90 ℃ for 15 hours. It was partitioned between 0.5M aqueous NaOH (40ml) and ethyl acetate (200ml) and the organic phase washed with water, dried and evaporated. Flash chromatography of the residue (SiO) ₂Ethyl acetate-methanol) to yield 19mg of the title compound. LC-MS (m/z)600.6 (MH)⁺)；t_R＝1.1。¹H NMR(500MHz，r.t，DMSO-d₆): broad signal, mixture of two atropisomers.

Reagents for the preparation of compounds

Reagents for preparing the compounds, proceeding

Ref.1. the compound is prepared according to the method described in s.c. gloss Synthesis 2007, 7, 981.

Ref.2. the compound was prepared according to the method described in T.Sugaya, Y.Mimura, N.Kato, M.Ikuta, T.Mimura et al Synthesis 1994, 73.

Example 9NK3 receptor binding assay

Cell membrane preparation: BHK cells stably expressing the human NK3 receptor were seeded onto collection plates in Dulbeccos MEM containing GlutaMax (862mg/l), 1mM sodium pyruvate, 10% fetal bovine serum, 1% Pen/Strep, 1mg/ml G418, and contained 10% CO at 34 deg.C₂In a humid atmosphere. To increase receptor expression, 10 μ M trichostatin A was added to the medium and cells were harvested at about 90% confluence after 24 hours. Before harvesting, cells were used Mg-free²⁺og Ca²⁺Washed twice with PBS, and then collected by scraping each collection plate with 10ml PBS. The cell suspension was centrifuged at 150OxG for three minutes and then resuspended in a suspension containing 2mM MgCl₂0,3mM EDTA and 1mM EGTA in 15mM Tris-HCl pH 7.5 buffer (buffer A). The cell suspension was homogenized and then centrifuged at 4000OxG for 30 minutes. The cell membrane-pellet was resuspended in buffer A containing 250mM sucrose, aliquoted and stored at-80 ℃.

Description of affinity assay: in a medium containing 120mM NaCl,3mM MnCl₂The assay was performed based on the SPA competition-binding assay in 50mM Tris pH 7.4 assay buffer with 40. mu.g/ml bacitracin, 2. mu.g/ml broom-corn-millet-plus-minus (phosphoamidion), 1. mu.g/ml phosphonyl dipeptide and 4. mu.g/ml leupeptin. About 0.02nM¹²⁵I-NKB was mixed with test compound, and then 4. mu.g of homogenized NK3 cell membrane preparation and 0.025mg of SPA beads were added in a total volume of 60. mu.l. The assay plates were then incubated at room temperature for 90 minutes with shaking. Plates were centrifuged at 50OxG for 10 minutes and counted in a counter (topcounter) for 5 minutes per well.

Total binding was determined using assay buffer containing less than 5% added radioligand, whereas non-specific binding was determined in the presence of 1 μ M osanetant. Non-specific binding accounts for about 5% of the total binding.

To be provided with¹²⁵The percentage of I-NKB specific binding represents these data points, and IC was determined by nonlinear regression analysis using sigmoidal variable slope curve fitting (sigmoidal variable slope curve fitting)₅₀Value (cause to)¹²⁵Concentration at which I-NKB specifically binds 50% inhibition). According to the ChengPrusoff equation (K)_i＝IC₅₀/(1+(L/K_D) )) to calculate the dissociation constant (K)_i) Wherein the concentration of free radioligand L is about that added in the assay ¹²⁵Concentration of I-NKB (about 0.02 nM). From three independent saturation measurements, each performed in duplicate, determined¹²⁵K of I-NKB_DWas 0.7 nM. The maximum binding (Bmax) was about 2 pmol/mg.

The compounds of the invention generally have a K of 500nM or less_iThe value is obtained. In fact most compounds have a K below 100nM and as low as a single place value_iThe value is obtained.

The following table gives the K of the NK3 receptor_iValue of

Compound (I)	KinM
		Example 2a	180
Example 2bm	8.2
		Example 2hs	5.3
Example 2hz	3
		Example 3a	72
Example 5a	55

For further affinity data for the compounds of the invention, see also the table in example 10.

Example 10NK3 receptor potency and potency assay

BHK cells stably expressing the human NK3 receptor were seeded in a black-walled clear matrix 96-well plate (Costar) in 100. mu.l of medium to achieve 95-100% fusion on the day of assay. The Assay was performed according to the FLIPR Calcium 4 Assay kit (Molecular Devices). On the day of the assay, the medium was removed, the cells were washed once with HBSS buffer (Hanks BSS buffer, pH 7.4, containing 20mM Hepes), and then 100. mu.l of a buffer solution containing 2.5m was added to the cellsA solution of calcium assay reagents in HBSS buffer with probenecid (probinicid). At 34 deg.C, 10% CO ₂Plates were incubated for 60 minutes next, and fluorescence was detected using FLIPR.

In the established protocol (which started adding HBSS buffer to the wells, and after 15 minutes various concentrations of NKB were added to determine the EC of NKB₅₀And EC₈₅) NKB was used to test the dose-response curve of a representative plate. Plates of all compounds for NKB were pre-coated with 1% BSA solution, followed by H₂O washes three times. NKB was diluted with HBSS buffer containing 0.1% BSA.

To evaluate the efficacy and potency (potency) of the compounds, these samples were diluted with HBSS buffer prior to testing. To test for agonist activity, 25 μ l of diluted compound solution was added and the plates were analyzed in a FLIPR for 5 minutes. To test for antagonist activity, plates were incubated for another 45 minutes, then 25 μ l of EC as described above was added₈₅Concentration of NKB (about 4 nM). The plate was then analyzed for 5 minutes, and the assay was terminated. The maximum increase in fluorescence over background was determined with the addition of each ligand. Calculating IC by using S-shaped deformation slope curve fitting₅₀Value, applying equation (cIC)₅₀＝IC₅₀/(1+(EC₈₅/EC₅₀) )) determination cIC₅₀Value, EC of NKB₈₅And EC₅₀As determined above.

All of the isoquinolinones of the present invention (isoquinolinone) were characterized in the NK3 receptor potency and potency assays as antagonists at the relevant doses, and without any significant agonistic activity observed. The affinity data (obtained as described in example 9) and potency data obtained with the compounds of the invention are given in the table. The small difference between the tabulated values in examples 9 and 10 is reflected only in: more than one test batch is performed and/or more than one test batch is performed.

	Affinity of		Potency of the drug
				Example numbering	Ki/nM		cIC50/nM
2e	330		470
				1i	41		130
3a	88		270
				2r	320		420
2s	200		340
				2u	90		96
2ah	290		360
				2bg	160		220
2bm	8.8		14
				2bn	160		300
2cw	8.4		45
				2cz	76		49
2df	340		450
				2ec	210		520
2eg	240		610
				2es	140		240
2ey	240		480
				2fm	33		140
2gt	9.2		22
				2hq	10		44
2hs	7.5		21
				2hu	6.2		29
2hv	14		35
				2hw	8.2		63
2hx	9.3		68
				2hy	8.8		63
2hz	4.5		35
				2ia	12		100

2iy	17		92
				lt	27		44
2kh	82		120
				2kn	8.7		41
2ko	11		5.6
				3d	16		46
2lj	18		16
				3b	32		47
1bh	21		81
				2ll	7.9		6.3
8a	7		9.9
				1bn	23		23
6c	23		24
				1bl	470

Claims (100)

1. A compound according to formula I

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, -C (O) -C_1-6Alkyl, -C (O) -C_2-6Alkenyl, -C (O) -C_2-6Alkynyl, -C (O) -O-C_1-6Alkyl, -C (O) -O-C_2-6Alkenyl, -C (O) -O-C_2-6Alkynyl or phenyl, wherein said phenyl, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein X represents hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Or X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic, bicyclic or tricyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) — O₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -C_2-6Alkenyl, -C (O) -C_2-6Alkynyl, -C (O) -O-C_1-6Alkyl, -C (O) -O-C_2-6Alkenyl, -C (O) -O-C _2-6Alkynyl, -O-C (O) -C_1-6Alkyl, -O-C (O) -C_2-6Alkenyl, -O-C (O) -C_2-6Alkynyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein each R⁴-R⁸、R⁹-R¹²And R¹³-R¹⁷Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, NR²R³Hydroxy, cyano, nitro, C_1-6Alkoxy, halo C_1-6Alkyl or hydroxy C_1-6An alkyl group;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein R ⁴-R⁸Represents hydrogen.

3. A compound according to claim 1, wherein R⁹-R¹²Represents hydrogen.

4. A compound according to claim 1, wherein R¹³-R¹⁷Represents hydrogen.

5. Formula I according to claim 1_aOf (a) a compound

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein X represents hydrogen, C_1-6Alkyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Or X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic, bicyclic or tricyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) — O₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

Wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano, or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, which areWherein said substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein each R⁴-R⁸、R⁹-R¹²And R¹³-R¹⁷Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halogen, NR²R³Hydroxy, cyano, nitro, C_1-6Alkoxy, halo C_1-6Alkyl or hydroxy C_1-6An alkyl group;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

6. A compound according to claim 5, wherein A represents CH.

7. A compound according to claim 6, wherein R¹Represents C_1-6An alkyl group.

8. A compound according to claim 7, wherein R¹Represents ethyl or cyclopropyl.

9. Compounds according to any one of claims 5 to 8, wherein X represents hydrogen, C _1-6Alkyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³-、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl.

10. A compound according to claim 9, wherein X represents hydrogen, methyl, or NR²R³Wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, or hydroxy C_1-6An alkyl group.

11. A compound according to claim 10, wherein R²And R³Independently represents hydrogen, cyclopropylmethyl, methyl, ethyl or cyclopropyl.

12. A compound according to any one of claims 5 to 8 wherein X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic, bicyclic or tricyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -O-C (O) -, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

Wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl radicalA hydroxyl group, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl.

13. A compound according to claim 12 wherein X represents a monocyclic moiety having 5 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be heteroatoms selected from N, O and S, and wherein the monocyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C _1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -O-C (O) -, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or benzeneAnd (4) a base.

14. A compound according to claim 12 wherein X represents a monocyclic moiety having 6 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be heteroatoms selected from N, O and S, and wherein the monocyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) ₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -O-C (O) -, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl.

15. A compound according to claim 12 wherein X represents a monocyclic moiety of 7 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms are each nitrogen May be a heteroatom selected from N, O and S, and wherein the monocyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C _1-6Alkyl or phenyl.

16. A compound according to claim 12 wherein X represents a monocyclic or bicyclic moiety of 8 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH)₂)_C-O-whereinc is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl.

17. A compound according to claim 12 wherein X represents a monocyclic or bicyclic moiety of 9 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl.

18. A compound according to claim 12 wherein X represents a monocyclic or bicyclic moiety having 10 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C(O)、-C(O)-O-、-NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl.

19. Formula I according to claim 1_bOf (a) a compound

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

20. A compound according to claim 19, wherein A represents CH, and R¹Represents C_1-6An alkyl group.

21. A compound according to claim 20, wherein R¹Represents ethyl or cyclopropyl.

22. Compounds according to any of claims 19-21, wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano groups or bagsA monocyclic or fused bicyclic moiety of 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein said monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

Wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl.

23. A compound according to claim 22, wherein Y represents a bond, C (O) or S (O)₂(ii) a Wherein a + b is O, 1, 2, 3, or 4; and wherein Z represents a monocyclic or fused bicyclic moiety comprising 4 to 12 carbon ring atoms and optionally one, two or three heteroatoms selected from N, O, and S, and wherein said monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl.

24. A compound according to claim 23, wherein Y represents a bond or c (O), and a + b is O, 1, 2, or 3.

25. Compounds according to any of claims 22-24, wherein Z represents morpholinyl optionally substituted by one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl.

26. A compound according to claim 25, wherein the morpholinyl is linked to the remainder of the W moiety via the nitrogen.

27. Compounds according to any of claims 22-24, wherein Z represents piperidinyl optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl.

28. A compound according to claim 27 wherein the piperidinyl group is attached to the remainder of the W moiety via a nitrogen.

29. Compounds according to any of claims 22-24, wherein Z represents pyridyl optionally substituted by one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl.

30. The compound according to claim 29, wherein the pyridyl is linked to the remainder of the W moiety via position 2, 3 or 4 of the pyridyl.

31. Compounds according to any of claims 22-24, wherein Z represents phenyl optionally substituted by one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl.

32. Compounds according to any of claims 22-24, wherein Z represents pyrrolidinyl optionally substituted with one or more substituents selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl.

33. Compounds according to any of claims 22-24, wherein Z represents indolyl optionally substituted with one or more substituents selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyrazinyl, pyridyl, and halo-substituted phenyl.

A compound according to claim 33, wherein the indolyl is attached to the remainder of the W moiety at the 4, 5, 6, or 7 position of the indolyl.

35. Compounds according to any of claims 22-24, wherein Z represents cyclopentyl.

Compounds according to any of claims 22-24, wherein Z represents furopyridinyl.

37. Compounds according to any of claims 22-24, wherein Z represents tetrahydrofuranyl.

38. A compound according to claim 22, wherein Y represents a bond, C (O), -C (O) -O-, C (O) -NH-, -O-, or S (O)₂(ii) a a + b is O, 1, 2, 3, or 4; and wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Or a cyano group.

39. A compound according to claim 38, wherein Y represents a bond, C (O), -C (O) -O-, C (O) -NH-, -O-, or S (O)₂A + b is O, 1, 2 or 3, and wherein Z represents hydrogen, methyl, ethyl, -N (CH) ₃)₂Cyano, isopropyl, isobutyl, or tert-butyl.

40. Compounds according to any of claims 19-21, wherein W is selected from hydrogen, hydroxy, halogenElement, cyano, (═ O), - (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH.

41. A compound according to claim 40, wherein W is selected from- (CH)₂)_d- (where d is 5 or 6) (spiro) and C_1-6An alkyl group.

42. Formula I according to claim 1_cOf (a) a compound

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

Wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

43. A compound according to claim 42, wherein A represents CH, and R¹Represents C_1-6An alkyl group.

44. A compound according to claim 43, wherein R¹Represents ethyl or cyclopropyl.

45. Compounds according to any of claims 42-44, wherein W independently represents hydrogen, hydroxy, phenyl, C_1-6Alkoxy-substituted phenyl, piperidinyl, pyridinyl, -O- (CH)₂)_C-O- (wherein c is 2 or 3) (spiro), N (CH)₃)₂、C_1-6Alkyl, - (CH)₂)_a-C(O)-O-(CH₂)_b-H (wherein a + b is 1, 2, or 3), or

(wherein a represents 1, 2, or 3).

46. According to claim1 of the formula I_dOf (a) a compound

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

wherein R is⁹-R¹²Independently represents hydrogen or halogen;

and pharmaceutically acceptable salts thereof.

47. The compound according to claim 46, wherein A is CH; r¹Represents C_1-6Alkyl, and each R⁹-R¹²Independently represents hydrogen or halogen.

48. A compound according to claim 47, wherein R¹Represents ethyl or cyclopropyl; and each R⁹-R¹²Represents hydrogen.

49. Formula I according to claim 1_eOf (2) to (b)Article (A)

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C _1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is ²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

50. The compound according to claim 49, wherein A is CH, and R¹Represents C_1-6An alkyl group.

51. A compound according to claim 50, wherein R¹Represents ethyl or cyclopropyl.

52. Formula I according to claim 1_fOf (a) a compound

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

53. The compound according to claim 52, wherein A is CH, and R¹Represents C_1-6An alkyl group.

54. A compound according to claim 53, wherein R¹Represents ethyl or cyclopropyl.

55. Formula I according to claim 1_gOf (a) a compound

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro))、(CH₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -N (R)²)-C(O)-R³-C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR ²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

56. The compound according to claim 55, wherein A is CH and R¹Represents C_1-6An alkyl group.

57. A compound according to claim 56, wherein R¹Represents ethyl or cyclopropyl.

58. Formula I according to claim 1_hOf (a) a compound

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH) ₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

59. The compound according to claim 58, wherein A is CH, and R¹Represents C_1-6An alkyl group.

60. A compound according to claim 57, wherein R¹Represents ethyl or cyclopropyl.

61. Formula I according to claim 1_iOf (a) a compound

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein W is selected from hydrogen, hydroxy, halogen, cyano, (═ O), -O- (CH)₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein X represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, NR²、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano, or a monocyclic or fused bicyclic moiety containing 4 to 12 ring atoms, wherein optionally one, two or threeWherein the ring atoms are heteroatoms selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents selected from halogen, cyano, C _1-6Alkyl, hydroxy, and C_1-6Alkoxy, pyrazinyl, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

The compound according to claim 61, wherein A is CH, and R¹Represents C_1-6An alkyl group.

63. A compound according to claim 62, wherein R¹Represents ethyl or cyclopropyl.

64. A compound of formula Ij according to claim 1

Wherein A represents N, CH or CR¹；

Wherein each R¹Independently represent hydrogen, C_1-6Alkyl, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, or phenyl, wherein said phenyl or C_1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, halo C_1-6Alkyl, nitro, C_1-6Alkoxy, and NR²R³Substituted with the substituent(s);

wherein X represents hydrogen, C_1-6Alkyl, cyano, -OR²、-O-C(O)R²、-OC(O)NR²R³、-C(O)-NR²R³、-N(R²)C(O)R³、-N(R²)-C(O)NR²R³Or NR²R³Or X represents a monocyclic, bicyclic or tricyclic moiety having 4 to 16 ring atoms, wherein one ring atom is nitrogen and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic, bicyclic or tricyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, halo, cyano, (═ O), -O- (CH) — O ₂)_C-O-wherein c is 2 or 3 (spiro), (CH)₂)_dWherein d is 5 or 6 (spiro), C_1-6Alkyl radical, C_1-6Alkoxy, -C (O) -C_1-6Alkyl, -C (O) -O-C_1-6Alkyl, -O-C (O) -C_1-6Alkyl, -C (O) H, COOH; or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

wherein Y represents a bond, C (O), O, S, -O-C (O), -C (O) -O-, -NR²-、-NR²-C (O) -, -C (O) -NH-, or S (O)₂；

Wherein Z represents hydrogen, C_1-6Alkyl, NR²R³Cyano or a monocyclic or fused bicyclic moiety comprising 4 to 12 ring atoms, wherein optionally one, two or three ring atoms is a heteroatom selected from N, O, and S, and wherein the monocyclic or fused bicyclic moiety is optionally substituted with one or more substituents, wherein the substituents are selected from halogen, cyano, C_1-6Alkyl, hydroxy, and C_1-6Alkoxy, phenyl, pyridyl, and halo-substituted phenyl;

wherein R is⁴-R⁸One represents halogen and the others represent hydrogen; wherein R is¹³-R¹⁷One represents halogen and the others represent hydrogen;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl, hydroxy C_1-6Alkyl, halo C_1-6Alkyl or phenyl;

and pharmaceutically acceptable salts thereof.

65. The compound according to claim 64, wherein A isTable CH; r ¹Represents ethyl or cyclopropyl; r¹⁴Represents halogen; and R⁵Or R⁸Represents halogen.

66. A compound according to claim 65, wherein X represents piperazinyl or 1-piperidinyl substituted with one or two substituents W, wherein W is of formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z; wherein a and b independently represent O, 1, 2 or 3; y represents a bond, O, -NR²-c (o) -; and wherein Z represents hydrogen, C_1-6Alkyl, piperidinyl, morpholinyl, pyridinyl, phenyl, or C_1-6Alkoxy-substituted phenyl, or pyrrolidinyl.

67. Formula I according to claim 1_kOf (a) a compound

Wherein R is¹Represents hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

wherein X represents hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or NR²R³Or X represents a monocyclic or bicyclic moiety having 5 to 9 ring atoms, wherein one ring atom is nitrogen, and wherein one, two or three further ring atoms may be a heteroatom selected from N, O and S, and wherein the monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, halogen, hydroxy, (═ O), C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, or wherein W represents a group of formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

Wherein Y represents a bond, and wherein Z represents a monocyclic moiety comprising 5 to 6 ring atoms, optionally one, twoOr three ring atoms are heteroatoms selected from N, O, and S, and wherein the monocyclic moiety is optionally substituted with one or more substituents selected from halogen, C_1-6Alkyl, hydroxy, and C_1-6The substituent of the alkoxy group is substituted,

wherein each R⁴-R⁸Independently represents hydrogen or halogen;

wherein each R⁹-R¹²Independently represents hydrogen or halogen, provided that R⁹-R¹²At least one of them represents halogen;

wherein each R¹³-R¹⁷Independently represents hydrogen or halogen;

wherein R is²And R³Independently represent hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6An alkynyl group;

and pharmaceutically acceptable salts thereof.

68. Formula I according to claim 67_k' Compounds

Wherein R is¹Is selected from C_1-6An alkyl group;

wherein X represents hydrogen, C_1-6Alkyl, or NR²R³Or X represents a monocyclic or bicyclic moiety having 5 to 9 ring atoms, wherein one ring atom is nitrogen and wherein another ring atom may be a heteroatom selected from N, and wherein said monocyclic or bicyclic moiety may be optionally substituted by one or more substituents W, wherein W is selected from hydrogen, hydroxy, (═ O), C_1-6Alkyl or wherein W represents formula- (CH)₂)_a-Y-(CH₂)_b-a moiety of Z;

wherein a and b independently represent an integer selected from O, 1, 2 and 3;

Wherein Y represents a bond, and wherein Z represents a monocyclic moiety comprising 5 to 6 ring atoms, wherein optionally one ring atom is a heteroatom selected from N, O, and S, and wherein the monocyclic moiety is optionally substituted with one or moreIs selected from halogen and C_1-6Alkyl, hydroxy, and C_1-6The substituent of the alkoxy group is substituted,

wherein R is¹²Represents halogen;

R¹³-R¹⁵each independently represents hydrogen or halogen;

and pharmaceutically acceptable salts thereof.

69. Compounds according to any one of claims 67-68, wherein R¹Represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

70. A compound according to claim 69, wherein X represents

-NR²R³Or hydrogen.

71. A compound according to claim 70, wherein X represents

And wherein W represents hydrogen, (═ O), C_1-6-alkyl, or- (CH)₂)_a-Y-(CH₂)_b-Z。

72. A compound according to claim 71, wherein W represents hydrogen, methyl, cyclopropylmethyl, isopropyl, isobutyl, tert-butyl, (═ O), or- (CH)₂)_a-Y-(CH₂)_a-Z, wherein a + b is 2 and Z is selected from 4-morpholinyl, phenyl, 1-piperidine or 1-pyrrolidinyl.

73. A compound according to claim 70, wherein X represents

Wherein W represents hydrogen, hydroxy, C_1-6-alkyl, or- (CH)₂)_a-Y-(CH₂)_a-Z。

74. A compound according to claim 73, wherein W represents hydrogen, hydroxy, tert-butyl, or a + b is 0 or 2, and Z represents 4-morpholinyl, optionally substituted by C _1-6Alkoxy-substituted phenyl, or 4-piperidinyl.

75. A compound according to claim 70, wherein X represents

And W represents (═ O).

76. A compound according to claim 70, wherein X represents-NR²R³。

77. A compound according to claim 76, wherein R²And R³Independently represent hydrogen or C_1-6-an alkyl group.

78. A compound according to claim 77, wherein R²Represents hydrogen, and R³Represents cyclopropyl, isobutyl or tert-butyl.

79. The compound according to claim 70, wherein X is hydrogen.

80. Formula I according to claim 1_k"of

Wherein R is¹Represents ethyl, cyclopropyl or cyclobutyl;

wherein R is¹²Represents fluorine or chlorine; and

R¹³、R¹⁴and R¹⁵Each independently represents hydrogen, fluorine or chlorine, wherein R¹³、R¹⁴And R¹⁵Two of which represent hydrogen.

81. A compound according to claim 80, wherein said compound is substantially of formula I_k' "described S enantiomer

Wherein R is¹Represents ethyl or cyclopropyl;

wherein R is¹²Represents fluorine or chlorine; and

R¹³、R¹⁴and R¹⁵Each independently represents hydrogen, fluorine or chlorine, wherein R¹³、R¹⁴And R¹⁵Two of which represent hydrogen.

82. Formula I according to claim 1_d' the compound

Wherein R is¹Represents ethyl or cyclopropyl;

R¹²represents halogen;

R¹³、R¹⁴and R¹⁵Each independently represents hydrogen, or halogen;

and pharmaceutically acceptable salts thereof.

83. Formula I according to claim 1_d"of

Wherein R is¹Represents ethyl or cyclopropyl;

wherein R is¹²Represents chlorine or fluorine;

R¹²、R¹⁴and R¹⁵Each independently represents hydrogen, chlorine or fluorine, wherein R¹²、R¹⁴And R¹⁵Two of them represent hydrogen;

and pharmaceutically acceptable salts thereof.

84. A compound according to claim 83, wherein said compound is substantially the S enantiomer described by formula Id' "

Wherein R is¹Represents ethyl or cyclopropyl;

wherein R is¹²Represents chlorine or fluorine;

R¹²、R¹⁴and R¹⁵Each independently represents hydrogen, chlorine or fluorine, wherein R¹²、R¹⁴And R¹⁵Two of them represent hydrogen;

and pharmaceutically acceptable salts thereof.

85. A compound according to claim 1 selected from

1a 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1b 3, 6-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1c 7-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1d 7-bromo-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1e 6-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1f 3, 5-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1g 7-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1h 3, 7-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1i 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1r 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide

1S 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1j 3, 8-dimethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1k 2- (2-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1l 3-methyl-1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1m 2- (2-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1n 2- (2, 6-difluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1o 2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1p 3-methyl-1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1q 2- (3-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1t 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2a 3-dimethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2b 3-methylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2c 3-Ethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2d 3-Cyclopropylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2e 3- [ (cyclopropylmethyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2f 3- (3, 6-dihydro-2H-pyridin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2g 3- [4- (2-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2h 3- [4- (4-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2i 3- (4-formyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2j 4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-carboxylic acid ethyl ester

2k 3- (4-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2l 1-oxo-2-phenyl-3- (1, 3, 4, 9-tetrahydro- β -carbolin-2-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2m 1-oxo-2-phenyl-3-piperazin-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2n 3- (3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2o 3- (3, 5-dimethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2p 3- (4-benzyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2q 1-oxo-3- [4- (2-oxo-2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2r 3-Morpholin-4-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2S 3- (2, 6-dimethyl-morpholin-4-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2t 1-oxo-2-phenyl-3-thiomorpholin-4-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2u 3- (1, 4-dioxa-8-aza-spiro [4.5] dec-8-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2v 1-oxo-2-phenyl-3-piperidin-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2w 3- (2-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2x 3- (2, 6-dimethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2y 3- (2-hydroxymethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2z 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine-3-carboxylic acid ethyl ester

2aa 3- (3-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ab 3- (4-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ac 1-oxo-2-phenyl-3- (4-phenyl-piperidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ad 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine-4-carboxylic acid ethyl ester

2ae 3- (4-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2af 1-oxo-2-phenyl-3- (4-pyridin-2-yl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ag 3- (octahydro-quinolin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ah 3-azepan-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ai 3- (3-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

aj 3- [4- (2, 4-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ak 3- [4- (3, 4-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2al 3- (4-dimethylamino-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2am 3- [4- (2, 5-dimethyl-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2an 3- [4- (2-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ao 3- [4- (3-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ap 1-oxo-2-phenyl-3- (4-m-tolyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2aq 3- [4- (4-methoxy-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ar 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2as 1-oxo-2-phenyl-3- (4-pyrimidin-2-yl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2at 3- [4- (2-cyano-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2au 3- [4- (4-chloro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2av 3- ((1S, 3R, 5R) -3-hydroxy-8-aza-bicyclo [3.2.1] oct-8-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2aw 3- (4-acetyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ax 3- (4-methyl- [1, 4] diazepan-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ay 3- (4-ethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2az 3- ((2S, 6R) -2, 6-dimethyl-morpholin-4-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ba 3- [4- (2, 4-difluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bb 3- [4- (3-dimethylamino-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bc 3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bd 3- (3-aza-bicyclo [3.2.2] non-3-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2be 3- (4-cyclopentyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bf 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bg 3- (3, 4-dihydro-1H-isoquinolin-2-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bh 3- [4- (2-dimethylamino-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bi 3- (4-hydroxymethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bj 1-oxo-2-phenyl-3- [4- (tetrahydro-furan-2-carbonyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bk 3- (4-isobutyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bl 3- [4- (2-methoxy-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bm 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bn 3- (1, 3-dihydro-isoindol-2-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bo 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bp 1-oxo-2-phenyl-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bq 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2br 3- (4-dimethylcarbamoylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bs 3- (octahydro-pyrido [1, 2-a ] pyrazin-2-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bt 3- (4-formyl- [1, 4] diazepan-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bu 3- [4- (4-cyano-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bv 1-oxo-2-phenyl-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bw 1-oxo-2-phenyl-3- [4- (3-pyrrolidin-1-yl-propyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bx 1-oxo-2-phenyl-3- (4-pyridin-2-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2by 3- (4-ethanesulfonyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2bz 3- (4-sec-butyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ca 3- [4- (1-ethyl-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cb 3- [4- (2-cyano-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cc 3- (4-methanesulfonyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cd {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -acetic acid ethyl ester

2ce 3- [4- (3-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cf 1-oxo-2-phenyl-3- ((S) -3-phenyl-piperidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cg 1-oxo-2-phenyl-3- [4- (pyrrolidine-1-carbonyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ch 3- [4- (morpholine-4-carbonyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ci 3- (4-methoxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

cj 3- (4 '-hydroxy-3', 4 ', 5', 6 '-tetrahydro-2' H- [3, 4 '] bipyridinyl-1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ck 3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cl 3- (3H-spiro [ isobenzofuran-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cm 3- (4-hydroxy-4-methyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cn 3- (hexahydro-spiro [ benzo [1, 3] dioxol-2, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2co 1-oxo-2-phenyl-3- (3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cp 3- [4- (2-dimethylamino-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cq 3- (4-dimethylsulfamoyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cr 3- (1, 1-dioxo-thiomorpholin-4-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cs 1-oxo-2-phenyl-3- (2-pyridin-2-ylmethyl-piperidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ct 3- (2-morpholin-4-ylmethyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cu 3- (4-furo [3, 2-c ] pyridin-4-yl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cv 3- (4-cyclopropylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cw 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl 1-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cx 1-oxo-2-phenyl-3- (4-pyrimidin-2-yl- [1, 4] diazepan-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cy 3- (4-methyl-6, 7-dihydro-4H-thieno [3, 2-c ] pyridin-5-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2cz 3- [1, 4] diazepan-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2da 3- ((2S, 5R) -2, 5-dimethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2db 3- ((S) -3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dc 3- ((R) -3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dd 3- [3- (3-chloro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2de 3- [4- (1H-indol-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2df 1-oxo-3- (3-oxo-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dg 3- [4- (1H-indol-5-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dh 3- (6, 9-diaza-spiro [4.5] decan-9-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2di 3- (1, 4-diaza-spiro [5.5] undec-4-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dj 3- (3-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dk 3- (3, 3-dimethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dl 3- [3- (4-fluoro-phenyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dm 1-oxo-2-phenyl-3- (3-p-tolyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dn 4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-carboxylic acid tert-butyl ester

2do 3- (4-methylcarbamoylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dp 8-chloro-3-dimethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dr 3-cyclopentylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ds 3-Cyclohexylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dt 3- { [ (2-hydroxy-ethyl) -methyl-amino ] -methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2du 3-imidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dv 3- (2-methyl-imidazol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dw 3- (4-methyl-imidazol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dx 3- (2, 5-dihydro-pyrrol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dy 3- (2, 5-dimethyl-2, 5-dihydro-pyrrol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2dz 1-oxo-2-phenyl-3-pyrrolidin-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ea 1-oxo-2-phenyl-3- (thiazol-2-ylaminomethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eb 1-oxo-2-phenyl-3- (pyrimidin-4-ylaminomethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ec 3- (tert-butylamino-methyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ed 3- [ (2-hydroxy-1, 1-dimethyl-ethylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ee 3- (isopropylamino-methyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ef 3- [ (2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eg 3- [ (1-hydroxymethyl-propylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eh 3- [ (2, 2-dimethyl-propylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ei 1-oxo-2-phenyl-3-prop-2-ynylaminomethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ej 3-allylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ek 3- [ (methyl-prop-2-ynyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2el 3-Diallylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2em 3-diethylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2en 3- [ (isopropyl-methyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eo 3- [ ((S) -2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ep 3- [ ((R) -2-hydroxy-1-methyl-ethylamino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eq 3- { [ (2-methoxy-ethyl) -methyl-amino ] -methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2er 3- ((R) -3-hydroxy-pyrrolidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2es 3- ((S) -3-hydroxy-pyrrolidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2et 3- [ (cyclopentyl-methyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2eu 3- { [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ev 3- { [ ethyl- (2-hydroxy-ethyl) -amino ] -methyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ew 3- [ (ethyl-methyl-amino) -methyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ex 3-Cyclobutylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ey 3-azetidin-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ez 3- (4-tert-butyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fa 3- [4- (2-hydroxy-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fb 3- {4- [2- (2-hydroxy-ethoxy) -ethyl ] -piperazin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fc 3- [4- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fd 3- [4- (3, 5-dichloro-pyridin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fe 4- [ 1-oxo-2-phenyl-4- ((S) -1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazine-1-carboxylic acid benzyl ester

2ff 3- [4- (3-morpholin-4-yl-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fg 1-oxo-2-phenyl-3- [4- (3-piperidin-1-yl-propyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fh 3- [4- (4, 6-dimethoxy-pyrimidin-2-ylmethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fi 3- [4- (3-hydroxy-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fj 3- [4- (2, 3-dihydroxy-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fk (2-oxo-2- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazin-1-yl } -ethyl) -carbamic acid tert-butyl ester

2fl 3- [4- (1H-indazol-5-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fm 1-oxo-2-phenyl-3- (4-quinolin-6-yl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fn 3- [4- (6, 7-dimethoxy-quinazolin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fo 4- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazin-1-yl } -piperidine-1-carboxylic acid tert-butyl ester

2fp 3- {4- [2- (4-chloro-phenoxy) -ethyl ] -piperazin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fq {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazin-1-yl } -acetic acid tert-butyl ester

2fr 1-oxo-2-phenyl-3- [4- (3, 3, 3-trifluoro-2-hydroxy-propyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fs 3- [4- (2-hydroxy-propyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fu 3- [4- (4-amino-6, 7-dimethoxy-quinazolin-2-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fv (2- {4- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperazin-1-yl } -ethyl) -carbamic acid tert-butyl ester

2fw 1-oxo-3- {4- [2- (2-oxo-imidazolidin-1-yl) -ethyl ] -piperazin-1-ylmethyl } -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fx 3- {4- [ (4, 6-dimethoxy-pyrimidin-2-yl) -phenyl-methyl ] -piperazin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fy 3- (4-benzo [1, 2, 5] thiadiazol-4-yl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2fz 3- [4- (2, 3-dihydro-benzo [1, 4] dioxin-5-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ga 3- [4- (4-methyl-quinolin-2-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gb 1-oxo-2-phenyl-3- [4- (pyridin-2-ylcarbamoylmethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gc 3- [4- (6-chloro-3-oxo-3, 4-dihydro-2H-benzo [1, 4] oxazin-8-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gd 3- (4-carbamoylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ge 3- (4-hydroxy-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gf 3- [4- (4-chloro-phenyl) -4-hydroxy-piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gg 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidine-4-carboxylic acid

2gh 3- (4-cyano-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gi 3- (4-benzyl-4-hydroxy-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gj 1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -4-phenyl-piperidine-4-carboxylic acid ethyl ester

2gk 1-oxo-2-phenyl-3- [4- (phenyl-propionyl-amino) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gl methyl- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -carbamic acid tert-butyl ester

2gm 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gn 3- {4- [5- (4-fluoro-phenyl) - [1, 3, 4] oxadiazol-2-yl ] -piperidin-1-ylmethyl } -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2go 1-oxo-2-phenyl-3- [4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gp 1-oxo-2-phenyl-3- [4- (3-pyrazin-2-yl- [1, 2, 4] oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gq 1-oxo-2-phenyl-3- [4- (3-pyridin-4-yl- [1, 2, 4] oxadiazol-5-yl) -piperidin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gr 3- (4 '-hydroxy-3', 4 ', 5', 6 '-tetrahydro-2' H- [2, 4 '] bipyridinyl-1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gs of 3- (spiro [ isochroman-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gt 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gu 3- [4- (3-chloro-phenyl) -4-hydroxy-piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gv 3- (6-chloro-3H-spiro [ isobenzofuran-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gw 3- (4- { [ 4-chloro-3- (4-fluoro-phenyl) -indan-1-yl ] -methyl-amino } -piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gx 3- (1-acetyl-spiro [ indoline-3, 4 '-piperidine ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gy 3- (1-acetyl-5-fluoro-spiro [ indoline-3, 4 '-piperidine ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2gz 1-oxo-3- (4-oxo-1-phenyl-1, 3, 8-triaza-spiro [4.5] decan-8-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ha 3- (4-acetylamino-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hb 1-oxo-3- (1-oxo-2, 8-diaza-spiro [4.5] decan-8-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hc 3- [ 4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hd 1-oxo-2-phenyl-3- (4-trifluoromethyl-piperidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2he 3- [4- (4-methyl-piperazine-1-carbonyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hf 3- (5-isopropyl-3H-spiro [ isobenzofuran-1, 4 '-piperidin ] -1' -ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hg 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hh 4- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -piperazine-1-carboxylic acid tert-butyl ester

2hi (2- {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -ethyl) -carbamic acid tert-butyl ester

2hj 3- (4-methylamino-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hk 3- (4-acetylamino-4-phenyl-piperidin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hl 3- [ 4-acetylamino-4- (3-fluoro-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hm 1-oxo-3- [4- (4-oxo-piperidine-1-carbonyl) -piperidin-1-ylmethyl ] -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2hn 3- [4, 4' ] bipiperidinyl-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ho {1- [ 1-oxo-2-phenyl-4- (1-phenyl-propylcarbamoyl) -1, 2-dihydro-isoquinolin-3-ylmethyl ] -piperidin-4-yl } -carbamic acid tert-butyl ester

2hp 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hq 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hr 3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hs 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ht 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hu 1-oxo-2-phenyl-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hv 1-oxo-2-phenyl-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hw 1-oxo-2-phenyl-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hx 3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hy 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2hz 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ia 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2ib 2- (2-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ic 2- (2-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2id 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (2-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ie 2- (2-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2if 2- (2-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ig 2- (2-fluoro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ih 2- (2-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ii 2- (2-fluoro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ij 2- (2-fluoro-phenyl) -3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ik 2- (2-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2il 2- (2-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2im 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2in 1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2io 1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -2-o-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ip 2- (3-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iq 2- (3-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ir 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (3-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2is 2- (3-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2it 2- (3-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iu 2- (3-fluoro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iv 2- (3-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iw 2- (3-fluoro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ix 2- (3-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iy 2- (3-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2iz 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -2- (3-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ja 2- (3-chloro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jb 2- (3-chloro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jc 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (3-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jd 2- (3-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2je 2- (3-chloro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jf 2- (3-chloro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jg 2- (3-chloro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jh 2- (3-chloro-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ji 2- (3-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jj 2- (3-chloro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jk 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -2- (3-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jl 1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jm 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jn 3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jo 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jp 1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jq 1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jr 1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2js 3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2jt 3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ju 3- [4- (acetyl-methyl-amino) -4-phenyl-piperidin-1-ylmethyl ] -1-oxo-2-m-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

3a 1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

3b 8-chloro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

4a 3-cyanomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

5a 3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid N, N-diphenyl-hydrazide

5b N' - (3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carbonyl) -N-phenyl-hydrazinecarboxylic acid methyl ester

1aa 2- (3-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ab 2- (4-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ac 2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ad 2- (4-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ae 3-methyl-1-oxo-2-p-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1af 2- (3-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ag 2- (4-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl 1-amide

1ah 2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ai 2- (4-chloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1aj 3-methyl-1-oxo-2-p-tolyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ak 2- (2-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1al 2- (2-methoxy-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1am 3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1an 3-methyl-8-nitro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1ao 8-methoxy-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ap 8-methoxy-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1aq 8-amino-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1ar 8-cyano-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

1as 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (4-chloro-phenyl) -propyl ] -amide

1at 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (4-fluoro-phenyl) -propyl ] -amide

1au 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (2-fluoro-phenyl) -propyl ] -amide

1av 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (3-chloro-phenyl) -propyl ] -amide

1aw 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) - (3-chloro-phenyl) -cyclopropyl-methyl ] -amide

1ax 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) - (4-chloro-phenyl) -cyclopropyl-methyl ] -amide

1ay 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (3-fluoro-phenyl) -propyl ] -amide

1az 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -2-methyl-1-phenyl-propyl) -amide

1ba 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (4-fluoro-phenyl) -methyl ] -amide

1bb 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -1- (2-chloro-phenyl) -propyl ] -amide

1bc 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopentyl-phenyl-methyl) -amide

1bd 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) - (2-chloro-phenyl) -cyclopropyl-methyl ] -amide

1be 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (2-fluoro-phenyl) -methyl ] -amide

1bf 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclohexyl-phenyl-methyl) -amide

1bg 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide

1bh 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclobutyl- (3-fluoro-phenyl) -methyl ] -amide

1bi 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclobutyl- (4-fluoro-phenyl) -methyl ] -amide

1bl 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (R) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

1bn 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) cyclobutyl-phenyl-methyl) -amide

1bo 8-chloro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ cyclobutyl- (2-fluoro-phenyl) -methyl ] -amide

2ka 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

2kb 8-chloro-3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kc 8-chloro-3- (4-isobutyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kd 8-chloro-3- (octahydro-pyrido [1, 2-a ] pyrazin-2-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ke 8-chloro-3- (4-hydroxy-3, 4, 5, 6-tetrahydro-2H- [4, 4' ] bipyridinyl-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kf 8-chloro-3- (4-cyclopropylmethyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kg of 8-chloro-3- [4- (2-morpholin-4-yl-ethyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kh 8-chloro-3- [1, 4] diazepan-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ki 8-chloro-3- ((S) -3-methyl-piperazin-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kj 8-chloro-3-imidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kk 8-chloro-3- (4-methyl-imidazol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kl 3- (tert-butylamino-methyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2km 8-chloro-3- (isopropylamino-methyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kn 8-chloro-3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ko 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kp 3-benzimidazol-1-ylmethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kq 1-oxo-2-phenyl-3-pyrazol-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kr 3- (4-methyl-pyrazol-1-ylmethyl) -1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ks 1-oxo-2-phenyl-3- [1, 2, 3] triazol-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kt 2- (3-methoxy-phenyl) -1-oxo-3- (4-pyridin-4-ylmethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ku 2- (4-methoxy-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kv 2- (4-fluoro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kw 2- (4-fluoro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kx 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (4-fluoro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2ky 2- (4-fluoro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

2kz 2- (4-fluoro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21a 2- (4-fluoro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21b 2- (4-fluoro-phenyl) -3- [ 4-hydroxy-4- (3-methoxy-phenyl) -piperidin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21c 2- (4-chloro-phenyl) -1-oxo-3- (4-phenethyl-piperazin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21d 2- (4-chloro-phenyl) -3- (4-isopropyl-piperazin-1-ylmethyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21e 3- [1, 4 '] bipiperidinyl-1' -ylmethyl-2- (4-chloro-phenyl) -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21f 2- (4-chloro-phenyl) -3- [4- (2-morpholin-4-yl-ethyl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21g 2- (4-chloro-phenyl) -3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-ylmethyl ] -1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21h 2- (4-chloro-phenyl) -1-oxo-3- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21i 2- (4-chloro-phenyl) -1-oxo-3- [4- (2-pyrrolidin-1-yl-ethyl) -piperazin-1-ylmethyl ] -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21j 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-fluoro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21k 8-chloro-3-cyclopropylaminomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

21l 3- (4-tert-butyl-piperazin-1-ylmethyl) -8-fluoro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

21m 8-fluoro-1-oxo-2-phenyl-3-piperazin-1-ylmethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

21n 8-fluoro-1-oxo-3- (3-oxo-pyrazolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

21o 8-fluoro-1-oxo-3- (3-oxo-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3c 1-oxo-2-phenyl-3- (1H- [1, 2, 4] triazol-3-ylthiomethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

3d 8-chloro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3e 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

3f 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3g 8-fluoro-1-oxo-3- (5-oxo-pyrazolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3h 8-fluoro-1-oxo-3- (2-oxo-piperazin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

3i 8-fluoro-1-oxo-3- (2-oxo-piperidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

4b 8-chloro-3-cyanomethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

6a 2- (3, 4-dichloro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

6b 8-fluoro-1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide

6c 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -cyclopropyl-phenyl-methyl) -amide

7a 3-Ethyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

7b 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

7c 8-fluoro-2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

7d 8-fluoro-2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

7e 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7f 8-fluoro-2- (3-fluoro-phenyl) -1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7g 8-fluoro-2- (4-fluoro-phenyl) -1-oxo-3- (2-oxo-pyrrolidin-1-ylmethyl) -1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7h 8-fluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclobutyl- (3-fluoro-phenyl) -methyl ] -amide

7i 8-fluoro-2- (2-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7j 8-fluoro-2- (3-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7k 8-fluoro-2- (4-fluoro-phenyl) -3-methyl-1-oxo-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7l 6, 8-difluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7m 5, 8-difluoro-3-methyl-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide

7n 3-methyl-1-oxo-2-phenyl-8-trifluoromethyl-1, 2-dihydro-isoquinoline-4-carboxylic acid ((S) -1-phenyl-propyl) -amide

8a 3- (1-tert-butyl-piperidin-4-ylmethyl) -8-chloro-1-oxo-2-phenyl-1, 2-dihydro-isoquinoline-4-carboxylic acid [ (S) -cyclopropyl- (3-fluoro-phenyl) -methyl ] -amide;

And pharmaceutically acceptable salts of any of these compounds.

86. A compound according to any one of claims 1-85 for use in therapy.

87. A method of treating a disease selected from the group consisting of treating a psychotic disorder; schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; an induced psychotic disorder; psychiatric disorders due to general medical conditions; substance or drug induced psychotic disorders (cocaine, alcohol, amphetamine, etc.); schizoid personality disorder; personality disorder of the schizophrenic type; psychosis or schizophrenia associated with major depression, bipolar disorder, alzheimer's disease, or parkinson's disease; major depression; generalized anxiety disorder; bipolar disorder (maintenance therapy, relapse prevention and stabilization); mania; hypomania; cognitive impairment; ADHD; obesity; a decline in appetite; alzheimer's disease; parkinson's disease; pain; convulsions; cough; asthma; airway hyperresponsiveness; microvascular hypersensitivity; bronchoconstriction; chronic obstructive pulmonary disease; urinary incontinence; intestinal inflammation; and inflammatory bowel syndrome, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-85.

88. The method according to claim 87, wherein said disorder is schizophrenia.

89. The method according to claim 88, wherein said treating comprises treating positive, negative and/or cognitive symptoms of schizophrenia.

90. The method according to claim 88 or 89, further comprising administering simultaneously or sequentially a therapeutically effective amount of a compound selected from the group consisting of a D2 antagonist, a D2 partial agonist, a PDE1O antagonist, 5-HT_2AAntagonists, 5-HT₆Antagonists and KCNQ4 antagonists.

91. A compound according to any one of claims 1-85 for use in the treatment of a disease, wherein the disease is selected from psychosis; schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; an induced psychotic disorder; psychiatric disorders due to general medical conditions; substance or drug induced psychotic disorders (cocaine, alcohol, amphetamine, etc.); schizoid personality disorder; personality disorder of the schizophrenic type; psychosis or schizophrenia associated with major depression, bipolar disorder, alzheimer's disease, or parkinson's disease; major depression; generalized anxiety disorder; bipolar disorder (maintenance therapy, relapse prevention and stabilization); mania; hypomania; cognitive impairment; ADHD; obesity; a decline in appetite; alzheimer's disease; parkinson's disease; pain; convulsions; cough; asthma; airway hyperresponsiveness; microvascular hypersensitivity; bronchoconstriction; chronic obstructive pulmonary disease; urinary incontinence; intestinal inflammation; and inflammatory bowel syndrome.

92. A compound according to claim 91, wherein the disease is schizophrenia.

93. The compound according to claim 92, wherein said disorder is a positive, negative and/or cognitive symptom of schizophrenia.

94. The use of a compound according to any one of claims 1-85 for the manufacture of medicaments for the treatment of diseases selected from psychosis; schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; an induced psychotic disorder; psychiatric disorders due to general medical conditions; substance or drug induced psychotic disorders (cocaine, alcohol, amphetamine, etc.); schizoid personality disorder; personality disorder of the schizophrenic type; psychosis or schizophrenia associated with major depression, bipolar disorder, alzheimer's disease, or parkinson's disease; major depression; generalized anxiety disorder; bipolar disorder (maintenance therapy, relapse prevention and stabilization); mania; hypomania; cognitive impairment; ADHD; obesity; a decline in appetite; alzheimer's disease; parkinson's disease; pain; convulsions; cough; asthma; airway hyperresponsiveness; microvascular hypersensitivity; bronchoconstriction; chronic obstructive pulmonary disease; urinary incontinence; intestinal inflammation; and inflammatory bowel syndrome.

95. The use according to claim 93, wherein the disease is schizophrenia.

96. The use according to claim 95, wherein the disease is a positive, negative and/or cognitive symptom of schizophrenia.

97. The use according to claim 95 or 96, wherein said preparation further comprises the use of an antagonist selected from the group consisting of D2 antagonists, D2 partial agonists, PDE1O antagonists, 5-HT_2AAntagonists, 5-HT₆Antagonists and KCNQ4 antagonists.

98. A pharmaceutical composition comprising a compound according to any one of claims 1-85 and one or more pharmaceutically acceptable carriers or diluents.

99. The composition of claim 98, further comprising a compound selected from the group consisting of a D2 antagonist, a D2 partial agonist, a PDE1O antagonist, and 5-HT_2AAntagonists, 5-HT₆Antagonists and KCNQ4 antagonists.

100. Kit comprising a compound according to any one of claims 1 to 85 and a compound selected from D2 antagonists, D2 partial agonists, PDE1O antagonists, 5-HT_2AAntagonist, 5-HT₆Antagonists and KCNQ4 antagonists.