HK1195302B - Bicyclic dihydroisoquinoline-1-one derivatives - Google Patents

Description

bicyclic dihydroisoquinolin-1-one derivatives

The present invention relates to organic compounds useful for the treatment or prevention in mammals, and in particular to aldosterone synthase (CYP11B2 or CYP11B1) inhibitors useful for the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

The present invention provides novel compounds of formula (I)

Wherein

R¹，R²，R³And R⁴Independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl, and substituted heteroarylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl, and substituted heteroarylalkyl are substituted with R¹²，R¹³And R¹⁴Substitution;

or R²And R⁴Together form a double bond, provided that R is²And R⁴Together form a double bond, then R⁵Is H;

or R¹And R²Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkylWherein substituted cycloalkyl and substituted heterocycloalkyl are substituted by R²²，R²³And R²⁴Substitution;

or R³And R⁴Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R²⁹，R³⁰And R³¹Substitution;

or R¹And R³Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R⁴⁴，R⁴⁵And R⁴⁶Substitution;

A¹is CR⁸Or N;

A²is CR⁹Or N;

A³is CR¹⁰Or N;

A⁴is CR¹¹Or N;

A⁵is CR⁶Or N;

R⁵，R⁶，R⁷and R⁸One is selected from the group consisting of halogen, cyano, alkoxy, hydroxyalkoxy, haloalkyl, haloalkoxy and hydroxy, and the others are each independently selected from the group consisting of H, halogen, cyano, alkoxy, hydroxyalkoxy, haloalkoxy and hydroxy;

R⁹is H, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkylalkoxyalkylAlkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl, substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl or substituted heteroarylalkyl wherein substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl and substituted heteroarylalkyl are substituted by R³²，R³³And R³⁴Substitution;

R¹⁰is-O_m-(CR¹⁵R¹⁶)_p-(CR¹⁷R¹⁸)_q-(CR¹⁹R²⁰)_r-R²¹；

Or R⁹And R¹⁰Together with the carbon atom to which they are attached form a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl, wherein substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl are substituted by R³⁵，R³⁶And R³⁷Substitution;

R¹¹is H;

R¹⁵，R¹⁷and R¹⁹Each independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl and halocycloalkyl;

R¹⁶，R¹⁸and R²⁰Each independently selected from H, hydroxy, halogen and alkyl;

or R¹⁵And R¹⁶Together with the carbon atom to which they are attached form a cycloalkyl group;

or R¹⁷And R¹⁸Together with the carbon atom to which they are attached form a cycloalkyl group;

or R¹⁹And R²⁰Together with the carbon atom to which they are attached form a cycloalkyl group;

or R¹⁵And R¹⁷Together form- (CH)₂)_v-；

Or R¹⁵And R¹⁹Together form (A) to (CH₂)_w-；

Or R¹⁷And R^1wTogether form- (CH)₂)_x-；

R²¹Is H, halogen, cyano, -OR²⁵，-SR²⁵，-S(O)R²⁵，-S(O)₂R²⁵，-NR²⁵R²⁶，-NR²⁶SO₂R²⁵，-NR²⁶SO₂NR²⁵R²⁷，-NR²⁶C(O)R²⁵，-NR²⁶C(O)NR²⁵R²⁷，-C(O)R²⁸，-C(O)NR²⁵R²⁶Cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl or substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl, substituted heteroarylalkyl and substituted aryl are substituted by R³⁸，R³⁹And R⁴⁰Substitution;

R²⁵is H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, halocycloalkoxyalkyl, alkylcycloalkoxyalkyl, alkoxyalkyl, haloalkoxyalkyl, haloalkoxyalkoxyalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted by R⁴¹，R⁴²And R⁴³Substitution;

R²⁶and R²⁷Each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl;

or R¹⁵And R²⁶Together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted heteroaryl group, whereinSubstituted heterocycloalkyl and substituted heteroaryl with R⁴⁷，R⁴⁸And R⁴⁹Substitution;

or R¹⁷And R²⁶Together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R⁴⁷，R⁴⁸And R⁴⁹Substitution;

or R¹⁹And R²⁶Together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R⁴⁷，R⁴⁸And R⁴⁹Substitution;

R²⁸is H, hydroxy, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcyclooxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl-substituted heterocycloalkyl, substituted heterocycloalkyl alkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl with R⁵⁰，R⁵¹And R⁵²Substitution;

R¹²，R¹³，R¹⁴，R²²，R²³，R²⁴，R²⁹，R³⁰，R³¹，R³²，R³³，R³⁴，R³⁵，R³⁶，R³⁷，R³⁸，R³⁹，R⁴⁰，R⁴¹，R⁴²，R⁴³，R⁴⁴，R⁴⁵，R⁴⁶，R⁴⁷，R⁴⁸，R⁴⁹，R⁵⁰，R⁵¹and R⁵²Each independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkylcarbonylamino, alkylsulfonyl, alkylsulfonylamino, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcyclooxyalkyl, alkoxy, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl, chloropyridylcarbonyl, and heterocycloalkyl;

n is 0 or 1;

m is 0 or 1;

p, q and R are independently selected from 0 and 1;

v and x are independently selected from 1, 2, 3 or 4;

w is 0, 1, 2 or 3;

with the proviso that A²，A³And A⁴No more than two of which are N;

and pharmaceutically acceptable salts thereof.

The inventors herein describe inhibitors of aldosterone synthase that have the potential to protect against organ/tissue damage caused by absolute or relative excess of aldosterone. Hypertension affects approximately 20% of the adult population in developed countries. In the population over the age of 60, this percentage rises to above 60%. Hypertensive patients show an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal injury. The renin angiotensin aldosterone system is a pathway that has been linked to hypertension, volume and salt balance, and more recently to direct contribution to peripheral organ damage at the late stages of heart failure or renal disease. ACE inhibitors and Angiotensin Receptor Blockers (ARBs) have been successfully used to improve the duration and quality of a patient's life. These drugs do not give maximum protection. In a larger number of patients ACE and ARB lead to so-called aldosterone breakthrough, a phenomenon in which aldosterone levels return to pathological levels after first initially dropping. It has been shown that the detrimental effects of unfavorably elevated aldosterone levels (related to salt intake/levels) can be minimized by aldosterone blockade with a mineralocorticoid receptor antagonist. Direct inhibition of aldosterone synthesis is expected to provide even better protection as it will also reduce the non-genomic impact of aldosterone.

The effect of aldosterone on Na/K transport results in increased sodium and water reabsorption and potassium secretion in the kidney. Overall this leads to an increased blood volume and thus to an increased blood pressure. In addition to its role in regulating renal sodium reabsorption, aldosterone can exert deleterious effects on the kidney, heart and vascular system, particularly in "high sodium" conditions. It has been shown that: in this case, aldosterone causes increased oxidative stress, which may ultimately contribute to organ damage. Aldosterone injection into kidney-endangered safe rats (either by high salinity treatment or by unilateral nephrectomy) induced extensive damage to the kidney, including glomerular expansion, podocyte injury, interstitial inflammation, mesangial cell proliferation and fibrosis, which is reflected by proteinuria. More specifically, aldosterone has been shown to increase the expression of the adhesion molecule ICAM-1 in the kidney. ICAM-1 is critically included in glomerulonephritis. Similarly, aldosterone has been shown to increase the expression of inflammatory cytokines such as the interleukins IL-1b and IL-6, MCP-1 and osteopontin. At the cellular level, it was demonstrated that aldosterone increased the expression of type I collagen mRNA, a mediator of fibrosis, in vascular fibroblasts. Aldosterone also stimulates collagen type IV accumulation in rat mesangial cells and induces plasminogen activator inhibitor-1 (PAI-1) expression in smooth muscle cells. In summary, aldosterone has emerged as a key hormone involved in renal damage. Aldosterone plays an equally important role in mediating cardiovascular risk.

There is a lot of preclinical evidence as follows: MR-antagonists (spironolactone and eplerenone) improve blood pressure, heart and kidney function in various preclinical models.

Recent preclinical studies have highlighted the important contribution of CYP11B2 to cardiovascular and renal morbidity and mortality. The CYP11B2 inhibitor FAD286 and the MR antagonist spironolactone were evaluated in a rat model of chronic kidney disease (high angiotensin II exposure; high salt and mononephrectomy). Angiotensin II and high salinity treatments result in proteinuria, azotemia, renal vascular hypertrophy, glomerular injury, increased PAI-1, and osteopontin mRNA expression, as well as tubulointerstitial fibrosis. Both drugs prevent these renal effects and attenuate hypertrophy of the heart and the inner aorta. Plasma aldosterone decreased after 4 weeks of treatment with FAD286, while spironolactone increased aldosterone at 4 and 8 weeks of treatment. Similarly, only spironolactone, but not FAD286, increased angiotensin II and salinity-stimulated PAI-1mRNA expression in the aorta and heart. In other studies, the CYP11B2 inhibitor FAD286 improved blood pressure and cardiovascular function and structure in rats with experimental heart failure. In the same study, FAD286 was shown to improve kidney function and morphology.

Administration of an orally active CYP11B2 inhibitor, LCI699, to a patient with primary hyperaldosteronism led to the following conclusions: it effectively inhibits CYP11B2 in patients with primary hyperaldosteronism, resulting in significantly lower circulating aldosterone levels, and it corrects hypokalemia and mildly reduces blood pressure. The effect on the glucocorticoid axis is consistent with poor selectivity of the compound and potential inhibition of cortisol synthesis. Taken together, these data support the concept that CYP11B2 inhibitors can reduce undesirably high aldosterone levels. Obtaining good selectivity relative to CYP11B1 is important for the absence of undesirable side effects on the HPA axis and will distinguish different CYP11B2 inhibitors.

Objects of the present invention are the compounds of formula (I) and their above-mentioned salts and esters and their use as therapeutically active substances, processes for the preparation of said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, their pharmaceutically acceptable salts or esters, the use of said compounds, salts or esters for the treatment or prophylaxis of illnesses, especially for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom and the use of said compounds, salts or esters for the preparation of medicaments for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

The term "alkoxy" denotes a group of formula-O-R ', wherein R' is alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxy groups include methoxy.

The term "alkoxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group. Examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy. Particular alkoxyalkoxy groups include methoxymethoxy and methoxyethoxy.

The term "alkoxyalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group. Examples of alkoxyalkoxyalkyl groups include methoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl, ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl, methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethoxyethyl, methoxypropoxyethyl and ethoxypropoxyethyl.

The term "alkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, and isopropoxymethyl. Particular alkoxyalkyl groups include methoxymethyl, methoxyethyl, and isopropoxymethyl.

The term "alkoxycarbonyl" denotes a group of formula-C (O) -R ', wherein R' is alkoxy. Examples of alkoxycarbonyl groups include groups of the formula-C (O) -R ', wherein R' is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxycarbonyl groups are groups of the formula-C (O) -R ', wherein R' is methoxy.

The term "alkoxycycloalkylalkyl" denotes cycloalkylalkyl, wherein at least one of the hydrogen atoms of the cycloalkyl group is replaced by an alkoxy group. An example of alkoxycycloalkylalkyl is cyclopropylmethoxymethyl.

The term "alkyl" denotes a monovalent straight or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, the alkyl group has from 1 to 7 carbon atoms, and in more particular embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and. Particular alkyl groups include methyl, ethyl, propyl and isopropyl. More particular alkyl groups are methyl, isopropyl and ethyl.

The term "alkylcarbonyl" denotes a group of formula-c (o) -R ', wherein R' is alkyl. Examples of alkylcarbonyl groups include groups of the formula-c (o) -R ', wherein R' is methyl or ethyl.

The term "alkylcarbonylamino" denotes an amino group, wherein-NH₂One of the hydrogen atoms of the group is replaced by an alkylcarbonyl group. Examples of alkylcarbonylamino groups include groups wherein R' is methyl or ethyl. Particular alkylcarbonylamino groups include groups wherein R' is ethyl.

The term "alkylcarbonylaminoalkyl" denotes aminoalkyl, wherein-NH₂One of the hydrogen atoms of the group is replaced by an alkylcarbonyl group. Examples of alkylcarbonylaminoalkyl include groups wherein R' is methyl or ethyl.

The term "alkylcycloalkoxy" denotes a cycloalkoxy group wherein at least one of the hydrogen atoms of the cycloalkoxy group is replaced by an alkyl group. Examples of alkylcycloalkyl include methyl-cyclopropoxy, dimethyl-cyclopropoxy, methyl-cyclobutoxy, dimethyl-cyclobutoxy, methyl-cyclopentyloxy, dimethyl-cyclopentyloxy, methyl-cyclohexyloxy and dimethyl-cyclohexyloxy.

The term "alkylcycloalkoxyalkyl" denotes a cycloalkoxyalkyl group wherein at least one of the hydrogen atoms of the cycloalkoxyalkyl group is replaced by an alkyl group. Examples of alkylcycloalkyl include methyl-cyclopropoxymethyl, dimethyl-cyclopropoxymethyl, methyl-cyclobutoxymethyl, dimethyl-cyclobutoxymethyl, methyl-cyclopentyloxymethyl, dimethyl-cyclopentyloxymethyl, methyl-cyclohexyloxymethyl and dimethyl-cyclohexyloxymethyl.

The term "alkylcycloalkyl" denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group is replaced by an alkyl group. Examples of alkylcycloalkyl groups include methyl-cyclopropyl, dimethyl-cyclopropyl, methyl-cyclobutyl, dimethyl-cyclobutyl, methyl-cyclopentyl, dimethyl-cyclopentyl, methyl-cyclohexyl and dimethyl-cyclohexyl. Particular alkylcycloalkyl groups include methyl-cyclopropyl and dimethyl-cyclopropyl.

The term "alkylcycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkylcycloalkyl group. Examples of alkylcycloalkylalkyl groups include methyl-cyclopropylmethyl, dimethyl-cyclopropylmethyl, methyl-cyclopropylethyl, dimethyl-cyclopropylethyl, methyl-cyclobutylmethyl, dimethyl-cyclobutylmethyl, methyl-cyclobutylethyl, dimethyl-cyclobutylethyl, methyl-cyclopentylmethyl, dimethyl-cyclopentylmethyl, methyl-cyclopentylethyl, dimethyl-cyclopentylethyl, methyl-cyclohexylmethyl, dimethyl-cyclohexylmethyl, methyl-cyclohexylethyl, dimethyl-cyclohexylethyl, methyl-cycloheptylmethyl, dimethyl-cycloheptylmethyl, methyl-cycloheptylethyl, dimethyl-cycloheptylethyl, methyl-cyclooctylmethyl, dimethyl-cyclooctylmethyl, methyl-cyclooctylethyl and dimethyl-cyclooctylethyl.

The term "alkylsulfonyl" denotes the formula-S (O)₂-a radical of R ', wherein R' is an alkyl radical. Examples of alkylsulfonyl groups include those of the formula-S (O)₂-R 'wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The term "alkylsulfonylamino" denotes the formula-NH₂-S(O)₂-a radical of R ', wherein R' is an alkyl radical. Examples of alkylsulfonyl groups include those of the formula-NH₂-S(O)₂-R 'wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The term "amino" denotes-NH₂A group.

The term "aryl" denotes a monovalent aromatic carbocyclic mono-or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl groups include phenyl and naphthyl. A particular aryl group is phenyl.

The term "arylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an aryl group. A particular arylalkyl group is phenylalkyl. A more particular arylalkyl group is benzyl.

The term "arylalkyloxy" denotes an arylalkyl group wherein at least one of the hydrogen atoms of the arylalkyl group has been replaced by an aryl group. A particular arylalkyl group is phenylhydroxymethyl.

The term "bicyclic ring system" denotes two rings which are fused to each other via a common single or double bond (fused ring bicyclic ring system), via a series of three or more common atoms (bridged bicyclic ring system) or via a common single atom (spiro bicyclic ring system). The bicyclic ring system may be saturated, partially unsaturated, unsaturated or aromatic. The bicyclic ring system may comprise a heteroatom selected from N, O and S.

The term "carbonyl" denotes the group-C (O) -.

The term "carboxy" denotes a-C (O) OH group.

The term "carboxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a carboxy group. Examples are carboxymethyl, carboxyethyl, carboxypropyl and 1-carboxy-2-methylpropyl. A particular example is 1-carboxy-2-methylpropyl.

The term "cyano" denotes a-C ≡ N group.

The term "cycloalkoxy" denotes a group of formula-O-R ', wherein R' is cycloalkyl. Examples of the cycloalkoxy group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group and a cyclooctyloxy group. A particular cycloalkoxy group is cyclopropoxy.

The term "cycloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkoxy group. Examples of the cycloalkoxyalkyl group include a cyclopropyloxymethyl group, a cyclopropyloxyethyl group, a cyclobutyloxymethyl group, a cyclobutyloxyethyl group, a cyclopentyloxymethyl group, a cyclopentyloxyethyl group, a cyclohexyloxymethyl group, a cyclohexyloxyethyl group, a cycloheptyloxymethyl group, a cycloheptyloxyethyl group, a cyclooctyloxymethyl group and a cyclooctyloxyethyl group.

The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In a particular embodiment cycloalkyl represents a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having two carbon atoms in common. Particular cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutaneyl, cyclopentyl, cyclohexyl or cycloheptyl. An example of bicycloalkyl is bicyclo [2.2.1]Heptylalkyl or bicyclo [2.2.2]An octyl group. Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutaneyl, cyclopentyl and cyclohexyl. A more particular monocyclic cycloalkyl group is cyclopropyl. In particular, from R⁹And R¹⁰Cycloalkanes formed together with the carbon atom to which they are attachedThe radicals are cyclohexyl and cyclopentyl. More particularly from R⁹And R¹⁰The cycloalkyl groups formed together with the carbon atoms to which they are attached are cyclohexyl groups.

In particular, from R¹And R²The cycloalkyl group formed together with the carbon atom to which they are attached is cyclopropyl.

The term "cycloalkylalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a cycloalkyl group. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclooctylmethoxy.

The term "cycloalkylalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkylalkoxy group. Examples of cycloalkylalkoxyalkyl groups include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl, cyclohexylmethoxymethyl, cyclohexylmethoxyethyl, cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl and cyclooctylmethoxyethyl.

The term "cycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl and cyclopentylbutyl. Specific examples of cycloalkylalkyl groups are cyclopropylmethyl, cyclopropylbutyl and 2-cyclopropylbutyl.

The term "cycloalkylcarbonyl" denotes a group of formula-C (O) -R ', wherein R' is cycloalkyl. Examples of cycloalkylcarbonyl groups include groups of the formula-C (O) -R ', wherein R' is cyclopropyl.

The term "cycloalkylcarbonylamino" denotes an amino group, wherein-NH₂One of the hydrogen atoms of the group is replaced by a cycloalkylcarbonyl group. Examples of alkylcarbonylamino groups include groups wherein R' is cyclopropyl.

The term "cycloalkylcarbonylaminoalkyl" denotes an aminoalkyl group, wherein-NH₂One of the hydrogen atoms of the group is replaced by a cycloalkylcarbonyl group. Examples of alkylcarbonylaminoalkyl groups include groups wherein R' is cyclopropyl.

The term "dialkoxyalkyl" denotes an alkyl group wherein two of the hydrogen atoms of the alkyl group have been replaced by two alkoxy groups. Exemplary dialkoxyalkyls include dimethoxymethyl, diethoxymethyl, dimethoxyethyl, diethoxyethyl, dimethoxypropyl, diethoxypropyl, and diisopropoxymethyl. A particular dialkoxyalkyl group is dimethoxymethyl.

The term "haloalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atom. The term "perhaloalkoxy" denotes an alkoxy group wherein all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy groups are trifluoromethoxy and 2, 2-difluoroethoxy.

The term "haloalkoxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a haloalkoxy group. Examples of haloalkoxyalkyl groups include fluoromethoxymethoxy, difluoromethoxymethoxy, trifluoromethoxy, fluoroethyloxymethoxy, difluoroethoxymethoxy, trifluoroethoxymethoxy, fluoromethoxyethoxy, difluoromethoxyethoxy, trifluoromethoxyethoxy, fluoroethyloxyethoxy, difluoroethoxyethoxy, trifluoroethoxyethoxy, fluoromethoxypropoxy, difluoromethoxypropoxy, trifluoromethoxypropoxy, fluoroethoxypropoxy, difluoroethoxypropoxy and trifluoroethoxypropoxy.

The term "haloalkoxyalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxyalkoxy group. Examples of haloalkoxyalkyl groups include fluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxy-methyl, fluoroethoxymethyl, difluoroethoxymethoxymethyl, trifluoroethoxymethoxymethyl, fluoromethoxyethoxymethyl, difluoromethoxyethoxymethyl, trifluoromethoxyethoxymethyl, fluoroethoxyethoxymethyl, difluoroethoxyethoxyethoxymethyl, trifluoroethoxyethoxyethoxymethyl, fluoromethoxypropoxymethyl, difluoromethoxypropoxymethyl, trifluoromethoxy-propoxymethyl, fluoroethoxypropoxymethyl, difluoroethoxypropoxymethyl and trifluoroethoxypropoxymethyl.

The term "haloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxy group. Examples of haloalkoxyalkyl groups include fluoromethoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, fluoroethoxymethyl, difluoroethoxymethyl, trifluoroethoxymethyl, fluoromethoxyethyl, difluoromethoxyethyl, trifluoromethoxyethyl, fluoroethoxyethyl, difluoroethoxyethyl, trifluoroethoxyethyl, fluoromethoxypropyl, difluoromethoxypropyl, trifluoromethoxypropyl, fluoroethoxypropyl, difluoroethoxypropyl and trifluoroethoxypropyl groups. A particular haloalkoxyalkyl group is 2, 2-difluoroethoxyethyl.

The term "haloalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atom. The term "perhaloalkyl" denotes an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of the haloalkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a trifluoromethylethyl group and a pentafluoroethyl group. A particular haloalkyl group is trifluoromethyl. A particular group is also difluoromethyl.

The term "haloalkyloxy" denotes a cycloalkoxy group in which at least one of the hydrogen atoms of the cycloalkoxy group has been replaced by the same or different halogen atoms, in particular fluorine atoms. Examples of the haloalkyloxy group include fluorocyclopropoxy group, difluorocyclopropoxy group, fluorocyclobutoxy group and difluorocyclobutoxy group.

The term "halocycloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halocycloalkoxy group, in particular a fluorine atom. Examples of the haloalkoxyalkyl group include fluorocyclopropoxymethyl group, difluorocyclopropoxymethyl group, fluorocyclobutoxymethyl group and difluorocyclobutoxymethyl group.

The term "halocycloalkyl" denotes cycloalkyl groups wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by the same or different halogen atom, in particular a fluorine atom. Examples of the halogenated cycloalkyl group include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl and difluorocyclobutyl.

The term "halocycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halocycloalkyl group. Examples of the halocycloalkylalkyl group include fluorocyclopropylmethyl group, fluorocyclopropylethyl group, difluorocyclopropylmethyl group, difluorocyclopropylethyl group, fluorocyclobutylmethyl group, fluorocyclobutylethyl group, difluorocyclobutylethyl group and difluorocyclobutylethyl group.

The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine, or iodine. Particular halogens are chlorine and fluorine.

The term "heteroaryl" denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl,an azole group, a thiazole group, a triazole group,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,triazinyl, azaRadical, diazaBasic group, heteroAzolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolylAzolyl, benzisoylAzolyl, benzothiazolyl, benzisothiazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl groups. Particular heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, benzimidazolyl, indazolyl, indolyl, pyridinyl, isoxazolylAzolyl andan azole group.

In particular, from R⁹And R¹⁰Heteroaryl groups formed together with the carbon atom to which they are attached are pyrrolyl and pyrazolyl. In particular, for R²¹The term "heteroaryl" denotes imidazolyl, pyrazolyl, triazolyl, benzimidazolyl, indazolyl, indolyl, pyridinyl and isoimidazolylAn azole group. More particularly, pyrazolesAnd (4) a base.

In particular, for R²⁵The term "heteroaryl" denotes pyridyl, pyrazolyl andan azole group. In particular, for R²⁵The term "heteroaryl" denotes pyrazolyl andan azole group. For R²⁵More particular heteroaryl groups are pyrazolyl and pyridyl. More particularly pyrazolyl.

The term "heteroarylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a heteroaryl group. Examples are pyrazolylalkyl and imidazolylalkyl. More particular examples are pyrazolylmethyl and imidazolylmethyl.

In particular, for R²⁵The term "heteroarylalkyl" denotes pyrazolylmethyl and imidazolylmethyl. In particular, a pyrazolyl methyl group.

The term "heterocycloalkyl" denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In particular embodiments, heterocycloalkyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycloalkyl groups are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl-yl, 1, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl and thiazinoalkyl. Examples of bicyclic saturated heterocycloalkyl are 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl, 3-oxa-9-aza-bicyclo [3.3.1]Nonyl, 3-thia-9-aza-bicyclo [3.3.1]Nonyl and 2, 6-diaza-spiro [3.3]A heptalkyl group. Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, dihydro-Oxazolyl, tetrahydro-pyridyl, or dihydropyranyl. More specific examples of heterocycloalkyl groups are pyrrolidinyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinanyl, and 2, 6-diaza-spiro [3.3]A heptalkyl group. More particular examples of heterocycloalkyl are pyrrolidinyl, piperidinyl, thiomorpholinyl, thiazinoalkyl and 2, 6-diaza-spiro [3.3 [ ]]A heptalkyl group.

In particular, for R²¹The term "heterocycloalkyl" denotes pyrrolidinyl, thiazinan-2-yl, isothiazolidin-2-yl, piperidinyl, morpholinyl, thiomorpholinyl,oxazolidinyl, imidazolidinyl, piperazinyl, 2-oxa-6-aza-spiro [3.4]Heptylalkyl and 2-oxa-6-aza-spiro [3.4]An octyl group. Further especially piperazinyl and 2-oxa-6-aza-spiro [3.4]]An octyl group. More particularly, 2-oxa-6-aza-spiro [3.4]]An octyl group. Still more particularly still, the present invention is,a piperazinyl group.

In particular, for R²⁵The term "heterocycloalkyl" denotes an oxetanyl group.

In particular, for R²⁸The term "heterocycloalkyl" denotes morpholinyl, pyrrolidinyl and piperidinyl.

In particular, from R¹⁵And R²⁶The heterocycloalkyl groups formed together with the nitrogen and carbon atoms to which they are attached are azetidinyl, pyrrolidinyl and piperidinyl.

The term "heterocycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a heterocycloalkyl group. Examples are tetrahydrofurylalkyl, pyrrolidinylalkyl and piperazin-1-ylalkyl. More particularly, tetrahydrofurylethyl, pyrrolidinylmethyl and piperazin-1-ylmethyl.

In particular, for R⁹The term "heterocycloalkylalkyl" denotes piperazin-1-ylalkyl. More particularly, piperazin-1-ylalkyl.

In particular, for R²⁵The term "heterocycloalkylalkyl" denotes tetrahydrofurylalkyl and pyrrolidinylalkyl. More particularly, tetrahydrofurylethyl and pyrrolidinylmethyl.

The term "hydroxy" denotes an-OH group.

The term "hydroxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxyethoxy, hydroxypropoxy, and hydroxymethylpropoxy.

The term "hydroxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxy-1-methyl-ethyl, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. Particular examples are hydroxymethyl and hydroxyethyl.

The term "oxo" denotes a divalent oxygen atom ═ O.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, mesylate and citrate salts.

By "pharmaceutically acceptable ester" is meant that the compound of formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester and pivaloyloxymethyl ester. Furthermore, any physiologically acceptable equivalent of a compound of formula (I) that is similar to the metabolically labile ester and is capable of producing the parent compound of formula (I) in vivo is within the scope of the invention.

The term "protecting group" (PG) denotes a group: in the meaning conventionally associated therewith in synthetic chemistry, a reactive site in a polyfunctional compound is selectively blocked so that a chemical reaction can be selectively carried out at another unprotected reactive site. The protecting group may be removed at an appropriate point in time. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Still more particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc).

The abbreviation uM denotes micromolar concentration and is equivalent to the marker μ M.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the invention also includes isotopically-labeled variants of the invention, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element specified are contemplated to be within the scope of the compounds of the invention and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as²H(“D”)，³H(“T”)，¹¹C，¹³C，¹⁴C，¹³N，¹⁵N，¹⁵O，¹⁷O，¹⁸O，³²P，³³P，³⁵S，¹⁸F，³⁶Cl，¹²³I and¹²⁵I. certain isotopically-labeled compounds of the present invention (e.g., with³H or¹⁴C-labeled ones) can be used for compound and/or substrate tissue distribution assays. Tritiated (a)³H) And carbon-14 (¹⁴C) Isotopes are useful for their ease of preparation and detection. With heavier isotopes such as deuterium (i.e.,²H) certain therapeutic advantages may be obtained from further substitutions of (a) which result from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances. Positron emitting isotopes such as¹⁵O，¹³N，¹¹C and¹⁸f can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopes of the inventionLabeled compounds can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by replacing a non-isotopically labeled reagent with an isotopically labeled reagent. In particular, in which one or more H atoms have been replaced²Compounds of formula (I) in which the H atom is replaced are also embodiments of the present invention.

The compounds of formula (I) may contain several asymmetric centers and may exist as: optically pure enantiomers, mixtures of enantiomers, such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

According to Cahn-Ingold-Prelog Convention, the asymmetric carbon atoms may be in either the "R" or "S" configuration.

Also an embodiment of the invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more in particular compounds according to formula (I) as described herein.

Also an embodiment of the invention are compounds according to formula (I) as described herein, wherein

R¹，R²，R³And R⁴Independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl, and substituted heteroarylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl, and substituted heteroarylalkyl are substituted with R¹²，R¹³And R¹⁴Substitution;

or R²And R⁴Together form a double bond, provided that R is²And R⁴Together form a double bond, then R⁵Is H;

or R¹And R²Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R²²，R²³And R²⁴Substitution;

or R³And R⁴Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R²⁹，R³⁰And R³¹Substitution;

or R¹And R³Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R⁴⁴，R⁴⁵And R⁴⁶Substitution;

A¹is CR⁸Or N;

A²is CR⁹Or N;

A³is CR¹⁰Or N;

A⁴is CR¹¹Or N;

A⁵is CR⁶Or N;

R⁵，R⁶，R⁷and R⁸One is selected from the group consisting of halogen, cyano, alkoxy, hydroxyalkoxy, haloalkyl, haloalkoxy and hydroxy, and the others are each independently selected from the group consisting of H, halogen, cyano, alkoxy, hydroxyalkoxy, haloalkoxy and hydroxy;

R⁹is H, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl,alkoxy, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl, substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl or substituted heteroarylalkyl wherein substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl and substituted heteroarylalkyl are substituted by R³²，R³³And R³⁴Substitution;

R¹⁰is-O_m-(CR¹⁵R¹⁶)_p-(CR¹⁷R¹⁸)_q-(CR¹⁹R²⁰)_r-R²¹；

Or R⁹And R¹⁰Together with the carbon atom to which they are attached form a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl, wherein substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl are substituted by R³⁵，R³⁶And R³⁷Substitution;

R¹¹is H;

R¹⁵，R¹⁷and R¹⁹Each independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl and halocycloalkyl;

R¹⁶，R¹⁸and R²⁰Each independently selected from H, hydroxy, halogen and alkyl;

or R¹⁵And R¹⁶Together with the carbon atom to which they are attached form a cycloalkyl group;

or R¹⁷And R¹⁸Together with the carbon atom to which they are attached form a cycloalkyl group;

or R¹⁹And R²⁰Together with the carbon atom to which they are attached form a cycloalkyl group;

or R¹⁵And R¹⁷Together form- (CH)₂)_v-；

Or R¹⁵And R¹⁹Together form- (CH)₂)_w-；

Or R¹⁷And R¹⁹Together form- (CH)₂)_x-；

R²¹Is H, halogen, cyano, -OR²⁵，-SR²⁵，-S(O)R²⁵，-S(O)₂R²⁵，

-NR²⁵R²⁶，-NR²⁶SO₂R²⁵，-NR²⁶SO₂NR²⁵R²⁷，-NR²⁶C(O)R²⁵，

-NR²⁶C(O)NR²⁵R²⁷，-C(O)R²⁸，

-C(O)NR²⁵R²⁶Cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl or substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl, substituted heteroarylalkyl and substituted aryl are substituted by R³⁸，R³⁹And R⁴⁰Substitution;

R²⁵is H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxyalkyl, cycloalkoxyalkyl, halocycloalkoxyalkyl, alkylcycloalkoxyalkyl, alkoxyalkyl, haloalkoxyalkyl, haloalkoxyalkoxyalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted by R⁴¹，R⁴²And R⁴³Substitution;

R²⁶and R²⁷Each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl; or R¹⁵And R²⁶Together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R⁴⁷，R⁴⁸And R⁴⁹Substitution;

or R¹⁷And R²⁶Together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R⁴⁷，R⁴⁸And R⁴⁹Substitution;

or R¹⁹And R²⁶Together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R⁴⁷，R⁴⁸And R⁴⁹Substitution;

R²⁸is H, hydroxy, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcyclooxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl-substituted heterocycloalkyl, substituted heterocycloalkyl alkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl with R⁵⁰，R⁵¹And R⁵²Substitution;

R¹²，R¹³，R¹⁴，R²²，R²³，R²⁴，R²⁹，R³⁰，R³¹，R³²，R³³，R³⁴，R³⁵，R³⁶，R³⁷，R³⁸，R³⁹，R⁴⁰，R⁴¹，R⁴²，R⁴³，R⁴⁴，R⁴⁵，R⁴⁶，R⁴⁷，R⁴⁸，R⁴⁹，R⁵⁰，R⁵¹and R⁵²Each independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkylcarbonylamino, alkylsulfonyl, alkylsulfonylamino, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcyclooxyalkyl, alkoxy, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, haloalkoxyalkoxy, haloalkoxyalkoxyalkyl and heterocycloalkyl;

n is 0 or 1;

m is 0 or 1;

p, q and R are independently selected from 0 and 1;

v and x are independently selected from 1, 2, 3 or 4;

w is 0, 1, 2 or 3;

with the proviso that A²，A³And A⁴No more than two of which are N;

and pharmaceutically acceptable salts thereof.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹，R²，R³And R⁴Independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halocycloalkyl, hydroxyalkyl, alkoxyalkyl, haloAlkoxylalkyl, halocycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted arylalkyl and substituted heteroarylalkyl are substituted with R¹²，R¹³And R¹⁴And (4) substitution.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²And R⁴Together form a double bond, provided that R is²And R⁴Together form a double bond, then R⁵Is H.

In another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹And R²Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R²²，R²³And R²⁴And (4) substitution.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³And R⁴Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R²⁹，R³⁰And R³¹And (4) substitution.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹And R³Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R⁴⁴，R⁴⁵And R⁴⁶And (4) substitution.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹Is H, alkyl or by R¹²，R¹³And R¹⁴Substituted arylalkyl.

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, whereinR¹Is H or alkyl.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹Is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is¹Is an alkyl group.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹Is methyl or ethyl.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹，R²，R³And R⁴Independently selected from H, alkyl or by R¹²，R¹³And R¹⁴Substituted arylalkyl.

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹，R²，R³And R⁴Independently selected from H or alkyl.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹Is H, alkyl or by R¹²，R¹³And R¹⁴Substituted arylalkyl and wherein R¹²，R¹³And R¹⁴Is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is²Is H or alkyl.

The invention also relates to compounds according to formula (I) as described herein, wherein R is²Is H.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²Is an alkyl group.

The invention also relates to compounds according to formula (I) as described herein, wherein R is²Is methyl.

Yet another embodiment of the present inventionEmbodiments are compounds according to formula (I) as described herein, wherein R is¹And R²Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted heterocycloalkyl group, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R²²，R²³And R²⁴And (4) substitution.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹And R²Together with the carbon atom to which they are attached form R²²，R²³And R²⁴A substituted cycloalkyl group.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is¹And R²Together with the carbon atom to which they are attached form a cyclopropyl group.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is³Is H or alkyl.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is⁴Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein A is¹Is CR⁸。

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein a is¹Is N.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein A is²Is CR⁹。

A particular embodiment of the invention are also compounds according to formula (I) as described herein, wherein A²Is N.

A particular embodiment of the present invention is also a compound according to formula (I) as described hereinWherein A is³Is CR¹⁰。

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein a is³Is N.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein a is⁴Is CR¹¹。

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein a⁴Is N.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein a⁵Is CR⁶。

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein a⁵Is N.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is⁵，R⁶，R⁷And R⁸One is selected from halogen, alkoxy and hydroxy and the others are each independently selected from H and halogen.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁵，R⁶And R⁸One is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is⁵，R⁶And R⁸One is H and R⁷Is halogen or alkoxy.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁵，R⁶，R⁷And R⁸At least one of which is different from H.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁵Is H or halogen and wherein R⁵，R⁶，R⁷And R⁸In at leastOne is different from H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁶Is H or halogen and wherein R⁵，R⁶，R⁷And R⁸At least one of which is different from H.

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁷Is H, halogen, alkoxy or hydroxy and wherein R⁵，R⁶，R⁷And R⁸At least one of which is different from H.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁷Is halogen or alkoxy.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁷Is a halogen.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁷Is chlorine.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁸Is H or halogen and wherein R⁵，R⁶，R⁷And R⁸At least one of which is different from H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is⁹Is H, halogen, hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, halocycloalkyl, alkylcycloalkylalkyl, alkoxycycloalkylalkyl, halocycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkylcycloalkoxy, alkylcycloalkoxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkoxyalkoxyalkylAlkyl, haloalkoxyalkyl, substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl or substituted heteroarylalkyl wherein substituted arylalkyl, substituted arylhydroxyalkyl, substituted heterocycloalkylalkyl and substituted heteroarylalkyl are substituted by R³²，R³³And R³⁴And (4) substitution.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁹Is H, halogen, cyano, alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, alkoxycycloalkylalkyl, dialkoxyalkyl, substituted arylhydroxyalkyl or substituted heterocycloalkylalkyl wherein substituted arylhydroxyalkyl and substituted heterocycloalkylalkyl are substituted by R³²，R³³And R³⁴And (4) substitution.

The invention also relates to compounds according to formula (I) as described herein, wherein R is⁹Is H or halogen.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁹Is H.

An embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁹And R¹⁰Together with the carbon atom to which they are attached form a substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl, wherein substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and substituted heteroaryl are substituted by R³⁵，R³⁶And R³⁷And (4) substitution.

An embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁹And R¹⁰Together with the carbon atom to which they are attached form a substituted cycloalkyl, substituted aryl or substituted heteroaryl group, wherein substituted cycloalkyl, substituted aryl and substituted heteroaryl are substituted by R³⁵，R³⁶And R³⁷And (4) substitution.

Embodiments of the invention are according to formula (I) as described hereinA compound of formula (I) wherein R⁹And R¹⁰Together with the carbon atom to which they are attached form a substituted cycloalkyl or substituted aryl, wherein the substituted cycloalkyl and substituted aryl are substituted with R³⁵，R³⁶And R³⁷And (4) substitution.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is⁹And R¹⁰Together with the carbon atom to which they are attached form R³⁵，R³⁶And R³⁷A substituted cycloalkyl group.

The invention also relates to compounds according to formula (I) as described herein, wherein R is⁹And R¹⁰Together with the carbon atom to which they are attached form R³⁵，R³⁶And R³⁷A substituted cycloalkyl group.

An embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁵，R¹⁷And R¹⁹Each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is¹⁵，R¹⁷And R¹⁹Each independently selected from the group consisting of H, alkyl, cycloalkyl and haloalkyl.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹⁷Is H.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹⁹Is H, alkyl, cycloalkyl and haloalkyl.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is¹⁹Is H or alkyl.

Another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹⁹Is H.

The invention also relates to compounds according to formula (I) as described herein, which areIn R¹⁹Is an alkyl group.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹⁹Is methyl.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹⁶，R¹⁸And R²⁰Each independently selected from H, hydroxy, halogen or alkyl.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹⁶，R¹⁸And R²⁰Each independently selected from H, hydroxy and alkyl.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹⁸Is H.

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²⁰Is H, hydroxy and alkyl.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²⁰Is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is¹⁹And R²⁰Together with the carbon atom to which they are attached form a cycloalkyl group.

The invention also relates to compounds according to formula (I) as described herein, wherein R is¹⁹And R²⁰Together with the carbon atom to which they are attached form a cyclopropyl group.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²¹Is H, halogen, cyano, -OR²⁵，-SR²⁵，-S(O)R²⁵，-NR²⁵R²⁶，-NR²⁶SO₂R²⁵，-NR²⁶C(O)R²⁵，-NR²⁶C(O)NR²⁵R²⁷，-C(O)R²⁸，-C(O)NR²⁵R²⁶Cycloalkyl, substituted heterocycloalkyl, substituted heteroarylOr substituted aryl, wherein substituted heterocycloalkyl, substituted heteroaryl and substituted aryl are substituted by R³⁸，R³⁹And R⁴⁰And (4) substitution.

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²¹Is H, halogen, -OR²⁵，-NR²⁵R²⁶，-NR²⁶SO₂R²⁵，-NR²⁶C(O)R²⁵Substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R³⁸，R³⁹And R⁴⁰And (4) substitution.

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²¹Is H, halogen, -OR²⁵，-NR²⁵R²⁶Substituted heterocycloalkyl or substituted heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R³⁸，R³⁹And R⁴⁰And (4) substitution.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²¹is-OR²⁵，-NR²⁵R²⁶，-NR²⁶SO₂R²⁵or-NR²⁶C(O)R²⁵。

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²¹is-NR²⁵R²⁶，-NR²⁶SO₂R²⁵or-NR²⁶C(O)R²⁵。

An embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²¹is-OR²⁵。

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²⁵Is H, alkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substitutedHeteroarylalkyl, substituted aryl or substituted arylalkyl, wherein substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted aryl and substituted arylalkyl are substituted with R⁴¹，R⁴²And R⁴³And (4) substitution.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is²⁵Is H, alkyl, haloalkyl, cycloalkyl, substituted heteroaryl or substituted heteroarylalkyl, wherein substituted heteroaryl and substituted heteroarylalkyl are substituted by R⁴¹，R⁴²And R⁴³And (4) substitution.

The invention also relates to compounds according to formula (I) as described herein, wherein R is²¹is-NR²⁵R²⁶And R is²⁵Is a substituted heteroaryl or substituted heteroarylalkyl group.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²⁵Is H, alkyl, haloalkyl, cycloalkyl, substituted heterocycloalkyl alkyl, substituted heteroaryl or substituted heteroarylalkyl, wherein substituted heteroaryl and substituted heteroarylalkyl are substituted by R⁴¹，R⁴²And R⁴³And (4) substitution.

The invention also relates to compounds according to formula (I) as described herein, wherein R is²⁶And R²⁷Each independently selected from H, alkyl, cycloalkyl, haloalkyl or halocycloalkyl.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is²⁶And R²⁷Each independently selected from H and alkyl.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²⁶Is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is¹²，R¹³，R¹⁴，R²²，R²³，R²⁴，R²⁹，R³⁰，R³¹，R³²，R³³，R³⁴，R³⁵，R³⁶，R³⁷，R³⁸，R³⁹，R⁴⁰，R⁴¹，R⁴²，R⁴³，R⁴⁴，R⁴⁵，R⁴⁶，R⁴⁷，R⁴⁸，R⁴⁹，R⁵⁰，R⁵¹And R⁵²Each independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy, chloropyridylcarbonyl and heterocycloalkyl.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is¹²，R¹³，R¹⁴，R²²，R²³，R²⁴，R²⁹，R³⁰，R³¹，R³²，R³³，R³⁴，R³⁵，R³⁶，R³⁷，R³⁸，R³⁹，R⁴⁰，R⁴¹，R⁴²，R⁴³，R⁴⁴，R⁴⁵，R⁴⁶，R⁴⁷，R⁴⁸，R⁴⁹，R⁵⁰，R⁵¹And R⁵²Each independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy and heterocycloalkyl.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹²，R¹³，R¹⁴，R³²，R³³，R³⁴，R³⁵，R³⁶，R³⁷，R³⁸，R³⁹，R⁴⁰，R⁴¹，R⁴²，R⁴³，R⁵⁰，R⁵¹And R⁵²Each independentlySelected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy and heterocycloalkyl.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹²，R¹³，R¹⁴，R³²，R³³，R³⁴，R³⁵，R³⁶，R³⁷，R³⁸，R³⁹，R⁴⁰，R⁴¹，R⁴²，R⁴³，R⁵⁰，R⁵¹And R⁵²Each independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, cyano, oxo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcarbonylamino, alkoxycarbonyl, alkoxyalkyl, haloalkoxy and heterocycloalkyl.

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹²，R¹³And R¹⁴Is H.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³²Is alkyl or halogen, and R³³And R³⁴Is H.

A particular embodiment of the invention is also a compound according to formula (I) as described herein, wherein R is³⁵Is H, halogen, hydroxy, alkyl, haloalkyl or alkylcarbonylamino, and R³⁶And R³⁷Is H.

A particular embodiment of the invention is also a compound according to formula (I) as described herein, wherein R is³⁵Is H or alkyl, and R³⁶And R³⁷Is H.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³⁸Is H, halogen, hydroxy, cyano, oxo, alkyl, alkylcarbonyl, alkylsulfonyl, hydroxyalkyl,haloalkyl, cycloalkyl, alkoxycarbonyl or alkoxyalkyl, R³⁹Is H, halogen, oxo, alkyl or hydroxyalkyl, and R⁴⁰Is H.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³⁸Is H, halogen, hydroxy, cyano, oxo, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxycarbonyl or alkoxyalkyl, R³⁹Is H, halogen, oxo, alkyl or hydroxyalkyl, and R⁴⁰Is H.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³⁸Is H, alkyl, alkylcarbonyl or alkylsulfonyl, and R³⁹And R⁴⁰Is H.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³⁸Is H or alkyl, and R³⁹And R⁴⁰Is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is⁴¹Is H, halogen, alkyl or haloalkyl, and R⁴²And R⁴³Is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is⁴¹Is an alkyl group, and R⁴²And R⁴³Is H.

An embodiment of the invention are also compounds according to formula (I) as described herein, wherein R is⁵⁰，R⁵¹And R⁵²Each independently selected from H, halogen, hydroxy or alkyl, R⁵¹Is H or halogen, and R⁵²Is H.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³⁵，R³⁶，R³⁷，R³⁸，R³⁹，R⁴⁰，R⁴¹，R⁴²And R⁴³Each independently selected from H and alkyl.

Yet another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein p is 0.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein q is 0.

Yet another embodiment of the invention are compounds according to formula (I) as described herein, wherein r is 0 or 1.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein m is 0.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein n is 0.

Yet another embodiment of the invention is a compound according to formula (I) as described herein, wherein n is 1.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R2 and R⁴Together form a double bond, R⁵Is H, n is 1 and has formula (Ia).

Particular examples of compounds of formula (I) as described herein are selected from:

6-chloro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -nicotinonitrile;

6-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-chloro-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-chloro-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

2- (5-bromo-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridine-3-carbaldehyde;

6-chloro-2- (5-methoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-isopropoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-hydroxy-1-methyl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((R) -1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methoxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

2- (5-amino-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-1-methoxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

6-chloro-2- [5- (cyclopropyl-hydroxy-methyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (cyclopropyl-methoxy-methyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-trifluoromethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methoxy-1-methyl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

ethanesulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -amide;

6-chloro-2- [5- (2-oxo-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (1-methyl-1H-pyrazolo [3, 4-c ] pyridin-4-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-8 '-hydroxy-3, 4, 5', 6 ', 7', 8 '-hexahydro- [2, 4' ] biisoquinolin-1-one;

n- (6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -propionamide;

6-chloro-2- {5- [ hydroxy- (1-methyl-1H-imidazol-2-yl) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (3, 4-difluoro-phenyl) -hydroxy-methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (3, 5-difluoro-phenyl) -hydroxy-methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (4-ethyl-phenyl) -hydroxy-methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (hydroxy-phenyl-methyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-hydroxy-1-phenyl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1- (3, 4-difluoro-phenyl) -1-hydroxy-ethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1- (3, 5-difluoro-phenyl) -1-hydroxy-ethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (6-methyl-pyrazin-2-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (morpholine-4-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-hydroxy-pyrrolidine-1-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -N, N-dimethyl-nicotinamide;

6-chloro-2- [5- (pyrrolidine-1-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -N-methyl-nicotinamide;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -N-cyclopropyl-nicotinamide;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -N- (4-fluoro-phenyl) -nicotinamide;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -N-phenyl-nicotinamide;

6-chloro-2- [5- (4, 4-difluoro-piperidine-1-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-methoxymethyl-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-hydroxymethyl-5-oxo-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2-pyrimidin-5-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2-pyridazin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2-pyridin-3-yl-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -2H-isoquinolin-1-one;

6-chloro-2- [4- (1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-hydroxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

2- [5- (1-amino-cyclopropyl) -pyridin-3-yl ] -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-4H- [1, 2, 4] triazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methylsulfanyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-difluoromethoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-dimethoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [ 5-fluoro-4- (1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {4- [ (4-fluoro-phenyl) -hydroxy-methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [4- (1-methoxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (1-methyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopropyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-2H- [1, 2, 4] triazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopropoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [ 5-fluoro-4- (1-hydroxy-1-methyl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (5-methyl-pyrazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (1H-pyrrolo [3, 2-c ] pyridin-7-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-3, 4-dihydro- [2, 4' ] biisoquinolin-1-one;

3- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -isonicotinonitrile;

6-chloro-2- (5-fluoro-4-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [ 5-fluoro-4- (1-methoxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-isopropoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [4- (cyclopropyl-methoxy-methyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-3H-imidazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1, 1-dioxo-1 λ 6- [1, 2] thiazinan-2-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1, 1-dioxo-1 λ 6-isothiazolidin-2-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-hydroxymethyl-5-oxo-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

(S) -1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -pyrrolidine-2-carboxylic acid methyl ester;

6-chloro-2- (5-methoxy-pyridin-3-yl) -3-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-isopropyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-3-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -3-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-3-methyl-2-pyrimidin-5-yl-3, 4-dihydro-2H-isoquinolin-1-one;

(R) -6-chloro-3-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

(S) -6-chloro-3-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

8-chloro-3-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-methoxy-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

5, 6-dichloro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

2-chloro-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

2-methoxy-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

2-methoxy-6-pyridin-3-yl-7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

6-chloro-5-fluoro-2- (5-methoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-7-fluoro-2- (5-methoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-7-fluoro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-4, 4-dimethyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methoxy-pyridin-3-yl) -4, 4-dimethyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -4, 4-dimethyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-4-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -4-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methoxy-pyridin-3-yl) -4-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

5-chloro-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (2-isopropyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5- [1, 2, 4] triazol-1-ylmethyl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (2-methyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (2-oxo-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (2-oxo-piperidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

ethanesulfonic acid [5- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

5-chloro-2- (1-methyl-1H-pyrazolo [3, 4-c ] pyridin-4-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (8-hydroxy-5, 6, 7, 8-tetrahydro-isoquinolin-4-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-3-methyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

6-chloro-3-methyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-methoxy-pyridin-3-yl) -3-methyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-methyl-2- (4-methyl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl ] -3-methyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-fluoro-pyridin-3-yl) -3-methyl-2, 3-dihydro-isoindol-1-one;

3-benzyl-5-chloro-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-ethyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-3-ethyl-2- (5-methoxy-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-fluoro-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-methoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-difluoromethoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-methyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

2-hydroxy-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

6-chloro-2- (5-imidazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-isopropyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-ethyl-4-methyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-hydroxy-piperidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

propane-2-sulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -amide

6-chloro-2- [5- (3-hydroxy-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -3-hydroxy-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((R) -2-hydroxymethyl-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-pyrazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

n- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide

N- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -acetamide 6-chloro-2- (5-morpholin-4-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxo-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1, 1-dioxo-1 λ 6-thiomorpholin-4-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxo-)Oxazolidin-3-ylmethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-methyl-2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-pyrazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-propyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -1H-imidazole-2-carboxylic acid ethyl ester;

6-chloro-2- [5- (2-hydroxymethyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (oxetan-3-ylaminomethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [4- (2-hydroxy-ethyl) -piperazin-1-ylmethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-isopropyl-piperazin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4, 4-difluoro-piperidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 3-difluoro-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxa-6-aza-spiro [3.4] oct-6-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxa-6-aza-spiro [3.3] hept-6-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 3-difluoro-piperidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxo-piperidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5- [1, 2, 3] triazol-2-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5- [1, 2, 3] triazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-chloro-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-methyl- [1, 2, 4] triazol-4-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (5-methyl- [1, 2, 4] triazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-methyl- [1, 2, 4] triazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5- [1, 2, 4] triazol-4-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5- [1, 2, 4] triazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-benzoimidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-indazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-indazol-2-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (6-fluoro-indol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (7-fluoro-indol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-fluoro-indol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-pyrazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-cyclopropyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-trifluoromethyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-methyl-pyrazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-ethyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

2- (5-aminomethyl-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-isopropoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-1-methyl-ethoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxymethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopentyloxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopropylmethoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-fluoro-phenoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-cyclopropylmethoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (tetrahydro-furan-2-ylmethoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-ethoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclobutoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-iso-methyl)Azol-4-ylmethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methanesulfonyl-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (6-methyl-pyridin-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (6-morpholin-4-yl-pyridin-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-2H-pyrazol-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-pyrazol-4-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 3-difluoro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-difluoro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 5-difluoro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-trifluoromethyl-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 6-dichloro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-chloro-6-fluoro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 4-dichloro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 5-dichloro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

ethanesulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -amide;

n- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -benzenesulfonamide;

n- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -methanesulfonamide;

cyclopropanesulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -amide;

6-chloro-2- [5- (4-fluoro-benzylamino) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-ethylamino) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-morpholin-4-yl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

n- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -propionamide;

6-chloro-2- {5- [ (2-methyl-2H-pyrazol-3-ylmethyl) -amino ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylamino ] -2-methyl-propionic acid;

6-chloro-2- {5- [ (1-methyl-1H-imidazol-4-ylmethyl) -amino ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-iso-methyl)Azol-4-yl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-fluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 4-difluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-difluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-chloro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 5-difluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-trifluoromethyl-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-trifluoromethoxy-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-chloro-3-fluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 4-dichloro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-trifluoromethyl-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-iso)Oxazol-4-yl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-imidazol-2-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 4-dimethyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -1-methyl-1H-pyrazole-4-carbonitrile

N- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -isobutyramide

Cyclopropanecarboxylic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -amide

N- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -4-fluoro-benzamide

1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -3-cyclohexyl-urea

1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -3- (3-trifluoromethyl-phenyl) -urea

6-chloro-2- (5-hydroxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -acetamide;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -N-methyl-acetamide;

[5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -acetic acid methyl ester;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -N, N-dimethyl-acetamide;

6-chloro-2- (5-phenylaminomethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (4-fluoro-phenylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (3-fluoro-phenylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (4-chloro-phenylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (3-chloro-phenylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-morpholin-4-yl-2-oxo-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -N- (2-hydroxy-ethyl) -acetamide;

6-chloro-2- [5- (1-methylamino-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-dimethylamino-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-imidazole-2-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-4H- [1, 2, 4] triazol-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1- [1, 2, 3] triazol-2-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-imidazol-1-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-pyrazol-1-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1-, (Azol-2-ylamino) -ethyl]-pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1- [1, 2, 4] triazol-1-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1- (2-oxo-pyrrolidin-1-yl) -ethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1- (2-oxo-)Oxazolidin-3-yl) -ethyl]-pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

n- {1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -ethyl } -methanesulfonamide;

6-chloro-2- {5- [1- (3-fluoro-phenylamino) -ethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-phenylamino-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methanesulfinyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

and pharmaceutically acceptable salts thereof.

Particular examples of compounds of formula (I) as described herein are also selected from:

5-chloro-3, 3-dimethyl-2- [5- (1-methyl-1H-pyrazol-4-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-difluoromethoxy-pyridin-3-yl) -3-ethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-ethyl-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (4-chloro-pyridin-3-yl) -3-ethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (4-chloro-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

6-chloro-5 '-nitro-3, 4-dihydro- [2, 4' ] biisoquinolin-1-one;

6-chloro-8 '-nitro-3, 4-dihydro- [2, 4' ] biisoquinolin-1-one;

8 '-amino-6-chloro-3, 4-dihydro- [2, 4' ] biisoquinolin-1-one;

ethanesulfonic acid (6-chloro-1-oxo-3, 4-dihydro-1H- [2, 4 '] biisoquinolin-8' -yl) -amide;

6 ' -chloro-2 ' - (5-fluoropyridin-3-yl) spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

6 ' -chloro-2 ' - [5- (difluoromethoxy) pyridin-3-yl ] spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

2-chloro-6- (5-fluoro-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-chloro-6- (5-difluoromethoxy-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

6- (5-fluoro-pyridin-3-yl) -2-methoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

6- (5-difluoromethoxy-pyridin-3-yl) -2-methoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

6 ' -chloro-2 ' - (pyridin-3-yl) spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

5-chloro-3-cyclopropyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

2-chloro-7, 7-dimethyl-6-pyridin-3-yl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-ethoxy-6- (5-fluoro-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-methoxy-7, 7-dimethyl-6-pyridin-3-yl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

5-chloro-3-cyclopropyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-cyclopropyl-2- (5-difluoromethoxy-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

6- (5-difluoromethoxy-pyridin-3-yl) -2-ethoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

5-chloro-2- (5-isopropoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

6 ' -chloro-2 ' - (4-chloropyridin-3-yl) spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

5-chloro-2- (5-cyclopropoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

(S or R) -6-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

(R or S) -6-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

(R or S) -5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

(S or R) -5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

2- (8-amino-5, 6, 7, 8-tetrahydro-isoquinolin-4-yl) -5-chloro-2, 3-dihydro-isoindol-1-one;

n- [ (R or S) -4- ((R or S) -5-chloro-1-ethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((S or R) -5-chloro-1-ethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

ethanesulfonic acid [4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -amide;

ethanesulfonic acid [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -amide;

ethanesulfonic acid [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -amide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- ((R or S) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -acetamide;

n- ((S or R) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -acetamide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- ((S or R) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -methanesulfonamide;

n- ((R or S) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -methanesulfonamide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- ((R or S) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -propionamide;

n- ((S or R) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -propionamide;

n- [ (S or R) -4- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (S or R) -4- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

ethanesulfonic acid [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -amide;

ethanesulfonic acid [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -amide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

5-chloro-2- ((S or R) -8-hydroxy-5, 6, 7, 8-tetrahydro-isoquinolin-4-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- ((R or S) -8-hydroxy-5, 6, 7, 8-tetrahydro-isoquinolin-4-yl) -2, 3-dihydro-isoindol-1-one;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [4- (5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-cyclopropyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-cyclopropyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-cyclopropyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-cyclopropyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

5-chloro-3, 3-dimethyl-2- (5-pyrazol-1-ylmethyl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one; 2- [5- (3-amino-pyrazol-1-ylmethyl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -2, 3-dihydro-isoindol-1-one;

2- [5- (3-amino-pyrazol-1-ylmethyl) -pyridin-3-yl ] -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

2-chloro-7, 7-dimethyl-6- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-methoxy-7, 7-dimethyl-6- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-ethoxy-7, 7-dimethyl-6- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

6 ' -chloro-2 ' - {5- [ (1H-pyrazol-3-ylamino) methyl ] pyridin-3-yl } spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

ethanesulfonic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

ethanesulfonic acid [5- (6-fluoro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

ethanesulfonic acid [5- (6-cyano-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

ethanesulfonic acid [5- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -N-methyl-methanesulfonamide;

n- { [5- (6 ' -fluoro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } ethanesulfonamide;

n- { [5- (6 ' -fluoro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } -N-methylethylsulfonamide;

ethanesulfonic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methyl-amide;

n- { [5- (6 ' -chloro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } propionamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -propionamide;

n- [5- (6-fluoro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -propionamide;

n- [5- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -propionamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -acetamide;

n- { [5- (5 ' -fluoro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } methanesulfonamide;

n- [5- (6-cyano-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- (6-fluoro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- { [5- (6 ' -fluoro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } methanesulfonamide;

n- [5- ((S or R) -5-chloro-1-ethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- (5-fluoro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- ((R or S) -5-chloro-1-ethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- (5-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

5-chloro-2- [5- (1, 1-dioxo-1 λ 6-isothiazolidin-2-ylmethyl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-oxo-piperidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-oxo-)Oxazolidin-3-ylmethyl) -pyridin-3-yl]-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-oxo-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (3-methyl-2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1, 1-dioxo-1 λ 6- [1, 2] thiazinan-2-ylmethyl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (3-isopropyl-2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- (1, 5-dimethyl-1H-imidazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- (3-methyl-1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-chloro-2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 5-dimethyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1, 5-dimethyl-1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [ 4-chloro-5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

2-chloro-7, 7-dimethyl-6- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-methoxy-7, 7-dimethyl-6- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

5-chloro-2- [5- (4-chloro-2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

(R or S) -5-chloro-3-ethyl-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

(S or R) -5-chloro-3-ethyl-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

3-methyl-pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

3-chloro-pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl 1-amide;

1-methyl-1H-imidazole-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

2-chloro-N- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -nicotinamide;

pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

3-methyl-3H-imidazole-4-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -6-methyl-nicotinamide;

3-chloro-N- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -isonicotinamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -nicotinamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -2-methyl-nicotinamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -4-methyl-nicotinamide;

2- [5- (1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- ((R) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- ((S) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (1-propionyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-methanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((R) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((S) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (1-acetyl-piperidin-4-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (1-acetyl-azetidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (1-propionyl-azetidin-3-yloxy) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-methanesulfonyl-azetidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-ethanesulfonyl-azetidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((S) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (4-acetyl-piperazin-1-yl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (4-propionyl-piperazin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (4-methanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (4-ethanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- {5- [4- (3-chloro-pyridine-2-carbonyl) -piperazin-1-yl ] -pyridin-3-yl } -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (1-acetyl-pyrrolidin-3-yl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- (1 '-acetyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [3, 4' ] bipyridinyl-5-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [6- (1-acetyl-piperidin-3-yl) -pyrazin-2-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [6- (1-propionyl-piperidin-3-yl) -pyrazin-2-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [6- (1-ethanesulfonyl-piperidin-3-yl) -pyrazin-2-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [6- (1-methanesulfonyl-piperidin-3-yl) -pyrazin-2-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

n- [ (S or R) -4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as described herein are selected from:

6-chloro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-chloro-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-isopropoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((R) -1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopropoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

2-methoxy-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-fluoro-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-difluoromethoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- (2-oxa-6-aza-spiro [3.4] oct-6-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-pyrazol-4-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (2-methyl-2H-pyrazol-3-ylmethyl) -amino ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as described herein are also selected from:

(R or S) -5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

(S or R) -5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

5-chloro-3, 3-dimethyl-2- {5- [ (1H- [ pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -2, 3-dihydro-isoindol-1-one;

6 ' -chloro-2 ' - {5- [ (1H-pyrazol-3-ylamino) methyl ] pyridin-3-yl } spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

3-methyl-pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

2- [5- ((R) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- ((S) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-methanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((R) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((S) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (1-acetyl-piperidin-4-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-ethanesulfonyl-azetidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (4-acetyl-piperazin-1-yl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (4-methanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (4-ethanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- (1 '-acetyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [3, 4' ] bipyridinyl-5-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

and pharmaceutically acceptable salts thereof.

The process for the preparation of the compounds of formula (I) as described herein is an object of the present invention.

The preparation of the compounds of formula (I) according to the invention can be carried out sequentially or via convergent routes. The synthesis of the present invention is shown in the following general scheme. The techniques required to carry out the reaction and the purification of the resulting product are known to those skilled in the art. If a mixture of enantiomers or diastereomers is produced during the course of the reaction, these enantiomers or diastereomers may be separated by methods described herein or known to those skilled in the art, such as, for example, chiral chromatography or crystallization. The substituents and symbols used in the following description of the process have the meanings given herein.

The following abbreviations are used herein:

AcOH ═ acetic acid, BOC ═ tert-butyloxycarbonyl, BuLi ═ butyllithium, CDI ═ 1, 1-carbonyldiimidazole, DCM ═ dichloromethane, DBU ═ 2, 3, 4, 6, 7, 8, 9, 10-octahydro-pyrimido [1, 2-a ] o]Aza derivativesDCE ═ 1, 2-dichloroethane, DIBALH ═ diisobutylaluminium hydride, DCC ═ N, N '-dicyclohexylcarbodiimide, DMA ═ N, N-dimethylacetamide, DMAP ═ 4-dimethylaminopyridine, DMF ═ N, N-dimethylformamide, EDCI ═ N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, EtOAc ═ ethyl acetate, EtOH ═ ethanol, Et ═ dimethyl₂Diethyl ether, Et₃N is triethylamine, eq is equivalent, HATU is equivalentO- (7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate, HPLC ═ high performance liquid chromatography, HOBT ═ 1-hydroxybenzo-triazole, suniting ═ iPr₂NEt ═ N-ethyldiisopropylamine, IPC ═ in-process control, LAH ═ lithium aluminum hydride, LDA ═ lithium diisopropylamide, LiBH₄Lithium borohydride, MeOH-methanol, NaBH₃CN, sodium cyanoborohydride, NaBH₄Sodium borohydride, NaI ═ sodium iodide, Red-Al ═ sodium bis (2-methoxyethoxy) aluminum hydride, RT ═ room temperature, TBDMSCl ═ tert-butyldimethylsilyl chloride, TFA ═ trifluoroacetic acid, THF ═ tetrahydrofuran, quant ═ quantitative.

Halogen or triflate substituted heterocyclic compound 2 with aryllactam 1 in solvent such as 1, 4-bisThe reaction is carried out in the presence of copper (I) iodide, potassium carbonate or cesium carbonate, chelating a1, 2-diamino compound such as N, N' -dimethylethylenediamine or trans-1, 2-diamino-hexane, at elevated temperature, preferably with the aid of microwave heating, to form the lactam-substituted heterocyclic compound 3 (step a), as depicted in scheme 1.

Scheme 1

X is halogen or OSO₂CF₃

The heteroaryl attached alcohol compound 51 (scheme 2b) is treated with a base such as sodium hydride in a solvent such as THF or DMF and then with a suitable alkylating agent such as a halide, mesylate or tosylate preferably between RT and the reflux temperature of the solvent to give compound 52 (step a). Alternatively (scheme 2a), the heteroaryl linked alcohol compound 51 may be converted to the corresponding chloride (step b), for example by treatment with thionyl chloride in a solvent such as dichloromethane, preferably between 0 ℃ and room temperature. The heteroaryl-linked chloride, compound 53, is reacted with the nucleophilic amino-moiety 54a or aryl, heteroaryl or heterocycloalkyl compound 54b itself or after formation with an anion, such as sodium hydride, in a solvent such as N, N' -dimethylformamide at a temperature ranging between 0 ℃ to about 100 ℃ to form an adduct 55a or 55b (step c).

Scheme 2a

Scheme 2b

Alternatively (scheme 2c), the heteroaryl-linked chloride compound 53 is reacted with a boronic acid or ester 56 as follows: i) by using Suzuki conditions, for example in the form of catalysts, such as tris-o-tolylphosphine/palladium (II) acetate, tetrakis- (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride or dichloro [1, 1' -bis (diphenylphosphino) -ferrocene ] optionally in the form of the dichloromethane complex (1: 1)]Palladium (II) in the presence of a base such as aqueous or non-aqueous potassium phosphate, sodium carbonate or potassium carbonate in a solvent such as dimethyl sulfoxide, toluene, ethanol, dimethyl sulfoxideAlkane, tetrahydrofuran or N, N-dimethylformamide and in an inert atmosphere, such as argon or nitrogen, at a temperature range preferably between room temperature and about 130 ℃, or ii) by using a nickel (0) catalyst, such as bis (1, 5-cyclooctadiene) nickel (0), in the presence of potassium phosphate, bis (1-methyl-1H-imidazol-2-yl) methane, in N, N-dimethylacetamide at a temperature of about 100 ℃, to give adduct 57 (step d).

Scheme 2c

Aldehyde or ketone 58 (scheme 2d) may be treated with a suitable amino-moiety 59 in NaBH (OAc)₃In the presence of a one-step procedure in a solvent such as methanol, preferably at about room temperature, or in a two-step procedure by first treating with titanium (IV) isopropoxide in a solvent such as methanol or toluene, preferably at a temperature between room temperature and the reflux temperature of the solvent, followed by treatment with NaBH, preferably between 0 ℃ and room temperature₄A reaction that converts the aldehyde or ketone 58 to an amino compound 60; alternatively, the imine obtained after treatment with titanium (IV) isopropoxide may be evaporated, then redissolved in a solvent such as THF and treated with a Grignard reagent R²⁰MgX, preferably treated at-40 ℃ to 0 ℃, produces compounds with a specific R²⁰Substituted amino compound 60 (step e).

Scheme 2d

Reaction of heteroaryl halide 101 (scheme 2e) with boronic acid or ester 102 using Suzuki conditions as described above gives adduct 103 (step a). The reaction of phenol 104 with alcohol 105 under Mitsunobu conditions, for example with triphenylphosphine and di-tert-butyl-, diisopropyl-, diethyl-azodicarboxylate or bis- (4-chlorobenzyl) azodicarboxylate as reagents, in a solvent such as toluene, dichloromethane or tetrahydrofuran, preferably at ambient temperature, gives adduct 106 (step b). Compound 106 can be converted to synthon 107 by additional standard modifications (step c).

Scheme 2e

Carbamate 201 (scheme 3) is reacted with polyphosphoric acid at elevated temperature (e.g., 100-. Trifluoroacetamide 203 can be prepared by reaction of paraformaldehyde in a mixture of concentrated sulfuric acid and acetic acid, preferably at about room temperatureThe treatment cyclizes to 1- (3, 4-dihydro-1H-isoquinolin-2-yl) -2, 2, 2-trifluoro-ethanone compound 204 (step b). Removal of the trifluoroacetyl group by treatment with, for example, potassium hydroxide in a solvent such as ethanol at a temperature of about room temperature affords tetrahydro-isoquinoline compound 205 (step c). Oxidation of tetrahydro-isoquinoline compound 205, for example, with iodosobenzene and potassium bromide, preferably in water, gives 3, 4-dihydro-2H-isoquinolin-1-one compound 202 (step d). Isoindole-1, 3-dione compounds 206 and Grignard reagents R¹Reaction of MgX in a solvent such as THF, preferably at about 0 ℃, gives adduct 207 (step e). Subsequent treatment with triethylsilane and trifluoroboron etherate in a solvent such as dichloromethane and at a temperature preferably in the range between-25 ℃ to RT gives the isoindolone compound 208 (step f). Introduction of a methoxybenzyl protecting group into isoindolone compound 209 (e.g., by treatment with sodium bis (trimethylsilyl) amide and 1-bromomethyl-4-methoxy-benzene in THF between 0 ℃ and RT) gave protected compound 210 (step g); similarly, a methoxybenzyl protecting group may be introduced into compound 208. Treatment of compound 208 or compound 210 with an additional methoxybenzyl protecting group with a base such as sodium hydride in a solvent such as THF followed by an alkyl halide, mesylate or tosylate preferably between RT and the reflux temperature of the solvent gives compounds having structurally different or structurally identical R¹And R²Compound 211 of group (step h). Alternatively, treatment of compound 208 or compound 210 with an additional methoxybenzyl protecting group with a base such as NaH, LDA or LiHMDS in a solvent such as DMF, tetrahydrofuran or 1, 2-dimethoxyethane followed by one or sequentially two different alkyl halides, mesylate or tosylate preferably at between-78 deg.C to the reflux temperature of the solvent gives compounds having a structurally different or structurally identical R¹And R²Compound 211 of the group (step h) removal of the protecting group, e.g. by treatment with trifluoroacetic acid at elevated temperature gives isoindolone compound 212 (step i) Compound 210 treatment with a base such as sodium hydride in a solvent such as THF followed by treatment with α, an omega di-or di-halo heteroalkane such as e.g. 1, 2-dibromoethane, preferably between RT and the reflux temperature of the solvent gives spiro compound 213 (step k) andafter subsequent removal of the protecting group, spiro compound 214 is given (step 1).

Scheme 3

Reaction of 5-halo-nicotinic acid or pyridazinecarboxylic acid compounds 301 or 305 (scheme 4a) with acrylate compounds 302 after deprotonation with a base such as LDA or LiHMDS in a solvent such as THF, preferably at about-78 deg.C, gives cyclic β ketoester compounds 303 and 306 (step a)¹¹¹The ester compounds 303 or 306 ═ H can be treated with a base such as NaH, LDA or LiHMDS in a solvent such as DMF, tetrahydrofuran or 1, 2-dimethoxyethane, followed by addition of an alkyl or cycloalkyl halide, mesylate or tosylate, or e.g. an N-halobenzenesulfonamide, the reaction preferably being carried out between-78 ℃ and room temperature, giving R substituents with substituents other than H¹¹¹With aqueous acid, preferably at reflux, to cause hydrolysis and subsequent decarboxylation of the ester compound 303 or 306, β ketoester compound 303 or 306, to provide ketones 304 and 307 (step b)¹¹¹H and R¹¹³The ketones 304 and 307 which are ═ H can be treated with a base such as NaH, LDA or LiHMDS in a solvent such as DMF, tetrahydrofuran or 1, 2-dimethoxyethane, followed by the addition of one or two different alkyl or cycloalkyl halides, mesylates or tosylates, or for example N-halobenzenesulfonamides, the reaction preferably being carried out at from-78 ℃ to room temperature, giving the substituents R¹¹¹Or R¹¹³At least one ketone 304 and 307 different from H. Optionally, ketones 304 and 307 can be converted to the corresponding imines (e.g., with n-butylamine by using a catalyst such as toluene sulfonic acid or pyridinium p-toluene sulfonate in a solvent such as ethanol, preferably at reflux); wherein R is¹¹¹Such imines of ═ H can be used with, for example, N-fluorobenzenesulfonylimide using K₂CO₃Or triethylamine as a base in a solvent such as DMFOr acetonitrile or mixtures thereof, in the presence of a molecular sieve, preferably at room temperature, to give an imine bearing a fluorine substituent, and wherein R is given after hydrolysis of the imine (e.g. with hydrochloric acid in acetonitrile)¹¹¹F ketones 304 and 307. Ketones 304 and 307, may be as compound 2 (scheme 1) or may be further structurally modified by using methods well known in the art such as, for example, reduction of the ketone functionality with an agent such as sodium borohydride in methanol to a secondary hydroxyl group or reduction of the ketone group by reductive amination, for example by reaction with an amine and NaBH (OAc)₃Reaction in methanol to reduce to primary or secondary amino functions and conversion to different compounds 2 (scheme 1).

Scheme 4a

Dihalopyridine or pyridazine compound 351 (scheme 4b) is reacted with bromo-tetramethyl-azethiirane reagent 352 after deprotonation with lithium diisopropylamide in a solvent such as tetrahydrofuran between-78 ℃ to 0 ℃ to give aminoalkyl substituted pyridine or pyridazine 353 (step a). Attached to compound 353 at a protecting group (e.g. by reaction with BOC)₂O or 2-trimethylsilanyl-ethanesulfonyl chloride, triethylamine, DMF at about 0 ℃ to introduce a BOC-or SES-protecting group), the amino-protected pyridine or pyridazine compound 354 is treated with a base such as potassium carbonate in a solvent such as toluene and in the presence of a catalyst such as tetrakis- (triphenylphosphine) -palladium at a temperature of about 100 ℃ to give the bicyclic compound 355, still bearing the protecting group (steps b, c). Standard BOC removal or use of tetrabutylammonium fluoride hydrate, acetonitrile preferably between room temperature and the reflux temperature of acetonitrile gives the bicyclic compound 356 (step d). Amino compound 356 can be used as compound 2 (scheme 1) as such or after further structural modification by methods well known in the art.

Scheme 4b

Reaction of 5-halo-nicotinic acid compound 305 (scheme 4c) with olefin compound 400 after deprotonation with a base such as LDA or LiHMDS in a solvent such as THF, preferably at about-78 ℃, to give olefin 401 (step a) diester compound 402 can be synthesized by methods known to those skilled in the art such as, for example, by ozonolysis of olefin 401 in the presence of NaOH methanol solution to give compound 402, which can be cyclized using Dieckmann condensation conditions to give β ketoester compound 403 (steps b, c). β ketoester compound 403 is treated with an aqueous acid, preferably at reflux temperature, to cause ester hydrolysis and subsequent decarboxylation to give ketone 404 (step e). ester compound 403 (R404)¹¹¹Is H) can be treated with a base such as NaH, LDA or LiHMDS in a solvent such as DMF, tetrahydrofuran or 1, 2-dimethoxyethane, followed by the addition of an alkyl or cycloalkyl halide, mesylate or tosylate, or for example an N-halobenzenesulfonamide, preferably at a temperature between-78 ℃ and room temperature, to give a R group with a substituent other than H¹¹¹Ester compound 403 (step d). Hydrolysis and decarboxylation as described above gives ketone 404 (step e). Ketone compound 404 can be as compound 2 (scheme 1) as such or after further structural modification by methods described herein or by methods well known in the art.

Scheme 4c

An embodiment of the present invention is also a process for the preparation of a compound of formula (I) as defined above, said process comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III);

wherein R is¹，R²，R³，R⁴，R⁵，R⁶，A¹，A²，A³，A⁴，A⁵And n is as defined above, and

wherein X is a halogen or a triflate group.

In particular, copper (I) iodide, potassium carbonate or cesium carbonate, chelated 1, 2-diamino compounds such as N, N' -dimethylethylenediamine or trans-1, 2-diamino-hexane, in the presence of copper (I) iodide, heating at elevated temperature, preferably by means of microwaves, and in a solvent such as 1, 4-bisIn an alkane.

Also object of the present invention are compounds according to formula (I) as described herein for use as therapeutically active substances.

Also object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of diabetic nephropathy.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of renal or cardiac fibrosis.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of chronic kidney disease.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of congestive heart failure.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of hypertension.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of primary hyperaldosteronism.

A particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

A particular embodiment of the invention is also a compound according to formula (I) as described herein for use in the treatment or prevention of diabetic nephropathy.

Another particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of renal or cardiac fibrosis.

A particular embodiment of the invention is also a compound according to formula (I) as described herein for use in the treatment or prevention of chronic kidney disease.

A particular embodiment of the invention is also a compound according to formula (I) as described herein for use in the treatment or prevention of congestive heart failure.

A particular embodiment of the invention is also a compound according to formula (I) as described herein for use in the treatment or prevention of hypertension.

A particular embodiment of the invention is also a compound according to formula (I) as described herein for use in the treatment or prevention of primary aldosteronism.

The invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

The invention also relates to the use of a compound according to formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of diabetic nephropathy.

The invention also relates to the use of a compound according to formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of renal or cardiac fibrosis.

An embodiment of the invention is also the use of a compound according to formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of chronic kidney disease.

An embodiment of the invention is also the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of congestive heart failure.

An embodiment of the invention is also the use of a compound according to formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of hypertension.

An embodiment of the invention is also the use of a compound according to formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of primary hyperaldosteronism.

Also object of the present invention is a method for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

Also object of the present invention is a method for the treatment or prevention of diabetic nephropathy, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

Also object of the present invention is a method for the treatment or prevention of renal or cardiac fibrosis, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

An embodiment of the present invention is also a method for the treatment or prevention of chronic kidney disease, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

An embodiment of the present invention is also a method for treating or preventing congestive heart failure, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

An embodiment of the present invention is also a method for the treatment or prophylaxis of hypertension, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

An embodiment of the invention is also a method for the treatment or prevention of primary aldosteronism, which comprises administering an effective amount of a compound according to formula (I) as described herein.

An embodiment of the invention is also a compound of formula (I) as described herein, prepared according to any one of the methods.

Test program

The inventors herein determined the use of the G-402 cell line as a host cell for ectopic expression (transiently or stably) of an enzyme of the CYP11 family. In particular, the inventors developed stable G-402 cells that ectopically express human CYP11B1, human CYP11B2, human CYP11a1, cynomolgus (cynomolgus) CYP11B1 or cynomolgus CYP11B2 enzyme activity. Importantly, the established cell line G-402 expressed cofactors (corticotoxin and corticotoxin reductase) important for the activity of the CYP11 family and no relevant enzyme activity of the CYP11 family (compared to H295R cells) was detected in these cells. The G-402 cell line is therefore uniquely suited as a host cell for ectopic expression of enzymes from the CYP11 family.

G-402 cells can be obtained from ATCC (CRL-1440) and originally derived from renal leiomyoma.

The expression plasmid contains the ORF for human/cynomolgus (cyno) CYP11B1 or CYP11B2 under the control of a suitable promoter (CMV-promoter) and a suitable resistance marker (neomycin). The expression plasmid is transfected into G-402 cells using standard techniques, and these cells are then selected for expression of a given resistance marker. Individual cell-clones were then selected and evaluated for exhibiting the desired enzyme activity using 11-deoxycorticosterone (Cyp11B2) or 11-deoxycorticosterol (Cyp11B1) as substrates.

G-402 cells expressing the CYP11 construct were established as described above and maintained in McCoy's 5a Medium Modified (Medium Modified), ATCC Catalog No. (Catalog No.)30-2007 at 37 ℃ under an atmosphere of 5% CO 2/95% air containing 10% FCS and 400. mu.g/ml G418 (Geneticin)). Cellular enzyme assays were performed in DMEM/F12 medium containing 2.5% charcoal-treated FCS and appropriate concentrations of substrate (0.3-10uM 11-deoxycorticosterone, 11-deoxycorticosterol or corticosterone). For testing enzyme activity, cells were seeded onto 96-well plates and incubated for 16 h. Aliquots of the supernatant were then transferred and analyzed for the concentration of the expected product (aldosterone for CYP 1182; cortisol for CYP11B 1). The concentrations of these steroids can be determined using HTRF tests from CisBio that analyze aldosterone or cortisol.

Inhibition of the release of the produced steroid can be used as a measure of the individual enzyme inhibition of the test compound added during the cellular enzyme test. The dose-dependent inhibition of enzyme activity by compounds was calculated by plotting the added inhibitor concentration (x-axis) against the measured steroid/product levels (y-axis). Inhibition was then calculated by fitting the following 4-parameter sigmoid function (Morgan-Mercer-flodin (mmf) model) to the raw data points using the least squares method:

where A is the maximum y value, B is the EC50 factor determined using XLFit, C is the minimum y value and D is the slope value.

The maximum value a corresponds to the amount of steroid produced in the absence of inhibitor and the value C corresponds to the amount of steroid detected when the enzyme is completely inhibited.

EC50 values for the compounds claimed herein were determined using the described G402-based test system. Cyp11B2 enzyme activity was measured in the presence of 1 μ M deoxycorticosterone and various amounts of inhibitor; cyp11B1 enzyme activity was measured in the presence of 1 μ M deoxycorticosterol and various amounts of inhibitor.

The compounds of formula (I) and pharmaceutically acceptable salts or esters thereof as described herein have an EC of between 0.000001uM and 1000uM₅₀(CYP11B2) values, particular compounds have an EC between 0.00005uM and 500uM₅₀(CYP11B2) values, more particularly compounds having an EC between 0.0005uM and 50uM₅₀(CYP11B2) values, yet particular compounds have an EC between 0.0005uM and 5uM₅₀(CYP11B2) value. These results have been obtained by using the enzyme test.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (for example in the form of nasal sprays) or rectally (for example in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g. in the form of injectable solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees and hard gelatine capsules. As such adjuvants for tablets, dragees and hard gelatine capsules, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like may be used, for example.

Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like.

Suitable auxiliaries for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable adjuvants for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain additional therapeutically valuable substances.

The dosage can vary within wide limits and will of course be adapted to the individual requirements in each particular case. In general, in the case of oral administration, the following should be appropriate: a daily dose of about 0.1mg to 20mg/kg body weight, preferably about 0.5mg to 4mg/kg body weight (e.g. about 300 mg/person), is divided into preferably 1-3 individual doses, which may for example consist of the same amount. However, it is clear that the upper limit given herein can be exceeded when the presentation necessitates.

According to the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prevention of aldosterone-mediated diseases.

The compounds of formula (I) herein or their pharmaceutically acceptable salts and esters are CYP11B2 inhibitors. The compounds of formula (I) herein or their pharmaceutically acceptable salts and esters also exhibit variable inhibition of CYP11B 1. These compounds may be used for CYP11B2 inhibition in combination with variable inhibition of CYP11B 1. Such compounds may be used for the treatment or prevention of conditions which show excessive cortisol production/level or both cortisol and aldosterone levels (e.g. cushing's syndrome, burn trauma patients, depression, post traumatic stress disorder, chronic stress, adrenocorticotropic adenoma, cushing's disease).

According to the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prevention of cardiovascular disorders (including hypertension and heart failure), vascular disorders, endothelial dysfunction, baroreceptor dysfunction, renal disorders, liver disorders, fibrotic disorders, inflammatory disorders, retinopathies, neuropathies (such as peripheral neuropathy), pain, insulinopathies, edema, edematous disorders, depression and the like.

Cardiovascular conditions include congestive heart failure, coronary heart disease, cardiac arrhythmia, arterial fibrillation, cardiac damage, decreased ejection fraction, diastolic and systolic cardiac dysfunction, fibrinoid necrosis of coronary arteries, cardiac fibrosis, hypertrophic cardiomyopathy, impaired arterial compliance, impaired diastolic filling, ischemia, left ventricular hypertrophy, myocardial and vascular fibrosis, myocardial infarction, myocardial necrotic lesions, cardiac arrhythmia, prevention of sudden cardiac death, restenosis, stroke, vascular damage.

Renal conditions include acute and chronic renal failure, nephropathy, end-stage renal disease, diabetic nephropathy, decreased creatinine clearance, decreased glomerular filtration rate, expansion of reticuloendothelial matrix with or without significant hypercytosis, focal thrombosis of glomerular capillaries, global (global) fibrinoid necrosis, glomerulosclerosis, ischemic lesions, malignant nephrosclerosis (such as ischemic contraction, microalbuminuria, proteinuria, decreased renal blood flow, renal arteriopathy, swelling and proliferation of the cells within the capillaries (endothelium and mesangium) and/or outside the capillaries (crescents).

Renal disorders also include glomerulonephritis (e.g., diffuse proliferation, focal proliferation, reticulocyte proliferation, membranous proliferation, morbid membranous glomerulonephritis), lupus nephritis, non-immune basement membrane abnormalities (e.g., alport syndrome), renal fibrosis, and glomerulosclerosis (e.g., nodular or complete and focal segmental glomerulonephritis).

Liver disorders include, but are not limited to, hepatic steatosis, nonalcoholic steatohepatitis, cirrhosis, hepatic ascites, hepatic congestion, and the like.

Vascular conditions include, but are not limited to, thrombotic vascular disease (e.g., parietal fibroid necrosis, extravasation and fragmentation of red blood cells, and luminal and/or parietal thrombosis), proliferative arterial disease (e.g., thickening of swollen endomysial (myointimal) cells and nodules surrounded by mucinous extracellular matrix), atherosclerosis, decreased vascular compliance (e.g., stiffness, decreased ventricular compliance, and decreased vascular compliance), endothelial dysfunction, and the like.

Inflammatory disorders include, but are not limited to, arthritis (e.g., osteoarthritis), inflammatory airway diseases (e.g., Chronic Obstructive Pulmonary Disease (COPD)), and the like.

Pain includes, but is not limited to, acute pain, chronic pain (e.g., joint pain), and the like.

Edema includes, but is not limited to, edema in peripheral tissues, liver congestion, liver ascites, spleen congestion, respiratory or pulmonary congestion, and the like.

Insulinopathies include, but are not limited to, insulin resistance, type I diabetes, type II diabetes, glucose sensitivity, prediabetic state, prediabetes, syndrome X, and the like.

Fibrotic diseases include, but are not limited to, cardiac and intrarenal fibrosis, renal interstitial fibrosis and liver fibrosis.

Furthermore, compounds of formula (I) as described herein or their pharmaceutically acceptable salts and esters may also be used for the treatment or prevention of cardiovascular disorders selected from the group consisting of: hypertension, heart failure (especially post-myocardial infarction heart failure), left ventricular hypertrophy, and stroke.

In another embodiment, the cardiovascular disorder is hypertension.

In particular embodiments, the cardiovascular disorder is the treatment of resistant hypertension.

In another embodiment, the cardiovascular disorder is heart failure.

In another embodiment, the cardiovascular disorder is left ventricular hypertrophy.

In another embodiment, the cardiovascular disorder is congestive heart failure, more particularly in patients with preserved left ventricular ejection fraction.

In another embodiment, the cardiovascular disorder is stroke.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of renal disorders.

In another embodiment, the renal disorder is nephropathy.

In another embodiment, the renal disorder is autoimmune glomerulonephritis.

In another embodiment, the chronic kidney disease is diabetic nephropathy.

In another embodiment, the fibrotic disease is renal or cardiac fibrosis.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of type II diabetes.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of type I diabetes.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of diabetic retinopathy.

The present invention is illustrated below by examples, which are not intended to be limiting.

If the preparation examples are obtained as mixtures of enantiomers, the pure enantiomers can be separated by the methods described herein or known to the person skilled in the art, such as, for example, chiral chromatography or crystallization.

Examples

All examples and intermediates were prepared under argon atmosphere if not otherwise stated.

Intermediate A-1

6-chloro-5-fluoro-3, 4-dihydro-2H-isoquinolin-1-one

[A](3-chloro-2-fluoro-phenyl) -methanol

To a solution of 2-fluoro-3-chloro-benzaldehyde (4.74g, 30mmol) in THF (20mL) was added NaBH₄(1.48g, 40 mmol). The resulting mixture was stirred at room temperature for 30min, after which it was diluted with DCM. The organic layer was washed with water and brine. The combined organic layers were washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the desired product without further purification (4.8g, 100%). MS: 161.0(M + H)⁺。

[B]1-bromomethyl-3-chloro-2-fluoro-benzene

To a solution of (3-chloro-2-fluoro-phenyl) -methanol (3.2g, 20mmol) in DCM (20mL) was added PBr dropwise at 0 deg.C₃(1 mL). The reaction mixture was stirred at room temperature for another 1 hour, after which it was washed with NaHCO₃Quenching with saturated aqueous solution. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the desired product without further purification (4.1g, 92%). MS: 223.2(M + H)⁺。

[C](3-chloro-2-fluoro-phenyl) -acetonitrile

To a solution of 1-chloro-3-bromomethyl-2-fluoro-benzene (2.22g, 10mmol) in CH₃CN (30mL) was added trimethylsilyl cyanide (1.5mL) and TBAF (1M in THF, 12mmol, 12 mL). The resulting reaction mixture was heated at reflux temperature for 30min. After cooling to room temperature, the volatiles were evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was then washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to give the title compound (1.48g, 88%). MS: 170.1(M + H)⁺。

[D]2- (3-chloro-2-fluoro-phenyl) -ethylamine

To a solution of (3-chloro-2-fluoro-phenyl) -acetonitrile (1.48g, 8.8mmol) in anhydrous THF (20mL) was added dropwise a borane solution (20mL, 1M in THF). The resulting reaction mixture was heated at reflux temperature for 2 hours. After cooling to room temperature, MeOH was added and the mixture was stirred at room temperature for another 30min. After removal of volatiles under reduced pressure, the desired title compound (1.30g, 90%) was obtained as an oil. MS: 174.0(M + H)⁺。

[E][2- (3-chloro-2-fluoro-phenyl) -ethylamine]-carbamic acid methyl ester

To 2- (3-chloro-2-fluoro-phenyl) -ethylamine (1.30g, 7.9mmol) in CH at 5 deg.C with vigorous stirring₂Cl₂(25mL) to a solution of methyl chloroformate (1.04g, 11mmol) and Et₃And N is added. The solution was then stirred at room temperature for 1 h. The reaction was poured into ice-water (5)0mL) with CH₂Cl₂(2X25 mL). The organic phase is treated with H₂O (2X25mL) washing with Na₂SO₄Drying, filtration and evaporation afforded the final product without purification (1.78g, 98%). MS: 232.1(M + H)⁺。

[F]6-chloro-5-fluoro-3, 4-dihydro-2H-isoquinolin-1-one

Reacting [2- (3-chloro-2-fluoro-phenyl) -ethylamine]Methyl carbamate (890mg, 3.85mmol) and polyphosphoric acid (15mL) were added to a 1-L round bottom flask equipped with a magnetic stir bar and reflux condenser. The reaction mixture was heated in an oil bath at 140 ℃ and 160 ℃ for 2 hours while maintaining vigorous stirring. The reaction mixture was then allowed to cool to room temperature and poured into H₂O (100 mL). After extraction with EtOAc, the organic layer was washed with brine, anhydrous MgSO₄Dried, filtered and concentrated to give a yellowish oil which was recovered from Et₂O crystallized to give the title compound as a white solid (30mg, 4%). MS: 200.1(M + H)⁺。

Intermediate A-2

6-chloro-3, 4-dihydro-2H-isoquinolin-1-one

[A][2- (3-chloro-phenyl) -ethyl]-carbamic acid methyl ester

Methyl chloroformate (4.6g, 48mmol) was added dropwise to 2- (3-chloro-phenyl) -ethylamine (5.0g, 32mmol) and Et at 0 deg.C₃Method for N (6.4g, 64mmol) in DCM (100mL)In solution. After the addition, the mixture was stirred at room temperature for 0.5 hour. The organic layer was washed with water (3X30mL), 1N HCl (20mL) and brine (30mL), over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. After drying in vacuo, the title compound (6.49g, 95%) was obtained as a white solid. MS: 214.1(M + H)⁺)。

[B]6-chloro-3, 4-dihydro-2H-isoquinolin-1-one

In N₂Under protection, [2- (3-chloro-phenyl) -ethyl]A mixture of methyl carbamate (5.0g, 23.4mmol) and PPA (polyphosphoric acid) (20g) was vigorously stirred in a 250mL round bottom flask at 120 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and treated with aqueous ammonia solution to adjust the pH to 8. The mixture was then extracted with EtOAc, and the organic layer was washed with brine, over anhydrous Na₂SO₄Dried and filtered. After removing the solvent under reduced pressure, the obtained crude product was further washed with diethyl ether to give the title compound (1.66g, 39%) as a white solid. MS: 182.0(M + H)⁺)。

Intermediate A-3-1

6-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one

Intermediate A-3-2

8-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one

[A]2- (3-chloro-phenyl) -1-methyl-ethylamine

Anhydrous acetonitrile (4.1g, 0.1mol) was added dropwise at room temperature to a solution of 3-chlorobenzyl magnesium chloride (0.1mol) in anhydrous diethyl ether (100mL) prepared from 3-chlorobenzyl chloride (16.1g, 0.1mol) and magnesium turnings (2.4g, 0.1mol) in anhydrous diethyl ether (100 mL). When the reaction mixture was stirred at 60 ℃ for 3 hours, it was cooled to 0 ℃ followed by addition of THF (50 mL). Lithium aluminum hydride (4.2g, 0.1mol) was then carefully added to the reaction mixture and heated to reflux temperature for 3 hours. Ice-water was added to quench the reaction. In ether and H₂After partitioning between O, the separated organic layer was washed with brine, and dried over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. Flash column chromatography (silica gel, 180g, 5% methanol in DCM) then gave the title compound as a yellowish oil (1.9g, 11%). MS: 170.1(M + H)⁺)。

[B][2- (3-chloro-phenyl) -1-methyl-ethyl]-carbamic acid methyl ester

Methyl chloroformate (0.67g, 7.1mmol) was added dropwise to a mixture of 2- (3-chloro-phenyl) -1-methyl-ethylamine (1.0g, 5.9mmol) and potassium carbonate (1.63g, 11.8mmol) in THF (20mL) at 0 deg.C. After addition, the mixture was stirred at room temperature overnight. After filtration and evaporation of volatiles, the crude product was purified by flash column chromatography (silica gel, 12g, 50% hexane in dichloromethane) to give the title compound as a white solid (1.2g, 90%). MS: 228.1(M + H)⁺)。

[C]6-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one and 8-chloro-3-methyl-3, 4-dihydro-2H-isoquinoline Lin-1-ones

In N₂[2- (3-chloro-phenyl) -1-methyl-ethyl in a 100mL round-bottomed flask with protection]A mixture of methyl carbamate (1.2g, 5.3mmol) and PPA (polyphosphoric acid) (10g) was stirred at 120 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and treated with aqueous ammonia solution to adjust the pH to 8. The mixture was then extracted with ethyl acetate and the organic layer was washed with brine, Na₂SO₄Dry anhydrous, filter and concentrate in vacuo. The crude product obtained was further washed with diethyl ether to give 6-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one (0.27g, 26%) (intermediate a-3-1) as a white solid. MS: 196.1(M + H)⁺). The ether filtrate was concentrated under reduced pressure and purified by flash chromatography to afford 8-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one (intermediate a-3-2) (54mg, 5.2%) as a white solid. MS: 196.1(M + H)⁺)。

Intermediate A-3-1a

(R) -6-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one

Intermediate A-3-1b

(S) -6-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one

Chiral HPLC separation of 6-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one (0.4g, 2.05mmol, intermediate A-3-1) provided (R) -6-chloro-3-methyl-3, 4-dihydro-2H-isoquinolin-1-one (0.15g, 37.5%) and (S) -6-chloro-3-methyl3, 4-dihydro-2H-isoquinolin-1-one (0.12g, 30%) as a white solid. MS: 196.1(M + H)⁺)。

Intermediate A-4

6-chloro-4-methyl-3, 4-dihydro-2H-isoquinolin-1-one

[A]2- (3-chloro-phenyl) -propionitrile

To a solution of 3-chlorobenzyl nitrile (15.2g, 0.1mol) in THF (300mL) was added dropwise lithium bis (trimethylsilyl) amide (100mL, 1M in THF, 0.1mol) at-78 ℃. After stirring at-78 ℃ for 1 hour, methyl iodide (14.2g, 0.1mol) was added dropwise. After stirring at-78 ℃ for a further 1h and subsequently warming to room temperature for 2h, the reaction is quenched with water and extracted with diethyl ether. The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. Flash column chromatography (silica gel, 180g, 1% to 4% ether in hexanes) then gave the title compound as an oil (7.3g, 44%).

[B]2- (3-chloro-phenyl) -propylamine hydrochloride

To a solution of 2- (3-chloro-phenyl) -propionitrile (5.0g, 30.2mmol) in THF (80mL) was added a solution of borane-tetrahydrofuran complex (45mL, 45.3 mmol). The reaction mixture was stirred at room temperature overnight. Ethanol (10mL) was then added to the reaction mixture; after stirring at room temperature for 20min, a solution of HCl in ether (2M, 12.5mL) was added. After stirring for another 1 hour, water was added to bring about the productPrecipitation of (4). The white solid was collected by filtration and dried in vacuo to give the title compound (3.6g, 70%). MS (for free amine): 170.1(M + H)⁺)。

[C][2- (3-chloro-phenyl) -propyl]-carbamic acid methyl ester

To 2- (3-chloro-phenyl) -ethylamine hydrochloride (6.22g, 30.2mmol) and Et at 0 deg.C₃A solution of N (6.1g, 60.4mmol) in DCM (20mL) was added methyl chloroformate (4.28g, 45mmol) dropwise, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was then washed with water (3 × 10mL), 1N HCl (10mL) and brine (10 mL). The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The resulting residue was dried in vacuo to give the title compound (5.5g, 80%) as a yellow oil. MS: 228.1(M + H)⁺)。

[D][ 6-chloro-4-methyl-3, 4-dihydro-2H-isoquinolin-1-one

In N₂[2- (3-chloro-phenyl) -propyl in a 100mL flask with protection]A mixture of methyl carbamate (3.0g, 13.2mmol) and PPA (polyphosphoric acid) (10g) was stirred at 120 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and treated with aqueous ammonia solution to adjust the pH to 8. The mixture was extracted with EtOAc and the organic layer was washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The resulting crude product was further washed with diethyl ether to give the title compound (0.52g, 20%) as a white solid. MS: 196.1(M + H)⁺)。

Intermediate A-5

6-chloro-4, 4-dimethyl-3, 4-dihydro-2H-isoquinolin-1-one

[A]2- (3-chloro-phenyl) -2-methyl-propionitrile

To a solution of 3-chlorobenzyl nitrile (15.2g, 0.1mol) in DMF (100mL) at 0 deg.C was added sodium hydride (6.0g, 0.15mol) in portions. After stirring at 0 ℃ for 0.5h, methyl iodide (14.2g, 0.1mol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for an additional 2 hours before being quenched with water. The mixture was washed with diethyl ether and H₂Extracting with O, and extracting the organic layer with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 180g, 1% to 4% ether in hexanes) to afford the title compound as an oil (6.4g, 36%).

[B]2- (3-chloro-phenyl) -2-methyl-propylamine

To a solution of 2- (3-chloro-phenyl) -2-methyl-propionitrile (6.4g, 35.7mmol) in THF (80mL) was added a solution of borane-tetrahydrofuran complex (71.3mL, 71.3mmol) and the resulting mixture was heated to reflux for 5 h. After cooling to 0 ℃, the reaction was quenched by the addition of aqueous HCl (2M, 10mL) dropwise. The mixture was then concentrated in vacuo to afford a solid residue which was taken up in aqueous ammonia (6M in H)₂O) treatment. After extraction with ethyl acetate, the organic layer was extracted with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 180g, 5% formazan in dichloromethane)Alcohol) to afford the title compound as an oil (2.8g, 43%). MS: 184.1(M + H)⁺)。

[C][2- (3-chloro-phenyl) -2-methyl-propyl]-carbamic acid methyl ester

To 2- (3-chloro-phenyl) -2-methyl-propylamine (1.4g, 7.63mmol) and Et at 0 deg.C₃A solution of N (1.54g, 15.26mmol) in DCM (20mL) was added methyl chloroformate (1.08g, 11.4mmol) dropwise. After the addition, the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then washed with water (3 × 10mL), 1N HCl (10mL) and brine (10 mL). The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The resulting residue was dried in vacuo to give the title compound (1.84g, 100%) as a yellow oil. MS: 242.1(M + H)⁺)。

[D]6-chloro-4, 4-dimethyl-3, 4-dihydro-2H-isoquinolin-1-one

In N₂[2- (3-chloro-phenyl) -2-methyl-propyl in a 100mL round-bottomed flask with protection]A mixture of methyl carbamate (1.84g, 7.63mmol) and PPA (polyphosphoric acid) (8g) was stirred at 120 ℃ for 2 hours. After cooling to room temperature, the mixture was treated with ice-water and treated with aqueous ammonia solution to adjust the pH to 8. After extraction with ethyl acetate, the organic layer was washed with brine, dried over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The resulting crude product was further washed with diethyl ether to give the title compound (0.32g, 20%) as a white solid. MS: 210.1(M + H)⁺)。

Intermediate A-6

6-chloro-2H-isoquinolin-1-one

6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (181.5mg, 1mmol, intermediate A-2) and DDQ (227mg, 1mmol) in bisThe mixture in alkane (3mL) was refluxed overnight. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO₃Aqueous solution treatment, followed by extraction with ethyl acetate (2 × 10 mL). The organic layer was washed with anhydrous Na₂SO₄Drying, filtration, and concentration in vacuo afforded the crude product, which was then purified by silica gel flash chromatography to afford the title compound (108mg, 60%) as a white solid. MS: 180.0(M + H)⁺)。

Intermediate A-7

6-chloro-7-fluoro-3, 4-dihydro-2H-isoquinolin-1-one

[A]4-bromomethyl-2-chloro-1-fluoro-benzene

To a solution of (3-chloro-4-fluoro-phenyl) -methanol (4.3g, 26.8mmol) in DCM (20mL) at 0 deg.C was added PBr₃(1 mL). The resulting mixture was stirred at room temperature for 1 hour, after which it was treated with saturated NaHCO₃The aqueous solution was quenched. The organic solution was washed with water, brine, and anhydrous Na₂SO₄Drying and concentration in vacuo gave the desired product (3.7g, 61.9%). It was used directly in the next step without further purification.

[B](3-chloro-4-fluoro-phenyl) -acetonitrile

To 4-bromomethyl-2-chloro-1-fluoro-benzene (3.7g, 16.5mmol) in CH₃To a solution in CN (30mL) was added trimethylsilyl cyanide (2.1mL) and TBAF (4.8g, 18.4 mmol). The resulting mixture was heated at reflux for 30min. After cooling the mixture to room temperature, it was extracted with EtOAc. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by silica gel flash column chromatography to give the title compound (1.7g, 60.7%) as an oil.

[C]2- (3-chloro-4-fluoro-phenyl) -ethylamine

To a solution of (3-chloro-4-fluoro-phenyl) -acetonitrile (1g, 5.9mmol) in THF (30mL) was slowly added BH₃THF (8.26 ml). After the addition, the reaction mixture was heated to reflux for 3 hours. MeOH was added to quench the reaction and volatiles were removed under reduced pressure. The crude product was first dissolved in aqueous HCl (30mL) and impurities were removed by extraction with EtOAc (2 × 30 mL). Using K₂CO₃The pH of the aqueous solution was adjusted to 8 and the mixture was extracted with DCM (3 × 30 mL). The combined organic layers were then washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound (570mg, 55.8%) as an oil.

[D]N- [2- (3-chloro-4-fluoro-phenyl) -ethyl]-2, 2, 2-trifluoro-acetamide

To 2- (3-chloro-4-fluoro-phenyl) -ethylamine (570mg, 3.3mmol) and Et at 5 ℃ with vigorous stirring₃N (1mL) in CH₂Cl₂To the solution in (25mL) was added dropwise trifluoroacetic anhydride (761mg, 3.6 mmol). The solution was then allowed to stir at room temperature for 3 hours before it was poured into ice-water (50mL) and extracted with DCM (2 × 25 mL). Subjecting the organic layer to H₂O (2X25mL) and washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound (700mg, 78.6%) as a white solid. It was used directly in the next step without further purification.

[E]1- (6-chloro-7-fluoro-3, 4-dihydro-1H-isoquinolin-2-yl) -2, 2, 2-trifluoro-ethanone

Adding N- [2- (3-chloro-4-fluoro-phenyl) -ethyl at 0 deg.C]-2, 2, 2-trifluoro-acetamide (400mg, 1.48mmol) and paraformaldehyde (89mg, 2.96mmol) were added sequentially to a solution of acetic acid (3mL) in sulfuric acid (2 mL). After stirring the reaction mixture at room temperature for 16 hours, the clear colorless solution was poured into ice-water (20 mL). The mixture was extracted with EtOAc (2 × 30mL) and the organic layer was extracted with saturated aqueous NaHCO₃(20mL)，H₂O (2X25mL) and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give the crude title product together with regioisomer (400mg) as a white solid.

[F]6-chloro-7-fluoro-1, 2,3, 4-tetrahydro-isoquinoline

To a solution of 1- (6-chloro-7-fluoro-3, 4-dihydro-1H-isoquinolin-2-yl) -2, 2, 2-trifluoroacetone (400mg) in MeOH (15mL) was added H₂K in O (10mL)₂CO₃(572mg, 4 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours before it was acidified to pH8 with HCl (1N). It was then extracted with EtOAc and the organic layer was washed with H₂O (2X25mL) and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give the crude title product together with regioisomer (170 mg). preparative-TLC separation (30% EtOAc in petroleum ether) then gave the desired title compound (130mg) as a white solid.

[G]6-chloro-7-fluoro-3, 4-dihydro-2H-isoquinolin-1-one

A mixture of 6-chloro-7-fluoro-1, 2,3, 4-tetrahydro-isoquinoline (130mg, 0.7mmol), potassium bromide (83.5mg, 0.7mmol) and iodosobenzene (0.46g, 2.1mmol) in water (4mL) was stirred at room temperature overnight. The mixture was then extracted with EtOAc and the organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product. Flash column chromatography (silica gel, 12g, 30% EtOAc in hexanes) then afforded the title compound (58mg, 41%) as a white solid.

Intermediate A-8

2-chloro-7, 8-dihydro-6H- [1, 6] naphthyridin-5-one

[A]2-chloro-7, 8-dihydro-5H- [1, 6]Naphthyridine-6-carboxylic acid methyl ester

To 2-chloro-5, 6,7, 8-tetrahydro- [1, 6]Dissolution of naphthyridine hydrochloride (1.54g, 7.5mmol) in DCM (25mL)Et was added to the solution₃N (3.1mL, 22 mmol). After addition and stirring at room temperature for 5min, the solution was cooled to 0 ℃ followed by the addition of methyl chloroformate (0.85mL, 11 mmol). The resulting reaction mixture was then allowed to stir at room temperature for 2 hours. It was then treated with saturated NaHCO₃Aqueous solution and brine. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product. Flash column chromatography (silica gel, 40g, 30% EtOAc in hexanes) then afforded the title compound (1.53g, 90%) as a white solid. MS: 227.3(M + H)⁺)。

[B]2-chloro-5-oxo-7, 8-dihydro-5H- [1, 6]Naphthyridine-6-carboxylic acid methyl ester

Reacting 2-chloro-7, 8-dihydro-5H- [1, 6] at room temperature]Naphthyridine-6-carboxylic acid methyl ester (226.7mg, 1mmol) dissolved in CCl₄(3.57mL) and MeCN (0.357mL), followed by addition of 1mL of H₂NaIO in O₄(0.643g), followed by addition of RuCl₃Hydrate (62.2 mg). The reaction mixture was stirred vigorously at room temperature for 2 hours. After dilution with DCM, it was filtered through celite and the filter cake was washed three times with DCM. The combined organic solutions were concentrated in vacuo to afford the crude product. Flash column chromatography (silica gel, 12g, 20% EtOAc in hexanes) then afforded the title compound (143mg, 60%) as a white solid. MS: 241.1(M + H)⁺)。

[C]2-chloro-7, 8-dihydro-6H- [1, 6]Naphthyridin-5-ones

P-2-chloro-5-oxo-7, 8-dihydro-5H- [1, 6]Naphthyridine-6-carboxylic acid methyl ester (60mg, 0.25mmol) and sodium methoxide (40mg, 0.75mmol) in 2mL1, 4-bisThe mixture in the alkane was subjected to microwave reaction at 110 ℃ for 30min. Removal of 1, 4-bisAfter the alkane, the residue was dissolved in DCM and the DCM solution was washed with water and brine. The organic layer was then washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product. preparative-TLC separation (30% EtOAc in hexanes) then provided the title compound (28mg, 63%) as a white solid. MS: 183.1(M + H)⁺)。

Intermediate A-9

2-methoxy-7, 8-dihydro-6H- [1, 6] naphthyridin-5-one

[A]2-chloro-7, 8-dihydro-5H- [1, 6]Naphthyridine-6-carboxylic acid tert-butyl ester

To 2-chloro-5, 6,7, 8-tetrahydro- [1, 6]To a solution of naphthyridine hydrochloride (1.54g, 7.5mmol) in DCM (25mL) was added Et₃N (2mL, 15 mmol). After addition and stirring at room temperature for 5min, the solution was cooled to 0 ℃ followed by addition of (Boc)₂O (1.88g, 8.63 mmol). The resulting reaction mixture was then allowed to stir at room temperature for 2 hours. Then using it with H₂O and brine wash. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound (1.87g, 93%) as a white solid. MS: 269.1(M + H)⁺). It was used directly in the next step without further purification.

[B]2-chloro-5-oxo-7, 8-dihydro-5H- [1, 6]Naphthyridine-6-carboxylic acid tert-butyl ester

Analogously to the preparation of intermediate A-8[ B ]]The procedure described, using 2-chloro-7, 8-dihydro-5H- [1, 6]Naphthyridine-6-carboxylic acid tert-butyl ester to give the title compound as a white solid. MS: 283.1(M + H)⁺)。

[C]2-methoxy-7, 8-dihydro-6H- [1, 6]Naphthyridin-5-ones

Analogously to the preparation of intermediate A-8[ C ]]The procedure described, using 2-chloro-5-oxo-7, 8-dihydro-5H- [1, 6]Naphthyridine-6-carboxylic acid tert-butyl ester to give the title compound as a white solid. MS: 179.2(M + H)⁺)。

Intermediate A-10

5-chloro-3-methyl-2, 3-dihydro-isoindol-1-one

Intermediate A-11

6-chloro-3-methyl-2, 3-dihydro-isoindol-1-one

[A]5-chloro-3-hydroxy-3-methyl-2, 3-dihydro-isoindol-1-one and 6-chloro-3-hydroxy-3-methyl-2, 3-di Hydro-isoindol-1-ones

To a solution of 5-chloro-isoindole-1, 3-dione (3.63g, 20mmol) in DCM (150mL) was added methyl magnesium chloride (3M in THF, 20mL) dropwise at 0 ℃. After the addition, the mixture was stirred at 0 ℃ for 3 hours, after which it was saturated with NH₄Aqueous Cl solution was quenched. After extraction with DCM, the organic layer was washed with brine, dried over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product containing a mixture of the two regioisomers (3.95g, 100%). MS: 198.1(M + H)⁺)。

[B]5-chloro-3-methyl-2, 3-dihydro-isoindol-1-one and 6-chloro-3-methyl-2, 3-dihydro-isoindol-1-one

In N₂Triethylsilane (23g, 200mmol) and trifluoroboron etherate (8.51g, 60mmol) were added sequentially to a mixture of 5-chloro-3-hydroxy-3-methyl-2, 3-dihydro-isoindol-1-one and 6-chloro-3-hydroxy-3-methyl-2, 3-dihydro-isoindol-1-one (3.95g, 20mmol) in anhydrous DCM (100mL) at-15 deg.C under protection. Thereafter, the reaction mixture was stirred at room temperature for 2 hours and NaHCO was added₃Saturated aqueous solution (30 mL). The mixture was then extracted with DCM and the organic layer was washed with brine, anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give a crude mixture of the product. The two regioisomers were separated by preparative-HPLC to give the title compound, 5-chloro-3-methyl-2, 3-dihydro-isoindol-1-one (0.4g, 11%) and 6-chloro-3-methyl-2, 3-dihydro-isoindol-1-one (0.35g, 9.6%) as a white solid. MS: 182.0(M + H)⁺)。

Intermediate A-12

5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]5-chloro-2- (4-methoxy-benzyl) -2, 3-dihydro-isoindol-1-one

Sodium bis (trimethylsilyl) amide (2mL, 2M in THF, 2mmol) was added dropwise to a solution of 5-chloro-2, 3-dihydro-isoindol-1-one (0.34g, 2mmol) in THF (10mL) at 0 deg.C. After stirring for 10min, 1-bromomethyl-4-methoxy-benzene (0.52g, 2.6mmol) was added dropwise. The resulting reaction mixture was allowed to stir at room temperature for 48 hours before quenching with saturated aqueous ammonium chloride solution. After extraction with EtOAc, the organic layer was washed with brine, dried over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (0.6g, 100%) as a yellow oil. MS: 288.0(M + H)⁺). It was used directly in the next step without further purification.

[B]5-chloro-2- (4-methoxy-benzyl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

To a solution of 5-chloro-2- (4-methoxy-benzyl) -2, 3-dihydro-isoindol-1-one (0.6g, 2.0mmol) in THF (10mL) at room temperature was added sodium hydride (60% in mineral oil, 0.17g, 4.2 mmol). The resulting reaction mixture was stirred for 30min, after which methyl iodide (0.60g, 4.2mmol) was added. After stirring at room temperature overnight, the mixture was quenched with brine and extracted with EtOAc. The organic layer was then washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was then purified by flash column chromatography (silica gel 14g, 5% to 20% ethyl acetate in DCM). To obtainThe title compound (0.38g, 57%) as a white solid. MS: 316.2(M + H)⁺)。

[C]5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

A solution of 5-chloro-2- (4-methoxy-benzyl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (0.38g, 1.2mmol) in trifluoroacetic acid (5mL) was heated to reflux for 20 h. After removal of trifluoroacetic acid under reduced pressure, the crude product was purified by flash column chromatography (silica gel 14g, 5% to 50% ethyl acetate in DCM) to give the title compound (0.20g, 85%) as a white solid. MS: 196.1(M + H)⁺)。

Intermediate A-12-1

5-chloro-2- (5-chloromethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A](5-bromo-pyridin-3-yl) -methanol

Sodium borohydride (2.2g, 59.1mmol) was added to a suspension of 5-bromo-pyridine-3-carbaldehyde (10.0g, 53.7mmol) in MeOH (100mL) at 0 deg.C. The mixture was stirred at 0 ℃ for 1 hour, after which it was quenched by the addition of water (5.0 mL). Evaporation of the solvent afforded a pale yellowish oil, which was redissolved in EtOAc and washed with water. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound (9.6g, 95%) as a colorless oil. MS: 188.0&190.0(M+H⁺)。

[B]5-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

(5-bromo-pyridin-3-yl) -methanol (900mg, 4.8mmol), 5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate A-12[ C ] in a 25-mL sealed tube]，858mg，4.4mmol)，CuI(200mg，1.1mmol)，Cs₂CO₃(3.0g, 9.2mmol) and (+) - (S, S) -1, 2-diaminocyclohexane (0.4mL, 3.2mmol) were dissolved in dioxaneAlkane (8.0 mL). The resulting reaction mixture was heated at 150 ℃ for 3 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 125 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexanes gradient) to afford the title compound (1.2g, 90%) as a light yellow solid. MS: 303.2(M + H)⁺)。

[C]5-chloro-2- (5-chloromethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

Thionyl chloride (1.4mL, 19.0mmol) was slowly added to a solution of 5-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (1.14g, 3.8mmol) in DCM (50mL) at 0 ℃. After addition, the reaction mixture was stirred at 2-5 ℃ for 2 hours, after which it was poured into saturated NaHCO₃Aqueous (50mL) and extracted with EtOAc (2 × 150 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying and filteringAnd concentrated in vacuo to give the crude product (1.42g, 92%) as a pale yellowish solid. MS: 322.1(M + H)⁺)。

Intermediate A-13

5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

[A]5-chloro-3-ethyl-3-hydroxy-2, 3-dihydro-isoindol-1-one and 6-chloro-3-ethyl-3-hydroxy-2, 3-di Hydro-isoindol-1-ones

To a solution of 5-chloro-isoindole-1, 3-dione (5.0g, 27.5mmol) in DCM (200mL) was added ethyl magnesium chloride (2M in THF, 41.3mL) dropwise at 0 ℃. After the addition, the mixture was allowed to stir at 0 ℃ for 3 hours, after which it was treated with saturated NH₄Aqueous Cl solution was quenched. After extraction with DCM, the organic layer was washed with brine, dried over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product containing a mixture of the two regioisomers (5.82g, 100%). MS: 212.0(M + H)⁺)。

[B]5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

In N₂Triethylsilane (19.3g, 166mmol) and TFA (20mL) were added sequentially to a mixture of 5-chloro-3-ethyl-3-hydroxy-2, 3-dihydro-isoindol-1-one and 6-chloro-3-ethyl-3-hydroxy-2, 3-dihydro-isoindol-1-one (3.52g, 16.6mmol) under protection. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was taken up in saturated NaHCO₃Aqueous solution (30mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give a crude mixture of the product. The desired regioisomer, 5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one, was obtained as a white solid by preparative-HPLC separation (0.65g, 20%). MS: 196.1(M + H)⁺)。

Intermediate A-13-1

5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

Intermediate A-13-2

6-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

[A]5-chloro-3-ethyl-3-hydroxy-2, 3-dihydro-isoindol-1-one and 6-chloro-3-ethyl-3-hydroxy-2, 3-di Hydro-isoindol-1-ones

To a solution of 5-chloro-isoindole-1, 3-dione (5.0g, 27.5mmol) in DCM (200mL) was added ethyl magnesium chloride (2M in THF, 41.3mL) dropwise at 0 ℃. After the addition, the mixture was allowed to stir at 0 ℃ for 3 hours, after which it was treated with saturated NH₄Aqueous Cl solution was quenched. After extraction with DCM, the organic layer was washed with brine, dried over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product containing a mixture of the two regioisomers (5.82g, 100%). MS: 212.0(M + H)⁺)。

[B]5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one and 6-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

In N₂Triethylsilane (19.3g, 166mmol) and TFA (20mL) were added sequentially to a mixture of 5-chloro-3-ethyl-3-hydroxy-2, 3-dihydro-isoindol-1-one and 6-chloro-3-ethyl-3-hydroxy-2, 3-dihydro-isoindol-1-one (3.52g, 16.6mmol) under protection. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was taken up in saturated NaHCO₃Aqueous solution (30mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give a crude mixture of the product. Isolation by preparative-HPLC to give 5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one (0.65g, 20%) MS: 196.1(M + H)⁺) And 6-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one (0.62g, 19%) MS: 196.1(M + H)⁺) All are white solids.

Intermediate A-13-1a

(R or S) -5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

Intermediate A-13-1b

(S or R) -5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

Intermediate A-13-2a

(R or S) -6-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

Intermediate A-13-2b

(S or R) -6-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one

SFC separation of a mixture of 5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one and 6-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one (IC250mm x50mm, 5um, mobile phase a: supercritical CO2, B: IPA (0.05% NH3H2O), a: B ═ 60: 40, 140mL/min) gave (R or S) -5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one (intermediate a-13-1a) and (S or R) -5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one as a pair of enantiomers, and (R or S) -6-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one and (S or R) -6-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one, as the other pair of enantiomers.

Intermediate A-13-3

(S or R) -5-chloro-2- (5-chloromethyl-pyridin-3-yl) -3-ethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of intermediate a-12-1, using (S or R) -5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one, the title compound was provided as yellowish oil. MS: 322.1(M + H)⁺)。

Intermediate A-13-4

(R or S) -5-chloro-2- (5-chloromethyl-pyridin-3-yl) -3-ethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of intermediate a-12-1, using (R or S) -5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one, the title compound was provided as yellowish oil. MS: 322.1(M + H)⁺)。

Intermediate A-14

3-benzyl-5-chloro-2, 3-dihydro-isoindol-1-one

[A]3-benzyl-5-chloro-3-hydroxy-2, 3-dihydro-isoindol-1-one and 3-benzyl-6-chloro-3-hydroxy-2, 3-di Hydro-isoindol-1-ones

To a solution of 5-chloro-isoindole-1, 3-dione (3.63g, 20mmol) in DCM (150mL) was added benzyl magnesium chloride (2M in THF, 30mL) dropwise at 0 deg.C. After the addition, the reaction mixture was allowed to stir at 0 ℃ for 3 hours, after which it was washed with saturated NH₄Aqueous Cl solution was quenched. After extraction with DCM, the organic layer was washed with brine, dried over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product containing a mixture of the two regioisomers (5.47g, 100%). MS: 274.1(M + H)⁺)。

[B]3-benzyl-5-chloro-2, 3-dihydro-isoindol-1-one

In N₂Triethylsilane (23g, 200mmol) and TFA (10mL) were added sequentially to a mixture of 3-benzyl-5-chloro-3-hydroxy-2, 3-dihydro-isoindol-1-one and 3-benzyl-6-chloro-3-hydroxy-2, 3-dihydro-isoindol-1-one (5.47g, 20mmol) with protection. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was taken up in saturated NaHCO₃Aqueous solution (30mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give a crude mixture of the product. The desired regioisomer, 3-benzyl-5-chloro-2, 3-dihydro-isoindol-1-one, was obtained as a white solid by preparative-HPLC separation (1.03g, 20%). MS: 258.1(M + H)⁺)。

Intermediate A-15

5-chloro-3-cyclopropyl-2, 3-dihydro-isoindol-1-one

[A](2-bromo-5-chlorophenyl) (cyclopropyl) methylamine

To a solution of 2-bromo-5-chlorobenzonitrile (20g, 93mmol) in THF (200mL) was added cyclopropylmagnesium bromide (558mL, 279mmol) at 0 ℃. The resulting reaction mixture was stirred at 0-5 ℃ for 5 hours, after which MeOH (100mL) was added and stirring continued at room temperature for 15 min. Followed by the addition of NaBH₄(7.1g, 186mmol) was added and the reaction mixture was stirred at room temperature overnight. Water was added and the reaction mixture was extracted with AcOEt (300mL x 3). The combined organic layers were concentrated in vacuo to give the crude product, which was then purified by chromatography to give (2-bromo-5-chlorophenyl) (cyclopropyl) methylamine (8.2g, 34% yield).

[B]5-chloro-3-cyclopropyl-2, 3-dihydro-isoindol-1-one

(2-bromo-5-chlorophenyl) (cyclopropyl) methylamine (2g, 7.7mmol), Pd (dppf) Cl₂A mixture of (0.2g), DIPEA (3g, 23.1mmol) in 20mL DMF was heated at 130 deg.C under 2MPa of CO (g) in an autoclave for 16 h. After the reaction, the mixture was diluted with AcOEt (150mL) and washed with brine (30mL × 3). The organic layer was washed with anhydrous Na₂SO₄Drying, filtration, and concentration in vacuo gave a crude product which was purified by chromatography to give the title compound (1.1g, yield 68.7%) as a yellow solid. MS: 207.9(M + H)⁺，1C1)。

Intermediate A-16

2-chloro-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one

[A]3- (methoxycarbonyl) -2-methylpyridine 1-oxide

To a stirred solution of methyl 2-methylnicotinate (95g, 629mmol) in DCM (1.5L) was added m-CPBA (119g, 692mmol) at 0 deg.C. After the reaction mixture was stirred at room temperature for 16 hours, it was saturated with Na₂SO₃Aqueous solution and NaHCO₃The mixture of aqueous solutions is washed. The organic layer was then washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (60g, 57% yield), which was used in the next step reaction without further purification.

[B]2- (chloromethyl) nicotinic acid methyl ester

Crude 3- (methoxycarbonyl) -2-methylpyridine-1-oxide (35g, 210mmol) was added in small portions to POCl at room temperature₃(300g) In (1). After addition, the reaction mixture was refluxed for 3 hours, after which it was concentrated in vacuo. The residue was poured into ice-water and washed with NaHCO₃The aqueous solution was neutralized and extracted with AcOEt (125mL x 3). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration, and concentration in vacuo afforded the crude product, which was then purified by column chromatography to afford the title compound (12g, 30% yield).

[C]2- (chloromethyl) -3- (methoxycarbonyl) pyridine 1-oxide

To a stirred solution of methyl 2- (chloromethyl) nicotinate (20g, 108mmol) in DCM (300mL) was added m-CPBA (20.5g, 119mmol) at 0 deg.C. After stirring it at room temperature for 16 hours, the reaction mixture was taken up with saturated Na₂SO₃Aqueous solution and NaHCO₃The mixture of aqueous solutions is washed. The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give the crude title product (20g, 92% yield), which was used in the next step reaction without further purification.

[D]6-chloro-2- (chloromethyl) nicotinic acid methyl ester

Reacting 2- (chloromethyl) -3-, (Methoxycarbonyl) pyridine-1-oxide crude (20g, 99.5mmol) was added in small portions to POCl₃(200g) In (1). The mixture was refluxed for 3 hours, after which it was concentrated in vacuo. The residue was poured into ice-water and washed with NaHCO₃The solution was neutralized and extracted with AcOEt (125mL x 3). The combined organic layers were concentrated to give the crude title product (17g, 78% yield), which was used in the next step reaction without further purification.

[E]2-chloro-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b]Pyridin-5-ones

To a stirred solution of crude methyl 6-chloro-2- (chloromethyl) nicotinate (10g, 45.4mmol) in THF (150mL) at 0 deg.C was added PMBNH₂(15.5g, 113.5 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, after which it was concentrated under reduced pressure to give the crude product. After washing with MTBE (100mL x3), the title compound was obtained (8.8g, yield 67%) as a white solid. MS: 288.8(M + H)⁺，1C1)。

[F]2-chloro-6- (4-methoxy-benzyl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b]Pyridin-5-ones

To 2-chloro-6- (4-methoxy-benzyl) -6, 7-dihydro-pyrrolo [3, 4-b ] at room temperature]To a solution of pyridin-5-one (5.8g, 20.0mmol) in THF (50mL) was added sodium hydride (60% in mineral oil, 1.7g, 42.0 mmol). The resulting reaction mixture was stirred for 30min, after which methyl iodide (6.0g, 42.0mmol) was added. After stirring at room temperature overnight, the mixture was quenched with water and extracted with EtOAc. The organic layer was then washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then passed throughPurification was by flash column chromatography (silica gel 20g, 5% to 20% ethyl acetate in DCM). The title compound (3.8g, 57%) was obtained as a white solid. MS: 316.2(M + H)⁺)。

[G]2-chloro-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b]Pyridin-5-ones

To 2-chloro-6- (4-methoxy-benzyl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] at room temperature]Pyridin-5-one (1.58g, 5.0mmol) in CH₃To a solution in CN (20mL) was added cerous ammonium nitrate (8.2g, 15.0 mmol). The reaction mixture was stirred at rt for 3h, after which water and EtOAc were added to the mixture. Separating the organic layer with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was then purified by silica gel column chromatography to give the title compound (617mg, 63%) as a solid. MS: 197.2(M + H)⁺)。

Intermediate A-16-1

2-chloro-6- (5-chloromethyl-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one

[A]2-chloro-6- (5-hydroxymethyl-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b]Pyridine- 5-ketones

2-chloro-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b)]Pyridin-5-one (intermediate A-16[ G ]]39.2mg, 0.2mmol), (5-bromo-pyridin-3-yl) -methanol (exampleExample 3[ A]74.8mg, 0.4mmol), CuI (3.8mg, 0.02mmol), (1S,2S) -cyclohexane-1, 2-diamine (4.5mg, 0.04mmol) and Cs₂CO₃(130mg, 0.4mmol) was dissolved in IIIn an alkane (5 mL). The reaction mixture was subjected to a microwave reaction at 140 ℃ for 1 hour, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (55.7mg, 92%) as a solid. MS: 304.1(M + H)⁺)。

[B]2-chloro-6- (5-chloro-methyl-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b]Pyridine (II) Pyridin-5-ones

Thionyl chloride (0.14mL, 1.9mmol) was slowly added to 2-chloro-6- (5-hydroxymethyl-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] at 0 deg.C]Pyridin-5-one (55.7mg, 0.18mmol) in DCM (10 mL). After addition, the reaction mixture was stirred at 2-5 ℃ for 0.5h, after which it was poured into saturated NaHCO₃Aqueous (10mL) and extracted with DCM (2 × 15 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (58mg 100%) as a pale yellowish solid. MS: 322.1(M + H)⁺)。

Intermediate A-17

2-methoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one

[A]2-methoxy-6- (4-methoxy)-benzyl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b]Pyridine- 5-ketones

To 2-chloro-6- (4-methoxy-benzyl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] at room temperature]Pyridin-5-one (intermediate A-16[ F ]]3.15g, 10mmol) in DMF (30mL) was added sodium methoxide (0.813g, 15 mmol). The reaction mixture was stirred at rt for 4h, after which it was quenched with water and extracted with EtOAc. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound (2.8g, 90%) as a solid. MS: 313.1(M + H)⁺)。

[B]2-methoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b]Pyridin-5-ones

To 2-methoxy-6- (4-methoxy-benzyl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] at room temperature]Pyridin-5-one (0.31g, 1.0mmol) in CH₃To a solution in CN (5mL) was added cerous ammonium nitrate (1.64g, 3.0 mmol). The reaction mixture was stirred at rt for 3h, after which water and EtOAc were added to the mixture. Separating the organic layer with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was then purified by silica gel column chromatography to give the title compound (0.12g, 63%) as a solid. MS: 193.1(M + H)⁺)。

Intermediate A-17-1

6- (5-chloromethyl-pyridin-3-yl) -2-methoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one

In analogy to the procedure described for the preparation of intermediate a-12-1, the title compound was obtained as yellowish oil. MS: 318.3(M + H)⁺)。

Intermediate A-18

2-ethoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one

[A]2-ethoxy-6- (4-methoxy-benzyl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b]Pyridine- 5-ketones

To 2-chloro-6- (4-methoxy-benzyl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] at room temperature]Pyridin-5-one (intermediate A-16[ F ]]3.15g, 10mmol) in DMF (30mL) was added sodium ethoxide (1.02g, 15 mmol). The reaction mixture was stirred at rt for 4h, after which it was quenched with water and extracted with EtOAc. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title product (2.9g, 89%) as a solid. MS: 327.2(M + H)⁺)。

[B]2-ethoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ]]Pyridin-5-ones

To 2-methoxy-6- (4-methoxy-benzyl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] at room temperature]Pyridin-5-one (0.33g, 1.0mmol) in CH₃To a solution in CN (5mL) was added cerous ammonium nitrate (1.64g, 3.0 mmol). The reaction mixture was stirred at rt for 3h, after which water and EtOAc were added to the mixture. Separating the organic layer with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was then purified by silica gel column chromatography to give the title compound (0.15g, 72%) as a solid. MS: 207.1(M + H)⁺)。

Intermediate A-18-1

6- (5-chloromethyl-pyridin-3-yl) -2-ethoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one

In analogy to the procedure described for the preparation of intermediate a-12-1, the title compound was obtained as yellowish oil. MS: 332.1(M + H)⁺)。

Intermediate A-19

5-fluoro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]4-fluoro-2-methyl-benzoic acid methyl ester

To a stirred solution of 4-fluoro-2-methyl-benzoic acid (13g, 84mmol) in MeOH (500mL) at 0 deg.C was added SOCl dropwise₂(20g, 168 mmol). After the addition, the reaction mixture was stirred at room temperature for 16 hours. When TLC showed no starting material remaining, the mixture was concentrated under reduced pressure to give the crude product (12.7g, yield 90.7%) It was used in the next reaction step without further purification.

[B]2-Bromomethyl-4-fluoro-benzoic acid methyl ester

4-fluoro-2-methyl-benzoic acid methyl ester (12.7g, 75.5mmol), NBS (13.4g, 75.5mmol), and dibenzoyl peroxide (BPO) (0.85g, 3.5mmol) in CCl₄The mixture in (200mL) was heated to reflux for 3 hours until all starting material was consumed. After vacuum filtration, the filtrate was concentrated in vacuo to give the crude product (17g, 91% yield), which was used in the next step reaction without further purification.

[C]5-fluoro-2- (4-methoxy-benzyl) -2, 3-dihydro-isoindol-1-one

To a stirred solution of methyl 2-bromomethyl-4-fluoro-benzoate (17g, 68.8mmol) in THF (200mL) at 0 deg.C was added PMBNH₂(23.6g, 172 mmol). After stirring at room temperature for 16 h, the reaction mixture was concentrated in vacuo to give the crude product, which was then purified by column chromatography to give the title compound (13g, yield 69%) as a solid.

[D]5-fluoro-2- (4-methoxy-benzyl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

To a solution of 5-fluoro-2- (4-methoxy-benzyl) -2, 3-dihydro-isoindol-1-one (6g, 22mmol) in THF (30mL) at 0 deg.C was slowly added NaH (4.42g, 110 mmol). After stirring at 0 ℃ for 30min, MeI (18.8g, 132mmol) was added dropwise and the resulting solution was concentratedThe reaction mixture was heated to 70 ℃ for 5 hours. After cooling to room temperature, the reaction mixture was poured into NH₄Aqueous Cl and extracted with EtOAc. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration gave the crude product which was then purified by column chromatography to give the title product (4.8g, yield 72.5%) as a solid.

[E]5-fluoro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

To 5-fluoro-2- (4-methoxy-benzyl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (3.8g, 12.7mmol) in MeCN (80ml) and H at 0 deg.C₂To a stirred solution of O (40mL) was added CAN (20.9g, 38.1 mmol). After stirring at 0 ℃ for 2h, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo afforded the crude product, which was purified by column chromatography to afford the title product (1.03g, 45% yield) as a solid.

Intermediate A-19-1

2- (5-chloromethyl-pyridin-3-yl) -5-fluoro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of intermediate a-12-1, the title compound was obtained as yellowish oil. MS: 305.1(M + H)⁺)。

Intermediate A-20

6-fluoro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]1- (2-bromo-4-fluoro-phenyl) -1-methyl-ethylamine

To a stirred solution of 2-bromo-4-fluorobenzonitrile (5g, 25mmol) in diethyl ether (100mL) was added MeMgBr (25mL, 75mmol) at room temperature. The solution was stirred at room temperature for 0.5 hour, after which Ti (Oi-Pr) was added₄(41mL, 25mmol) was added and the resulting mixture was heated to reflux for 6 hours. Aqueous NaOH (10%, 200mL) solution was then added slowly to the reaction mixture at 0 ℃ and the reaction mixture was stirred at room temperature for another 30 minutes. In the presence of Na₂CO₃After dilution with aqueous solution (5%, 400mL), it was extracted with t-BuOMe (100mLx 3). The combined organic layers were concentrated under reduced pressure. The residue obtained was diluted with aqueous HCl (5%) and the aqueous layer was washed with t-BuOMe (50mLx2) and basified to pH-10 with 20% aqueous NaOH. The resulting aqueous layer was further extracted with t-BuOMe (100mLx 3). The combined organic layers were then washed with anhydrous Na₂SO₄Drying, filtration, and concentration in vacuo gave a crude product which was purified by column chromatography to give the title product (3.0g, 51.7% yield) as a yellowish oil. MS: 231.7(M + H)⁺，1Br)

[B]6-fluoro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

Will be provided with1- (2-bromo-4-fluoro-phenyl) -1-methyl-ethylamine(1.5g，6.52mmol)，Pd(dppf)Cl₂A mixture of (0.15g), DIPEA (2.52g, 19.6mmol) in DMF (20mL) was stirred in an autoclave at 2MPa of CO (g) at 130 ℃ for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (300 mL). Use the organic layerWashed with brine, filtered, and concentrated under reduced pressure to give the crude product, which was purified by chromatography to give the title compound (100mg, yield 8.6%) as a brown solid.

Intermediate A-20-1

2- (5-chloromethyl-pyridin-3-yl) -6-fluoro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]6-fluoro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

The 6-fluoro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate A-20[ B ]]35.8mg, 0.2mmol), (5-bromo-pyridin-3-yl) -methanol (74.8mg, 0.4mmol), CuI (3.8mg, 0.02mmol), (1S,2S) -cyclohexane-1, 2-diamine (4.5mg, 0.04mmol) and Cs₂CO₃(130mg, 0.4mmol) of the mixture was dissolved in IIIn an alkane (5 mL). The reaction mixture was subjected to a microwave reaction at 140 ℃ for 1 hour, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to afford the crude product (52mg, 92%) as a solid. MS: 287.1(M + H)⁺)。

[B]2- (5-chloromethyl-pyridin-3-yl) -6-fluoro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

To a solution of 6-fluoro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (52mg) in DCM (10mL) was slowly added thionyl chloride (0.14mL, 1.9mmol) at 0 ℃. After addition, the reaction mixture was stirred at 2-5 ℃ for 0.5h, after which it was poured into saturated NaHCO₃Aqueous (10mL) and extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (58mg 100%) as a pale yellowish solid. MS: 322.1(M + H)⁺)。

Intermediate A-21

3, 3-dimethyl-1-oxo-2, 3-dihydro-1H-isoindole-5-carbonitrile

[A]4-bromo-2-methyl-benzoic acid methyl ester

To a solution of 4-bromo-2-methyl-benzoic acid (30.0g, 0.14mol) in 115mL of methanol was slowly added thionyl chloride (20.25mL, 0.28mol) and the reaction mixture was stirred at 70 ℃ for 2 hours before it was concentrated to afford the crude product, which was then purified by column chromatography to give the title compound (30.03g, 93.6%) as a solid.

[B]4-cyano-2-methyl-benzoic acid methyl ester

A mixture of methyl 4-bromo-2-methyl-benzoate (26.0g, 113.5mmol) and CuCN (12.48g, 140.7mmol) was heated at 180 ℃ for 5 hours before being poured into ice-water. The solid precipitate was collected by vacuum filtration to give the crude product, which was then purified by column chromatography to afford the title compound (12.53g, 63%) as a solid.

[C]2-Bromomethyl-4-cyano-benzoic acid methyl ester

4-cyano-2-methyl-benzoic acid methyl ester (12.5g, 71.35mmol), NBS (12.7g, 71.35mmol) and dibenzoyl peroxide (BPO) (0.8g, 3.28mmol) in CCl₄The mixture in (200mL) was heated to reflux temperature for 3 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the crude product (18.2g), which was used in the next step reaction without further purification.

[D]2- (4-methoxy-benzyl) -1-oxo-2, 3-dihydro-1H-isoindole-5-carbonitrile

To a solution of methyl 2-bromomethyl-4-cyano-benzoate (18.1g, 71.24mmol) in THF (300mL) at 0 deg.C was added PMBNH₂(23.4g, 178.1mmol) and the reaction mixture was stirred at room temperature for 16 h. After vacuum filtration, the filtrate was concentrated in vacuo. The obtained residue was redissolved in EtOAc and washed with water and brine. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product, which was purified by column chromatography (11.69g, 56.0%) as a solid.

[E]2- (4-methoxy-benzyl) -3, 3-dimethyl-1-oxo-2, 3-dihydro-1H-isoindole-5-carbonitrile

To a solution of 2- (4-methoxy-benzyl) -1-oxo-2, 3-dihydro-1H-isoindole-5-carbonitrile (11.6g, 41.7mmol) in THF (300mL) was added NaH (8.34g, 208.4mmol, 60% in mineral oil) and the reaction mixture was stirred at room temperature for 1 hour, after which iodomethane (35.5g, 250.1mmol) was added. After addition, the reaction mixture was stirred at 70 ℃ for 2 hours until all starting material was consumed. After cooling it to room temperature, saturated NH was added₄Aqueous Cl was added and the mixture was extracted with EtOAc (200mL × 3) the combined organic layers were dried over anhydrous MgSO₄Drying, filtration and concentration under reduced pressure gave the crude product which was purified by column chromatography to give the title compound (7.22g, 56.5%) as a solid.

[F]3, 3-dimethyl-1-oxo-2, 3-dihydro-1H-isoindole-5-carbonitrile

To a solution of 2- (4-methoxy-benzyl) -3, 3-dimethyl-1-oxo-2, 3-dihydro-1H-isoindole-5-carbonitrile (3.5g, 11.42mmol) in MeCN (70mL) at 0 deg.C was added CAN (18.79g, 34.27mmol) in 30mL water. The resulting reaction mixture was stirred at 0 ℃ for 1 hour until all starting materials were consumed. The reaction mixture was extracted between water and EtOAc and the combined organic layers were extracted with anhydrous MgSO₄Drying, filtration and concentration under reduced pressure gave the crude product which was purified by column chromatography to give the title compound (1.06g, 49.8%) as a solid.

Intermediate A-21-1

2- (5-chloromethyl-pyridin-3-yl) -3, 3-dimethyl-1-oxo-2, 3-dihydro-1H-isoindole-5-carbonitrile

In analogy to the procedure described for the preparation of intermediate a-12-1, the title compound was obtained as yellowish oil. MS: 312.1(M + H)⁺)。

Intermediate A-22

6 ' -Chlorospiro [ cyclopropane-1, 1 ' -isoindoline ] -3 ' -one

[A]1- (2-bromo-5-chlorophenyl) cyclopropylamine

To a mixture of 2-bromo-5-chlorobenzonitrile (10g, 46mmol) and Ti (Oi-Pr)₄(16.64mL, 55mmol) EtMgBr (138mL, 138mmol) was added dropwise to a stirred solution at-78 ℃ in THF (200 mL). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. BF mixing₃-Et₂O (17.2mL) was added and the solution was stirred for another 16 hours before it was quenched with aqueous HCl and washed with EtOAc. The aqueous phase was adjusted to pH-10 with aqueous NaOH and extracted with EtOAc (3X). The combined organic layers were concentrated to give the crude product, which was purified by chromatography to provide the title compound (2g, yield 17.6%). MS: 246.7(M + H)⁺1Cl) as an oil.

[B]6 '-Chlorospiro [ cyclopropane-1, 1' -isoindoline]-3' -ketones

1- (2-bromo-5-chlorophenyl) cyclopropylamine (2g, 8.1mmol), Pd (dppf) Cl₂A mixture of (0.2g), DIPEA (3.1g, 24.3mmol) in DMF (20mL) in an autoclave at 2MPa of CO (g) at 13Stirred at 0 ℃ for 16 hours. The reaction mixture was diluted with EtOAc (300mL) and washed with brine. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration, and concentration under reduced pressure gave a crude product which was purified by chromatography to give the title compound (700mg, yield 44.6%) as a yellow solid. MS: 193.8(M + H)⁺，1Cl)。

Intermediate A-22-1

6 '-chloro-2' - (5- (chloromethyl) pyridin-3-yl) spiro [ cyclopropane-1, 1 '-isoindoline ] -3' -one

In analogy to the procedure described for the preparation of intermediate a-12-1, the title compound was obtained as yellowish oil. MS: 320.1(M + H)⁺)。

Intermediate A-23

6 ' -Fluorospiro [ cyclopropane-1, 1 ' -isoindoline ] -3 ' -one

[A]1- (2-bromo-5-fluoro-phenyl) -cyclopropylamine

To 2-bromo-5-fluoro-benzonitrile (1g, 5mmol) and Ti (Oi-Pr) at-78 deg.C₄(1.81mL, 5.5mmol) to a stirred solution in ether (20mL) was added EtMgBr (3.67mL, 11 mmol). After stirring at-78 ℃ for 10min, the solution was warmed to room temperature and stirred for 1 h. BF mixing₃-Et₂O (1.25mL) was added, after which it was stirred for another 1 hour. After addition of 1N aqueous HCl (15mL) and diethyl ether (30mL), aqueous NaOH (10%,45mL) to give two clear phases. The mixture was extracted with EtOAc (30mLx 5). The combined organic layers were washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by column chromatography (PE: EA ═ 5: 1) to afford the title compound (800mg, 70%) as an oil.

[B]6 '-Fluorospiro [ cyclopropane-1, 1' -isoindoline]-3' -ketones

1- (2-bromo-5-fluoro-phenyl) -cyclopropylamine (4.2g, 18.3mmol), Pd (dppf) Cl₂A solution of (0.42g), DIPEA (7g, 54.8mmol) in 40mL DMF was heated at 130 ℃ under 2MPa CO for 12 h. After cooling to room temperature, EtOAc was added and washed with brine. The organic layer was washed with anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound (0.3g, yield 65.2%) as a solid, while 3.3g of the starting material was recovered.

Intermediate A-23-1

2 '- (5- (chloromethyl) pyridin-3-yl) -6' -Fluorospiro [ cyclopropane-1, 1 '-isoindoline ] -3' -one

In analogy to the procedure described for the preparation of intermediate a-12-1, the title compound was obtained as yellowish oil. MS: 303.1(M + H)⁺)。

Intermediate A-24

5 ' -Fluorospiro [ cyclopropane-1, 1 ' -isoindoline ] -3 ' -one

[A]1- (2-bromo-4-fluorophenyl) cyclopropylamines

To a mixture of 2-bromo-4-fluorobenzonitrile (5g, 25mmol) and Ti (Oi-Pr)₄(9.05mL, 27.5mmol) EtMgBr (18.3mL, 55mmol) was added dropwise to a stirred solution at-78 ℃ in diethyl ether (100 mL). The solution was allowed to warm to room temperature and stirred for 1 hour, after which time BF was removed₃-Et₂O (6.25mL) was added and stirring continued at room temperature for another 1 hour. The reaction solution was quenched with 1N HCl solution and washed with EtOAc. The aqueous layer was adjusted to pH-10 with aqueous NaOH (2N) and then extracted with EtOAc (3X). The combined organic layers were washed with anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was then purified by column chromatography to give the title compound (3.0g, yield 52.2%) as a yellowish oil.

[B]5 '-Fluorospiro [ cyclopropane-1, 1' -isoindoline]-3' -ketones

1- (2-bromo-4-fluorophenyl) cyclopropylamine (3.0g, 17.4mmol), Pd (dppf) Cl₂A mixture of (0.4g), DIPEA (5.05g, 39.1mmol) in DMF (40mL) was stirred in an autoclave at 2MPa of CO (g) at 130 ℃ for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAt (300mL) and washed with brine. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave the crude product which was purified by chromatography to give the title compound (600mg, yield 26%) as a brown solid.

Intermediate A-24-1

2 '- (5- (chloromethyl) pyridin-3-yl) -6' -Fluorospiro [ cyclopropane-1, 1 '-isoindoline ] -3' -one

In analogy to the procedure described for the preparation of intermediate a-12-1, the title compound was obtained as yellowish oil. MS: 303.1(M + H)⁺)。

Intermediate A-25

6-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of intermediate a-20, using 2-bromo-4-chloro-benzonitrile (step a) and 1- (2-bromo-4-chloro-phenyl) -1-methyl-ethylamine (step B), the title compound was obtained as a solid (yield 40%). MS: 196.1(M + H)⁺)。

Intermediate A-25-1

6-chloro-2- (5-chloromethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of intermediate a-12-1, the title compound was obtained as yellowish oil. MS: 322.1(M + H)⁺)。

Intermediate B-1

3-bromo-5- (2-isopropyl-imidazol-1-ylmethyl) -pyridine

[A]3-bromo-5-chloromethyl-pyridine

To a solution of (5-bromopyridin-3-yl) methanol (3g, 16.0mmol) in DCM (15mL) cooled to 0 deg.C was added thionyl chloride (7.59g, 63.8mmol) dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was poured onto ice/water (20mL), basified with concentrated NaOH (8mL) and extracted with EtOAc (2 × 50 mL). The combined organics were washed with Na₂SO₄Dried, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 40% EtOAc-heptane to give the title compound (3.08g, 93%) as a white solid. MS: 206.0, 207.9(M + H)⁺)。

[B]3-bromo-5- (2-isopropyl-imidazol-1-ylmethyl) -pyridine

To a suspension of sodium hydride (60% in mineral oil, 0.073g, 1.82mmol) in DMF (3mL) was added 2-isopropyl-1H-imidazole (0.173g, 1.57mmol) and the reaction mixture was stirred at room temperature for 20 min. Then 3-bromo-5-chloromethyl-pyridine (0.25g, 1.21mmol) was added and the resulting suspension was heated at 60 ℃ overnight. The mixture was quenched with water (2mL) and extracted with EtOAc (2 × 10 mL). The combined organics were washed with Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 5% MeOH-DCM to give the title compound (0.275g, 81%) as a light yellow oil. MS: 280.0, 282.0(M + H)⁺)。

Intermediate B-2

3-bromo-5- (2-methyl-imidazol-1-ylmethyl) -pyridine

Analogously to the preparation of intermediate B-1[ B]The procedure described, coupling 2-methyl-imidazole to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ a)]) The title compound was obtained as a light brown solid. MS: 251.9, 254.0(M + H)⁺)。

Intermediate B-3

3-bromo-5- [1, 2, 4] triazol-1-ylmethyl-pyridine

Analogously to the preparation of intermediate B-1[ B]The procedure described, 1H-1, 2, 4-triazole coupled to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ a)]) The title compound was obtained as a white solid. MS: 238.9, 241.3(M + H)⁺)。

Intermediate B-4

1- (5-bromo-pyridin-3-ylmethyl) -pyrrolidin-2-one

Analogously to the preparation of intermediate B-1[ B]The procedure described, coupling of pyrrolidin-2-one to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ A ]]) The title compound was obtained as a white solid. MS: 251.1, 257.1(M + H)⁺)。

Intermediate B-5

1- (5-bromo-pyridin-3-ylmethyl) -piperidin-2-one

Analogously to the preparation of intermediate B-1[ B]The procedure described, coupling piperidin-2-one to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ A ]]) The title compound was obtained as a colorless oil. MS: 269.2, 271.2(M + H)⁺)。

Intermediate B-6

3-bromo-5- ((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -pyridine

Analogously to the preparation of intermediate B-1[ B]The procedure described, coupling of (S) -2- (methoxymethyl) pyrrolidine to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ a)]) The title compound was obtained as a yellow oil. MS: 285.0, 286.9(M + H)⁺)。

Intermediate B-7

Ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl) -amide

The flask was charged with 5-bromonicotinaldehyde (2.55g, 13.7mmol), ethanesulfonamide (2.99g, 27.4mmol) and toluene (250mL), followed by dropwise addition of titanium isopropoxide (5.84g, 20.6 mmol). The reaction mixture was stirred at 115 ℃ overnight and then concentrated in vacuo. The residue was taken up in DCM (200mL) and MeOH (200mL) and NaBH was added at 0 deg.C₄(1.04g, 27.4mmol) was added in portions. The reaction mixture was stirred at 0 ℃ for 30min then poured into water (100mL) and the resulting suspension was filtered through a pad of celite. The celite layer was washed with DCM (3 × 100 mL). The resulting aqueous layer was separated and extracted with DCM (500 mL). The combined organics were washed with Na₂SO₄Dried, filtered and pre-adsorbed on silica gel. The residue is taken up by washing with 0 toFlash chromatography on silica gel eluting with a gradient of 5% MeOH-DCM gave the title compound (3.01g, 79%) as an orange solid. MS: 279.0, 281.0(M + H)⁺)。

Intermediate B-8

(S) -1- (5-bromo-pyridin-3-yl) -5-hydroxymethyl-pyrrolidin-2-one

In a sealed tube, 3, 5-dibromopyridine (0.5g, 2.11mmol) was mixed with (S) -5- (hydroxymethyl) pyrrolidin-2-one (0.243g, 2.11mmol), copper (I) iodide (0.040g, 0.021mmol), potassium carbonate (0.583g, 4.22mmol) and N, N' -dimethylethylenediamine (0.037g, 0.042mmol) in 1, 4-bis (methylene chloride)Combined in an alkane (20 mL). The reaction mixture was heated at 110 ℃ overnight. The mixture was cooled to room temperature, filtered through celite and washed with DCM. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% MeOH-DCM to give the title compound (0.140g, 25%) as a light yellow oil. MS: 271.1, 273.1(M + H)⁺)。

Intermediate B-9

1- (5-bromo-pyridin-3-yl) -pyrrolidin-2-one

In analogy to the procedure described for the preparation of intermediate B-8, pyrrolidin-2-one was coupled to 3, 5-dibromopyridine to give the title compound as light yellow solid. MS: 241.0, 243.0(M + H)⁺)。

Intermediate B-10

3-bromo-5- ((S) -2-methoxymethyl-pyrrolidin-1-yl) -pyridine

Analogously to preparation example 135[ B ]]The procedure described is to react (S) -2-methoxymethyl-pyrrolidine with 3, 5-dibromopyridine in Pd₂(dba)₃rac-BINAP and sodium tert-butoxide in the presence of a base to give the title compound as a yellow oil. MS: 271.1, 273.1(M + H)⁺)。

Intermediate B-11

4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-ol

[A]5-bromo-4-methylnicotinic acid ethyl ester

To a stirred, light brown suspension of 5-bromo-4-methylnicotinic acid (10.00g, 46.3mmol) and ethanol (2.97mL) in DCM (231mL) at 0 ℃ under argon was added EDCI (10.9g, 55.5 mmol) and DMAP (566mg, 4.63 mmol); stirring was continued overnight and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then poured onto 10% KH₂PO₄On the aqueous solution, followed by extraction with AcOEt (3 ×). Mixing the organic phase with 10% KH₂PO₄Aqueous solution of saturated NaHCO₃And washed once with saturated aqueous NaCl solution. The combined organic phases were dried (Na)₂SO₄) Filtered and evaporated to give the title compound (9.49g, 84%) as a brown solid. MS: 244.0(M + H)⁺，1Br)。

[B]4-bromo-8-oxo-5, 6,7, 8-tetrahydroisoquinoline-7-carboxylic acid methyl ester

Ethyl 5-bromo-4-methylnicotinate (7.04g, 28.8mmol) in THF (28.8mL) was added to LDA (31.7mmol) [ generated from N, N-diisopropylamine (4.52mL, 31.7mmol) in 144mL THF and N-butyllithium (19.8mL, 31.7mmol, 1.6M in hexanes)]In solution at-78 ℃. The resulting dark red solution was stirred for 20min, then methyl acrylate (6.21g, 72.1mmol) in THF (28.8mL) was added over 15 min. The reaction was stirred for an additional 1.5h, then 10% AcOH in water was added (pH 4-5 obtained) and the reaction was allowed to warm to room temperature. After evaporation, the residue was poured into saturated NaHCO₃On aqueous solution and extracted with EtOAc (3 ×). The combined organic layers were dried (Na)₂SO₄) And concentrated to provide the title compound (7.80g, 95% purity 70% 30% starting material) as a brown solid. MS: 284.0(M + H)⁺，1Br)。

[C]4-bromo-6, 7-dihydroisoquinolin-8 (5H) -one

Crude methyl 4-bromo-8-oxo-5, 6,7, 8-tetrahydroisoquinoline-7-carboxylate (7.79g, 27.4mmol) was dissolved (small amount of insoluble material) in 6M aqueous HCl (84.1ml, 505mmol) and heated at reflux for 2.5 h. The acidic solution was concentrated in vacuo, suspended in water (about 25mL), cooled in ice and basified with 6.0M KOH. The aqueous solution was washed with diethyl ether (2X) and CH₂Cl₂(3X) extraction, the combined organic layers were washed with Na₂SO₄Drying, filtration and concentration afforded the title compound (4.30g, 69%) as a brown solid. MS: 226.0(M + H)⁺，1Br)。

[D]4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-ol

4-bromo-6, 7-dihydroisoquinolin-8 (5H) -one (2.135g, 9.44mmol) was suspended in MeOH (18.9mL), cooled to 0 deg.C and treated with NaBH over 30min₄(357mg, 9.44mmol) was treated in 5 portions; the reaction was then stirred 3/4h at 0 ℃ (TLC showed no more starting material after 30 min). AcOH was then added dropwise until pH 5-6 and the reaction mixture was evaporated. The residue was diluted with water and poured over saturated NaHCO₃On aqueous solution, followed by extraction with EtOAc (3 ×). The organic layer was washed with saturated NaHCO₃The aqueous solution and 10% NaCl aqueous solution were washed once with Na₂SO₄Dried and concentrated in vacuo. Redissolving the residue in CH₂Cl₂In (5), evaporating (3X) to about 20ml each time with n-pentane while the product precipitates; the solvent was then decanted and the residue was washed with n-pentane and dried in high vacuum to provide the title compound (1.98g, 92%) as a dark brown viscous oil. MS: 227 (M)⁺，1Br)。

Intermediate B-12

N- (4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-yl) propanamide

[A]4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-amine

Reacting 4-bromo-6, 7-dihydroisoquinoline-8 (5H) -one (intermediate B-11[ C ]]) (4.81g, 21.3mmol), titanium (IV) isopropoxide (12.1g, 42.6mmol) and ammonia, 2.0M solution in MeOH (53.2mL, 106mmol) were stirred at room temperature for 5 h. The reaction was cooled to 0 ℃ and the NaBH was allowed to cool within 10min₄(1.21 g, 31.9mmol) in portionsAdding; the resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched by pouring it into a 25% aqueous solution of ammonium hydroxide, the precipitate was filtered and washed with EtOAc (3x, each time suspended in AcOEt and stirred for 5 min). The organic layer was separated and the remaining aqueous layer was extracted with EtOAc. The combined organic extracts were extracted with 1M HCl. The acidic aqueous extract was washed with ethyl acetate (1 ×), then treated with aqueous sodium hydroxide (2M) to give a pH of 10-12 and extracted with EtOAc (3 ×). The combined organic extracts were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo to afford the title compound (4.11g, 85%) as a brown solid. MS: 225 (M)⁺，1Br)。

[B] N- (4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-yl) propanamide

To the solution of 4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-amine (318mg, 1.4mmol) and propionic acid (114mg, 1.54mmol) in CH₂Cl₂To a stirred brown solution at 0 deg.C under argon (7.0mL) was added EDCI (63.3mg, 0.330. mu. mol). Stirring was continued overnight and the reaction mixture was allowed to warm to room temperature. The reaction mixture was poured onto 10% KH₂PO₄The aqueous solution was then extracted with AcOEt (3 ×). Mixing the organic phase with 10% KH₂PO₄Aqueous solution, saturated NaHCO₃The aqueous solution and washed once with saturated aqueous NaCl solution; the combined organic phases were washed with Na₂SO₄Dried, filtered and evaporated. Dissolving the residue in CH₂Cl₂Evaporating (3x) to about 10ml each time with n-pentane while the product precipitates; the solvent was then decanted and the residue was washed twice with n-pentane to provide the title compound (0.365g, 92%) as a light brown solid. MS: 283.0(M + H)⁺，1Br)。

Intermediate B-13

2- (5-bromo-pyridin-3-ylmethyl) - [1, 2] thiazinane 1, 1-dioxide

Analogously to the preparation of intermediate B-1[ B]The procedure described is to mix [1, 2]]Thiazazane 1, 1-dioxide coupling to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ A ]]) The title compound was obtained as an off-white solid. MS: 305.1, 307.1(M + H)⁺)。

Intermediate B-14

3-bromo-5- (1, 1-dioxo-1)⁶-isothiazolidin-2-ylmethyl) -pyridine

Analogously to the preparation of intermediate B-1[ B]The procedure described, coupling of isothiazolidine 1, 1-dioxide to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ a)]) The title compound was obtained as a pale yellow oil. MS: 290.9, 292.8(M + H)⁺)。

Intermediate B-15

(S) -1- (5-bromo-pyridin-3-ylmethyl) -5- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidin-2-one

Analogously to the preparation of intermediate B-1[ B]The procedure described (S) -5- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidin-2-one coupling to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ a)]) The title compound was obtained as a colorless oil. MS: 399.2, 401.2(M + H)⁺)。

Intermediate B-16

(S) -1- (5-bromo-pyridin-3-ylmethyl) -pyrrolidine-2-carboxylic acid methyl ester

Analogously to the preparation of intermediate B-1[ B]The procedure described, coupling of (S) -pyrrolidine-2-carboxylic acid methyl ester to 3-bromo-5-chloromethyl-pyridine (intermediate B-1[ a)]) The title compound was obtained as a pale yellow oil. MS: 299.2, 301.1(M + H)⁺)。

Intermediate B-17

N- (4-bromo-5, 6,7, 8-tetrahydro-isoquinolin-8-yl) -acetamide

To 4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-amine (intermediate B-12[ A ]) at 0 deg.C]318mg, 1.4mmol) and Et₃To a stirred solution of N (3.0mL) in DCM (10mL) was added acetyl chloride (0.106mL, 1.4mmol) and stirring was continued at 0 ℃ for 1 h. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organics were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo afforded the crude product, which was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to afford the title compound (346mg, 92%) as a light yellow solid. MS: 269.1&271.1(M+H⁺)。

Intermediate B-18

N- (4-bromo-6, 7-dihydro-5H- [2] pyridin-7-yl) -propionamide

[A]3- (3, 5-Dibromopyridin-4-yl) propionic acid ethyl ester

A solution of 3, 5-dibromo-4-methylpyridine (20g, 0.08mol) in THF (50mL) was added to LDA (0.088mol) [ N, N-diisopropylamine (8.9g, 0.088mol) generated from 400mL THF and N-butyllithium (35mL, 0.088mol, 2.5M in hexane) over a period of 1 hour]In solution at-78 ℃. The resulting dark red solution was stirred at-78 ℃ for 30min, after which ethyl bromoacetate (33.4g, 0.2mol) in THF (50mL) was added during 30min. The reaction mixture was stirred at-78 ℃ for an additional 2.5 hours before 10% AcOH was added (to give pH 4-5). The reaction mixture was then allowed to warm to room temperature. After evaporation of the solvent, the residue was poured into saturated NaHCO₃Aqueous and extracted with EtOAc (100mLx 3). The combined organic layers were washed with anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (9g, 33.5%) as a yellow solid. MS: 337.7(M + H)⁺，2Br)。

[B]4-bromo-5H-cyclopenta [ c)]Pyridin-7 (6H) -ones

To a solution of ethyl 3- (3, 5-dibromopyridin-4-yl) propionate (4g, 11.9mmol) in THF (60mL) was slowly added n-BuLi (9.52mL, 23.8mmol, 2.5M in hexanes) while maintaining the internal temperature below-70 ℃. After addition, the reaction mixture was stirred for an additional 2 hours at below-65 ℃. The reaction was quenched with water and then extracted with EtOAc (100mLx 3). The combined organic layers were washed with anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was then purified by column chromatography to give the title compound (1.2g, 47.6%) as a solid. MS: MS: 213.7(M + H)⁺，1Br)。

[C]4-bromo-6, 7-dihydro-5H- [2]Pyridin-7-ylamines

CH in EtOH (10mL)₃COONH₄(4.8g，62mmol)，NaCNBH₃(315mg, 5mmol) and 4-bromo-5H-cyclopenta [ c]Pyridin-7 (6H) -one (1.0g, 4.15mmol) was added to a sealed microwave vial. The mixture was subjected to microwave irradiation at 130 ℃ for 4 min. After most of the EtOH was evaporated under reduced pressure, it was treated with 2N aqueous NaOH until pH > 10 and extracted with EtOAc (50mLx 2). The combined organic layers were washed with anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure to give the crude title product (800mg), which was used in the next step reaction without further purification. MS: 212.9(M + H)⁺，1Br)。

[D]N- (4-bromo-6, 7-dihydro-5H-cyclopenta [ c)]Pyridin-7-yl) propionamide

To 4-bromo-6, 7-dihydro-5H-cyclopenta [ c ] at 0 deg.C]Pyridin-7-amine (650mg, 3.05mmol, 65% purity) and Et₃To a solution of N (400mg, 3.97mmol) in THF (20mL) was added propionyl chloride (219mg, 2.38mmol) and stirring was continued for 2 h. Water (10mL) and EtOAc (10mL) were added and the aqueous layer was extracted with EtOAc (10mL x 3). The combined organic layers were washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by column chromatography to afford the title compound (200mg, 37.6%) as a white solid. MS: 270.9(M + H)⁺，1Br)。

Intermediate B-19

N- (4-bromo-6, 7-dihydro-5H- [2] pyridin-7-yl) -acetamide

In analogy to the procedure described for the preparation of intermediate B-18 (step D), the title compound was obtained as white solid using acetyl chloride as starting material. MS: 256.9(M + H)⁺，1Br)。

Example 1

6-chloro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one

In a sealed tube, 3-bromopyridine (0.1g, 0.633mmol) and 6-chloro-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate A-2) (0.115g, 633mmol), copper (I) iodide (0.012g, 0.063mmol), potassium carbonate (0.175g, 1.27mmol) and N, N' -dimethylethylenediamine (0.013g, 0.127mmol) were placed in a 1, 4-bis (ethyl-phenyl) -etherCombined in an alkane (2 mL). The reaction mixture was heated at 110 ℃ overnight. The mixture was cooled to room temperature, filtered through celite and washed with DCM. The residue was purified by flash chromatography on silica gel eluting with a gradient of 5 to 100% EtOAc-heptane to give the title compound (0.107g, 65%) as a white solid. MS: 259.1(M + H)⁺)。

Example 2

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -nicotinonitrile

Reacting 6-chloro-3, 4-dihydro-2H-isoquinoline-1-one (intermediate A-2) (36mg, 0.2mmol), 5-bromo-nicotinonitrile (73mg, 0.4mmol), CuI (3.8mg, 0.02mmol), (1S,2S) -cyclohexane-1, 2-diamine (4.5mg, 0.04mmol) and Cs₂CO₃(130mg, 0.4mmol) was dissolved in IIIn an alkane (5 mL). The reaction mixture was subjected to a microwave reaction at 150 ℃ for 2.5 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by prep-HPLC to give the title compound (15mg, 26%) as a white solid. MS: 284.1(M + H)⁺)。

Example 3

6-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

[A](5-bromo-pyridin-3-yl) -methanol

Sodium borohydride (2.2g, 59.1mmol) was added to a suspension of 5-bromo-pyridine-3-carbaldehyde (10.0g, 53.7mmol) in MeOH (100mL) at 0 deg.C. The mixture was stirred at 0 ℃ for 1 hour, after which it was quenched by the addition of water (5.0 mL). Evaporation of the solvent afforded a pale yellowish oil, which was redissolved in EtOAc and washed with water. The organic layer was washed with Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound (9.6g, 95%) as a colorless oil. MS: 188.0&190.0(M+H⁺)。

[B]6-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

(5-bromo-pyridin-3-yl) -methanol (900mg, 4.8mmol), 6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (800mg, 4.4mmol), CuI (200mg, 1.1mmol), Cs in a 25mL sealed tube₂CO₃(3.0g, 9.2mmol) and (+) - (S, S) -1, 2-diaminocyclohexane (0.4mL, 3.2mmol) were dissolved in dioxaneAlkane (8.0 mL). The resulting reaction mixture was heated at 150 ℃ for 3 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 125 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexanes gradient) to afford the title compound (1.1g, 90%) as a light yellow solid. MS: 289.2(M + H)⁺)。

The following compounds listed in Table 1 were prepared analogously to the procedure described for the preparation of examples 1,2 or 3[ B ] using the appropriate starting materials.

TABLE 1

Example 135

6-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

[A](S) -2- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidine

To a solution of (S) -pyrrolidin-2-ylmethanol (0.69g, 6.82mmol) in DCM (3mL) cooled to 0 deg.C was added TEA (1.38g, 13.6mmol) followed by TBDMS-Cl (1.03g, 6.82mmol) in DCM (3 mL). The reaction mixture was then stirred at room temperature overnight and poured into NH₄Cl (20 mL). The aqueous layer was extracted with DCM (2 × 50 mL). The combined organics were washed with brine, washed with Na₂SO₄Drying, filtration and evaporation to dryness gave the title compound (1.11g, 76%) as a yellow oil. MS: 216.2(M + H)⁺)。

[B]3-bromo-5- [ (S) -2- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidin-1-yl]-pyridine

To a solution of crude (S) -2- ((tert-butyldimethylsilyloxy) methyl) pyrrolidine (0.455g, 2.11mmol) in toluene (20mL) was added Pd₂(dba)₃(0.039g, 0.042mmol) and rac-BINAP (0.066g, 0.106 mmol). The solution was purged with argon and heated to 85 ℃ for 10 min. After cooling to room temperature, sodium tert-butoxide (0.406g, 4.22mmol) and 3, 5-dibromopyridine (0.5g, 2.11mmol) were added and the reaction mixture was heated at 85 ℃ overnight. The mixture was poured into NH₄Cl (20mL) andthe aqueous layer was extracted with DCM (2 × 25 mL). The combined organics were washed with brine, washed with Na₂SO₄Dried, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 5% MeOH-DCM to give the title compound (0.412g, 53%) as a yellow oil. MS: 371.0, 372.9(M + H)⁺)。

[C]2- {5- [ (S) -2- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidin-1-yl]-pyridine-3- 6-chloro-3, 4-dihydro-2H-isoquinolin-1-one

In analogy to the procedure described for the preparation of intermediate B-8, 6-chloro-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate a-2) was coupled to 3-bromo-5- [ (S) -2- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidin-1-yl]Pyridine to obtain the title compound as a yellow oil. MS: 472.2(M + H)⁺)。

[D]6-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinoline Lin-1-ones

To 2- {5- [ (S) -2- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidin-1-yl]-pyridin-3-yl } -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (0.110g, 0.233mmol) in MeOH (2mL) was added 4M in bisHCl in an alkane (0.233ml, 0.932mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness and the residue was diluted with DCM (20mL) and NaHCO₃(10mL) washing. The organic layer was washed with Na₂SO₄Dried, filtered and evaporated to dryness. The residue is purified by washing with 0 to 5% MeOH(1％NH₄OH) -DCM gradient elution on silica gel flash chromatography gave the title compound (0.06g, 72%) as a light yellow solid. MS: 358.0(M + H)⁺)。

Example 136

5-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 135, 3-bromo-5- [ (S) -2- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidin-1-yl]Pyridine (example 135[ B ]]) Reaction with 5-chloro-2, 3-dihydro-isoindol-1-one gave 2- {5- [ (S) -2- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidin-1-yl]-pyridin-3-yl } -5-chloro-2, 3-dihydro-isoindol-1-one which is then reacted with 4M in bisHCl in the alkane deprotects to give the title compound as a white solid. MS: 344.0(M + H)⁺)。

Example 137

6-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

[A](R) -3-bromo-5- (3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) pyridine

Analogously to preparation example 135[ A]The procedure described, reacting (R) -pyrrolidin-3-ol with TBDMS-Cl in the presence of TEA gave the title compound as a yellow oil. MS: 202.2(M + H)⁺)。

[B]3-bromo-5- [ (R) -3- (tert-butyl-dimethyl-silanyloxy) -pyrrolidin-1-yl]-pyridine

Analogously to preparation 135[ B ]]The procedure described is to react (R) -3-bromo-5- (3- (tert-butyldimethylsilyloxy) pyrrolidin-1-yl) pyridine with 3, 5-dibromopyridine in Pd₂(dba)₃rac-BINAP and sodium tert-butoxide in the presence of a base to give the title compound as a yellow oil. MS: 357.1, 359.0(M + H)⁺)。

[C]2- {5- [ (R) -3- (tert-butyl-dimethyl-silanyloxy) -pyrrolidin-1-yl]-pyridin-3-yl } -6- Chloro-3, 4-dioxo-2H-isoquinolin-1-one

In analogy to the procedure described for the preparation of intermediate B-8, 6-chloro-3, 4-dihydroisoquinolin-1 (2H) -one (intermediate a-2) was coupled to 3-bromo-5- [ (R) -3- (tert-butyl-dimethyl-silanyloxy) -pyrrolidin-1-yl]Pyridine, giving the title compound as a yellow oil. MS: 458.2(M + H)⁺)。

[D]6-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl]-3, 4-dioxo-2H-isoquinoline- 1-ketones

Analogously to example 135[ D ]]The procedure described in (1), 2- {5- [ (R) -3- (tert-butyl-dimethyl-silanyloxy) -pyrrolidin-1-yl]-pyridin-3-yl } -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one with 4M in bisHCl in the alkane deprotects to give the title compound as a white foam. MS: 344.0(M + H)⁺)。

Example 138

5-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 137, 3-bromo-5- [ (R) -3- (tert-butyl-dimethyl-silanyloxy) -pyrrolidin-1-yl]Pyridine (example 137[ B ]]) Reaction with 5-chloro-2, 3-dihydro-isoindol-1-one gave 2- {5- [ (R) -3- (tert-butyl-dimethyl-silanyloxy) -pyrrolidin-1-yl]-pyridin-3-yl } -5-chloro-2, 3-dihydro-isoindol-1-one which is then reacted with 4M in bisHCl in the alkane deprotects to give the title compound as a light yellow solid. MS: 330.1(M + H)⁺)。

Example 139

2-hydroxy-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one

2-methoxy-6- (5-methoxy-pyridine-3-yl) -7, 8-dihydro-6H- [1, 6]Naphthyridin-5-one (445mg, 1.56mmol) (example 97) was suspended in concentrated HCl in 1, 4-bis2mL of aqueous solution in an alkane (2: 1) and heated at 80 ℃ for 3 hours, after which the solvent was removed in vacuo. In EtOAc and H₂After extraction between O, the organic layer was washed with saturated NaHCO₃Aqueous solution, brine washing, anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by prep-HPLC to give the title compound (4.9mg) as a white solid. MS: 270.2(M + H)⁺)。

Example 140

6-chloro-2- (5-imidazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

[A]6-chloro-2- (5-chloromethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

Thionyl chloride (1.4mL, 19.0mmol) was added slowly to 6-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one (example 3[ B ] at 0 ℃]) (1.1g, 3.8mmol) in DCM (50 mL). After addition, the reaction mixture was stirred at 2-5 ℃ for 2 hours, after which it was poured into saturated NaHCO₃Aqueous (50mL) and extracted with EtOAc (2 × 150 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtering andconcentration in vacuo gave the crude product (1.42g, 92%) as a pale yellowish solid. MS: 307.0&309.0(M+H⁺)。

[B]6-chloro-2- (5-imidazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

To a solution of 1H-imidazole (50mg, 0.73mmol) dissolved in DMF (5.0mL) was added NaH (60% dispersion in mineral oil, 25mg, 0.63mmol) at 0 ℃. The reaction mixture was stirred at 2-5 ℃ for 0.5H, after which 6-chloro-2- (5-chloromethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one (example 140[ A)]) (85mg, 0.28 mmol). The mixture was then stirred at 2-5 ℃ for an additional 2 hours before it was warmed to room temperature and poured into water (5.0 mL). After extraction with EtOAc (2 × 50mL), the organic layer was washed with brine, dried over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product, which was purified by prep-HPLC to give the title compound (30mg, 31%) as a white foam. MS: 339.2(M + H)⁺)。

The following compounds listed in table 2 were prepared in analogy to the procedure described for the preparation of example 140 using the appropriate starting materials.

TABLE 2

Example 193

6-chloro-2- (5-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

To a solution of 6-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one (example 3) (28.8mg, 0.1mmol) in THF (5mL) was added NaH (8mg, 0.2mmol, 60% dispersion in mineral oil) at room temperature. After the evolution of hydrogen had ceased, a solution of methyl iodide (0.2mmol) in THF (5mL) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then saturated with NH₄Aqueous Cl and extracted three times with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na₂SO₄Dried and concentrated in vacuo. The crude product was purified by prep-HPLC to give the title compound (4.5mg, 14.8%) as a white solid. MS: (M + H)⁺303.1

Example 194

6-chloro-2- (5-isopropoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

To a solution of propan-2-ol (3.6mg, 0.06mmol) in anhydrous DMF (1mL) at 0 deg.C was added NaH (1.5mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 5min, after which 6-chloro-2- (5-chloromethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one (15mg, 0.05mmol, example 140[ A]). The resulting reaction mixture was then stirred at room temperature for 1 hour, after which it was poured into ice-water and extracted with EtOAc (2 × 5 mL). The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by preparative-HPLC to give the title compound (8mg, 48%) as whiteAnd (3) a solid. MS: 331.1(M + H)⁺)。

The following compounds listed in table 3 were prepared in analogy to the procedure described for the preparation of example 194 using the appropriate starting materials.

TABLE 3

Example 204

6-chloro-2- [5- (3, 5-dimethyl-iso-methyl)Azol-4-ylmethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one

6-chloro-2- (5-chloromethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one (example 140[ A)])(75mg，0.25mmol)，Pd(PPh₃)₂Cl₂(18mg，0.025mmol)，Na₂CO₃(80mg, 0.75mmol) and 3, 5-dimethylisoAzole-4-boronic acid (45mg, 0.32mmol) dissolved in bisAlkane (4.0 mL). The resulting reaction mixture was heated at 120 ℃ for 3 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 125 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by preparative-HPLC to give the title compound (10mg, 10.9%) as a pale yellowish solid. MS: 368.2(M + H)⁺)。

The following compounds listed in table 4 were prepared analogously to the procedure described for the preparation of example 204 using the appropriate starting materials.

TABLE 4

Example 218

Ethanesulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -amide

Mixing CuI (1.9mg, 0.01mmol), L-proline (2.3mg, 0.02mmol) and Cs₂CO₃(65mg, 0.2mmol) 2- (5-bromo-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (example 7) (33.7mg, 0.1mmol) and ethanesulfonic acid amide (10.9mg, 0.1mmol) in bisAlkane (3 mL). The resultant reaction mixture was subjected to a microwave reaction at 150 ℃ for 2.5 hours. The reaction mixture was filtered and concentrated in vacuo to give the crude product, which was then purified by preparative-HPLC to give the title compound (7.3mg, 20%) as a white solid. MS: 366.1(M + H)⁺)。

The following compounds listed in table 5 were prepared in analogy to the procedure described for the preparation of example 218 using the appropriate starting materials.

TABLE 5

Example 229

6-chloro-2- [5- (1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

2- (5-bromo-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (example 7) (34mg, 0.1mmol), Pd (PPh)₃)₄(5.8mg，0.005mmol)，K₂CO₃(27.6mg, 0.2mmol) and 1H-pyrazole-4-boronic acid pinacol ester (29.1mg, 0.15mmol) were dissolved in bisAlkane (1 mL). The resulting reaction mixture was subjected to microwave reaction at 150 ℃ for 45min, after which it was poured into H₂O (25mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by prep-HPLC to give the title compound (9mg, 28%) as a white solid. MS: 325.1(M + H)⁺)。

The following compounds listed in table 6 were prepared analogously to the procedure described for the preparation of example 229, using the appropriate starting materials.

TABLE 6

Example 244

6-chloro-2- [5- (1-methyl-1H-imidazol-2-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

To a stirred suspension of zinc powder (130mg, 1.98mmol) in THF (2.0mL) was added 1, 2-dibromoethane (0.02 mL). The mixture was heated with a blower until the evolution of ethylene gas was complete. TMS-Cl (0.02mL) and 2-bromo-1-methyl-1H-imidazole (0.07mL, 0.66mmol) were then added to the above suspension and allowed to stir at RT for 30 minutes, after which 2- (5-bromo-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (74mg, 0.22mmol, example 7) and Pd (PPh) were added₃)₄(14mg, 0.011 mmol). The resulting reaction mixture was then heated to 90 ℃ for 6 hours before it was poured into H₂O (50mL) and extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by prep-HPLC to give the title compound (12.0mg, 16.2%) as a white foam. MS: 339.1(M + H)⁺)。

Example 245

6-chloro-2- [5- (2, 4-dimethyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

To a stirred solution of 2- (5-bromo-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (example 7) (80mg, 0.25mmol) and 1, 4-dimethyl-1H-pyrazole (23mg, 0.25mmol) in NMP (2.0mL) was added Pd (OAc)₂(2.0mg, 0.008mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (DavePhos) (6.3mg, 0.016mmol), Bu₄NOAc (153mg, 0.5mmol) and isobutyric acid (0.085mL, 0.08 mmol). The resulting reaction mixture was heated to 100 ℃ for 6 hours before it was poured into H₂O (25mL) and extracted with EtOAc (2 × 90 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by preparative-HPLC to give the title compound (8.7mg, 9.9%) as a yellow solid. MS: 353.1(M + H)⁺)。

Example 246

5- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -1-methyl-1H-pyrazole-4-carbonitrile

The title compound was prepared in analogy to the procedure described for the preparation of example 245 using 1-methyl-1H-pyrazole-4-carbonitrile as starting material.

Example 247

N- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -isobutyramide

To a solution of 2- (5-amino-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (27.3mg, 0.1mmol, example 15) in dry DMF (2mL) at 0 deg.C was added NaH (3.0mg, 0.12 mmol). The reaction mixture was allowed to stir at room temperature for 5min, after which isobutyryl chloride (12.7mg, 0.12mmol) was added to the reaction mixture. The reaction mixture was stirred for an additional 1 hour then poured into ice-water and extracted with EtOAc (2 × 5 mL). The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by prep-HPLC to give the title compound (8.1mg, 24%) as a white solid. MS: 344.1(M + H)⁺)。

Example 248

Cyclopropanecarboxylic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -amide

The title compound was synthesized in analogy to the procedure described for the preparation of example 247, using cyclopropanecarbonyl chloride as corresponding starting material. MS: 342.1(M + H)⁺)。

Example 249

N- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -4-fluoro-benzamide

The title compound was synthesized in analogy to the procedure described for the preparation of example 247, using 4-fluoro-benzoyl chloride as corresponding starting material. MS: 396.1(M + H)⁺)。

Example 250

1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -3-cyclohexyl-urea

2- (5-amino-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (27.3mg, 0.1mmol, example 17) was added to a solution of isocyanato-cyclohexane (12.5mg, 0.1mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 2 hours. After evaporation of the solvent under reduced pressure, the crude product was obtained, which was purified by preparative-HPLC to give the title compound as a white solid (8.0mg, 20%). MS: 399.2(M + H)⁺)。

Example 251

1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -3- (3-trifluoromethyl-phenyl) -urea

The title compound was synthesized in analogy to the procedure described for the preparation of example 250, using 1-isocyanato-3-trifluoromethyl-benzene as corresponding starting material. MS: 461.3(M + H)⁺)。

Example 252

6-chloro-2- (5-hydroxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

6-chloro-2- (5-methoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one (1.44g, 5mmol, example 10) was dissolved in aqueous HBr (48%, 20 mL). The reaction mixture was heated to reflux temperature and stirred overnight. After cooling to room temperature, it was carefully treated with saturated NaHCO₃The aqueous solution was neutralized and extracted with EtOAc (2 × 25 mL). The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (1.02g, 74%) as a brown oil. MS: 275.1(M + H)⁺)。

Example 253

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -acetamide

[A][5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy]-tert-butyl acetate

NaH (38mg, 1.5mmol) was added to a solution of 6-chloro-2- (5-hydroxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one (288mg, 1.0mmol, example 252) in dry DMF (5mL) at 0 ℃. After stirring for 10min at RT, bromo-tert-butyl acetate (234mg, 1.2mmol) was added and the reaction mixture was stirred for 1h at RT before it was poured into ice-water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give the crude product (320mg, 82%) as a solid MS: 389.8(M + H)⁺)。

[B][5-(6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy]-acetic acid

Trifluoroacetic acid (3mL) was added to 5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy]-tert-butyl acetate (388mg, 1mmol) in DCM (5mL) and the reaction mixture stirred at RT for 2h before it was poured into water and extracted with EtOAc (2 × 10 mL). The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give the crude product (320mg, 96%) as a solid MS: 333.1(M + H)⁺)。

[C]2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy]-acetamide

HATU (38mg, 0.1mmol), Et₃N (10.1mg, 0.1mmol) and ammonia (1.6M in 1, 4-bisIn an alkane, 125. mu.L, 0.2mmol) was added to [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy]-acetic acid (33.2mg, 0.1mmol) in DMF (2 mL). The reaction mixture was stirred at RT overnight, after which it was poured into water and extracted with EtOAc (2 × 5 mL). The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product, which was purified by prep-HPLC to give the title compound (5.4mg, 16%) as a white solid. MS: 332.1(M + H)⁺)。

Example 254

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -N-methyl-acetamide

Analogously to preparation example 253[ C]The title compound was synthesized using the procedure described, using methylamine as the corresponding starting material. MS: 346.2(M + H)⁺)。

Example 255

[5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -acetic acid methyl ester

Analogously to preparation example 253[ A]The title compound was synthesized using bromo-methyl acetate as the corresponding starting material. MS: 347.1(M + H)⁺)。

Example 256

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -N, N-dimethyl-acetamide

Analogously to preparation example 253[ C]The procedure described, using dimethylamine as the corresponding starting material, the title compound was synthesized. MS: 360.1(M + H)⁺)。

Example 257

6-chloro-2- (5-phenylaminomethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

Reacting NaBH (OAc)₃(84mg, 0.4mmol) was added to a solution of 5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridine-3-carbaldehyde (28.6mg, 0.1mmol, example 9) and aniline (9.3mg0.1mmol) in MeOH (3mL) and the resulting reaction mixture was stirred at RT overnight before it was poured into ice-water and extracted with EtOAc (2X10 mL). The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product, which was purified by prep-HPLC to give the title compound (7.2mg, 20%) as a white solid. MS: 364.2(M + H)⁺)。

The following compounds listed in table 7 were prepared in analogy to the procedure described for the preparation of example 257 using the appropriate starting materials.

TABLE 7

Example 263

6-chloro-2- [5- (2-morpholin-4-yl-2-oxo-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

[A](5-bromo-pyridin-3-yl) -acetic acid methyl ester

To a solution of (5-bromo-pyridin-3-yl) -acetic acid (4.2g, 20mmol) in methanol (50mL) at 0 deg.C was slowly added thionyl chloride (4.4mL, 60 mmol). After the addition, the reaction mixture was warmed and heated to reflux temperature for 2 hours. After cooling back to room temperature, the reaction mixture was concentrated in vacuo and the residue was redissolved in EtOAc (250mL) and treated with NaHCO₃Aqueous solution and brine. The organic layer was washed with Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (4.6g, quantitative) as a pale yellow solid. MS: 230.1&232.0(M+H⁺)。

[B][5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl]-acetic acid

The reaction mixture was washed with (5-bromo-pyridin-3-yl) -acetic acid methyl ester (230mg, 1.0mmol), 6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (182mg, 1.0mmol), CuI (40mg, 0.21mmol), Cs₂CO₃(650mg, 2.0mmol) and (+) - (1S, 1S) -1, 2-diaminocyclohexane (0).1mL, 0.8mmol) was dissolved in IIAlkane (4.0ml) and the resulting reaction mixture was heated at 150 ℃ for 2 hours, after which it was poured into H₂O (20mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (230mg, 72.5%) as a light brown oil. MS: 317.1(M + H)⁺)。

[C]6-chloro-2- [5- (2-morpholin-4-yl-2-oxo-ethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinoline- 1-ketones

Reacting [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl]Acetic acid (50mg, 0.16mmol), HATU (122mg, 0.32mmol), Et₃N (64mg, 0.64mmol) and morpholine (56mg, 0.64mmol) were dissolved in DCM (4.0mL) and the resulting reaction mixture was stirred at room temperature overnight. After distilling off DCM, the residue was redissolved in EtOAc and washed with brine. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by preparative-HPLC to give the title compound (8.5mg, 13.9%) as a light yellow oil. MS: 386.1(M + H)⁺)。

Example 264

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -N- (2-hydroxy-ethyl) -acetamide

The title compound was synthesized in analogy to the procedure described for the preparation of example 263[ C ] using [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -acetic acid and 2-amino-ethanol as starting materials.

MS：360.1(M+H⁺)。

Example 265

6-chloro-2- [5- (1-methylamino-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

[A]1- (5-bromo-pyridin-3-yl) -ethanol

Methyl magnesium bromide (1M in THF, 12mL, 12mmol) was added dropwise to a solution of 5-bromo-pyridine-3-carbaldehyde (1.85, 10mmol) in dry THF (20mL) at-78 ℃. The resulting mixture was slowly warmed to 0 ℃ over a 2 hour period and then saturated with NH₄Aqueous Cl solution was quenched. After extraction with DCM, the organic layer was washed with brine, dried over anhydrous Na₂SO4 was dried, filtered and concentrated in vacuo to give the title compound as a crude product (1.9g, 98%).

[B]3-bromo-5- (1-chloro-ethyl) -pyridine

To a solution of 1- (5-bromo-pyridin-3-yl) -ethanol (201mg, 1mmol) in DCM (10mL) was added thionyl chloride (200uL) dropwise. The resulting reaction mixture was heated to reflux for 3 hours, after which the solvent was removed in vacuo to afford the crude product as a white solid. It was used directly in the next step without further purification.

[C][1- (5-bromo-pyridin-3-yl) -ethyl]-methyl-amine

To a solution of 3-bromo-5- (1-chloro-ethyl) -pyridine (221mg, 1mmol) in DMF (10mL) was added methylamine hydrochloride (134mg, 2mmol) and K₂CO₃(572mg, 4 mmol). The resulting reaction mixture was heated to reflux for 3 hours, after which it was washed with H₂O quenches it. After extraction with DCM, the organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration gave the title compound as a crude product, which was used directly in the next step without further purification.

[D]6-chloro-2- [5- (1-methylamino-ethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one

6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (36mg, 0.2mmol), [1- (5-bromo-pyridin-3-yl) -ethyl]Methyl-amine (85.6mg, 0.4mmol), CuI (3.8mg, 0.02mmol), (1S,2S) -cyclohexane-1, 2-diamine (4.5mg, 0.04mmol) and Cs₂CO₃(130mg, 0.4mmol) was dissolved in 1, 4-bisIn an alkane (5 mL). The reaction mixture was subjected to a microwave reaction at 150 ℃ for 2.5 hours, after which it was poured into H₂O (15mL) and extracted with EtOAc (2 × 10 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by prep-HPLC to give the title compound (15mg, 26%) as a white solid. MS: 316.2(M + H)⁺)。

Example 266

6-chloro-2- [5- (1-dimethylamino-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

In analogy to the procedure described for the preparation of example 265, dimethylamine (step C) and [1- (5-bromo-pyridin-3-yl) -ethyl ] were used]-dimethyl-amine (step D) as the corresponding starting material. MS: 330.2(M + H)⁺)。

Example 267

6-chloro-2- [5- (1-methyl-1H-imidazole-2-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

[A](5-bromo-pyridin-3-yl) - (1-methyl-1H-imidazol-2-yl) -methanol

At-78 ℃ under N₂n-BuLi (0.16mL, 1.6M, 1.0mmol) was added to a solution of 1-methyl-1H-imidazole (82mg, 1.0mmol) in THF (10mL) with protection and the reaction mixture was stirred at-78 deg.C for 0.5H; 5-bromo-pyridine-3-carbaldehyde (186mg, 1.0mmol) was then added to the above solution and stirring was continued at-78 ℃ for an additional 2 hours. The reaction mixture was poured into water (5.0mL) and extracted with EtOAc (2 × 50 mL). The organic layer was washed with anhydrous Na₂SO₄The mixture is dried and then is dried,filtration and concentration in vacuo gave the crude product (210mg, 78.4%) as a white solid. MS: 268.1&270.1(M+H⁺)。

[B]6-chloro-2- [5- (1-methyl-1H-imidazole-2-carbonyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinoline-1- Ketones

(5-bromo-pyridin-3-yl) - (1-methyl-1H-imidazol-2-yl) -methanol (150mg, 0.56mmol), 6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (90mg, 0.49mmol) (intermediate A-2), CuI (30mg, 0.16mmol), Cs₂CO₃(330mg, 1.0mmol) and (+) - (1S, 1S) -1, 2-diaminocyclohexane (0.08mL, 0.64mmol) were dissolved in bisAlkane (4.0 mL). The resulting mixture was heated at 150 ℃ for 2 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 75 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by preparative-HPLC to give the title compound (4.5mg, 2.5%) as a light yellow oil. MS: 367.1(M + H)⁺)。

Example 268

6-chloro-2- [5- (4-methyl-4H- [1, 2, 4] triazol-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

[A][5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl]-methyl acetate

To [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] at 0 deg.C]Acetic acid (example 263[ B ]]) (217mg, 0.68mmol) in methanol (25mL) was added slowly thionyl chloride (0.44mL, 6.0 mmol). After the addition, the reaction mixture was warmed and heated at 80 ℃ for 2 hours. After cooling back to room temperature, it was concentrated in vacuo and the residue was dissolved in EtOAc (150mL) and washed with saturated NaHCO₃The aqueous solution was then washed with brine. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (224mg, quantitative) as a pale brown oil. MS: 331.1(M + H)⁺)。

[B][5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl]-acetyl hydrazine

Reacting [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl]Methyl acetate (100mg, 0.30mmol) and hydrazine monohydrate (0.75mL) were dissolved in ethanol (8.0mL) and the reaction mixture was heated at 90 ℃ for 3h, after which it was cooled and concentrated in vacuo to give the crude product (100mg, quantitative) as a light yellow oil. MS: 331.1(M + H)⁺)。

[C]6-chloro-2- [5- (4-methyl-4H- [1, 2, 4]]Triazol-3-ylmethyl) -pyridin-3-yl]-3, 4-dihydro-2H- Isoquinolin-1-ones

In a 5mL sealed tube, [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl]-Acetylhydrazine (100mg, 0.30mmol) and trimethyl orthoformate (0.07mL) were dissolved in dimethyl formamideIn an alkane (0.8mL) and heated at 100 ℃ for 2 hours. After cooling to room temperature, methylamine (1.0mL, 2.0M in THF), acetic acid (0.03mL) and di (R) were addedAlkane (2.0 mL). The vial was resealed and heated to 130 ℃ for 2 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was then purified by preparative-HPLC to give the title compound (8.3mg, 7.8%) as a pale yellowish oil. MS: 354.1(M + H)⁺)。

Example 269

6-chloro-2- [5- (1- [1, 2, 3] triazol-2-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

[A]2- [5- (1-bromo-ethyl) -pyridin-3-yl]-6-chloro-3, 4-dihydro-2H-isoquinolin-1-one

PBr is prepared from₃(541mg, 2mmol) was added dropwise to 6-chloro-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one (example 13) (302mg, 1mmol) in 5mL of DCM at 0 ℃. The reaction was stirred at RT for 2 hours, after which it was washed with saturated NaHC0₃The aqueous solution was neutralized and extracted with DCM (10mL, 2 ×). The organic layer was washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to afford the crude product as an oil, which was used in the next step without further purification (380mg, 100%). MS: 365.2(M + H)⁺。

[B]6-chloro-2- [5- (1- [1, 2, 3)]Triazol-2-yl-ethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinoline- 1-ketones

NaH (30mg, 0.12mmol) was added to 2H- [1, 2,3]Triazole (8.3mg, 0.12mmol) in DMF (5mL) at 0 deg.C and the resulting reaction mixture was stirred for 10min before 2- [5- (1-bromo-ethyl) -pyridin-3-yl was added]-6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (36.5mg, 0.1 mmol). After stirring for an additional 1 hour at RT, it was poured into ice-water (5mL) and extracted with EtOAc (2 × 10 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by prep-HPLC to give the title compound (7.5mg, 21%) as a white solid. MS: 354.2(M + H)⁺)。

The following compounds listed in table 8 were prepared in analogy to the procedure described for the preparation of example 269 using the appropriate starting materials.

TABLE 8

Example 279

6-chloro-2- (5-methanesulfinyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one

MCPBA (17.3mg, 0.1mmol) was added to a solution of 6-chloro-2- (5-methylsulfanyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one (example 59) (30.5mg, 0.1mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 2 hours before it was neutralized with 5% aqueous NaOH and extracted with DCM (5mL, 2 ×). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was then purified by prep-HPLC to give the title compound (6mg, 19%) as a white solid. MS: 321.1(M + H)⁺)。

Example 280

6-chloro-2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

[A]5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridine-3-carbaldehyde

CuI (190mg, 1mmol), (1S,2S) -cyclohexane-1, 2-diamine (228mg, 2mmol) and Cs₂CO₃(6.5g, 20mmol) was added to 6-chloro-3, 4-dihydro-2H-isoquinolin-1-one (1.82g, 10mmol, intermediate A-2) and 5-bromo-pyridine-4-carbaldehyde (3.72g, 20mmol) in dichloromethaneIn an alkane (15 mL). The reaction mixture was heated to 150 ℃ for 2.5 hours using microwaves, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 20 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (2.0g, 70%) as a brown oil. MS: 287.0(M + H)⁺)。

[B]6-chloro-2- [4 (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one

Reacting NaBH (OAc)₃(84mg, 0.4mmol) was added to a solution of 5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridine-4-carbaldehyde (28.6mg, 0.1mmol) and 1-methyl-piperazine (10mg, 0.1mmol) in DCM and MeOH (10mL, 1: 1). The reaction mixture was stirred at RT overnight, after which it was poured into ice-water (10mL) and extracted with EtOAc (2 × 10 mL). The organic layer was washed with brine, over anhydrous MgSO₄Dried, filtered and concentrated in vacuo to give the crude product, which was then purified by prep-HPLC to give the title compound (7.2mg, 16%),as a white solid. MS: 371.1(M + H)⁺)。

Example 281

5-chloro-3, 3-dimethyl-2- [5- (1-methyl-1H-pyrazol-4-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 204, using 5-chloro-2- (5-chloromethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate a-12-1) and 1-methylpyrazole-4-boronic acid pinacol ester, the title compound was obtained as light yellowish solid (yield 15%). MS: 367.2(M + H)⁺)。

The following compounds listed in Table 9 were prepared analogously to the procedure described for the preparation of examples 1,2 or 3[ B ], using the appropriate starting materials, where appropriate followed by separation by preparative chiral HPLC.

TABLE 9

Example 315

Ethanesulfonic acid [4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl ] -amide

[A]2- (8-amino-5, 6,7, 8-tetrahydro-isoquinolin-4-yl) -5-chloro-2, 3-dihydro-isoindol-1-one

In a 25mL sealed tube, 5-chloro-2, 3-dihydro-isoindol-1-one (801mg, 4.8mmol), 4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-ylamine (intermediate B-12[ A ] was placed]，999mg，4.4mmol)，CuI (200mg，1.1mmol)，Cs₂CO₃(3.0g, 9.2mmol) and (+) - (S, S) -1, 2-diaminocyclohexane (0.4mL, 3.2mmol) were dissolved in dioxaneAlkane (16 mL). The resulting reaction mixture was heated at 150 ℃ for 3 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 125 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexanes gradient) to afford the title compound (1.2g, 80%) as a light yellow solid. MS: 314.2(M + H)⁺)。

[B]Ethanesulfonic acid [4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinoline-8- Base of]-amides of

To 2- (8-amino-5, 6,7, 8-tetrahydro-isoquinolin-4-yl) -5-chloro-2, 3-dihydro-isoindol-1-one (156mg, 0.5mmol) and Et at 0 deg.C₃To a stirred solution of N (210uL) in DCM (10mL) was added ethanesulfonyl chloride (48uL mg, 0.5mmol) and stirring continued at 0 ℃ for 1 h. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organics were washed with brine, washed with Na₂SO₄Drying, filtration and concentration afforded the title compound. The residue was isolated by preparative-HPLC to give a racemic mixture of the title compound (170mg, 84%) as a light yellow solid. MS: 406.1(M + H)⁺)。

Example 316

(+) -Ethanesulfonic acid [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl ] -amide

Example 317

(-) -ethanesulfonic acid [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl ] -amide

Para-ethanesulfonic acid [4- (5-chloro-1-oxo-1, 3-dihydro-iso-isomerIndol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl]Chiral HPLC separation of the racemic mixture of (170mg, example 315) to provide (+) -ethanesulfonic acid [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl ] -5, 6, 7-tetrahydro-isoquinolin-8-yl]Amide (47mg, example 316), MS: 406.2(M + H)⁺) And (-) -ethanesulfonic acid [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl)]Amide (39mg, example 317). MS: 406.2(M + H)⁺。

Example 318

(-) -N- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide

Example 319

(+) -N- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide

[A]2- (7-amino-6, 7-dihydro-5H- [ 2)]Pyridin-4-yl) -5-chloro-2, 3-dihydro-isoindol-1-one

In a 25mL sealed tube, 5-chloro-2, 3-dihydro-isoindol-1-one (801mg, 4.8mmol), 4-bromo-6, 7-dihydro-5H- [ 2[ -O]Pyridin-7-ylamine (intermediate B-18[ C ]]，937mg，4.4mmol)，CuI(200mg，1.1mmol)，Cs₂CO₃(3.0g, 9.2mmol) and (+) - (S, S) -1, 2-diaminocyclohexane (0.4mL, 3.2mmol) were dissolved in dioxaneAlkane (16 mL). The resulting reaction mixture was heated at 150 ℃ for 3 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (2 × 125 mL). The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexanes gradient) to afford the title compound (1.02g, 80%) as a light yellow solid. MS: 300.2(M + H)⁺)。

[B]N- [4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2]Pyridin-7-yl]- Acetamide

To 2- (7-amino-6, 7-dihydro-5H- [2] at 0 DEG C]Pyridin-4-yl) -5-chloro-2, 3-dihydro-isoindol-1-one (126mg, 0.42mmol) and Et₃To a stirred solution of N (1.0mL) in DCM (10mL) was added acetyl chloride (0.032mL, 0.44mmol) and stirred at 0 ℃ for 1 h. The resulting mixture was extracted with EtOAc (2 × 100mL) and the combined organic layers were washed with brine, anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc-heptane to give the racemic mixture of the title compound (121mg, 85%) as a light yellow solid. MS: 342.1(M + H)⁺). This racemic mixture is then separated by chiral HPLC to provide (-) -N- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [ 2[ -2 ]]Pyridin-7-yl]-acetamide (33mg, example 318), MS: 342.1(M + H)⁺) And (+) -N- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2]Pyridin-7-yl]-acetamide (27mg, example 319). MS: 342.1(M + H)⁺。

The following compounds listed in table 10 were prepared analogously to the procedure described for the preparation of examples 316 and 317 or 318 and 319 using the appropriate starting materials.

Watch 10

Example 342

(+) -N- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide

Example 343

(-) -N- [ (R or S) -4- ((S or R) -5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro- 5H-[2]Pyridin-7-yl]-acetamide

Example 344

(+) -N- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6,7- dihydro-5H- [2]Pyridin-7-yl]-acetamide

Example 345

(-) -N- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6,7- dihydro-5H- [2]Pyridin-7-yl]-acetamide

[A]2- (7-amino-6, 7-dihydro-5H 2]Pyridin-4-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindoles Indole-1-ones

Reacting 5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one (intermediate A-13-1, 390mg, 2mmol), 4-bromo-6, 7-dihydro-5H- [ 2[ -O]Pyridin-7-ylamine (intermediate B-18[ C ]]318mg, 1.5mmol), CuI (38mg, 0.2mmol), (1S,2S) -cyclohexane-1, 2-diamine (45mg, 0.4mmol) and CsCO₃(750mg, 4mmol) of the mixture was dissolved in IIAlkane (10 mL). The resulting reaction mixture was heated at 140 ℃ for 12 hours, after which it was cooled to room temperature and filtered through a pad of silica gel (0.5-1cm) and washed with diethyl ether. The combined filtrates were concentrated in vacuo to give the crude product, which was used in the next reaction step without purification. MS: 328.1(M + H)⁺)。

[B]N- [4- (5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2]Pyridine (II) Pyridin-7-yl-acetamides

To 2- (7-amino-6, 7-dihydro-5H 2 at 0 DEG C]Pyridin-4-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (490mg, 1.5mmol) in DCM (15mL) was added Et₃N (3mmol) and acetyl chloride (156mg, 2 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, after which it was poured into 1N in twoHCl in alkane (15mL) and washed with EtOAc (15mL x 2). After decanting the organic layer, the aqueous layer was adjusted to pH with saturated aqueous sodium bicarbonate solution>8. It was extracted with EtOAc (20mL x2) and the combined organic layers were washed with brine, anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give the desired product (228mg, 62%) as a mixture of four diastereomers, which was subjected to SFC separation (IC250mm X50mm, 5um, mobile phase A: supercritical CO)₂，B：IPA(0.05％NH₃H₂O), a: B ═ 60: 40, 140mL/min), giving (+) -N- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] methyl ester]Pyridin-7-yl]-acetamide (31mg, example 342), MS: 370.1(M + H)⁺) (-) -N- [ (R or S) -4- ((S or R) -5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2]Pyridin-7-yl]-acetamide (35mg, example 343), MS: 370.1(M + H)⁺) (+) -N- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2]Pyridin-7-yl]-acetamide (39mg, example 344), MS: 370.1(M + H)⁺) And (-) -N- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2]Pyridin-7-yl]-acetamide (34mg, example 345), MS: 370.1(M + H)⁺)。

Example 346

N- [4- (5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7,8-tetrahydro-isoquinoline-8- Base of]-methanesulfonamide

[A]2- (8-amino-5, 6,7, 8-tetrahydro-isoquinolin-4-yl) -5-chloro-3-ethyl-2, 3-dihydro-isoindole-1-carboxylic acid Ketones

Reacting 5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one (intermediate A-13-1, 390mg, 2mmol), 4-bromo-5, 6,7, 8-tetrahydroisoquinolin-8-amine (intermediate B-12[ A ] to form a reaction mixture]339mg, 1.5mmol), CuI (38mg, 0.2mmol), (1S,2S) -cyclohexane-1, 2-diamine (45mg, 0.4mmol) and CsCO₃(750mg, 4mmol) of the mixture was dissolved in IIIn an alkane (10mL) and heated at 140 ℃ for 12 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of silica gel (0.5-1cm) and rinsed with diethyl ether. The combined filtrates were concentrated in vacuo to afford the crude product, which was used in the next step reaction without further purification. MS: 342.1(M + H)⁺)

[B]N- [4- (5-chloro-3-ethyl-1-oxo-1, 3-didn-isoindol-2-yl) -5, 6,7, 8-tetraradon-isoquinoline Lin-8-yl radical]-methanesulfonamide

To a solution of 2- (8-amino-5, 6,7, 8-tetrahydro-isoquinolin-4-yl) -5-chloro-3-ethyl-2, 3-dihydro-isoindol-1-one (511.5mg, 1.5mmol) in DCM (15mL) at 0 deg.C was added Et₃N (3mmol) and methanesulfonyl chloride (228mg, 2 mmol). The resulting reaction mixture was stirred at room temperature for 1 hourThen, pour it into 1N in twoHCl in alkane (15mL) and washed with EtOAc (15mL x 2). After decanting the organic layer, saturated NaHCO was used₃The aqueous layer is basified to pH>8. After extraction with EtOAc (20mL x2), the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound (228mg, 62%) as a mixture of the four diastereomers. MS: 420.1(M + H)⁺)。

The mixture of diastereomers was then subjected to SFC separation (IC250mm X50mm, 5um, mobile phase A: supercritical CO)₂，B：IPA(0.05％NH₃H₂O), a: B60: 40, 140mL/min), giving four separate diastereomers (examples 347, 348, 349 and 350). MS: 420.1(M + H)⁺)。

The following compounds listed in table 11 were prepared analogously to the procedure described for preparation examples 342, 343, 344 and 345 or examples 347, 348, 349 and 350 using the appropriate starting materials.

TABLE 11

The following compounds listed in table 12 were prepared in analogy to the procedure described for the preparation of example 140 using the appropriate starting materials.

TABLE 12

In analogy to the procedure described for preparation example 229, the following compounds listed in table 13 were prepared using the appropriate starting materials as shown by or very similar to the procedure described for preparation example 7.

Watch 13

Example 430

3-methyl-pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide

[A](5-bromo-pyridin-3-yl) -methanol

To a suspension of 5-bromo-pyridine-3-carbaldehyde (10.0g, 53.7mmol) in MeOH (100mL) at 0 deg.C was added sodium borohydride (2.2g, 59.1 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour, after which it was quenched with water (5.0 mL). Evaporation of the solvent afforded a pale yellowish oil, which was redissolved in EtOAc and washed with brine. The organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the title compound (9.6g, 95%) as a colorless oil. MS: 188.0&190.0(M+H⁺)。

[B]3-bromo-5-chloromethyl-pyridine

To a solution of (5-bromopyridin-3-yl) methanol (3g, 16.0mmol) in DCM (15mL) was added thionyl chloride (7.59g, 63.8mmol) dropwise at 0 deg.C and the reaction mixture was stirred at room temperature overnight. The mixture was poured onto ice/water (20mL) and basified with concentrated NaOH solution (8 mL). The mixture was extracted with EtOAc (2 × 50mL) and the combined organic layers were extracted with anhydrous Na₂SO₄Dried, filtered and evaporated to dryness. The remainder is led toPurification by flash chromatography on silica gel eluting with a gradient of 0 to 40% EtOAc-heptane afforded the title compound (3.08g, 93%) as a white solid. MS: 206.0, 207.9(M + H)⁺)。

[C](5-bromo-pyridin-3-yl) -methylamines

3-bromo-5-chloromethyl-pyridine (10.3g, 50mmol) was dissolved in methanolic ammonia (7N, 250ml) and heated at 60 ℃ overnight. After adjusting the pH to > 12 by addition of aqueous NaOH (1N), the mixture was extracted with EtOAc. The organic layer was washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The crude product was purified by recrystallization to give the title compound as a solid (2.5g, 27%). MS: 187.1(M + H)⁺)。

[D]2- (5-aminomethyl-pyridin-3-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

(5-bromo-pyridin-3-yl) -methylamine (281mg, 1.5mmol), 5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate A-12, 196mg, 1.0mmol), CuI (38mg, 0.2mmol), Cs, in a 25mL sealed tube₂CO₃A mixture of (652mg, 2.0mmol) and (+) - (S, S) -1, 2-diaminocyclohexane (68.4mL, 0.6mmol) was dissolved in bisIn an alkane (3 mL). The resulting reaction mixture was heated at 150 ℃ for 7 h before it was poured into water (10mL) and extracted with EtOAc (20mLx 2). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product (320mg, 100%). Without further purification, it was taken directlyUsed in the next step. MS: 302.1(M + H)⁺)。

[E]3-methyl-pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindole-2-) Phenyl) -pyridin-3-ylmethyl]-amides of

To 2- (5-aminomethyl-pyridin-3-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (30mg, 0.1mmol), Et at room temperature₃To a solution of N (15.3mg, 0.15mmol) and 3-methyl-pyridine-2-carboxylic acid (13.7mg, 0.1mmol) in DMF (3mL) was added HATU (57.0mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 1 hour. Both water and EtOAc were added and the organic layer was washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a residue which was then purified by preparative HPLC to give the title compound (10mg, 24%) as a solid. MS: 421.2(M + H)⁺)。

The following compounds listed in table 14 were prepared analogously to the procedure described for the preparation of example 430 using the appropriate starting materials.

TABLE 14

Example 441

2- [5- (1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]5-chloro-2- (5-iodo-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate A-12) (390mg, 2mmol), 3, 5-diiodo-pyridine (662mg, 2mmol), CuI (38mg, 0.2mmol), (1S,2S) -cyclohexane-1, 2-diamine (45mg, 0.4mmol) and K₃PO₄(888mg, 4mmol) of the mixture was dissolved in IIAlkane (10 mL). The reaction mixture was heated at 110 ℃ for 3 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (25mL x 2). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave a crude product which was then purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to afford the title compound (495mg, 62%) As a white solid. MS: 399.0(M + H)⁺)。

[B]3- [5- (6-chloro-1, 1-dimethyl-3-oxo-3-dihydro-isoindol-2-yl) -pyridin-3-yloxy]-pyridine Pyrrolidine-1-carboxylic acid tert-butyl ester

The sealed microwave tube was charged with CuI (19.1mg, 0.1mmol), 1, 10-phenanthroline (36mg, 0.2mmol), Cs₂CO₃(750mg, 2.0mmol), 5-chloro-2- (5-iodo-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (399mg, 1.0mmol), 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (374mg, 2mmol), and toluene (5 mL). The reaction mixture was heated at 110 ℃ for 24 hours. The resulting suspension was cooled to room temperature and filtered through a pad of silica gel (0.5-1cm) and rinsed with diethyl ether. The filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography to give the title compound (310mg, 68%). MS: 458(M + H)⁺)。

[C]5-chloro-3, 3-dimethyl-2- [5- (pyrrolidin-3-yloxy) -pyridin-3-yl]-2, 3-dihydro-isoindoline- 1-Ketone trifluoroacetic acid salt

To a solution of 3- [5- (6-chloro-1, 1-dimethyl-3-oxo-3-dihydro-isoindol-2-yl) -pyridin-3-yloxy ] -pyrrolidine-1-carboxylic acid tert-butyl ester (310mg, 0.67mmol) in DCM was added TFA (1mL) and the resulting mixture was stirred at room temperature for 3 hours. After removal of the solvent in vacuo, the crude product was obtained as a yellowish oil and used in the next step without further purification.

[D]2- [5- (1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl]-5-chloro-3, 3-dimethyl-2, 3-di Hydro-isoindol-1-ones

To 5-chloro-3, 3-dimethyl-2- [5- (pyrrolidin-3-yloxy) -pyridin-3-yl at 0 deg.C]Et was added to a solution of (e) -2, 3-dihydro-isoindol-1-one trifluoroacetate (94.2mg, 0.2mmol)₃N (1mmol) and acetyl chloride (23.4mg, 0.3 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, after which it was poured into H₂O (1mL) and extracted with EtOAc (15mL x 2). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product, which was purified by preparative HPLC to give the title compound (25.5mg, 35%) as a white solid. MS: 400.2(M + H)⁺)。

Example 442

2- [5- ((R) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using (R) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (step B), the title compound was obtained as white solid. MS: 400.2(M + H)⁺)。

Example 443

2- [5- ((S) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using (S) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (step B), the title compound was obtained as white solid. MS: 400.2(M + H)⁺)。

Example 444

5-chloro-3, 3-dimethyl-2- [5- (1-propionyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using propionyl chloride (step D), the title compound was obtained as white solid. MS: 414.2(M + H)⁺)。

Example 445

5-chloro-2- [5- (1-methanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using methanesulfonyl chloride (step D), the title compound was obtained as white solid. MS: 436.2(M + H)⁺)。

Example 446

5-chloro-2- [5- (1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using ethanesulfonyl chloride (step D), the title compound was obtained as white solid. MS: 450.2(M + H)⁺)。

Example 447

5-chloro-2- [5- ((R) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using (R) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (step B) and ethanesulfonyl chloride (step D), the title compound was obtained as white solid. MS: 450.2(M + H)⁺)。

Example 448

5-chloro-2- [5- ((S) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using (S) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (step B) and ethanesulfonyl chloride (step D), the title compound was obtained as white solid. MS: 450.2(M + H)⁺)。

Example 449

2- [5- (1-acetyl-piperidin-4-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (step B), the title compound was obtained as white solid. MS: 414.3(M + H)⁺)

Example 450

2- [5- (1-acetyl-azetidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using tert-butyl 3-hydroxy-cyclobutanecarboxylate (step B), the title compound was obtained as white solid. MS: 386.2(M + H)⁺)。

Example 451

5-chloro-3, 3-dimethyl-2- [5- (1-propionyl-azetidin-3-yloxy) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using tert-butyl 3-hydroxy-cyclobutanecarboxylate (step B) and propionyl chloride (step D), the title compound was obtained as white colorAnd (3) a solid. MS: 400.1(M + H)⁺)。

Example 452

5-chloro-2- [5- (1-methanesulfonyl-azetidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using tert-butyl 3-hydroxy-cyclobutanecarboxylate (step B) and methanesulfonyl chloride (step D), the title compound was obtained as white solid. MS: 422.1(M + H)⁺)。

Example 453

5-chloro-2- [5- (1-ethanesulfonyl-azetidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 441, using tert-butyl 3-hydroxy-cyclobutanecarboxylate (step B) and ethanesulfonyl chloride (step D), the title compound was obtained as white solid. MS: 436.1(M + H)⁺)。

Example 454

5-chloro-2- [5- ((S) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 137, 5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate a-12), 3-bromo-5- [ (S) -3- (tert-butyl-dimethyl-silanyloxy) -pyrrolidin-1-yl was used]Pyridine (step C), to obtain the title compound as a white solid. MS: 358.1 (M + H)⁺)。

Example 455

2- [5- (4-acetyl-piperazin-1-yl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]4- (5-bromo-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester

Piperazine-1-carboxylic acid tert-butyl ester (1.86g, 10mmol), 3, 5-dibromopyridine (2.37g, 10mmol), palladium (II) acetate (0.11g, 0.5mmol), anphos (0.35g, 0.6mmol), and sodium tert-butoxide (1.68g, 15mmol) in dioxaneThe mixture in alkane (10mL) was heated in a microwave reactor at 130 ℃ for 2 hours. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate: hexane ═ 1: 5) to afford the title compound as a white solid (1.84g, 54%). MS: 342.2 (M)⁺)。

[B]4- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-yl]-piperazine Oxazine-1-carboxylic acid tert-butyl ester

5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate A-12, 690mg, 3.51mmol), 4- (5-bromo-pyridin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester (1.0g, 2.92mmol), CuI (166.8mg, 0.88mmol), (1S,2S) -cyclohexane-1, 2-diamine (120mg, 1.75mmol), and Cs₂CO₃(1.90g, 5.84mmol) was dissolved in IIAlkane (10 mL). The reaction mixture was subjected to a microwave reaction at 150 ℃ for 2.5 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (50mL x 2). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product which was purified by flash chromatography (eluting with ethyl acetate: hexane ═ 1: 1) to give the title compound as a yellowish oil (340mg, 25.6%). MS: 457.3(M + H)⁺)。

[C]5-chloro-3, 3-dimethyl-2- (5-piperazin-1-yl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one

Reacting 4- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-yl]A mixture of tert-butyl-piperazine-1-carboxylate (0.34g, 0.74mmol) and trifluoroacetic acid (2mL) in DCM (5mL) was stirred at room temperature for 1 hour. After removal of the solvent, the residue was treated with aqueous ammonia to adjust the pH to-9 and then extracted with DCM. The organic layer was washed with water and anhydrous Na₂SO₄And (5) drying. After removal of the solvent, the crude product was obtained as a yellowish oil (266mg, 100%). MS: 357.2(M + H)⁺)。

[D]2- [5- (4-acetyl-piperazin-1-yl) -pyridin-3-yl]-5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindole Indole-1-ones

To a solution of 5-chloro-3, 3-dimethyl-2- (5-piperazin-1-yl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one (52mg, 0.146mmol) and TEA (29.5mg, 0.292mmol) in DCM (5mL) was added acetyl chloride (17.2mg, 0.219mmol) dropwise at 0 ℃. After stirring at room temperature for 1 hour, the mixture was treated with water and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄And (5) drying. After removal of the solvent, the residue was purified by preparative HPLC to provide the title compound as a white solid (23mg, 40%). MS: 399.2(M + H)⁺)。

Example 456

5-chloro-3, 3-dimethyl-2- [5- (4-propionyl-piperazin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 455, using propionyl chloride (step D), the title compound was obtained as white solid (yield 41%). MS: 413.2(M + H)⁺)。

Example 457

5-chloro-2- [5- (4-methanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydroisoindol-1-one

In analogy to the procedure described for the preparation of example 455, using methanesulfonyl chloride (step D), the title compound was obtained as white solid (yield 35%). MS: 435.2(M + H)⁺)。

Example 458

5-chloro-2- [5- (4-ethanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydroisoindol-1-one

In analogy to the procedure described for the preparation of example 455, using ethanesulfonyl chloride (step D), the title compound was obtained as white solid (yield 40%). MS: 449.2(M + H)⁺)。

Example 459

5-chloro-2- {5- [4- (3-chloro-pyridine-2-carbonyl) -piperazin-1-yl ] -pyridin-3-yl } -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

The reaction mixture was washed with 5-chloro-3, 3-dimethyl-2- (5-piperazin-1-yl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one (example 455[ C)]) (52mg, 0.146mmol), 3-chloro-pyridine-2-carboxylic acid (25.3mg, 0.161mmol), HATU (83.3mg, 0.219mmol) and Et₃A mixture of N (29.5mg, 0.292mmol) in DCM (5mL) was stirred at room temperature for 2 h. The mixture was treated with water and extracted with DCM. The organic layer was washed with anhydrous Na₂SO₄After drying and removal of solvent, the residue was purified by preparative HPLC to provide the titleCompound (33mg, 45%) as a white solid. MS: 496.3(M + H)⁺)。

Example 460

2- [5- (1-acetyl-pyrrolidin-3-yl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]1- (2, 5-dihydro-pyrrol-1-yl) -ethanones

To a solution of 2, 5-dihydro-1H-pyrrole (1.0g, 14.5mmol) and triethylamine (2.93g, 29mmol) in DCM (20mL) was added acetic anhydride (2.2g, 21.7mmol) dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes, after which water was added. The organic layer was washed with saturated aqueous sodium bicarbonate and brine in this order and with anhydrous Na₂SO₄And (5) drying. After removal of the solvent, the crude product was obtained as a white solid (2.89g) and used in the next step without further purification. MS: 112.2(M + H)⁺)。

[B]1- [3- (5-bromo-pyridin-3-yl) -pyrrolidin-1-yl]-ethanones

A mixture of 1- (2, 5-dihydro-pyrrol-1-yl) -ethanone (70mg, 0.63mmol), 3-bromo-5-iodo-pyridine (283 mg, 1mmol), triethylamine (130mg, 1.26mmol), formic acid (41mg, 0.88mmol) and tetrakis (triphenylphosphine) palladium (0) (72.8mg, 0.063mmol) in DMF (3mL) was stirred at 90 ℃ under nitrogen for 24 h. After cooling to room temperature, the mixture is taken up in waterTreated and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After removal of the solvent, the residue was purified by flash chromatography to afford the title compound as a yellowish oil (25mg, 15%). MS: 269.1(M + H)⁺)。

[C]2- [5- (1-acetyl-pyrrolidin-3-yl) -pyridin-3-yl]-5-chloro-3, 3-dimethyl-2, 3-dihydro-iso Indol-1-ones

The reaction mixture was washed with 5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate A-12, 160mg, 0.82mmol), 1- [3- (5-bromo-pyridin-3-yl) -pyrrolidin-1-yl]Ethanone (160mg, 0.6mmol), CuI (34mg, 0.8mmol), (1S,2S) -cyclohexane-1, 2-diamine (41mg, 0.36mmol) and Cs₂CO₃(390mg, 1.2mmol) of the mixture was dissolved in IIIn an alkane (5 mL). The reaction mixture was subjected to a microwave reaction at 150 ℃ for 2.5 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (25mL x 2). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Drying, filtration and concentration in vacuo gave the crude product, which was then purified by preparative-HPLC to give the title compound (23mg, 10%) as a white solid. MS: 384.2(M + H)⁺)。

Example 461

2- (1 '-acetyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [3, 4' ] bipyridinyl-5-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]1- (3, 6-dihydro-2H-pyridin-1-yl) -ethanones

Analogously to preparation example 460[ A]The procedure described, using 1,2, 3, 6-tetrahydropyridine, gave the crude product as a white solid (yield 90%). MS: 126.0(M + H)⁺)。

[B]1- (5-bromo-3 ', 4', 5 ', 6' -tetrahydro-2 'H- [3, 4']Bipyridyl-1' -yl) -ethanones

Analogously to preparation example 460[ B]The procedure described, using 1- (3, 6-dihydro-2H-pyridin-1-yl) -ethanone, gave the title compound as a yellowish oil (yield 15%). MS: 283.2(M + H)⁺)。

[C]2- (1 '-acetyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [3, 4']Bipyridin-5-yl) -5-chloro-3, 3-di Methyl-2, 3-dihydro-isoindol-1-ones

Analogously to preparation example 460[ C]The procedure described was followed using 1- (5-bromo-3 ', 4', 5 ', 6' -tetrahydro-2 'H- [3, 4']Bipyridin-1' -yl) -ethanone to give the title compound (28mg, 10%) as a white solid. MS: 398.2(M + H)⁺)。

Example 462

2- [6- (1-acetyl-piperidin-3-yl) -pyrazin-2-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

[A]3- (6-chloro-pyrazin-2-yl) -piperidine-1, 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester

To a solution of piperidine-1, 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester (90g, 350.1mmol) in dry THF (180mL) at 0 deg.C was slowly added bis- (trimethylsilyl) -amide sodium (1M in THF, 450mL, 450 mmol). The reaction mixture was stirred at the same temperature for 0.5hr, after which it was slowly added under argon to a solution of 2, 6-dichloropyrazine (60g, 401.6mmol) in dry THF (180 mL). The resulting reaction mixture was stirred at 0 ℃ for 1hr, then allowed to warm to room temperature and quenched by the addition of saturated NH₄Aqueous Cl (360mL) was quenched. The organic layer was washed with anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo to provide the crude title product. It was then used directly in the next step without further purification.

[B]3- (6-chloro-pyrazin-2-yl) -piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester

A solution of 3- (6-chloro-pyrazin-2-yl) -piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (350.1mmol) in THF (360mL) and 1.5N aqueous NaOH (360mL) was heated at 80 ℃ for 5hr after it was cooled to room temperature, the aqueous layer was separated and then carefully acidified to pH 5 by addition of 1N aqueous HCl solution the resulting mixture was extracted with DCM (300mL × 3) and the combined organic layers were extracted with anhydrous Na₂SO₄Drying, filtering and concentrating under reduced pressureThis gave the crude title compound (46g), which was used directly in the next step without further purification.

[C]3- (6-chloro-pyrazin-2-yl) -piperidine-1-carboxylic acid tert-butyl ester

A solution of 1-tert-butyl 3- (6-chloro-pyrazin-2-yl) -piperidine-1, 3-dicarboxylate (46g) in o-xylene (300mL) and DMA (30mL) was heated at reflux for 5hrs₂SO₄Dried, filtered, and concentrated in vacuo. The residue obtained was then purified on a silica gel column eluting with EA: DCM: Hex 1: 3 to give the title compound (18g) as a white solid. MS: 298.7(M + H)⁺)。

[D]3- [6- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyrazin-2-yl]-piperazine Pyridine-1-carboxylic acid tert-butyl ester

3- (6-chloro-pyrazin-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (892.5mg, 3.0mmol), 5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (intermediate A-12, 586.5mg, 3.0mmol), CuI (171.4mg, 0.9mmol), (1S,2S) -cyclohexane-1, 2-diamine (205.2mg, 1.8mmol) and Cs₂CO₃(1.956g, 6.0mmol) of the mixture was dissolved in bisAlkane (15 mL). The reaction mixture was subjected to a microwave reaction at 150 ℃ for 2.5 hours, after which it was poured into H₂O (50mL) and extracted with EtOAc (50mL x 2). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give the crudeThe product was then purified by flash chromatography to afford the title compound (450mg, 33%) as a white solid. MS: 457.2(M + H)⁺)。

[E]5-chloro-3, 3-dimethyl-2- (6-piperidin-3-yl-pyrazin-2-yl) -23-dihydro-isoindol-1-one

Reacting 3- [6- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyrazin-2-yl]A mixture of tert-butyl-piperidine-1-carboxylate (0.45g, 0.99mmol) and trifluoroacetic acid (2mL) in DCM (10mL) was stirred at room temperature for 1 h. After removal of the solvent, the residue was treated with water and extracted with DCM. The aqueous solution was treated with saturated aqueous sodium carbonate and extracted with EtOAc. The combined organic layers were washed with anhydrous Na₂SO₄And (5) drying. After removal of the solvent, the crude product was obtained as a yellowish oil (352.9mg, 100%). MS: 357.2(M + H)⁺)。

[F]2- [6- (1-acetyl-piperidin-3-yl) -pyrazin-2-yl]-5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindole Indole-1-ones

To 5-chloro-3, 3-dimethyl-2- (6-piperidin-3-yl-pyrazin-2-yl) -2, 3-dihydro-isoindol-1-one (80mg, 0.22mmol) and Et at 0 deg.C₃To a mixture of N (44.4mg, 0.44mmol) in DCM (2mL) was added acetyl chloride (26.4mg, 0.34 mmol). After removal of the solvent, the residue was purified by prep-HPLC to obtain the title compound (30.6mg, 35%) as a white solid. MS: 399.2(M + H)⁺)。

Example 463

5-chloro-3, 3-dimethyl-2- [6- (1-propionyl-piperidin-3-yl) -pyrazin-2-yl ] -2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 462, using propionyl chloride (step F), the title compound was obtained (36.3mg, 40%) as white solid. MS: 413.2(M + H)⁺)。

Example 464

5-chloro-2- [6- (1-ethanesulfonyl-piperidin-3-yl) -pyrazin-2-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 462, using ethanesulfonyl chloride (step F), the title compound was obtained (29.6mg, 30%) as white solid. MS: 449.2(M + H)⁺)。

Example 465

5-chloro-2- [6- (1-methanesulfonyl-piperidin-3-yl) -pyrazin-2-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one

In analogy to the procedure described for the preparation of example 462, using methanesulfonyl chloride (step F), the title compound was obtained (19.1mg, 20% yield) as a white solid. MS: 435.0(M + H)⁺)。

Example 466

N- [ (S or R) -4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide

Example 467

N- [ (R or S) -4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide

[A]4 '-bromo-5, 5-dimethyl-6', 7 '-dihydro-5' H-spiro [1, 3-di Alkane-2, 8' -isoquinolines]

4-bromo-6, 7-dihydro-5H-isoquinolin-8-one (intermediate B-11[ C ]]5.0g, 22mmol), 2, 2-dimethyl-propane-1, 3-diol (2.8g, 26.5mmol) and toluene-4-sulfonic acid (85mg, 0.44mmol) in toluene (100mL) were heated at 135 ℃ for 12 h. After cooling to room temperature, it was concentrated under reduced pressure to give a residue, which was extracted between EtOAc and water. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying, filtration, and concentration in vacuo gave the crude product (6.1g, 88.9%) as a pale yellow solid. MS: 312.2&314.2(M+H⁺)。

[B]5-chloro-2- (5, 5-dimethyl-6 ', 7 ' -dihydro-5 ' H-spiro [1, 3-di Alkane-2, 8' -isoquinolines]-4′- 2, 3-dihydro-1H-isoindol-1-ones

4 '-bromo-5, 5-dimethyl-6', 7 '-dihydro-5' H-spiro [1, 3-diAlkane-2, 8' -isoquinolines](5.0g, 16mmol), 5-chloro-2, 3-dihydro-isoindol-1-one (2.7g, 16mmol), (+) - (1S, 1S) -1, 2-diaminocyclohexane (0.576mL, 4.8mmol), copper (I) iodide (456mg, 2.4mmol) and Cs₂CO₃(10.4g, 32mmol) in bisThe mixture in alkane (80mL) was heated at 150 ℃ for 4 hours. After cooling to room temperature, it was diluted with water (50mL) and extracted with EtOAc (200mL × 2). The combined organic layers were washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo afforded the crude product (5.5g, 86%) as a pale yellow solid. MS: 399.1(M + H)⁺)。

[C]5-chloro-2- (5, 5-dimethyl-6 ', 7 ' -dihydro-5 ' H-spiro [1, 3-di Alkane-2, 8' -isoquinolines]-4′- Yl) -3, 3-dimethyl-2, 3-dihydro-1H-isoindol-1-one

To 5-chloro-2- (5, 5-dimethyl-6 ', 7 ' -dihydro-5 ' H-spiro [1, 3-di-n) at 0 deg.CAlkane-2, 8' -isoquinolines]To a stirred solution of (4' -yl) -2, 3-dihydro-1H-isoindol-1-one (2.38g, 6mmol) in THF was added LiHMDS (18mL1.0M in THF, 18 mmol). Stirring at 0 deg.C for 30min, and adding CH₃I (1.5mL, 24 mmol). The resulting mixture was stirred at 0 ℃ for another 30min before it was diluted with water (10mL) and extracted with EtOAc (2x100 mL). The combined organic layers were washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo afforded the crude product which was then purified by silica gel flash chromatography eluting with a gradient of 0 to 5% MeOH-DCM to give the title compound (664mg, 26%) as a yellow foam. MS: 427.1(M + H)⁺)。

[D]4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H-isoquine Quinoline-8-ones

To 5-chloro-2- (5, 5-dimethyl-6 ', 7 ' -dihydro-5 ' H-spiro [1, 3-diAlkane-2, 8' -isoquinolines](iii) -4' -Yl) -3, 3-dimethyl-2, 3-dihydro-1H-isoindol-1-one (0.66g, 1.55mmol) in MeOH (2mL) was added 4N in bisHCl in an alkane (1.5mL, 6mmol) and the reaction mixture was stirred at room temperature for 2 hours. After evaporation of the solvent, the residue was diluted with DCM (20mL) and saturated NaHCO₃(10mL) of the aqueous solution. The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and evaporated to dryness. The residue obtained is quenched through silica gel eluted with a gradient of 0 to 50% hexane-ethyl acetatePurification by flash chromatography gave the title compound (421mg, 80%) as a pale yellow solid. MS: 341.1(M + H)⁺)。

[E]2- (8-amino-5, 6,7, 8-tetrahydro-isoquinolin-4-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindole Indole-1-ones

4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H-isoquinolin-8-one (408mg, 1.2mmol), NaBH₃CN (75mg, 1.2mmol) and CH₃COONH₄A mixture of (1.0g, 12mmol) in isopropanol (10mL) was heated to reflux for 3 hours. After cooling to room temperature, it was concentrated to give a yellowish oil, which was extracted between water and EtOAc (2 × 100 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to afford the crude title compound (327mg, 80%) as a brown solid. MS: 342.1&325.1(M+H⁺)。

[F]N- [4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-iso Quinolin-8-yl]-acetamide

To 2- (8-amino-5, 6,7, 8-tetrahydro-isoquinolin-4-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one (140mg, 0.42mmol) and Et at 0 deg.C₃To a stirred solution of N (1.0mL) in DCM (10mL) was added acetyl chloride (0.032mL, 0.44mmol) and stirring was continued at 0 ℃ for 1 h. After evaporation of the solvent, the residue was extracted between water and EtOAc (2 × 100 mL). The combined organic layers were washed with brine, over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to provide the crude product, which is then purified by washing with 0 to 50% EtOAc-heptaneFlash chromatography on silica gel with gradient elution gave the racemic mixture of the title compound (117mg, 73%) as a light yellow solid. MS: 384.1(M + H)⁺). The racemic mixture was then separated by chiral HPLC to provide N- [ (S or R) -4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl]-acetamide (35mg, example 466), MS: 384.1(M + H)⁺) And N- [ (R or S) -4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl]-acetamide (38mg, example 467) MS: 384.1(M + H)⁺。

Example 468

N- [4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6,7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide

In analogy to the procedure described for the preparation of examples 466 and 467, propionyl chloride (step E) was used to provide the racemic mixture of the title compound (19.1mg, 20%) as a white solid. MS: 398.1(M + H)⁺)。

Example A

The compounds of formula (I) can be used in a manner known per se as active ingredients in the preparation of tablets of the following composition:

example B

The compounds of formula (I) can be used in a manner known per se as active ingredients in the preparation of capsules of the following composition:

Claims (8)

1. A compound selected from:

6-chloro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -nicotinonitrile;

6-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-chloro-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-chloro-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

2- (5-bromo-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridine-3-carbaldehyde;

6-chloro-2- (5-methoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-isopropoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-hydroxy-1-methyl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((R) -1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methoxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

2- (5-amino-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-1-methoxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one

6-chloro-2- [5- (cyclopropyl-hydroxy-methyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (cyclopropyl-methoxy-methyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-trifluoromethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methoxy-1-methyl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

ethanesulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -amide;

6-chloro-2- [5- (2-oxo-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (1-methyl-1H-pyrazolo [3, 4-c ] pyridin-4-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-8 '-hydroxy-3, 4, 5', 6 ', 7', 8 '-hexahydro- [2, 4' ] biisoquinolin-1-one;

n- (6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -propionamide;

6-chloro-2- {5- [ hydroxy- (1-methyl-1H-imidazol-2-yl) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (3, 4-difluoro-phenyl) -hydroxy-methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (3, 5-difluoro-phenyl) -hydroxy-methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (4-ethyl-phenyl) -hydroxy-methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (hydroxy-phenyl-methyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-hydroxy-1-phenyl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1- (3, 4-difluoro-phenyl) -1-hydroxy-ethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1- (3, 5-difluoro-phenyl) -1-hydroxy-ethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (6-methyl-pyrazin-2-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (morpholine-4-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-hydroxy-pyrrolidine-1-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -N, N-dimethyl-nicotinamide;

6-chloro-2- [5- (pyrrolidine-1-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -N-methyl-nicotinamide;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) N-cyclopropyl-nicotinamide;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) N- (4-fluoro-phenyl) -nicotinamide;

5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -N-phenyl-nicotinamide;

6-chloro-2- [5- (4, 4-difluoro-piperidine-1-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-methoxymethyl-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-hydroxymethyl-5-oxo-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2-pyrimidin-5-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2-pyridazin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2-pyridin-3-yl-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -2H-isoquinolin-1-one;

6-chloro-2- [4- (1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-hydroxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

2- [5- (1-amino-cyclopropyl) -pyridin-3-yl ] -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-4H- [1, 2, 4] triazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methylsulfanyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-difluoromethoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-dimethoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [ 5-fluoro-4- (1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {4- [ (4-fluoro-phenyl) -hydroxy-methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [4- (1-methoxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (1-methyl-1H-pyrrolo [3, 2-c ] pyridin-7-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopropyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-2H- [1, 2, 4] triazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopropoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [ 5-fluoro-4- (1-hydroxy-1-methyl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (5-methyl-pyrazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (1H-pyrrolo [3, 2-c ] pyridin-7-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-3, 4-dihydro- [2, 4' ] biisoquinolin-1-one;

3- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -isonicotinonitrile;

6-chloro-2- (5-fluoro-4-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [ 5-fluoro-4- (1-methoxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-isopropoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [4- (cyclopropyl-methoxy-methyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-3H-imidazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1, 1-dioxo-1 λ 6- [1, 2] thiazinan-2-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1, 1-dioxo-1 λ 6-isothiazolidin-2-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-hydroxymethyl-5-oxo-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

(S) -1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -pyrrolidine-2-carboxylic acid methyl ester;

6-chloro-2- (5-methoxy-pyridin-3-yl) -3-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-isopropyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-3-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -3-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-3-methyl-2-pyrimidin-5-yl-3, 4-dihydro-2H-isoquinolin-1-one;

(R) -6-chloro-3-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

(S) -6-chloro-3-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

8-chloro-3-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-methoxy-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

5, 6-dichloro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

2-chloro-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

2-methoxy-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

2-methoxy-6-pyridin-3-yl-7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

6-chloro-5-fluoro-2- (5-methoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-7-fluoro-2- (5-methoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-7-fluoro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-4, 4-dimethyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methoxy-pyridin-3-yl) -4, 4-dimethyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -4, 4-dimethyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-4-methyl-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-fluoro-pyridin-3-yl) -4-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methoxy-pyridin-3-yl) -4-methyl-3, 4-dihydro-2H-isoquinolin-1-one;

5-chloro-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (2-isopropyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5- [1, 2, 4] triazol-1-ylmethyl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (2-methyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (2-oxo-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((S) -2-methoxymethyl-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (2-oxo-piperidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

ethanesulfonic acid [5- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

5-chloro-2- (1-methyl-1H-pyrazolo [3, 4-c ] pyridin-4-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (8-hydroxy-5, 6, 7, 8-tetrahydro-isoquinolin-4-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-3-methyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

6-chloro-3-methyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-methoxy-pyridin-3-yl) -3-methyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-methyl-2- (4-methyl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl ] -3-methyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-fluoro-pyridin-3-yl) -3-methyl-2, 3-dihydro-isoindol-1-one;

3-benzyl-5-chloro-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-ethyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-3-ethyl-2- (5-methoxy-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-fluoro-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-methoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-difluoromethoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-hydroxymethyl-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-methyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

2-hydroxy-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

6-chloro-2- (5-imidazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-isopropyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-ethyl-4-methyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-hydroxy-piperidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

propane-2-sulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -amide

6-chloro-2- [5- (3-hydroxy-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((R) -3-hydroxy-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -3-hydroxy-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((S) -2-hydroxymethyl-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((R) -2-hydroxymethyl-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-pyrazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

n- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide

N- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -acetamide

6-chloro-2- (5-morpholin-4-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxo-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1, 1-dioxo-1 λ 6-thiomorpholin-4-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxo-)Oxazolidin-3-ylmethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-methyl-2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-pyrazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-propyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylmethyl ] -1H-imidazole-2-carboxylic acid ethyl ester;

6-chloro-2- [5- (2-hydroxymethyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (oxetan-3-ylaminomethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [4- (2-hydroxy-ethyl) -piperazin-1-ylmethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-isopropyl-piperazin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4, 4-difluoro-piperidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 3-difluoro-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxa-6-aza-spiro [34] oct-6-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxa-6-aza-spiro [3.3] hept-6-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 3-difluoro-piperidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-oxo-piperidin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5- [1, 2, 3] triazol-2-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5- [1, 2, 3] triazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-chloro-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-methyl- [1, 2, 4] triazol-4-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (5-methyl- [1, 2, 4] triazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-methyl- [1, 2, 4] triazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5- [1, 2, 4] triazol-4-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5- [1, 2, 4] triazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-benzoimidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-indazol-1-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-indazol-2-ylmethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (6-fluoro-indol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (7-fluoro-indol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-fluoro-indol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-pyrazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-cyclopropyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-trifluoromethyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-methyl-pyrazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-ethyl-imidazol-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

2- (5-aminomethyl-pyridin-3-yl) -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-isopropoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-1-methyl-ethoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [2- (1-methyl-pyrrolidin-2-yl) -ethoxymethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopentyloxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopropylmethoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-fluoro-phenoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-cyclopropylmethoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (tetrahydro-furan-2-ylmethoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-ethoxymethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclobutoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-iso-methyl)Azol-4-ylmethyl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methanesulfonyl-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (6-methyl-pyridin-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (6-morpholin-4-yl-pyridin-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-2H-pyrazol-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-pyrazol-4-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 3-difluoro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-difluoro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 5-difluoro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-trifluoromethyl-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 6-dichloro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-chloro-6-fluoro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 4-dichloro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 5-dichloro-benzyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

ethanesulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -amide;

n- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -benzenesulfonamide;

n- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -methanesulfonamide;

cyclopropanesulfonic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -amide;

6-chloro-2- [5- (4-fluoro-benzylamino) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 2, 2-trifluoro-ethylamino) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-morpholin-4-yl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

n- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -propionamide;

6-chloro-2- {5- [ (2-methyl-2H-pyrazol-3-ylmethyl) -amino ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-ylamino ] -2-methyl-propionic acid;

6-chloro-2- {5- [ (1-methyl-1H-imidazol-4-ylmethyl) -amino ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-dimethyl-iso-methyl)Azol-4-yl) -pyridin-3-yl]-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-fluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 4-difluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 5-difluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-chloro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 5-difluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-trifluoromethyl-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3-trifluoromethoxy-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-chloro-3-fluoro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (3, 4-dichloro-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-trifluoromethyl-phenyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-iso)Oxazol-4-yl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-imidazol-2-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 4-dimethyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -1-methyl-1H-pyrazole-4-carbonitrile

N- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -isobutyramide

Cyclopropanecarboxylic acid [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -amide

N- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -4-fluoro-benzamide

1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -3-cyclohexyl-urea

1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -3- (3-trifluoromethyl-phenyl) -urea

6-chloro-2- (5-hydroxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -acetamide;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -N-methyl-acetamide;

[5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -acetic acid methyl ester;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yloxy ] -N, N-dimethyl-acetamide;

6-chloro-2- (5-phenylaminomethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (4-fluoro-phenylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (3-fluoro-phenylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (4-chloro-phenylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (3-chloro-phenylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-morpholin-4-yl-2-oxo-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

2- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -N- (2-hydroxy-ethyl) -acetamide;

6-chloro-2- [5- (1-methylamino-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-dimethylamino-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-imidazole-2-carbonyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-4H- [1, 2, 4] triazol-3-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1- [1, 2, 3] triazol-2-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-imidazol-1-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-pyrazol-1-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1-, (Azol-2-ylamino) -ethyl]-pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1- [1, 2, 4] triazol-1-yl-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1- (2-oxo-pyrrolidin-1-yl) -ethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [1- (2-oxo-)Oxazolidin-3-yl) -ethyl]-pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

n- {1- [5- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -pyridin-3-yl ] -ethyl } -methanesulfonamide;

6-chloro-2- {5- [1- (3-fluoro-phenylamino) -ethyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-phenylamino-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methanesulfinyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

and pharmaceutically acceptable salts thereof.

2. A compound selected from:

5-chloro-3, 3-dimethyl-2- [5- (1-methyl-1H-pyrazol-4-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-difluoromethoxy-pyridin-3-yl) -3-ethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-ethyl-2- [5- (1-hydroxy-ethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (4-chloro-pyridin-3-yl) -3-ethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (4-chloro-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

6-chloro-5 '-nitro-3, 4-dihydro- [2, 4' ] biisoquinolin-1-one;

6-chloro-8 '-nitro-3, 4-dihydro- [2, 4' ] biisoquinolin-1-one;

8 '-amino-6-chloro-3, 4-dihydro- [2, 4' ] biisoquinolin-1-one;

ethanesulfonic acid (6-chloro-1-oxo-3, 4-dihydro-1H- [2, 4 '] biisoquinolin-8' -yl) -amide;

6 ' -chloro-2 ' - (5-fluoropyridin-3-yl) spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

6 ' -chloro-2 ' - [5- (difluoromethoxy) pyridin-3-yl ] spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

2-chloro-6- (5-fluoro-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-chloro-6- (5-difluoromethoxy-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

6- (5-fluoro-pyridin-3-yl) -2-methoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

6- (5-difluoromethoxy-pyridin-3-yl) -2-methoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

6 ' -chloro-2 ' - (pyridin-3-yl) spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

5-chloro-3-cyclopropyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

2-chloro-7, 7-dimethyl-6-pyridin-3-yl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-ethoxy-6- (5-fluoro-pyridin-3-yl) -7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-methoxy-7, 7-dimethyl-6-pyridin-3-yl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

5-chloro-3-cyclopropyl-2-pyridin-3-yl-2, 3-dihydro-isoindol-1-one;

5-chloro-3-cyclopropyl-2- (5-difluoromethoxy-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

6- (5-difluoromethoxy-pyridin-3-yl) -2-ethoxy-7, 7-dimethyl-6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

5-chloro-2- (5-isopropoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

6 ' -chloro-2 ' - (4-chloropyridin-3-yl) spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

5-chloro-2- (5-cyclopropoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

(S or R) -6-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

(R or S) -6-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

(R or S) -5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

(S or R) -5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

2- (8-amino-5, 6, 7, 8-tetrahydro-isoquinolin-4-yl) -5-chloro-2, 3-dihydro-isoindol-1-one;

n- [ (R or S) -4- ((R or S) -5-chloro-1-ethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((S or R) -5-chloro-1-ethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

ethanesulfonic acid [4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -amide;

ethanesulfonic acid [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -amide;

ethanesulfonic acid [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl-1-amide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- ((R or S) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -acetamide;

n- ((S or R) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -acetamide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- ((S or R) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -methanesulfonamide;

n- ((R or S) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -methanesulfonamide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- ((R or S) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -propionamide;

n- ((S or R) -6-chloro-1-oxo-3, 4, 5 ', 6', 7 ', 8' -hexahydro-1H- [2, 4 '] biisoquinolin-8' -yl) -propionamide;

n- [ (S or R) -4- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (S or R) -4- (6-chloro-1-oxo-3, 4-dihydro-1H-isoquinolin-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

ethanesulfonic acid [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -amide;

ethanesulfonic acid [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -amide;

n- [ (S or R) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (R or S) -4- (5-chloro-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

5-chloro-2- ((S or R) -8-hydroxy-5, 6, 7, 8-tetrahydro-isoquinolin-4-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- ((R or S) -8-hydroxy-5, 6, 7, 8-tetrahydro-isoquinolin-4-yl) -2, 3-dihydro-isoindol-1-one;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -acetamide;

n- [4- (5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-cyclopropyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-cyclopropyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-cyclopropyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-cyclopropyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (S or R) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

5-chloro-3, 3-dimethyl-2- (5-pyrazol-1-ylmethyl-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

2- [5- (3-amino-pyrazol-1-ylmethyl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -2, 3-dihydro-isoindol-1-one;

2- [5- (3-amino-pyrazol-1-ylmethyl) -pyridin-3-yl ] -6-chloro-3, 4-dihydro-2H-isoquinolin-1-one;

2-chloro-7, 7-dimethyl-6- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-methoxy-7, 7-dimethyl-6- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-ethoxy-7, 7-dimethyl-6- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

6 ' -chloro-2 ' - {5- [ (1H-pyrazol-3-ylamino) methyl ] pyridin-3-yl } spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

ethanesulfonic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

ethanesulfonic acid [5- (6-fluoro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

ethanesulfonic acid [5- (6-cyano-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

ethanesulfonic acid [5- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -N-methyl-methanesulfonamide;

n- { [5- (6 ' -fluoro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } ethanesulfonamide;

n- { [5- (6 ' -fluoro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } -N-methylethylsulfonamide;

ethanesulfonic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methyl-amide;

n- { [5- (6 ' -chloro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } propionamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -propionamide;

n- [5- (6-fluoro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -propionamide;

n- [5- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -propionamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -acetamide;

n- { [5- (5 ' -fluoro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } methanesulfonamide;

n- [5- (6-cyano-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- (6-fluoro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- { [5- (6 ' -fluoro-3 ' -oxospiro [ cyclopropane-1, 1 ' -isoindol ] -2 ' (3 ' H) -yl) pyridin-3-yl ] methyl } methanesulfonamide;

n- [5- ((S or R) -5-chloro-1-ethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- (5-fluoro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- ((R or S) -5-chloro-1-ethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

n- [5- (5-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

5-chloro-2- [5- (1, 1-dioxo-1 λ 6-isothiazolidin-2-ylmethyl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-oxo-piperidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-oxo-)Oxazolidin-3-ylmethyl) -pyridin-3-yl]-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-oxo-pyrrolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (3-methyl-2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1, 1-dioxo-1 λ 6- [1, 2] thiazinan-2-ylmethyl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (3-isopropyl-2-oxo-imidazolidin-1-ylmethyl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- (1, 5-dimethyl-1H-imidazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

5-chloro-3, 3-dimethyl-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- (3-methyl-1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (4-chloro-2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2, 5-dimethyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1, 5-dimethyl-1H-pyrazol-4-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [ 4-chloro-5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

2-chloro-7, 7-dimethyl-6- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

2-methoxy-7, 7-dimethyl-6- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -6, 7-dihydro-pyrrolo [3, 4-b ] pyridin-5-one;

5-chloro-2- [5- (4-chloro-2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

(R or S) -5-chloro-3-ethyl-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

(S or R) -5-chloro-3-ethyl-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

3-methyl-pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

3-chloro-pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

1-methyl-1H-imidazole-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

2-chloro-N- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -nicotinamide;

pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

3-methyl-3H-imidazole-4-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -6-methyl-nicotinamide;

3-chloro-N- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -isonicotinamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -nicotinamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -2-methyl-nicotinamide;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -4-methyl-nicotinamide;

2- [5- (1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- ((R) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- ((S) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (1-propionyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-methanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((R) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((S) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (1-acetyl-piperidin-4-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (1-acetyl-azetidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (1-propionyl-azetidin-3-yloxy) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-methanesulfonyl-azetidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-ethanesulfonyl-azetidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((S) -3-hydroxy-pyrrolidin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (4-acetyl-piperazin-1-yl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [5- (4-propionyl-piperazin-1-yl) -pyridin-3-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (4-methanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (4-ethanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- {5- [4- (3-chloro-pyridine-2-carbonyl) -piperazin-1-yl ] -pyridin-3-yl } -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (1-acetyl-pyrrolidin-3-yl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- (1 '-acetyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [3, 4' ] bipyridinyl-5-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [6- (1-acetyl-piperidin-3-yl) -pyrazin-2-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-3, 3-dimethyl-2- [6- (1-propionyl-piperidin-3-yl) -pyrazin-2-yl ] -2, 3-dihydro-isoindol-1-one;

5-chloro-2- [6- (1-ethanesulfonyl-piperidin-3-yl) -pyrazin-2-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [6- (1-methanesulfonyl-piperidin-3-yl) -pyrazin-2-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

n- [ (S or R) -4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [4- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

and pharmaceutically acceptable salts thereof.

3. A compound selected from:

6-chloro-2-pyridin-3-yl-3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (4-chloro-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-isopropoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- ((R) -1-hydroxy-ethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-cyclopropoxy-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

2-methoxy-6- (5-methoxy-pyridin-3-yl) -7, 8-dihydro-6H- [1, 6] naphthyridin-5-one;

5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-fluoro-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- (5-difluoromethoxy-pyridin-3-yl) -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

6-chloro-2- [5- (2-oxa-6-aza-spiro [3.4] oct-6-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- (5-methoxymethyl-pyridin-3-yl) -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (1-methyl-1H-pyrazol-4-ylmethyl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (2-methyl-2H-pyrazol-3-ylmethyl) -amino ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- [5- (2-methyl-2H-pyrazol-3-yl) -pyridin-3-yl ] -3, 4-dihydro-2H-isoquinolin-1-one;

6-chloro-2- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -3, 4-dihydro-2H-isoquinolin-1-one;

and pharmaceutically acceptable salts thereof.

4. A compound selected from:

(R or S) -5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

(S or R) -5-chloro-3-ethyl-2- (5-fluoro-pyridin-3-yl) -2, 3-dihydro-isoindol-1-one;

n- [ (R or S) -4- ((R or S) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -propionamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -5, 6, 7, 8-tetrahydro-isoquinolin-8-yl ] -acetamide;

n- [ (R or S) -4- ((S or R) -5-chloro-3-ethyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -methanesulfonamide;

n- [ (R or S) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

n- [ (S or R) -4- ((R or S) -5-chloro-3-methyl-1-oxo-1, 3-dihydro-isoindol-2-yl) -6, 7-dihydro-5H- [2] pyridin-7-yl ] -propionamide;

5-chloro-3, 3-dimethyl-2- {5- [ (1H-pyrazol-3-ylamino) -methyl ] -pyridin-3-yl } -2, 3-dihydro-isoindol-1-one;

6 ' -chloro-2 ' - {5- [ (1H-pyrazol-3-ylamino) methyl ] pyridin-3-yl } spiro [ cyclopropane-1, 1 ' -isoindol ] -3 ' (2 ' H) -one;

n- [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -methanesulfonamide;

3-methyl-pyridine-2-carboxylic acid [5- (6-chloro-1, 1-dimethyl-3-oxo-1, 3-dihydro-isoindol-2-yl) -pyridin-3-ylmethyl ] -amide;

2- [5- ((R) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- ((S) -1-acetyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-methanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((R) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- ((S) -1-ethanesulfonyl-pyrrolidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (1-acetyl-piperidin-4-yloxy) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (1-ethanesulfonyl-azetidin-3-yloxy) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- [5- (4-acetyl-piperazin-1-yl) -pyridin-3-yl ] -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (4-methanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

5-chloro-2- [5- (4-ethanesulfonyl-piperazin-1-yl) -pyridin-3-yl ] -3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

2- (1 '-acetyl-1', 2 ', 3', 4 ', 5', 6 '-hexahydro- [3, 4' ] bipyridinyl-5-yl) -5-chloro-3, 3-dimethyl-2, 3-dihydro-isoindol-1-one;

and pharmaceutically acceptable salts thereof.

5. A compound according to any one of claims 1 to 2 for use as therapeutically active substance.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a therapeutically inert carrier.

7. A compound according to any one of claims 1 to 2 for use in the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

8. The use of a compound according to any one of claims 1 to 4 for the preparation of medicaments for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.