EA043353B1 - SOMATOSTATIN MODULATORS AND THEIR APPLICATIONS - Google Patents

Description

Link to related applications

This application claims benefit from U.S. Provisional Patent Application Serial No. 62/472,480, filed March 16, 2017, which is incorporated herein by reference in its entirety.

Application for federal research funding

The present invention was made in part with the support of the United States Government under SBIR 1R44NS092231-01 from the National Institutes of Health.

Field of technology to which the present invention relates

Disclosed herein are compounds that are somatostatin modulators, pharmaceutical compositions, and the use of such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.

BACKGROUND OF THE INVENTION

Somatostatin is a peptide hormone that regulates the endocrine system and influences nerve transmission and cell proliferation through interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Six subtypes of somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5), which are encoded by five different somatostatin receptor genes. Modulation of a particular somatostatin receptor subtype or combination thereof is attractive for the treatment of conditions, diseases or disorders that would benefit from modulation of somatostatin activity.

Summary of the present invention

The compounds described herein are somatostatin modulator compounds. In some embodiments, the compounds described herein modulate one or more subtypes of somatostatin receptor proteins. In some embodiments, the compounds described herein modulate one subtype of somatostatin receptor. In some embodiments, the compounds described herein modulate the somatostatin receptor SSTR2. Somatostatin peptide analogues, such as octreotide and pasireotide, formulated as depot injections, have traditionally been used to normalize hormone levels for the treatment of growth hormone (GH)-secreting adenomas, pancreatic neuroendocrine tumors, and carcinoid tumors. Unfortunately, these analogues are effective in only about half of acromegalic patients with GH adenomas, and patients with carcinoid tumors often become resistant to therapy due to internalization and desensitization of the SST2a receptor. Additionally, these peptide drugs are extremely expensive and require frequent visits to the doctor's office for painful injections, which can lead to reactions at the injection site. The compounds described herein are molecules that are structurally different from their peptide analogues. The compounds described herein are somatostatin modulators, which are potent inhibitors of hormone secretion.

In one aspect, a compound of formula (III) or a pharmaceutically acceptable salt thereof is disclosed herein.

Formula (III) where

R ¹ is -NR ² R ³ , -OR ² or R ⁴ ;

R ² represents hydrogen, substituted or unsubstituted C ₁ -C ₄ -alkyl, substituted or unsubstituted C ₁ -C ₄ -heteroalkyl or substituted or unsubstituted C ₃ -C ₆ -cycloalkyl;

R ³ represents hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₄ heteroalkyl or substituted or unsubstituted C3-C6 cycloalkyl; or R ² and R ³ are taken together with the N atom to which they are attached to form substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl;

R ⁴ represents F, Cl, Br, -CN, -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH( CH ₃ ) ₂ ,

- 1 043353

-CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CF3, -S(=O)2CH ₃ , -CO2CH3, -CO2CH2CH3,

-C(=O)NH2, -C(=O)NHCH3 or -C( O)\(CH;) _: :

R ⁵ represents hydrogen or C1- _C4 alkyl;

each R ⁶ and R ⁷ independently represents hydrogen, halogen, substituted or unsubstituted C ₁ -C ₄ -alkyl, substituted or unsubstituted C ₂ -C ₄ -alkenyl, substituted or unsubstituted C ₂ -C ₄ -alkynyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted monocyclic C ₃ -C ₅ -heterocycloalkyl, which has 1 N atom, substituted or unsubstituted monocyclic C1-C5-heteroaryl , -CN, -OR ¹⁵ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -C(=O)N(R ¹⁵ )OR ¹⁵ , -N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁵ , -NR ¹⁵ C(=O)OR ¹⁵ , -OC(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁵ , -C(R ¹⁵ )=N-OR ¹⁵ , -SR ¹⁵ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

R ⁸ is hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -NH2, azetidinyl or pyrrolidinyl;

R ⁹ is hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ;

X ¹ represents N or CR ¹⁰ ;

R ¹⁰ represents hydrogen, F, Cl, Br, -CN, -N(R ¹⁵ ) ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -αalkoxy, C ₁ -C ₄ -fluoroalkyl or C ₁ - C ₄ -fluoroalkoxy;

X ² represents CR ⁷ or N;

X ³ represents CR ⁷ or N;

R ¹¹ represents hydrogen;

R ¹² represents hydrogen, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C ₃ -C ₅ -heterocycloalkyl, which has 1 O atom;

R ¹³ is hydrogen, -OR ¹⁵ , -N(R ¹⁵ )2, -CN, -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -fluoroalkyl; or R ¹² and R ¹³ are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted monocyclic 4-7 membered heterocyclic ring selected from substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperazinyl or substituted or unsubstituted azepanil; each R ¹⁴ is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; each R ¹⁵ is independently selected from hydrogen, substituted or unsubstituted C 1 -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₃ -C ₇ -cycloalkyl, substituted or unsubstituted monocyclic C ₂ -C ₆ - heterocycloalkyl which has 1 O atom, substituted or unsubstituted phenyl and substituted or unsubstituted monocyclic heteroaryl;

where substituted means that the group in question is optionally substituted by one or more added group(s) individually and independently selected from halogen, CN, -NH2, -OH, -NH(CH3), -N(CH3) 2, -CH3, -CH2CH3, -CF3, -OCH3 and -OCF3, where the term heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from oxygen, -NH-, -I(alkyl)- or sulfur, where the term monocyclic heteroaryl refers to a C ₁ -C ₅ -heteroaryl that contains 1-4 N atoms, 0-1 O atom and 0-1 S atom in the ring.

This document contemplates any combination of the groups described above for various variables. Throughout the present description, groups and their substituents are selected by one skilled in the art to provide stable moieties and compounds.

Also described herein is a pharmaceutical composition for the treatment of acromegaly, neuroendocrine tumor, neuropathy, nephropathy, malignancy, pain, or combinations thereof, comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. . In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

Any of the above aspects relate to further embodiments wherein an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof (a) is systemically administered to a mammal; and/or (b) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; and/or (f) administered by injection to a mammal; and/or (g) administered locally to a mammal; and/or (h) administered by ophthalmic administration; and/or (III) administered rectally to a mammal;

and/or (j) administered non-systemically or locally to a mammal.

Any of the foregoing aspects relates to additional embodiments wherein an effective amount of the compound is administered in single doses, including further embodiments wherein the compound is administered once per day to the mammal or the compound is administered to the mammal multiple times during the same day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, the compounds provided herein are orally administered to a human.

Presented are finished products that include packaging material, a compound of formula (III) or a pharmaceutically acceptable salt thereof in the packaging material and a label indicating that the compound or composition or a pharmaceutically acceptable salt thereof is used to modulate one or more protein subtypes somatostatin receptor or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulation of one or more somatostatin receptor protein subtypes.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed disclosure. It should be noted, however, that the detailed disclosure and specific examples, although describing specific embodiments, are provided for illustrative purposes only, as various changes and modifications to the spirit and scope of the present disclosure will become apparent to those skilled in the art from the present detailed disclosure.

Detailed Description of the Present Invention

Somatostatin (SST), also known as somatotropin release inhibitory factor (SRIF), was originally isolated from the sheep hypothalamus as a 14 amino acid peptide (Brazeau et al., Science 179, 77-79, 1973). An N-terminally extended 28 amino acid peptide with biological activity similar to the 14 amino acid somatostatin was then isolated (Pradayrol et al., FEBS Letters, 109, 5558, 1980; Esch et al., Proc. Natl. Acad. Sci. USA, 77, 6827-6831, 1980). SST is a regulatory peptide produced by certain cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts through both endocrine and paracrine pathways to influence its target cells. Many of these effects are due to inhibition of the secretion of other hormones, primarily growth hormone (GH). They are produced by a wide range of cell types in the central nervous system (CNS) and intestine and are characterized by numerous functions, including modulating the secretion of growth hormone (GH), insulin, glucagon, as well as many other hormones that are antiproliferative.

These pleotropic actions of somatostatins are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5). The six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997). All receptors are members of the class A subgroup of the GPCR superfamily. The SST2a receptor is the most widely expressed subtype in human tumors and is the dominant receptor by which GH secretion is inhibited. Unless otherwise specified, the term SSTR2 means SSTR2a.

Any one of the somatostatin receptor subtypes or a combination thereof can be selectively modulated. In some embodiments, selective modulation of any somatostatin receptor subtype relative to other somatostatin receptor subtypes reduces unwanted side effects in various clinical applications.

For example, selective modulation of SSTR2 activity mediates inhibition of growth hormone (GH) release from the anterior pituitary gland and glucagon release from the pancreas. SSTR2 is also involved in many other biological functions such as, but not limited to, cell proliferation, nociception, inflammation, and angiogenesis. In some embodiments, the selective SSTR2 modulator is used in the treatment of acromegaly, neuroendocrine tumors, pain, neuropathies, nephropathies and inflammation, as well as retinopathy resulting from abnormal blood vessel growth. In some other embodiments, the selective SSTR2 modulator is used in the treatment of arthritis, pain, cancer, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, Cushing's disease, acute lung injury, acute respiratory distress syndrome, and ophthalmic disorders such as age-related macular degeneration macular edema (AMD), diabetic retinopathy, diabetic macular edema, and Graves' ophthalmopathy, among others.

In one aspect, the compounds described herein are SSTR2 modulators. In some embodiments, the compounds described herein selectively modulate the activity of SSTR2 over other somatostatin receptors.

In some embodiments, the compounds described herein are suitable for oral administration to a mammal in need of treatment with a somatostatin modulator.

In some embodiments, the somatostatin receptor modulators described herein are useful in a wide range of therapeutic applications. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of a variety of diseases or conditions, such as, but not limited to, acromegaly, neuroendocrine tumors, retinopathy and other ophthalmic disorders, neuropathy, nephropathy, respiratory diseases, malignancies, pain, neurodegenerative diseases , inflammatory diseases, as well as psychiatric and neurodegenerative disorders. In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of acromegaly in a mammal.

In some embodiments, the somatostatin receptor modulators described herein inhibit the secretion of various hormones and trophic factors in mammals. In some embodiments, the compounds are used to suppress certain endocrine secretions such as, but not limited to, GH, insulin, glucagon, and prolactin. Suppression of certain endocrine secretions is useful in the treatment of disorders such as acromegaly; endocrine tumors such as carcinoids, VIPomas, insulinomas and glucagonomas; or diabetes mellitus and diabetes-related pathologies, including retinopathy, neuropathy and nephropathy. In some embodiments, somatostatin receptor modulators described herein are used to suppress exocrine secretions in the pancreas, stomach, and intestines to treat disorders such as pancreatitis, fistula, bleeding ulcers, and diarrhea associated with diseases such as AIDS or cholera. Disorders involving autocrine or paracrine secretion of trophic factors such as IGF-1 (as well as certain endocrine factors) that can be treated by administration of the compounds described herein include breast, prostate and lung malignancies (as small cell , and non-small cell epidermoids), as well as hepatomas, neuroblastomas, adenocarcinomas of the colon and pancreas (ductal type), chondrosarcomas and melanomas, diabetic retinopathy and atherosclerosis associated with vascular grafts, and restenosis after angioplasty.

In some embodiments, somatostatin receptor modulators described herein are used to inhibit neurogenic inflammatory mediators (eg, substance P or tachykinins) and can be used in the treatment of rheumatoid arthritis; psoriasis; topical inflammation, for example, associated with sunburn, eczema or other sources of itching; inflammatory bowel disease; irritable bowel syndrome; allergies, including asthma and other respiratory diseases. In some other embodiments, the somatostatin receptor modulators described herein function as neuromodulators in the central nervous system and are useful in the treatment of Alzheimer's disease and other forms of dementia, pain and headaches. In some embodiments, the somatostatin receptor modulators described herein provide cytoprotection for disorders involving visceral blood flow, including cirrhosis and esophageal varices.

Connections

The compounds of formula (III), including their pharmaceutically acceptable salts, are somatostatin receptor modulators. In some embodiments, the compounds of formula (III), including pharmaceutically acceptable salts thereof, are SSTR2 modulators. In some embodiments, somatostatin receptor modulators are somatostatin receptor agonists.

In some embodiments, the compounds described herein are at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times, at least 200 times, at least 300 times, or more than 400 times more selective in modulating SSTR2 activity than SSTR4 receptor activity. In some embodiments, the R ¹ moiety of the compounds described herein provides selectivity for modulating SSTR2 activity.

In some embodiments, it is desirable for SSTR2 modulators to have reduced propensity associated with inhibition of CYP2D6 and/or hERG. According to some

- 4 043353 embodiments of the compounds described herein reduce the propensity associated with inhibition of CYP2D6 and/or hERG. In some embodiments, the compounds described herein reduce the tendency associated with inhibition

CYP2D6 and hERG. In some embodiments, the R ¹ group of the compounds described herein reduces the propensity associated with inhibition of CYP2D6 and/or hERG.

The CYP2D6 gene encodes an enzyme that is predominantly expressed in the liver. CYP2D6 is a member of the cytochrome P450 family and is one of the more important enzymes involved in the metabolism of xenobiotics in humans. Drugs may function as inhibitors of CYP2D6 activity or inducers of CYP2D6 enzyme expression, resulting in decreased or increased CYP2D6 activity, respectively. If such a drug is taken concomitantly with a second drug that is metabolized by CYP2D6, the first drug may affect the rate of elimination of the second drug through a so-called drug-drug interaction. Thus, monitoring and minimizing CYP2D6 inhibition during drug discovery and development has become an important selectivity criterion when evaluating compounds that may move into clinical development (Wolf & Smith, I ARC Sci Publ 1999, 148, 209-229).

The hERG (human Ether-d-go-go-Related Gene) gene encodes the alpha subunit of the potassium ion channel K _v 11.1. When this channel's ability to conduct electrical current across the cell membrane is inhibited or compromised by drugs or mutations, it can lead to a potentially fatal disorder called long QT syndrome. Thus, monitoring and minimizing hERG inhibition during drug discovery and development has become an important selectivity criterion when evaluating compounds that may move into clinical development (Abbott et al., Cell 1999, 97, 175-187; Sanguinetti & Tristani-Firouzi, Nature 2006, 440, 463-9).

In some embodiments, group X of compounds of formula (III) improves the properties of the compounds compared to similar compounds in which X is CH. For example, as discussed herein, in some cases, Group X of compounds of formula (III) provides selectivity for modulating SSTR2 activity and/or reduces the susceptibility associated with CYP2D6 and/or hERG inhibition. In some embodiments, when X is C-NR2R ³ , the solubility in water in a pH 7.4 buffer is increased compared to compounds where X is CH.

In one aspect, provided herein is a compound of formula (III) or a pharmaceutically acceptable salt thereof

R4 A ¹²

Formula (III) where

R ¹ is -NR2R ³ , -OR ² or R ⁴ ;

R ² represents hydrogen, substituted or unsubstituted C ₁ -C ₄ -alkyl, substituted or unsubstituted C ₁ -C ₄ -heteroalkyl or substituted or unsubstituted C ₃ -C ₆ -cycloalkyl;

R ³ represents hydrogen, substituted or unsubstituted C ₁ -C ₄ -alkyl, substituted or unsubstituted C ₁ -C ₄ -heteroalkyl or substituted or unsubstituted C ₃ -C ₆ -cycloalkyl; or R ² and R ³ are taken together with the N atom to which they are attached to form substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl;

R ⁴ represents F, Cl, Br, -CN, -CH2CH3, -CH2CH2CH3, -CH( _CH3 ) ₂ , -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3 )3, -CH2F, -CHF2, -CF3, -CH2CF3, -S(=O) ₂ CH3, -CO2CH3, -CO2CH2CH3, -C(=O)NH2, -C(=O)NHCH3 or -C(= O)N(CH3)2;

R ⁵ represents hydrogen or C ₁ -C ₄ -alkyl;

each R ⁶ and R ⁷ independently represents hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C6-cycloalkyl, substituted or unsubstituted monocyclic C3-C5-heterocycloalkyl which has 1 N atom, substituted or unsubstituted monocyclic C1-C5-heteroaryl, -CN, -OR ¹⁵ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -C(=O)N(R ¹⁵ )OR ¹⁵ , -N(R ¹⁵ ) ₂ , -NR ¹⁵ C(=O)R ¹⁵ ,

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-NR ¹⁵ C(=O)OR ¹⁵ , -OC(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁵ , -C(R ¹⁵ )=N-OR ¹⁵ , -sr ¹⁵ ,

-S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

R ⁸ represents hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ , -OCF ₃ , -NH2, azetidinyl or pyrrolidinyl;

R ⁹ is hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ;

X ¹ represents N or CR ¹⁰ ;

R ¹⁰ represents hydrogen, F, Cl, Br, -CN, -N(R ¹⁵ ) ₂ , C1- _C4 alkyl, C1- _C4 alkoxy, C1- _C4 fluoroalkyl or C1- _C4 fluoroalkoxy ;

X ² represents CR ⁷ or N;

X ³ represents CR ⁷ or N;

R ¹¹ represents hydrogen;

R ¹² represents hydrogen, substituted or unsubstituted C1-C ₆ -alkyl, substituted or unsubstituted C1-C ₆ -heteroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C ₃ -C ₅ -heterocycloalkyl, which has 1 O atom;

R ¹³ represents hydrogen, -OR ¹⁵ , -N(R ¹⁵ )2, -CN, -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, C1-C ₆ alkyl or C1-C ₆ - fluoroalkyl; or R ¹² and R ¹³ are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted monocyclic 4-7 membered heterocyclic ring selected from substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperazinyl or substituted or unsubstituted azepanil; each R ¹⁴ is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; each R ¹⁵ is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1- _C6 heteroalkyl, substituted or unsubstituted _C3 - _C7 cycloalkyl, substituted or unsubstituted monocyclic _C2 - _C6 heterocycloalkyl, which has 1 O atom, substituted or unsubstituted phenyl and substituted or unsubstituted monocyclic heteroaryl;

where substituted means that the group in question is optionally substituted by one or more added group(s) individually and independently selected from halogen, -CN, -NH2, -OH, -NH(CH ₃ ), -N( CH ₃ )2, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ and -OCF ₃ , where the term heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from oxygen, -NH- , -I(alkyl)- or sulfur, where the term monocyclic heteroaryl refers to a C1- _C5 heteroaryl that contains 1-4 N atoms, 0-1 O atom and 0-1 S atom in the ring.

In some embodiments, R ¹ is -NR2R ³ . In some embodiments, R ¹ is -NHR ² . In some embodiments, R ¹ is -NH ₂ .

In some embodiments, R ² is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl. In some embodiments, ^R2 is hydrogen, _-CH3 , _-CH2CH3 , _-CH2CH2CH3 , -CH( _CH3 ) ₂ , _{-CH2CH2CH2CH3 , CH2CH} ( _{CH3 ) 2} , - CH(CH ₃ )(CH ₂ CH ₃ ), -C(CH ₃ ) ₃ , -CH2CH2OH -CH2CH2OCH3 or -CH2CN; R ³ represents hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2OH - CH2CH2OCH3, -CH2CN or CH2CF3; or R ² and R ³ are taken together with the N atom to which they are added to form substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl. In some embodiments, R ² is hydrogen or C1-C4 alkyl; R ³ represents hydrogen or C1-C ₄ alkyl. In some embodiments, R ³ is hydrogen.

In some embodiments, R ¹ is -OR ² .

In some embodiments, R ² is hydrogen, -CH ₃ , CH ₂ CH ₃ , -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CHCHCHCH3, -CH(CH3)(CH2CH3), C(CH3)3, -CH2CH2OH, -CH2CH2OCH3, -CH2CN.

In some embodiments, R ¹ is R ⁴ ; R ⁴ represents F, Cl, Br, -CN, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3) 3, -CH2F, -CHF2, -CF3, -CH2CF3, -S(=O)2CH3, -CO2CH3, -CO2CH2CH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O) N(CH3)2.

In some embodiments, R ¹ is -NR2R ³ , OR ² , F, Cl, Br, -CN, C1-C4 alkyl, -CH2F, -CHF2, -CF3, or -CH2CF3.

In some embodiments, R ^a , R ¹ , R ¹¹ , R ⁸ and R ⁹ are described in table. 4. In some embodiments, R ^a , R ⁸ and R ⁹ are described in table. 1, table. 2, table. 3 or table 4.According to

- 6 043353 some embodiments of R ¹¹ are described in table. 4.

Any combination of the groups described above for various variables is contemplated herein. Throughout the present description, the groups and their substituents are selected by one skilled in the art to provide stable moieties and compounds.

Typical connections described herein include those described in the following tables.

Table 1

Connection no. R ^a R ¹³ R ² R ⁸ R ⁹ 1-1 N Y Y/N ci- '- n N N 3-F 5-CH ₃ 1-2 F hee NN N n 3-F 5-СНз 1-3 with ^NHI n n 3-F 5-СНз 1-4 XXn n n 3-F 5-СНз 1-5 J. th LL LL n n 3-F 5-СНз 1-6 Η G Gn n n 3-F 5-СНз 1-7 II n cr ⁵ - n OSNZ transracemic) n 3-F 5-СНз 1-8 n Y Y/N N n 3-F 5-СНз 1-9 I h? y 'P X. ΖΧ Ϊ n n 3-F 5-СНз

- 7 043353

1-10 X TZ z H H 3-F 5-CH ₃ 1-11 Z _v ZZ X H H 3-F 5-CH ₃ 1-12 H jT jT NC^^N H H 3-F 5-CH ₃ 1-13 Z. ΖΞ X H H 3-F 5-CH ₃ 1-14 ^yy H H 3-F 5-CH ₃ 1-15 F -iH L·IC H H 3-F 5-CH ₃ 1-16 H ηχιΝ H H 3-F 5-CH ₃ 1-17 / o <fy^ ^ZI Г\ '° ZI Ϊ H H 3-F 5-CH ₃ 1-18 X IZ Z Oh ^=( -MJ o / H H 3-F 5-CH ₃ 1-19 H cVOA H H 3-F 5-CH ₃ 1-20 H H H 3-F 5-CH ₃

- 8 043353

1-21 o\/z Z. ΖΣ ϊ Η Η 3-F 5-CH ₃ 1-22 ζ ο ζ. ζζ ϊ Η Η 3-F 5-CH ₃ 1-23 J ΧΤ/Η V ⁿ y^n 0 Η Η 3-F 5-CH ₃ 1-24 / ο Ζ, ΖΣ ϊ Η Η 3-F 5-CH ₃ 1-25 Η £ G/N CU^N Η Η 3-CN 5-CH ₃ 1-26 Η ί Γη n ^r ^ ^N Η Η 3-F 5-CH ₃ 1-27 0 %3^ΝΗ Η Η 3-F 5-CH ₃ 1-28 Λ h ζ. ζζ ϊ Η СНз- 3-F 5-CH ₃ 1-29 £Γ Η Η Η 3-F 5-CH ₃ 1-30 Η £ £Η Cl'N'N Η CH ₃ CH- 3-F 5-СНз 1-31 Η Х°ХХн Η Η 3-F 5-CH ₃

- 9 043353

1-32 I ΙΞ Ξ b And Η Η 3-CN 5-F 1-33 L o g Η Η 3-F 5-CH ₃ 1-34 Η Η 3-F 5-CH ₃ 1-35 Η Η 3-F 5-CH ₃ 1-36 Η Η 3-СНз 5-CH ₃ 1-37 ^A'n ^- Η Η 3-S1 5-CH ₃ 1-38 Η Η 3-S1 5-CH ₃ 1-39 He Η Η 3-S1 5-CH ₃ 1-40 / o b ^z ~ ϊ Η Η 3-F 5-СНз 1-41 Η Ν £ G/N SG -' Ν CN (transracemic) Η 3-СНз 5-CH ₃ 1-42 Η ΙΪΗ Cr-'-N CN (transracemic) Η 3-F 5-CH ₃ 1-43 Η £ G/N £Ν Ν Ν Η Η 3-F 5-СНз 1-44 \ Ο Ζ, ΖΖΣ ϊ Η Η 3-F 5-СНз

- 10043353

1-45 Η YAYYAN Η Η Η 3-F 5-СНз 1-46 at ΙΖ Y Ζ, ΖΙ X Η Η 3-F 5-СНз 1-47 Η Ν I ΗΟ' ^Ν №^Ν Η Η 3-F 5-СНз 1-48 F ί GY Η CH ₃ - 3-F 5-СНз 1-49 F la IN Ν Η CH3CH2- 3-F 5-СНз 1-50 X ΙΖ ζ Y Η CH3CH2- 3-F 5-СНз 1-51 Η Η Η 3-F 5-СНз 1-52 Η Cel Η Η 3-F 5-СНз 1-53 / I ζ. ζτ I Η Η 3-F 5-СНз 1-54 ο ζ. ζζ I Η Η 3-F 5-СНз 1-55 X χζ ζ Y Η СНз- 3-F 5-СНз 1-56 F LI And Η F'-'N Η CH ₃ OCH ₂ CH ₂ - 3-F 5-СНз

- 11 043353

1-57 I / -N “N Η Η 3-F 5-CH ₃ 1-58 XI N -N Η Η 3-F 5-СНз 1-59 O N Η Η 3-F 5-СНз 1-60 O Η £Ή Ν Η Η 3-F 5-СНз 1-61 F Η £ -^Ν Η Η 3-F 5-СНз 1-62 I -p O Chh-/ 'Ν Η Η 3-F 5-СНз 1-63 /Hu o t Η Η 3-F 5-СНз 1-64 _Z X/ o t Η Η 3-F 5-СНз 1-65 χθ Η Η 3-F 5-СНз 1-66 F Η ^Ν Η Η 3-F 5-СНз 1-67 To. Η -Ν^ * Ν Η Η 3-F 5-OSNZ

- 12 043353

1-68 F 1 Η G ΓΗ H H 3-F 5-OCH ₃ 1-69 F 1 Η £ ΓΗ H H 3-F 5-CH ₃ 1-70 tL-- H CH ₃ - 3-F 5-CH ₃ 1-71 X τζ ζ lЯ' H CH ₃ - 3-F 5-CH ₃ 1-72 Cl όΦ H CH ₃ - 3-F 5-CH ₃ 1-73 X τζ ζ ^Я H H 3-F 5-CH ₃ 1-74 Ν ι Τ Η |Γ I I H H 3-F 5-CH ₃ 1-75 F 1 h jC i H CH ₃ - 3-F 5-CH ₃ 1-76 ⁴ o 1 h Ν XI // _rf ^N NW'N H H 3-F 5-CH ₃ 1-77 G X H H 3-F 5-C1 1-78 X xz z i u- H H 3-CH ₃ 5-CH ₃

- 13 043353

1-79 I A I- H H 3-C1 5-CH ₃ 1-80 F 1H L W N H H 3-CH ₃ 5-OCH ₃ 1-81 I ΙΞ Ξ a and H H 3-F 5-F 1-82 F Di Ci^^N H H 3-F 5-F 1-83 ^x o ds H H 3-CH ₃ 5-CH ₃ 1-84 . ^Dyn H H 3-CH ₃ 5-CH ₃ 1-85 F 1 ^H G T/Y NC^- N H H 3-F 5-C1 1-86 IZ^''Z d o H H 3-F 5-F 1-87 H F^^^N H H 3-F 5-C1 1-88 o A- ^z \ ^ZT /VW* H H 3-F 5-C1 1-89 F iH JL X H CH ₃ - 3-F 5-CH ₃

- 14 043353

1-90 ABOUT 1 n XX Η Η 3-S1 5-F 1-91 1 n XX Η Η z-sn ₃ 4-F 1-92 ZI AA/V Η Η 3-S1 H 1-93 Ζ ^ζ γ ^ζι ΛΛΛΓ Η Η z-sn ₃ H 1-94 'Ο Η Η 3-F 5-CH ₃

Connections in the table. 1 have the following names:

1-1: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro5 methylphenyl)pyridin-2-amine;

1-2: 4-(4-aminopiperidin-1-yl)-3 -(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5 -(3-fluoro5-methylphenyl)pyridin-2 -amine;

1-3: 4-(4-aminopiperidin-1-yl)-3 -(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5 -(3 fluoro5-methylphenyl)pyridin-2- amine;

1-4: 4-(4-aminopiperidin-1-yl)-3-(1-ethenyl-5,6-difluoro-1H-1,3-benzodiazol-2yl) 5 -(3-fluoro-5-methyl eni l)pyr id in-2-amine;

1-5: 4-(4-aminopiperidin-1-yl)-3-(1-ethyl-5,6-difluoro-1H-1,3-benzodiazol-2-yl)5(3-fluoro-5-methylphenyl )pyr id in-2-amine;

1-6: 4-(4-aminopiperidin-1 -yl)-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5 -(3-fluoro5 methylphenyl)pyridin-2-amine;

1-7: 4-[da/?sh/s-4-amino-3-methoxypiperidin-1-yl]-3-(5-chloro-1H-1,3-benzodiazol2yl)-5-(3-fluoro- 5-methylphenyl)pyridin-2-amine;

1-8: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(5-methoxy-1H1,3benzodiazol-2-yl)pyridin-2-amine;

1-9: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridinyl]-1H-1,3-benzodiazol-5-sulfonamide;

1-10: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methyl-1H1,3benzodiazol-2-yl)pyridin-2-amine;

1-11: 4-(4-aminopiperidin-1-yl)-3-(7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-15 043353 methylphenyl)pyridin- 2-amine;

1-12: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridineZyl]-1H-1,3-benzodiazol-5-carbonitrile;

1-13: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methoxy-1H-

1,3 benzodiazol-2-yl)pyridin-2-amine;

1-14: 4-(4-aminopiperidin-1-yl)-5 -(3-fluoro-5-methylphenyl)-3-[5-(trifluoro-methoxy)1 Η-1,3-benzodiazol-2-yl ]pyride in-2-amine;

1-15: 4-(4-aminopiperidin-1-yl)-3-(6,7-difluoro-1H-1,3-benzodiazol-2-yl)-5 (3 fluoro-5-methylphenyl)pyridin- 2-amine;

1-16: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[5-(oxetan-3yloxy) 1 Η-1,3-benzode iazol-2 -yl]pyrid in-2-amine;

1-17: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridinyl]-N-methoxy-1 Η-1,3 - benzodiazole-7-carboxamide;

1-18: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridinyl]-N-methoxy-N-methyl-1 H- 1,3-benzode iazole-7-carboxamide;

1-19: 4-(4-aminopiperidin-1-yl)-3 -(5-cyclobutoxy-1H-1,3-benzodiazol-2-yl)-5 (3 fluoro-5-methylphenyl)pyridin-2- amine;

1-20: 4-(4-aminopiperidin-1-yl)-3 -(5-cyclopropoxy-1H-1,3-benzodiazol-2-yl)5 (3-fluoro-5-methylphenyl)pyride in- 2-amine;

1-21: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridineZyl]-1H-1,3-benzodiazol-7-carbonitrile;

1-22: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7[(hydroxyimino)methyl]-1 Η-1,3-benzodiazol-2- yl } pyrid in-2-amine;

1-23: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridinyl]-N-methoxy-1 Η-1,3 - benzodiazole-5-carboxamide;

1-24: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridinyl]-N-methoxy-N-methyl-1 H- 1,3-benzode iazole-5-carboxamide;

1-25: 3-[6-amino-4-(4-aminopiperidin-1-yl)-5-(5-chloro-1H-1,3-benzodiazol2yl)pyridin-3-yl]-5-methylbenzonitrile;

1-26: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[5-(3-fluoroazetidinyl)-1 Η-1,3-benzod iazole -2-yl]pyride in-2-amine;

1-27: methyl^-{2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro5 methylphenyl)pyridin-3 -yl]-1 Η-1,3 - benzodiazol-7-yl } carbamate;

1-28: 4-(4-aminopiperidin-1-yl)-3 -(5-chloro-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro5methylphenyl)-N-methylpyridin-2 -amine;

1-29: 4-(4-aminopiperidin-1-yl)-3-(6-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)-5(3 fluoro-5-methylphenyl)pyridine -2-amine;

1-30: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-M-ethyl-5(3 fluoro-5-methylphenyl) pyridine-2-amine;

1-31: 4-(4-aminopiperidin-1-yl)-3 -{5,5-difluoro-4,6-dioxa-10,12- 16 043353 diazatricyclo[7.3.0.0 ³ , ⁷ ]dodeca-1, 3(7),8,10-tetraen-11-yl}-5-(3-fluoromethylphenyl)pyridin-2-amine;

1-32: 3 - [6-amino-4-(4-aminopiperidin-1 -yl)-5 -(5-chloro-1 Η-1,3-benzodiazol2yl)pyridin-3-yl]-5-fluorobenzonitrile;

1-33: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin3 yl]-1 H-indol-6-carbonitrile;

1-34: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[(propan2yloxy)imino]methyl]pyridin-2-amine;

1-35: 4-(4-aminopiperidin-1-yl)-3-[(tert-butoxy)imino]methyl]-5-(3-fluoromethylphenyl)pyridin-2-amine;

1-36: 4-(4-aminopiperidin-1-yl)-3-[(tert-butoxy)imino]methyl]-5(3.5 d immethylphenyl)pyridin-2-amine;

1-37: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-[(propan2yloxy)imino]methyl]pyridin-2-amine;

1-38: 4-(4-aminopiperidin-1-yl)-3-[(tert-butoxy)imino]methyl]-5-(3-chloro5 methylphenyl)pyridin-2-amine;

1-39: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3[(hydroxyimino)methyl]pyridin-2-amine;

1-40: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{5[(methoxyimino)methyl]-1 Η-1,3-benzodiazol-2- yl } pyrid in-2-amine;

1-41: trans-4-amino-1-[2-amino-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5(3.5 d imethylphenyl)pyridin-4-yl ]piperidine-3-carbonitrile;

1-42: trans-4-amino-1 - [2-amino-3 -(5-chloro-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro5methylphenyl)pyridin-4-yl ]piperidine-3-carbonitrile;

1-43: 4-(4-aminopiperidin-1-yl)-3-[5-(azetidin-1-yl)-1H-imidazo[4,5-b]pyridin2yl]-5 -(3-fluoro-5 -methylphenyl)pyridin-2-amine;

1-44: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{4[(methoxyimino)methyl]-1 Η-1,3-benzodiazol-2- yl } pyrid in-2-amine;

1-45: methyl-M-{2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro5 methylphenyl)pyridin-3-yl]-1H-1,3-benzodiazole -5-yl (carbamate;

1-46: 1-{2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5methylphenyl)pyridin3-yl]-1 Η-1,3-benzode iazol- 5 -yl (-3 -methoxyurea;

1-47: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{5[(hydroxyimino)methyl]-1 Η-1,3-benzodiazol-2- yl } pyrid in-2-amine;

1-48: 4-(4-aminopiperidin-1-yl)-3 -(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5 (3fluoro-5-methylphenyl)-M- methylpyridin-2-amine;

1-49: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-N-ethyl5-(3-fluoro-5 -methylphenyl)pyridin-2-amine;

1-50: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1 Η-1,3-benzodiazol-2-yl)-M-ethyl5-(3-fluoro-5 -methylphenyl)pyridin-2-amine;

- 17 043353

1-51: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{1Nimide azo[4.5 c]pyridin-2-yl} pyridin-2 -amine;

1-52: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{1Nimidazo[4,5b]pyridin-2-yl}pyridin-2-amine;

1-53: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(5methanesulfonyl 1 Η-1,3-benzodiazol-2-yl)pyridin-2-amine ;

1-54: 4-(4-aminopiperidin-1-yl)-3 -(5-chloro-7-fluoro-1 Η-1,3-benzodiazol-2-yl)-5 (3 fluoro-5-methylphenyl) pyridine-2-amine;

1-55: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5(3fluoro-5-methylphenyl)-M-methylpyridine -2-amine;

1-56: 3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-M(2methoxyethyl)-4-(4-methylpiperidin- 1 -yl)pyride in-2-amine;

1-57: 4-(4-aminopiperidin-1 -yl)-3-(5,6-difluoro-1 -methyl-IH-1,3-benzodiazol-2yl)5 -(3-fluoro-5 -methylphenyl) pyride in-2-amine;

1-58: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-IH-1,3-benzodiazol-2-yl)-5(3-fluoro-5-methylphenyl) pir id in-2-amine;

1-59: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(4-fluoro-6-methoxy1H1,3-benzodiazol-2-yl)pyride in- 2-am.

1-60: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5methylphenyl)pyridin-3-yl]-4-fluoro-IH- 1,3-benzodiazol-6-yl } oxy)acetonitrile;

1-61: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7-fluoro5 [(methoxyimino)methyl]-1 Η-1,3-benzodiazol- 2-yl} pyride in-2-amine;

1-62: 4-(4-aminopiperidin-1-yl)-3-{6-fluoro-4-[(hydroxyimino)methyl]-1H-

1,3 benzodiazol-2-yl }-5-(3-fluoro-5-methylphenyl)pyride in-2-amine;

1-63: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{4[(hydroxyimino)methyl]-1H-imidazo[4,5 -c] pyridin-2-yl } pyridin-2-amine;

1-64: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3{ 7 [(hydroxyimino)methyl]-3H-imidazo[4,5-b]pyridin- 2-yl } pyridin-2-amine;

1-65: 4-(4-aminopiperidin-1-yl)-3-(5-ethynyl-IH-1,3-benzodiazol-2-yl)-5-(3-fluoro5-methylphenyl)pyridin-2-amine ;

1-66: 4-(4-aminopiperidin-1-yl)-3-(5-ethynyl-7-fluoro-1H-1,3-benzodiazol-2-yl)-5(3-fluoro-5-methylphenyl) pir id in-2-amine;

1-67: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5(3fluoro-5-methoxyphenyl)pyridin-2- amine;

1-68: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5(3fluoro-5-methoxyphenyl)pyridin- 2-amine;

1-69: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridinyl]-7-fluoro-1 Η-1,3 - benzodiazole-5-carbonitrile;

1-70: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-2(methylamino)pyridin-3-yl] -1 Η-1,3 - benzodiazole-6-carbonitrile;

- 18 043353

1-71: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methoxy-1H-

1,3 benzodiazol-2-yl)-M-methylpyridin-2-amine;

1-72: 4-(4-aminopiperidin-1-yl)-3-(7-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro5methylphenyl)-K-methylpyridin-2- amine;

1-73: 4-(4-aminopiperidin-1-yl)-3-(7-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro5methylphenyl)pyridin-2-amine;

1-74: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5methylphenyl)pyridin-3 -yl]-5-fluoro-1 Η -1,3-benzodiazol-7-yl]oxy)acetonitrile;

1-75: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3fluoro-5-methylphenyl)- M-methylpyridin-2-amine;

1-76: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7-methoxy-

[(methoxyimino)methyl] -1 Η-1,3 -benzodiazol-2-yl} pyride in-2-amine;

1-77: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)-3-(5,7-difluoro-1H-

1,3 benzodiazol-2-yl)pyridin-2-amine;

1-78: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5(3,5 d imethylphenyl)pyridin-2- amine;

1-79: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-(5,7-difluoro-1H-

1,3 benzodiazol-2-yl)pyridin-2-amine;

1-80: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5(3-methoxy-5-methylphenyl)pyridin-2- amine;

1-81: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5(3,5 d iforophenyl)pyridin-2-amine;

1-82: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5(3,5-difluorophenyl)pyridine -2-amine;

1-83: 4-(4-aminopiperidin-1-yl)-5-(3,5-dimethylphenyl)-3-(6-fluoro-4-methoxy-1H-

1,3-benzodiazol-2-yl)pyride in-2-amine;

1-84: 4-(4-aminopiperidin-1-yl)-5-(3,5-dimethylphenyl)-3-(5-fluoro-7-methoxy-

1H1,3-benzodiazol-2-yl)pyridin-2-amine;

1-85: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridinyl]-7-fluoro-1 Η-1,3 - benzodiazole-5-carbonitrile;

1-86: 4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-3-[5-(trifluoromethoxy)1H1,3-benzodiazol-2-yl]pyridin-2-amine;

1-87: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridin-

-yl]-5 -fluoro-1 Η-1,3 -benzod iazol-7-yl} oxy)acetonitrile;

1-88: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)pyridin-

-yl]-7-fluoro-1 Η-1,3-benzod iazol-5 -yl } oxy)acetonitrile;

1-89: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-2(methylamino)pyridin-3-yl]-7-fluoro-1 H- 1,3-benzode iazole-5-carbonitrile;

1-90: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)-3-(5-fluoro-7-methoxy-1H-

1,3-benzodiazol-2-yl)pyride in-2-amine;

1-91: 4-(4-aminopiperidin-1-yl)-5 -(4-fluoro-3-methylphenyl)-3 -(5-fluoro-7-methoxy1H-1,3-benzodiazol-2-yl)pyridine -2-amine;

1-92: 4-(4-aminopiperidin-1-yl)-5 -(3-chlorophenyl)-3 -(5-fluoro-7-methoxy-1H-

1,3 benzodiazol-2-yl)pyridin-2-amine;

1-93: 4-(4-aminopiperidin-1-yl)-3 -(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-(3-methylphenyl)pyridin-2- amine;

1-94: 4-(4-aminopiperidin-1-yl)-3 -(5-chloro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)5(3-fluoro-5-methylphenyl) pyridine-2-amine.

In some embodiments, provided herein is a pharmaceutical

- 19 043353 a commercially acceptable salt of the compound described in table. 1.

table 2

ΝΗο

Connection no. R ^a R ¹ R ⁸ R ⁹ 2-1 N ST/N F N -OCH ₃ 3-F 5-СНз 2-2 Xin -OSNZ 3-F 5-СНз 2-3 H AXA £ £ cc -OSNZ 3-F 5-СНз 2-4 h a?\A X £ /I ci-^AA^n -HE 3-F 5-СНз 2-5 F 1 h Av-n X £ cc -OSNZ 3-F 5-СНз 2-6 H X £ /I ci-^AA^n -OSNZ 3-CN 5-СНз 2-7 X £ /I f^Wn -HE 3-F 5-СНз

- 20 043353

2-8 N XX -OSN ₃ 3-F 5-СНз 2-9 n 1 XM -OSN ₃ 3-F 5-СНз 2-10 n Xjm -HE 3-F 5-СНз 2-11 Η Χ,χΜ _F N -Cl 3-F 5-СНз 2-12 -OSNZ 3-S1 5-СНз 2-13 O X -OSNZ 3-F 5-СНз 2-14 Η X X -OSNZ 3-F 5-F 2-15 Μ 1 n αΜν § -SNz 3-F 5-СНз

Connections in the table. 2 have the following names:

2-1: 1 -[3 -(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)2methoxypyridin-4-yl]piperidin-4-amine ;

2-2: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)2methoxypyridin-4-yl]piperidin-4-amine;

2-3: 1 -[5-(3-fluoro-5-methylphenyl)-2-methox and-3-(5-methoxy-1Η-1,3-benzodiazol2yl)pyridin-4-yl]piperidin-4- amine;

2-4: 4-(4-aminopiperidin-1-yl)-3 -(5-chloro-1 Η-1,3-benzodiazol-2-yl)- 5 -(3-fluoro5methylphenyl)pyridin-2-ol;

2-5: 1 - [3 -(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)2methoxypyridin-4-yl]piperidine -4-amine;

2-6: 3 - [4-(4-aminopiperidin-1-yl)-5 -(5-chloro-1 Η-1,3-benzodiazol-2-yl)bmethoxypyridin-3-yl]-5-methylbenzonitr silt;

2-7: 4-(4-aminopiperidin-1 -yl)-3-(5,6-difluoro-1 Η-1,3-benzodiazol-2-yl)-5 -(3fluoro5-methylphenyl)pyridin-2- ol;

2-8: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin3 yl]-1H-1,3-benzodiazol-5-carbonitrile;

- 21 043353

2-9: 1 -(3 - {6-chloro-3N-imidazo[4,5-c]pyridin-2-yl} -5 -(3-fluoro-5-methylphenyl)2methoxypyridin-4-yl)piperidin- 4-amine;

2-10: 4-(4-aminopiperidin-1-yl)-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro5 methylphenyl)pyridin-2-ol;

2-11: 1-[2-chloro-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro5methylphenyl)pyridin-4-yl]piperidin-4-amine;

2-12: 1 - { 3 - [(1E)-[(tert-butoxy)imino]methyl]-5 -(3-chloro-5-methylphenyl)2methoxypyride in-4-yl} piperidin-4-amine;

2-13: 1-(3-{5-chloro-1H-imidazo[4,5-b]pyridin-2-yl}-5-(3-fluoro-5-methylphenyl)2methoxypyridin-4-yl)piperidin- 4-amine;

2-14: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3,5-difluorophenyl)2methoxypyridin-4-yl]piperidin-4-amine;

2-15: 1-[3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)2methylpyridin-4-yl]piperidin- 4-amine

In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table. 2.

Table 3

Connection no. R ^a R ¹³ R ⁸ R ⁹ 3-1 O N 3-F 5-CH ₃ 3-2 O N 3-F 5-CH ₃ 3-3 X IZ Z X o n 3-F 5-CH ₃ 3-4 XXJh n 3-F 5-CH ₃ 3-5 \ n 3-F 5-CH ₃

- 22 043353

3-6 Η χχο Cl H 3-F 5-CH ₃ 3-7 Cl i H exo H 3-F 5-СНз 3-8 H S G D F H 3-F 5-СНз 3-9 H X Y D H 3-F 5-СНз 3-10 Η XX y/ H 3-F 5-СНз 3-11 ri ^{n CI} \WN oxo 0CH ₃ (transracemic) 3-F 5-СНз 3-12 0X0 H 3-F 5-CH3 3-13 H XX H 3-F 5-СНз 3-14 ri ^{H Ck} 'A\^N exo Cl H 3-F 5-СНз 3-15 n~n NHH ^H oo^ H 3-F 5-СНз 3-16 H 0X0 H 3-F 5-СНз 3-17 H X GD MC'''^'-''''^ ⁷ H 3-F 5-СНз 3-18 O A ^H me°^eoo H 3-F 5-СНз

- 23 043353

3-19 O II n ^{H2N N} / j H 3-F 5-CH ₃ 3-20 o ⁿ L H 3-F 5-СНз 3-21 |_| MeO^^^N Cl H 3-F 5-СНз 3-22 n XX ή H 3-F 5-СНз 3-23 CN 1 n TsSN H 3-F 5-СНз 3-24 NC^^^N XXn Cl H 3-F 5-СНз 3-25 LJ n XXX CN H 3-F 5-СНз 3-26 NC_^. χχχ CN H 3-F 5-СНз

Connections in the table. 3 have the following names:

3-1: 1 - [3 -(5-chloro-1 H-indol-2-yl)- 5 -(3-fluoro-5-methylphenyl)pyride azin4yl]piperidin-4-amine;

3-2: 1 - [3 -(6-chloro-1 H-ind ol-2-yl)- 5 -(3-fluoro-5-methylphenyl)pyride azin4yl]piperidin-4-amine;

3-3: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin 4yl]piperidin-4-amine;

3-4: 1 - [3 -(6-fluoro-1H-ind ol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyride azin4yl]piperidin-4-amine;

3-5: 1-[5-(3-fluoro-5-methylphenyl)-3-(6-methoxy-1H-indol-2-yl)pyridazin4yl]piperidin-4-amine;

3-6: 1-[3-(4-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin4yl]piperidin-4-amine;

- 24 043353

3-7: 1 - [3 -(7-chloro-1 H-indol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyridazin4 yl] piper idin-4-amine;

3-8: 1 - [3 -(5-fluoro-1 H-indol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyrid az in4yl] piper idin-4-amine;

3-9: 1 - [5 -(3-fluoro-5-methylphenyl)-3 -(5-methoxy-1 H-indol-2-yl)pyr idazin4yl] piper idin-4-amine;

3-10: 1 - [5 -(3-fluoro-5-methylphenyl)-3 -(5-methoxy-1H-1,3-benzodiazol-2yl)pyridazin4-yl]piperidin-4-amine;

3-11: trans-1 -[3-(6-chloro-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4yl]3-methoxypiperide in-4-amine;

3-12: 2-[4-(4-aminopiperidin-1-yl)-5 -(3-fluoro-5-methylphenyl)pyridazin-3-yl] -

Nindole-6-carbonitrile;

3-13: 1 - [3 -(5-fluoro-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyridazin4yl] piper idin-4-amine;

3-14: 1 - [3 -(3,6-dichloro-1 H-indol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyridazin4yl] piper idin-4-amine;

3-15: 1-[5-(3-fluoro-5-methylphenyl)-3-[6-(2H-1,2,3,4-tetrazol-5-yl)-1H-indol2yl]pyridazin-4- yl]piperidin-4-amine;

3-16: 1 - [5 -(3-fluoro-5-methylphenyl)-3 -(6-methyl-1 H-indol-2-yl)pyride azin4yl] piper idin-4-amine;

3-17: 2-[4-(4-aminopiperidin-1-yl)-5 -(3-fluoro-5-methylphenyl)pyridazin-3-yl] -

Nindol-5-carbonitrile;

3-18: methyl-2-[4-(4-aminopiperid in-1 -yl)-5 -(3-fluoro-5-methylphenyl)pyrid az in-yl]-1 H-ind ol-6-carbox fees;

3-19: 2-[4-(4-aminopiperidin-1-yl)-5 -(3-fluoro-5-methylphenyl)pyridazin-3-yl] -

Nindole-6-carboxamide;

3-20: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]Nmethoxy-1H-indole-6-carboxamide;

3-21: 1 - [3 -(3-chloro-6-methoxy-1 H-indol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyride azin4yl] piper idin-4-amine;

3-22: 2-[4-(4-aminopiperidin-1-yl)-5 -(3-fluoro-5-methylphenyl)pyridazin-3-yl] - 1H1,3-benzodiazol-5-carbonitrile;

3-23: 2-[4-(4-aminopiperidin-1-yl)-5 -(3-fluoro-5-methylphenyl)pyridazin-3-yl] -

Nindole-7-carbonitrile;

3-24: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]3chloro-1H-indole-6-carbonitrile;

3-25: 2-[4-(4-aminopiperidin-1 -yl)-5 -(3-fluoro-5-methylphenyl)pyridazin-3 -yl]bmethoxy-1 H-indol-3-carbonitrile;

3-26: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl] 1Nindol-3,6-dicarbonitrile.

In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table. 3.

- 25 043353

Table 4

Connection no. R ^a R ¹ R ¹² R ⁸ R ⁹ 4-1 SG H HN-1/ ^ζ CH ₃ 3-F 5-CH ₃ 4-2 N.C. L H Y/N N _H2n4 CH ₃ 3-F 5-CH ₃ 4-3 NC' F H _H2n4 CH ₃ 3-F 5-CH ₃ 4-4 ABOUT L N N >4 H 3-F 5-CH ₃ 4-5 F 0 H N X H 3-F 5-CH ₃ 4-6 ^x o 0 H X H 3-F 5-CH ₃ 4-7 F ^x o 0 H -N _t ^f 4>4 H 3-F 5-CH ₃ 4-8 F^ F 0 H /N N 0 ⁴ n4 H 3-F 5-CH ₃ 4-9 4-10 F F^ 0 0 H -N _c H _c UL N ^f 4)h H ₂ n3 H CH ₃ 3-F 3-F 5-H 5-CH ₃ 4-11 cK 0 H r ^N HN ^Z Ν-ξ H 3-F 5-CH ₃

- 26 043353

Connections in the table 4 have the following names:

4-1: 3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-N-methyl-4[4(methylamino)piperidin- 1 -yl]pyridin-2-amine;

4-2: 2-[2-amino-5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)piperidin1yl]pyridin-3-yl]-1 Η-1,3-benzodiazole -6-carbonitr silt;

4-3: 2-[2-amino-5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)piperidin1yl]pyridin-3-yl]-7-fluoro-1H-1, 3-benzodiazole-5-carbonitrile;

4-4: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methoxy-1H-

1,3 benzod iazol-2-yl )-N, N-d and methyl p yrid and n-2-am in;

4-5: 4-(4-aminopiperidin-1-yl)-3 -(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5 -(3 fluoro5-methylphenyl)-T4, T4-dimethylpyridin-2-amine;

4-6: 4-(4-aminopiperidin-1-yl)-3 -(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-5 (3-fluoro-5-methylphenyl )-T4,T4-dimethylpyridin-2-amine;

4-7: 1 - [3 -(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)2(3-fluoroazetidine-1 -yl)pyrid in-4-yl] piper id in-4-amine;

4-8: 1 - [3 -(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)2(morpholin-4-yl) pyridin-4-yl]piperidin-4-amine;

4-9: 1 - [3 -(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-2-(3-fluoroazetidin-1-yl)-5 (3 fluorophenyl) pyridin-4-yl]piperidin-4-amine;

4-10: 3-(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)-4[4(methylamino)piperidin- 1 -yl]pyridin-2-amine;

4-11: 1 - [3 -(5-chloro-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)-2(piperazin1-yl)pyridin-4 -yl]piperidin-4-amine.

In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound that is described in Table. 4.

In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. Also included within the scope of this disclosure are the active metabolites of these compounds having the same type of activity. In addition, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered to be disclosed herein.

As used herein, the term pharmaceutically acceptable refers to a material, such as a carrier or diluent, that does not inhibit the biological activity or properties of the compound and is relatively non-toxic, i.e. the material is administered to an individual without causing undesirable biological effects or without harmful interaction with any of the components of the composition with which it comes into contact.

The term pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of a therapeutically active agent in combination with a suitable anion or, in alternative embodiments, an anionic form of a therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts are generally more soluble and more readily soluble in gastric and intestinal juices than nonionic compounds and are thus useful in solid dosage forms. Moreover, since their solubility is often a function of pH, selective dissolution in one part or another of the digestive tract is possible, and this possibility can be manipulated as an aspect of delayed and sustained release behavior. In addition, since the salt-forming molecule can be in equilibrium with the neutral form, passage through biological membranes can be controlled.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound of formula (III) with an acid. In some embodiments, the compound of formula (III) (ie, the free base form) is basic and reacts with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorus

- 27 043353 nic acid, nitric acid and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalinic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p) and undecylenic acid.

In some embodiments, the compound of formula (III) is prepared as a hydrochloride salt, sulfate salt, hydrobromide salt, mesylate salt, maleate salt, citrate salt, or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound of formula (III) with a base. In some embodiments, the compound of formula (III) is acidic and reacts with a base. In such situations, the acidic proton of the compound of formula (III) is replaced by a metal ion, for example, a lithium, sodium, potassium, magnesium, calcium or aluminum ion. In some cases, the compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Suitable inorganic bases used to form salts with compounds that contain an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are provided as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt, or ammonium salt.

It should be taken into account that the mention of a pharmaceutically acceptable salt includes forms of solvent addition. In some embodiments, the solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are formed by crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed if the solvent is water, or alcoholates are formed if the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed by the processes described herein. In addition, the compounds presented herein optionally exist in unsolvated as well as solvated forms.

In some embodiments, compounds of formula (III) have one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of formula (III) exists in the R configuration. In some embodiments, the compound of formula (III) exists in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers, as well as appropriate mixtures thereof.

Individual stereoisomers are obtained, if necessary, by methods such as stereoselective synthesis and/or separation of stereoisomers using chiral chromatography columns or separation of diastereomers using either non-chiral or chiral chromatography columns, or crystallization and recrystallization in an appropriate solvent or mixture of solvents. In some embodiments, compounds of formula (III) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a diastereomeric compound/salt pair, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, enantiomer resolution is performed using covalent diastereomeric derivatives of the compounds described herein. According to another

- 28 043353 embodiment, diastereomers are separated using separation/separation methods based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography or by formation of diastereomeric salts and separation by recrystallization or chromatography, or some combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are prepared by stereoselective synthesis.

Synthesis of compounds

The compounds of formula (I) described herein are synthesized using standard synthetic methods or using methods known in the art in combination with the methods described herein.

Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA methods and pharmacology are used.

The compounds are prepared using standard organic chemistry methods such as those described, for example, in March's Advanced Organic Chemistry, ^6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as a variety of solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

In some other embodiments, the compounds described herein are prepared as described in Scheme A.

Scheme A.

a) DIEA, ACN, b) NBS, ACN, c) ArR ⁸ R ⁹ B(OH) ₂ , Pd, d) DMF/H ₂ O, e) deprotection, f) EtOH

Nucleophilic displacement of compound I with 4-Boc-aminopiperidine gave intermediate compound II. Compound II was treated with NBS to yield intermediate III, which was then converted to intermediate IV by an organometallic coupling reaction such as the Suzuki-Miyaura reaction with ArR ⁸ R ⁹ B(OH)2. The formation of benzimidazole between compound IV and the corresponding 1,2-diaminobenzenes was achieved by heating in wet DMF or NMP or DMSO or other solvent with or without Na2S2O5 in atmospheric oxygen. Subsequent deprotection using appropriate deprotection methods provided Compound V. Intermediate IV was also converted to VI by formation of the R ⁸ O-NH2 oxime in the presence of pyridine and subsequent deprotection under appropriate acidic conditions.

In some other embodiments, the compounds described herein are prepared as described in Scheme B.

- 29 043353

Scheme B.

With)

a) DIEA, DMSO, b) Ar(R ⁸ R ⁹ )B(OH) ₂ , Pd, c) NBS, ACN, d) PD, e) removal of the protecting group

Commercially available compound VII was reacted with SN2 with 4-Vosaminopiperidine to give intermediate VIII, which was converted to compound IX by SuzukiMiyaura reactions with ArR ⁸ R ⁹ B(OH) ₂ . Selective bromination to intermediate X was then achieved by treatment with NBS. Compound X was then converted to compound XI by Suzuki-Miyaura reactions with the corresponding indole-2-borinic acids, and then deprotected using an appropriate deprotection method.

In some other embodiments, the compounds described herein are prepared as described in Scheme C.

Scheme C.

XII XIII XIV

XVI XV

a) DIEA, ACN, b) NBS, ACN, c) ArR ⁸ R ⁹ B(OH) ₂ , Pd, d) DMF/H ₂ O, e) TFA, f) HCl, g) POCI ₃ , h) ( Boc) ₂ O i) Zn(CN) ₂ , Pd, j) RSnBu ₃ , Pd, k) removal of the protecting group

Compound XIII was prepared in a manner similar to that described in step a) to step e) in Scheme A, starting from commercially available compound XII. Conversion to compound XIV was achieved by acid-catalyzed demethylation of compound XIII. Hydroxylpyridine was converted to compound XV by refluxing in POCl ₃ . Cyano analogs (XVI) were prepared by three steps: protection of the primary amine, replacement of Cl with CN, and deprotection under acidic condition. The introduction of alkyl groups at the 2-position can also be achieved through a Still coupling reaction.

In some other embodiments, the compounds described herein are prepared as described in Scheme D.

- 30 043353

Scheme D.

XVII χνιιι χιχ

R = Cl, CN XXIII a) NaHCO ₃ , b) ArR ⁸ R ⁹ B(OH) ₂ , Pd, c) POCI ₃ , d) NaOH, (Boc) ₂ O, e) Pd, f) removal of the protecting group, g) NCS, h) CISO ₂ NCO

The SN2 reaction between compound XVII and 4-Boc-aminopiperidine in the presence of an inorganic base such as NaHCO ₃ or KHCO 3 gave a mixture of two regioisomers (ratio ~1/1), which were separated to yield intermediate XVIII. Compound XVIII was then converted to compound XIX by Suzuki-Miyaura reactions with ArR ⁸ R ⁹ B(OH) ₂ . Compound XXI was prepared by two steps from compound XIX: chlorination with POCl ₃ and the Suzuki-Miyaura reaction with the corresponding indole-2borinic acids. Deprotection using an appropriate deprotection method gave compound XXII, and chlorination at the 3-position of indole by treatment with NCS and acid deprotection gave compound XXIII (R=Cl). Cyanation of the 3 position of indole (XXIII, R=CN) was achieved by treatment with chlorosulfonylisocyanate (CSI).

In some other embodiments, the compounds described herein are prepared as described in Scheme E.

Scheme E.

XXIV XXV

XXVI

a) PhCH=CHB(OH) ₂ , Pd, b) NalO ₄ , OsO ₄ , c) DMF/H ₂ O, d) removal of the protecting group

Intermediate XX was converted to XXIV by Suzuki-Miyaura reaction with 2-phenylvinylboric acid. The olefin was smoothly subjected to oxidative cleavage by

- 31 043353 Lemieux-Johnson oxidation to form compound XXV. The formation of benzimidazole with the corresponding 1,2-diaminobenzenes was achieved by heating in wet DMF, or DMSO, or other solvents in atmospheric oxygen. Subsequent deprotection using appropriate deprotection techniques provided compound XXVI.

In some other embodiments, the compounds described herein are prepared as described in Scheme F.

Scheme F.

XXIX XXX

a) Apkyl halide, NaOH, DMF, b) DMF/H ₂ O, c) deprotection

Aminopyridine IV was alkylated to compound XXVII using the appropriate alkyl halide (R2-X) and base. Formation of benzimidazole and removal of the protecting group as described in Scheme A gave compound XXVIII. N-alkylation of compound XXIX with an alkyl halide (R5-X) can be achieved regioselectively, and removal of the protecting group on the amino group also gave compound XXX.

In some embodiments, compounds are prepared as described in Scheme G.

Scheme G.

a) DMF, TEA; b) R ² R ² 'NH, 100°C, or MeSNa, THF, 70°C or alkylboronic acid, Pd(DTBPF)Cl ₂ , CsCO ₃ , dioxane, water, 100°C; c)NBS, DCE;

d) Pd ₂ dba ³ , P(t-Bu) ₃ ; e)Na ₂ S ₂ O ₅ , NMP, 120°C; f) m-CPBA, DCM, then R ² R ² 'NH, 100°C;

g) TFA or HCl

By stepwise substitution of 2,4-dichloropyridine-3-carboxaldehyde XXXI with a protected 4-aminopiperadine analogue (step a) followed by a substitution reaction with any other amine (R2R2NH), or sodium methanethiol salt, or alkylborine acid (step b), compound XXXII was obtained. Subsequent bromination (step c) and subsequent Suzuki coupling (step d) gave compound XXXIII, which was subjected to benzimidazole formation with phenylenediamine to give

- 32 043353 connection XXXIV (stage e). Subsequent deprotection in a manner similar to that described in Scheme A (step g) gave compound XXXV in which Y=NR2R2 or alkyl. If

Y=SCH ₃ , compound XXXIV was subjected to an oxidizing reagent such as m-CPBA to yield the corresponding sulfoxide, which was then displaced with R2R2NH, followed by deprotection on the amine to yield the desired product XXXV.

In some other embodiments, the compounds described herein are prepared as described in Scheme H.

Scheme H.

a) NBS, DCE, b) DIEA, ACN, c) ArR ⁸ R ⁹ B(OH) ₂ , Pd, d) DMF/H ₂ O, e) removal of the protecting group

Regioselective bromination of compound I with NBS gave intermediate XXXVI. The conversion of compound XXXVI to compound XXXIX was performed in a manner similar to that described in Scheme A.

In some other embodiments, the compounds described herein are prepared as described in Scheme I.

- 33 043353

Scheme I.

XLVI

Compound XXXIX was reacted with an amine to form compound XL. Bromination of compound XL and subsequent Suzuki coupling reaction gave compound XLI, which was heated with aryl diamine to give compound XLII. The introduction of carbon monoxide in the presence of alcohol resulted in the formation of compound XLIII, which can be converted to compound XLIVI using ammonia, and further dehydration gave compound XLV. Removal of the protecting group of compound XLIII, or compound XLVI, or compound XLV gave compound XLVI.

Some terminology

Unless otherwise specified, the following terms used in the present invention have the definitions given below. The use of the term including, as well as other forms such as include, includes and included, are not limiting. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

As used herein, the term C1-C _x includes C1-C2, C1-C3, ..., C ₁ -C _x . By way of example only, a group designated C1- _C6 indicates that there are from one to six carbon atoms in the moiety, i.e. groups contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, the term C ₁ -C ₄ -alkyl indicates that there are from one to four carbon atoms in the alkyl group, i.e. the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The term alkyl group refers to an aliphatic hydrocarbon group. An alkyl group has a branched or straight chain. In some embodiments, the alkyl group has from 1 to 10 carbon atoms, i.e. represents C ₁ -C ₁₀ -alkyl. Whenever a numeric range such as 1 to 10 appears herein, it refers to each integer in the range shown; for example, the phrase 1 to 10 carbons means that the alkyl group consists of 1 carbon, 2 carbons, 3 carbons, etc. up to and including 10 carbon atoms, although this definition also covers the possibility of the term alkyl if a numerical range is not specified. In some embodiments, alkyl is C ₁ -C ₆ -alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, nbutyl, isobutyl, sec-butyl or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

- 34 043353

The term alkylene group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be an alkylene upon elimination of the second hydrogen atom from the alkyl. In some embodiments, the alkylene is C1- _C6 alkylene. In other embodiments, the alkylene is C ₁ -C4 alkylene. Typical alkylene groups include, but are not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, CH2CH2CH2CH2- and the like. In some embodiments, alkylene is -CH ₂ -.

The term alkoxy group refers to an (alkyl)-O- group, in which alkyl is defined herein.

The term alkylamine refers to the group -N(alkyl) _xHy in which x is 0 and y is 2, or _in which x is 1 and y is 1, or in which x is 2 and y is 0.

The term hydroxyalkyl refers to an alkyl in which one hydrogen atom is replaced by hydroxyl. In some embodiments, the hydroxyalkyl is a C ₁ -C4 hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH and the like.

The term aminoalkyl refers to an alkyl in which one hydrogen atom is replaced by amino. In some embodiments, the aminoalkyl is a _C1 -C4amonoalkyl. Exemplary aminoalkyl groups include, but _{are not} limited to, -CH2NH2, -CH2CH2NH2, _{-CH2CH2CH2NH2} , _{-CH2CH2CH2CH2NH2 ,} and the like.

The term alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group is characterized by the formula -C(R)=CR ₂ , in which R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of the alkenyl group include -CH=CH ₂ , C(CH ₃ )=CH ₂ , -CH=CHCH ₃ , -C(CH ₃ )=CHCH ₃ and -CH2CH=CH2.

The term alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group is characterized by the formula -C^CR, in which R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of the alkynyl group include -C^CH, -C^CCH ₃ -C^CCH ₂ CH ₃ , -CH2C CH.

The term heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from an atom other than carbon, such as oxygen, nitrogen (eg, -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl is added to the rest of the molecule at the heteroalkyl carbon atom. In one aspect, heteroalkyl is C1-C6-heteroalkyl.

The term aromatic refers to a planar ring having a delocalized π electron system containing 4n+2 π electrons, with n being an integer. The term aromatic includes both carbocyclic aryl (aryl, eg phenyl) and heterocyclic aryl (or heteroaryl or heteroaromatic) groups (eg pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

The term carbocyclic or carbocycle refers to a ring or ring system in which all the atoms forming the backbone of the ring are carbon atoms. Thus, the term distinguishes between carbocyclic and heterocyclic rings, or heterocycles in which the ring backbone contains at least one atom that is different from another carbon atom. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. Carbocycles include aryls and cycloalkyls.

As used herein, the term aryl refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C ₆ -C ₁₀ -aryl. Depending on the structure, the aryl group is monoradical or diradical (ie, an arylene group).

The term cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each of the atoms forming the ring (ie, the skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyls are spirocyclic or bridged compounds. In some embodiments, the cycloalkyls are optionally fused to an aromatic ring, and

- 35 043353 the point of attachment is on a carbon atom that is not an aromatic ring carbon atom. Cycloalkyl groups include groups containing from 3 to 10 ring atoms. In some embodiments, the cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is C ₃ -C ₆ cycloalkyl.

The term halogen, or alternatively halogen or halide, means fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

The term fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, the fluoroalkyl is a C ₁ -C6 fluoroalkyl.

The term heterocycle or heterocyclic refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing from one to four heteroatoms in the ring(s), wherein each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group contains from 3 to 10 atoms in its ring system, and provided that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings containing from 3 to 10 atoms in its ring system, and aromatic heterocyclic groups include rings containing from 5 to 10 atoms in its ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetane yl, tietanil, homopiperidinil, oxepanil, tiepanil, oxazepinil, diazepinil, thiazepinil , 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl , dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1onyl, isoindolin-1,3-dionyl, 3 ,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1 H-benzo[ d]imidazol-2(3H)onyl, benzo[d]thiazol2(3H)-onyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolyl zinil, phthalazinil , pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The above groups are either C-attached (or C-linked) or N-linked, if possible. For example, a group derived from pyrrole includes both pyrrol-1-yl N-attached) and/or pyrrol-3-yl (C-attached). In addition, the group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached), or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

The terms heteroaryl or, alternatively, heteroaromatic refers to an aryl group that includes one or more ring heteroatoms that are selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolysine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine and pteridine. In some embodiments, the heteroaryl contains 0-4 N ring atoms. In some embodiments, the heteroaryl contains 1-4 N ring atoms. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S ring atoms. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms on the ring. In some embodiments, heteroaryl is C ₁ -C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is C ₁ -C ₅ heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is C ₆ -C ₉ heteroaryl.

- 36 043353

The term heterocycloalkyl or heteroalicyclic group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycloalkyl is fused with aryl or heteroaryl. In some embodiments, heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidin-2,5-dithionyl, pyrrolidin-2,5-dionyl, pyrrolidinonyl, imidazolidinyl , imidazolidin-2-onyl or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of carbohydrates, including without limitation monosaccharides, disaccharides and oligosaccharides. In one aspect, heterocycloalkyl is C ₂ -C ₁ o-heterocycloalkyl. In another aspect, heterocycloalkyl is C4-C ₁ o-heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 N ring atoms. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms on the ring.

The term bond or single bond refers to a chemical bond between two atoms or two units, with the atoms connected by the bond being considered as part of a larger substructure. In one aspect, if a group described herein is a link, then the group in question is absent, thereby allowing the formation of a link between the remaining established groups.

The term fragment refers to a specific segment or functional group of a molecule. Chemical moieties are often taken to be chemical entities embedded in or attached to a molecule.

The term optionally substituted or substituted means that the group in question is optionally substituted by one or more added groups individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl) ₂ , -OH, -CO2H, -CO ₂ -alkyl, -C(=O)NH ₂ , -C(=O)NH(alkyl), -C(=O)N(alkyl) ₂ , S(=O) ₂ NH ₂ , -S( =O) ₂ NH(alkyl), -S(=O) ₂ N(alkyl) ₂ , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone. In some other embodiments, the optimal substituents are independently selected from halogen, -CN, -NH2, -NH(CH ₃ ), -N(CH ₃ )2, -OH, -CO2H, -CO ₂ (C ₁ -C ₄ -alkyl ), -C(=O)NH2, -C(=O)NH(C ₁ -C ₄ -alkyl), -C(=O)N(C ₁ -C ₄ -alkyl) ₂ , -S(=O ) ₂ NH ₂ , S(=O) ₂ NH(C ₁ -C ₄ -alkyl), -S(=O) ₂ N(C ₁ -C ₄ -alkyl) ₂ , C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -heteroalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -fluoroalkoxy, -SC ₁ -C ₄ -alkyl, S( =O)C ₁ -C ₄ -alkyl and -S(=O) ₂ C ₁ -C ₄ -alkyl. In some embodiments, optimal substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH ₃ ), N(CH ₃ )2, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ and -OCF ₃ . In some embodiments, the substituted groups are replaced by one or two of the preceding groups. In some embodiments, the optimal substituent on the aliphatic carbon (acyclic or cyclic) includes oxo (=O).

In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, - CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ )2, NR ¹⁶ C(=O)R ¹⁷ ,-SR ¹⁶ , -S(=O )R ¹⁷ , -SO2R ¹⁷ or -SO2N(R ¹⁶ )2; wherein each R ¹⁶ is independently selected from hydrogen, C 1 -C ₆ -alkyl, C ₁ -C ₆ -heteroalkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₆ -heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle; each R ¹⁷ is independently selected from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -heteroalkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₆ -heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

The term acceptable in relation to a composition, composition or ingredient as used herein means no persistent adverse effect on the general health of the subject being treated.

As used herein, the term modulate means interacting with a target, either directly or indirectly, to modify the target's activity, including, by way of example only, enhancing target activity, inhibiting target activity, limiting target activity, or prolonging target activity.

As used herein, the term modulator refers to a molecule that interacts with a target either directly or indirectly. Interactions include, but are not limited to, agonist, partial agonist, reversible agonist, antagonist, cleaving agent, or combinations thereof. In some embodiments, the modulator is an agonist.

As used herein, the terms introduce, administration process, introduction, etc. refer to methods that can be used to ensure delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous,

- 37 043353 subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), local and rectal administration. Those skilled in the art will know methods of administration that can be used for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

As used herein, the terms co-administration or the like cover the administration of selected therapeutic agents to a single patient and include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

As used herein, the terms effective amount or therapeutically effective amount refer to a sufficient amount of an agent or compound to be administered that will alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result includes reduction and/or attenuation of signs, symptoms or causes of disease or any other desired change in a biological system. For example, an effective amount for therapeutic applications is the amount of a composition comprising a compound disclosed herein necessary to provide a clinically significant reduction in disease symptoms. The appropriate effective amount in any particular case is not necessarily determined using methods such as dose escalation studies.

As used herein, the terms enhance or enhance mean to increase or prolong either the strength or duration of the desired effect. Thus, with respect to enhancing the effect of therapeutic agents, the term enhancement refers to the ability to increase or prolong either the strength or duration of the effect of other therapeutic agents in the system. As used herein, the term enhancing effective amount refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

As used herein, the term pharmaceutical combination means a product that is the result of mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term fixed combination means that the active ingredients, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof and a co-administered agent are administered to a patient simultaneously in the form of a single substance or dosage. The term "unfixed combination" means that the active ingredients, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof and a co-administered agent, are administered to the patient in the form of separate substances either simultaneously, in parallel or sequentially without any specific restrictions on time intervals, at In this case, such an introduction ensures the effective content of the two compounds in the patient’s body. The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

The terms finished product and kit are used interchangeably.

The term subject or patient includes mammals. Examples of mammals include, without limitation, any member of the class Mammals: humans, non-human primates, such as chimpanzees and other apes, and ape species; farm animals such as cattle, horses, sheep, goats, pigs; pets such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. In one aspect, the mammal is a human.

As used herein, the terms treat, treatment process, or treatment include alleviating, alleviating, or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., stopping the progression of a disease or condition, alleviating a disease or condition, providing regression of a disease or condition, alleviating a condition caused by a disease or condition, or delaying symptoms of a disease or condition, either prophylactically and/or therapeutically.

Pharmaceutical compositions

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used for pharmaceutical purposes. The appropriate composition depends on the chosen route of administration. Brief descriptions of the pharmaceutical compositions described herein are found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for the purpose of such disclosure. In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. Administration of the compounds and compositions described herein can be accomplished by any method that provides delivery of the compounds to the site of action. Such methods include, but are not limited to, delivery by enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository, and rectal enema), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and local (including cutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the condition and impairment of the recipient. By way of example only, the compounds described herein can be administered locally to the area requiring treatment, for example, by local infusion during surgery, topical application, such as creams or ointments, injection, catheter or implant. Administration can also be accomplished by direct injection into a site of diseased tissue or organ.

In some embodiments, pharmaceutical compositions suitable for oral administration are presented in discrete units, such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented in the form of a bolus, electuary, or paste.

Pharmaceutical compositions that can be administered orally include tablets, hard capsules made from gelatin, and soft, sealed capsules made from gelatin and a plasticizer such as glycerin or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with binders, inert diluents or lubricants, surfactants or dispersants. Molded tablets can be prepared by molding a mixture of the powder compound moistened with an inert liquid diluent in a suitable machine. In some embodiments, the tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration must be in dosages acceptable for such administration. Hard capsules may contain the active ingredients in admixture with a filler such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, stabilizers are added. Pelleting of kernels is provided with acceptable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, varnish solutions and suitable organic solvents or mixtures of solvents. Dyes or pigments may be added to tablets or coatings for the purpose of identifying or distinguishing between different dosage combinations of the active compounds.

In some embodiments, the pharmaceutical compositions are formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations may be presented in single dosage form, such as ampoules or multi-dose containers, with an added preservative. The compositions may take forms such as suspensions, solutions or emulsions in oil or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the previously described type.

Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injectable solutions of the active compounds, which may contain antioxidants, buffers, bacteriostatics and solutes that render the formulation isotonic with the blood of the intended recipient; both aqueous and non-aqueous sterile suspensions, which can

- 39 043353 may include suspending agents and thickeners. Suitable lipophilic solvents or carriers include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or trigylcerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that enhance the solubility of the compounds to provide highly concentrated solutions.

Pharmaceutical compositions can also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compounds may be formulated, for example, with suitable polymeric or hydrophobic materials (eg, as an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, lozenges or gels formulated in a convenient manner. Such compositions may contain the active ingredient in a flavored base such as sucrose and gum acacia or gum tragacanth.

Pharmaceutical compositions can be administered by the local route, which is non-systemic administration. It involves applying a compound of the present invention externally to the epidermis or buccal cavity and instilling such compound into the ear, eye and nose so that substantially no compound enters the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin into the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, as well as drops suitable for administration to the eye, ear or nose. For topical administration, the active ingredient may be from 0.001 to 10% w/w, for example 1 to 2% by weight of the formulation.

Pharmaceutical compositions for administration by inhalation are conveniently delivered using an insufflator, nebulizer, pressure packs, or other convenient means of delivering a nebulized aerosol. Pressurized packages may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver the metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparations may take the form of a dry powder composition, for example a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, for example, in capsules, cartridges, gelatin or blister packs, from which the powder can be administered using an inhaler or insufflator.

It should be appreciated that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art, taking into account the type of formulation of interest, for example, agents acceptable for oral administration may include flavorings.

Dosage routes and treatment regimens

In one embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of medicinal products for the treatment of diseases or conditions in a mammal that will benefit from modulating the activity of somatostatin. Methods of treating any of the diseases or conditions described herein in a mammal in need thereof include administering pharmaceutical compositions that include at least one compound of formula (I) or a pharmaceutically acceptable salt, active metabolite, prodrug thereof or a pharmaceutically acceptable solvate, in therapeutically effective amounts to the specified mammal.

In some embodiments, compositions containing compound(s) described herein are administered for prophylactic and/or therapeutic treatment. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially delay at least one of the symptoms of the disease or condition. Amounts effective for such use depend on the severity and course of the disease or condition, pretreatment, the medical condition of the patient, weight and response to drugs, and the judgment of the attending physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials and/or optimal dose determination.

In prophylactic applications, compositions containing the compounds described herein are administered to a patient, susceptible, or otherwise at risk of contagion.

- 40 043353 specific disease, disorder or condition. Such amount is defined as a prophylactically effective amount or dose. In this application, the exact amounts also depend on the patient's health, weight, etc. When used in a patient, effective amounts for such use will depend on the severity and progression of the disease, disorder or condition, prior therapy, the patient's medical condition and response to medications, and the judgment of the attending physician. In one aspect, the prophylactic treatment comprises administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof to prevent recurrence of symptoms. diseases or conditions.

In some embodiments, if the patient's condition does not improve, the compounds are administered continuously, at the physician's discretion, over an extended period of time, including throughout the patient's life, to improve or otherwise control or limit the symptoms of the patient's disease or condition.

As soon as the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in certain embodiments, the dosage or frequency of administration, or both, is reduced as a function of symptoms to a level at which improvement of the disease, disorder, or condition is maintained. In some embodiments, however, the patient requires periodic treatment on a long-term basis for any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the characteristics (eg, weight, sex) of the subject or recipient in need of treatment, although determined according to specific circumstances, including including, for example, the particular agent to be administered, the route of administration, the condition to be treated, and the subject or recipient to be treated.

In general, however, doses useful for the treatment of an adult are typically in the range of 0.01 to 2000 mg per day. In one embodiment, the desired dose is conveniently provided as a single dose or divided doses administered simultaneously or at appropriate intervals, for example, two, three, four or more sub-doses per day.

In one embodiment, daily dosages corresponding to a compound of formula (I) or a pharmaceutically acceptable salt thereof disclosed herein range from about 0.01 to about 50 mg/kg body weight. In some embodiments, the daily dosage or amount of active ingredient per dosage form is lower or higher than the ranges specified herein based on a number of variables with respect to a particular treatment regimen. In various embodiments, daily and unit dosages are varied depending on a number of variables, including, but not limited to, the potency of the compound being used, the disease or condition being treated, the route of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the practitioner's judgment. doctor

The toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including, but not limited to, determination of LD ₅₀ and ED ₅₀ . The dose ratio between toxic and therapeutic effects is the therapeutic index and is expressed as the ratio of LD ₅₀ to ED ₅₀ . In some embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and/or a number of therapeutically effective unit dosages for use in mammals, including humans. In some embodiments, daily dosage amounts of the compounds described herein are within a range of circulating concentrations that include the ED ₅₀ with minimal toxicity. In some embodiments, the daily dosage range and/or the number of unit dosages varies within the range depending on the dosage form used and the route of administration used.

According to any of the above aspects, further embodiments are provided wherein an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (a) is systemically administered to a mammal; and/or (b) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) injected into a mammal; and/or (e) administered locally to a mammal; and/or (f) administered non-systemically or locally to a mammal.

In any of the foregoing aspects, further embodiments are provided that provide for single administrations of an effective amount of the compound, including further embodiments wherein (i) the compound is administered once daily, or (ii) the compound is administered to the mammal multiple times over a period of one day.

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In any of the foregoing aspects, further embodiments are provided that provide for multiple administrations of an effective amount of a compound, including further embodiments wherein (i) the compound is administered continuously or intermittently: as a single dose; (ii) the time between each of several administrations is 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In additional or alternative embodiments, the method comprises resting from the drug, wherein administration of the compound is temporarily stopped or the dose of the compound to be administered is temporarily reduced; at the end of the rest period from the drug, dosing of the compound is resumed. In one embodiment, the length of time off from the drug varies from 2 days to 1 year.

Combined treatments

In some cases, it is advisable to administer at least one compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an enhancing agent (i.e., the enhancing agent alone has minimal therapeutic benefit, but when combined with another therapeutic agent, there is a net therapeutic benefit to the patient intensifies).

Or, in some embodiments, the benefit experienced by a patient is enhanced by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has a therapeutic benefit.

In one specific embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate various aspects of the disease, disorder or condition being treated, thereby providing a greater net benefit than when administering either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition being treated, the net benefit experienced by the patient is the additive effect of the two therapeutic agents or the fact that the patient experiences a synergistic effect.

For the combination therapeutic agents described herein, the dosages of the co-administered compounds vary depending on the type of drug used together, the specific drug used, the disease or condition being treated, etc. In additional embodiments, when coadministered with one or more other therapeutic agents, a compound provided herein is administered either simultaneously with one or more other therapeutic agents or sequentially.

In combination therapies, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, multiple therapeutic agents are provided, by way of example only, in one unitary form or in multiple forms (eg, as a single pill or as two separate pills).

The compounds of formula (I) or a pharmaceutically acceptable salt thereof, as well as combination therapeutic agents, are administered before, during or after the onset of a disease or condition, and the timing of administration of the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used prophylactically and are administered continuously to subjects with a predisposition to developing conditions or diseases to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to the subject during or as soon as possible after the onset of symptoms. In certain embodiments, a compound described herein is administered as soon as possible after the onset of a disease or condition is identified or suspected and for a period of time necessary to treat the disease. In some embodiments, the period required for treatment varies and the treatment period is adjusted to suit the specific needs of each subject.

Examples

As used above and throughout the present description of the present invention, the following abbreviations, unless otherwise indicated, should be considered to have the following meanings.

Abbreviations

Pd(PPh ₃ ) ₄ : tetrakis(triphenylphosphine)palladium(0);

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium(P) dichloride;

Pd(PPh ₃ ) ₂ Cl ₂ : bis(triphenylphosphine) palladium(P) dichloride;

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PdAMphos or Pd(amphos)Cl ₂ : bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(P);

Pd(DTBPF)Cl2: [1,1 '-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(P);

P(t-Bu) ₃ : tri-tert-butylphosphine;

HBF ₄ : tetrafluoroboric acid;

DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene; DIEA: N,N-diisopropylethylamine;

preparative HPLC: preparative high performance liquid chromatography;

LC-MS: liquid chromatography-mass spectrometry;

MS: mass spectrometry;

AcOH: acetic acid;

TFA: trifluoroacetic acid;

HCl: hydrochloric acid or hydrochloride; MeCN or CH3CN or ACN: acetonitrile; mCPBA: 3-chloroperbenzoic acid;

H2O: water;

DMSO: dimethyl sulfoxide;

DMF: Dimethylformamide

DCM: dichloromethane

NBS: N-bromosuccinimide;

Br2: bromine;

NCS: N-chlorosuccinimide;

room temperature: room temperature;

SST: somatostatin;

SSTR: somatostatin receptor; TBAF: tetrabutylammonium fluoride;

h: hours;

h: hour;

min: minute;

N ₂ : nitrogen gas; mg: milligrams; ml: milliliter;

eq: equivalents; mmol: millimole precipitation: precipitation;

K2CO3: potassium carbonate;

NaHCO ₃ : sodium bicarbonate; OsO ₄ : osmium tetroxide; t-BuOH: tert-butyl alcohol;

EtOAc: ethyl acetate;

Na2SO4: sodium sulfate.

The following examples are presented for illustrative purposes only and do not limit the scope of the claims presented herein.

Synthesis of compounds

Example 1. 4-(4-Aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)5-(3-fluoro-5methylphenyl)pyridin-2-amine (connection 1-2).

nh ₂

Stage 1-1. Preparation of tert-butyl-N-[1-(2-amino-3-formylpyridin-4-yl)piperidin-4-yl]carbamate. A mixture of tert-butyl-N-(4-chloro-3-formulpyridin-2-yl)carbamate (0.81 g, 3.16 mmol), 4-Bosaminopiperidine (1.2 g, 1.9 eq.) and DIEA (1.6 ml, 2.5 eq.) in ACN (20 ml) was shaken at 85°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated to remove volatile solvent. The residue was purified by column chromatography to give the title compound (0.48 g, 48%). MS (M+H)+=321.3.

Stage 1-2. Preparation of tert-butyl-N-[1-(2-amino-5-bromo-3-formylpyridin-4-yl)piperidin-4yl]carbamate. NBS was added to a solution of tert-butyl-N-[1-(2-amino-3-formylpyridin-4-yl)piperidin-4-yl]carbamate (2.2 g, 6.87 mmol) in ACN (50 mL). (1.6 g, 1.3 eq.) at room temperature. The reaction mixture was shaken for 15 minutes at room temperature and concentrated. The residue was purified by column chromatography to give the title compound (1.7 g, 63%). MS (M+H)+=399.1.

Stage 1-3. Preparation of tert-butyl-N-{1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4yl)]piperidin-4-yl}carbamate. Mixture of tert-butyl-N-[1-(2-amino-5-bromo-3-formylpyridin-4yl)piperidin-4-yl]carbamate (1.6 g, 4.0 mmol), 3-fluoro-5- methylborinic acid (1.0 g, 1.7 eq.), PdCl ₂ (t-Bu ₂ PPhNMe ₂ ) ₂ (280 mg, 0.4 mmol) and K2CO3 (1.1 g, 2 eq.) in dioxane/ H ₂ O (10/1=20 ml/2.0 ml) was degassed with N ₂ for 5 minutes and then sealed. The reaction mixture was shaken for 1.2 hours at 80°C and cooled to room temperature. The reaction mixture was filtered through a celite pad and the volatile solvent was removed under vacuum. The residue was purified by column chromatography to give the title compound (1.35 g, 79%). MS (M+H)+=429.4.

Stage 1-4. Preparation of tert-butyl-N-{1-[2-amino-3-(5,7-Difluoro-1H-1,3-benzodiazol-2-yl)-5-(3fluoro-5-methylphenyl)pyridin-4- yl]piperidin-4-yl}carbamate.

Tert-Butyl-N-{1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl)]piperidin-4yl}carbamate mixture (1.7 g, 3.97 mmol) and 3,5-difluoro-1,2-diaminobenzene (0.69 g, 1.2 eq.) in DMF/H2O (9/1=15 ml/1.7 ml) were shaken at 100°C for 5 days in atmospheric oxygen. The reaction mixture was cooled to room temperature, diluted with H2O (~120 ml) to form precipitates, which were filtered, washed with H2O and hexane and dried. The solid was purified by reverse phase chromatography on a C18 column to give the title compound (0.81 g, 37%). MS (M+H) ⁺ =553.4.

Stage 1-5. Preparation of 4-(4-aminopiperidin-1-yl)-3-(5,7-Difluoro-1H-1,3-benzodiazol-2-yl)-5-(3fluoro-5-methylphenyl)pyridin-2-amine. Into a solution of tert-butyl-N-{1[2-amino-3-(5,7-difluoro-1H-1,3benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4- yl]piperidin-4-yl}carbamate (0.8 g, 1.44 mmol) in DCM (15 ml) was added with TFA (4 ml) at room temperature. The reaction mixture was shaken at room temperature for 1 hour and then concentrated to remove volatile solvent. The residue was purified by reverse phase chromatography on a C18 column using ACN/H2O with 0.1% TFA. The pure fractions were combined and made alkaline to pH ~10 with saturated NaHCO ₃ . The product precipitated in the aqueous layer during removal of volatile ACN. The solids were collected, washed with H2O and hexane and dried to give the title compound (0.46 g, 70%) as a white powder. MS (M+H) ⁺ =453.2.

Stage 1-6. Preparation of HCl salt. The product described in steps 1-5 was dissolved in dioxane or DCM. The resulting solution was treated with 4 N. HCl in dioxane (~2.5 eq) and shaken for 10 minutes at room temperature. The solution was concentrated under high vacuum to obtain the final product as two HCl salts.

The following compounds were prepared similarly to Example 1 with appropriate substitution reagents, solvents and substrates at various stages, and further modifications of the functional groups on the benzimidazoyl side chain may be required using well known chemistry with appropriate reagents, and another salt such as a TFA salt or salt of formic acid. _____________________________

Connection no. MS (M+N) ⁺ 1-1 451.3 1-3 453.1 1-6 435.4 1-7 481.2 1-8 447.3

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1-9 1-10 1-11 1-12 1-13 1-14 1-15 1-16 1-17 1-18 1-19 1-20 1-21 1-23 1-24 1-25 1-26 1-27 1-31 1-32 1-41 1-42 1-45 1-46 1-51 1-52 1-53 1-54 1-59 1-60

496.5 431.2 435.2 442.2 477.2 501.2 453.2 489.4 490.2 504.3 487.5 473.3 442.1 490.2 504.3 458.3 490.4 490.2 497.2 462.4 472.2 476.2 490.3 505.3 418.4 418.2 495.5 469.2 465.2 490.2

- 45 043353

Example 2. 2-[2-Amino-4-(4-aminopiperidin-1-yl)-5-(3-(fluoro-5-methylphenyl)pyridin-3-yl]-1Hindol-6-carbonitrile (compound 1- 33).

Stage 2-1. Preparation of tert-butyl-N-[1-(2-amino-5-bromopyridin-4-yl)piperidin-4-yl]carbamate. A mixture of 2-amino-5-bromo-4-fluoropyridine (0.15 g, 0.78 mmol), 4-Boc-aminopiperidine (0.31 g, 2.0 eq.) and DIEA (0.33 ml, 2 .5 eq.) in DMSO (3 ml) was shaken at 120°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with H2O to form a solid. The solid was collected, washed with H2O and ~10% AcOH in H2O and dried to give the title compound (0.23 g, 79%). MS (M+H)+=371.1.

Stage 2-2. Preparation of tert-butyl-N-{1-[2-amino-5-(3-fluoro-5-methylphenyl)]pyridin-4yl]piperidin-4-yl}carbamate. A mixture of tert-butyl-N-[1-(2-amino-5-bromopyridin-4-yl)piperidin-4yl]carbamate (0.11 g, 0.29 mmol), 3-fluoro-5-methylborinic acid (91 mg, 2.0 eq.), PdCl ₂ (tBu ₂ PPhNMe ₂ ) ₂ (21 mg, 0.03 mmol) and K2CO3 (82 mg, 2 eq.) in dioxane/H ₂ O (10/1=3 ml /0.3 ml) degassed with N2 for 5 minutes and then sealed. The reaction mixture was shaken for 1.5 hours at 75°C and cooled to room temperature. The reaction mixture was filtered through a celite pad and the volatile solvent was removed under vacuum. The residue was purified by column chromatography to give the title compound (0.1 g, 83%). MS (M+H)+=401.5.

Stage 2-3. Preparation of tert-butyl-N-{1-[2-amino-3-bromo-5-(3-fluoro-5-methylphenyl)pyridin-4yl)]piperidin-4-yl}carbamate. In a solution of tert-butyl-N-{1-[2-amino-5-(3-fluoro-5-methylphenyl)]pyridin4-yl]piperidin-4-yl}carbamate (0.1 g, 0.25 mmol) NBS (60 mg, 1.3 eq.) was added to ACN (2 mL) at room temperature. The reaction mixture was shaken for 10 minutes at room temperature and concentrated. The residue was purified by reverse phase chromatography on a C18 column to give the title compound (73 mg, 61%). MS (M+H)+=479.0.

Stage 2-4. Preparation of tert-butyl-N-{1-[2-amino-3-(6-cyano-1H-indol-2-yl)-5-(3-fluoro-5methylphenyl)pyridin-4-yl]piperidin-4- il}carbamate. Tert-Butyl-N-{1-[2-amino-3-bromo-5-(3fluoro-5-methylphenyl)pyridin-4-yl)]piperidin-4-yl}carbamate mixture (70 mg, 0.15 mmol ), (6-cyano-1H-indol-2yl)boric acid (55 mg, 2.0 eq.), PdCl ₂ (tBu ₂ PPhNMe ₂ ) ₂ (21 mg, 0.029 mmol) and K ₂ CO ₃ (42 mg , 2 eq.) in dioxane/H ₂ O (10/1=2.5 ml/0.25 ml) was degassed with N ₂ for 5 minutes and then capped. The reaction mixture was shaken for 1.0 hour at 80°C and cooled to room temperature. The reaction mixture was filtered through a celite pad and the volatile solvent was removed under vacuum. The residue was purified by column chromatography to give the title compound (40 mg, 51%). MS (M+H)+=541.3.

Stage 2-5. Preparation of 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3yl]-1H-indole-6-carbonitrile. Into a solution of tert-butyl-N-{1-[2-amino-3-(6-cyano-1H-indol-2-yl)-5-(3fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4 -yl}carbamate (38 mg, 0.07 mmol) in DCM (1.5 ml) was added to TFA (0.3 ml) at room temperature. The reaction mixture was shaken for 1.5 hours at room temperature and then concentrated. The residue was purified by reverse phase chromatography on a C18 column to give the title compound (16 mg, 53%). MS +H) ⁺ =441.5.

Stage 2-6. Preparation of HCl salt. The product described in steps 2-5 was dissolved in dioxane or DCM. The resulting solution was treated with 4 N. HCl in dioxane (~2.5 eq) and shaken for 10 minutes at room temperature. The solution was concentrated under high vacuum to obtain the final product as two HCl salts.

Example 3 4-(4-Aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-[(propan-2-yloxy)imino]methyl]pyridin-2-amine (compound 1- 37).

Stage 3-1. Preparation of benzyl-N-[1-[2-amino-5-(3-chloro-5-methylphenyl)-3[(propan-2-yloxy)imino]methyl]pyridin-4-yl]piperidin-4-yl] carbamate. Benzyl N-[1-[2amino-5-(3-chloro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl]carbamate (45 mg, 0. 09 mmol, 1.00 eq.), prepared in a manner similar to that described in Step 1-1 - Step 1-3 in Example 1, methanol (2 ml), O-(propan-2-yl)hydroxylamine hydrochloride (13 mg, 0.12 mmol, 1.20 eq.), pyridine (9 mg, 0.11 mmol, 1.20 eq.). The resulting solution was shaken overnight at room temperature. The resulting mixture was concentrated in vacuo to provide 50 mg (99%) of the title compound as a yellow solid. MS (M+H)+=536.2.

Stage 3-2. Preparation of 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3[(propan-2yloxy)imino]methyl]pyridin-2-amine trifluoroacetate. Benzyl-N[1-[2-amino-5-(3-chloro-5-methylphenyl)-3-[(1E)-[(propan-2-yloxy)imino]methyl]pyridine was placed in a 50 ml round bottom flask. -4-yl]piperidin4-yl]carbamate (50 mg, 0.09 mmol, 1.0 eq.), trifluoroacetic acid (2 ml). The resulting solution was shaken for 2 hours at 50°C in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (50 mg) was purified by preparative HPLC under the following conditions (Waters-2767): X-bridge RP18 5 µm, 19x100 mm column; mobile phase, A is 0.03% trifluoroacetic acid in water and B is _CH3CN (25% CH3CN to 80% in 15 minutes); detector, UV 220 and 254 nm. This gave 32.6 mg (68%) of the title compound as a light yellow solid. MS (M+H)+=402.2.

The following compounds, as either a mixture of cis/trans isomers, or only the trans isomer, or only the cis isomer, were prepared similarly to Example 3 with appropriate substitution reagents and substrates at various stages.

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Example 4. 1-[3-(5-Chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4yl]piperidin-4-amine ( connection 2-2).

Stage 4-1. Preparation of tert-butyl-N-[1-(3-formyl-2-methoxypyridin-4-yl)pineridin-4yl]carbamate. A mixture of 4-chloro-3-formyl-2-methoxypyridine (0.43 g, 2.51 mmol), 4-Boc-aminopiperidine (0.7 g, 3.5 mmol) and DIEA (1.0 ml, 2. 5 equiv.) in ACN (14 ml) was shaken at 100°C for 40 minutes. After removal of the volatile solvent, the residue was purified by column chromatography to give the title compound (0.84 g, 100%). MS (M+H)+: 336.5.

Stage 4-2. Preparation of tert-butyl-N-[1-(5-bromo-3-formyl-2-methoxypyridin-4-yl)piperidin-4yl]carbamate. NBS was added to a solution of tert-butyl-N-[1-(3-formyl-2-methoxypyridin-4-yl)piperidin-4-yl]carbamate (0.29 g, 0.86 mmol) in ACN (12 mL). (0.2 g, 1.13 mmol) at room temperature. The reaction was completed in 20 minutes and the product formed as precipitates during the reaction. The solid was filtered, washed with ACN and hexane and dried to give the title compound (0.27 g, 77%). MS (M+H) ⁺ =414.2.

Stage 4-3. Preparation of tert-butyl-N-{1-[5-(3-fluoro-5-methylphenyl)-3-formyl-2-methoxypyridin-4yl)]piperidin-4-yl}carbamate. The title compound was prepared in a manner similar to that described in steps 1-3 in Example 1. MS (M+H) ⁺ =444.4.

Stage 4-4. Preparation of N-[1-[3-(3-fluoro-5-methylphenyl)-5-[[(2methylpropoxy)imino]methyl]pyridin-4-yl]piperidin-4-yl]carbamate. Tert-Butyl-N-{1-[5-(3fluoro-5-methylphenyl)-3-formyl-2-methoxypyridin-4-yl)]piperidin-4-yl}carbamate mixture (85 mg, 0.19 mmol), 4 -chloro-1,2-diaminobenzene (30 mg, 1.1 eq.) in DMF/H2O (9/1=1.5 ml/0.16 ml) was shaken at 90°C overnight in atmospheric oxygen. The reaction mixture was directly purified by reverse phase chromatography on a C18 column to obtain the title compound (75 mg, 75%). MS (M+H) ⁺ =566.4.

Stage 4-5. Preparation of 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2methoxypyridin-4-yl]piperidin-4-amine. The title compound was prepared in a manner similar to that described in steps 1-5 in Example 1. MS (M+H) ⁺ =466.3.

Stage 4-6. Preparation of AcOH salt. The free base product described in step 45 was dissolved in ACN or DCM. The resulting solution was treated with AcOH (~2.0 eq) and shaken for 10 minutes at room temperature. The solution was concentrated under high vacuum to obtain the final product as the AcOH salt.

The following compounds were prepared similarly to Example 4 with appropriate substitution reagents and substrates at various stages.

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Connection no. MS (M+N) ⁺ 2-1 450.2 2-3 462.4 2-5 468.4 2-6 473.2 2-8 457.2 2-9 467.0 2-13 467.4 2-14 470.2

Example 5 ol (compound 2-4).

Stage 5-1. Preparation of 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro5-methylphenyl)pyridin-2-ol. In a solution of 1-[3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5methylphenyl)-2-methoxypyridin-4-yl]piperidin-4-amine (20 mg, 0.04 mmol) in dioxane (1 ml) was added 4 N. HCl (53 µl, 5 eq.). The reaction mixture was shaken for 2 hours at 70°C. After removal of the volatile solvent, the residue was purified by reverse phase chromatography on a C18 column to give the title compound (6.5 mg, 34%). MS (M+H)+=452.3.

The following compounds were prepared similarly to Example 5 with appropriate substitution reagents and substrates at various stages.

Example 6. 1 -[2-Chloro-3 -(5-fluoro-1H-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyridin-4yl]piperidin-4-amine (connection 2-11).

Stage 6-1. Preparation of 1-[2-chloro-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-amine . Suspension of 4-(4-aminopiperidin-1-yl)3-(5-fluoro-1H-1,3-benzodiazol-2yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-ol (180 mg, 0.41 mmol) in POCl ₃ (3.5 ml) was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature and carefully poured onto ice.

The reaction mixture was made basic with 50% NaOH and extracted with DCM (3 times). The combined organic layers were washed with brine (1 time), dried and concentrated. The residue was purified by reverse phase chromatography on a C18 column to give the title compound (26 mg, 14%). MS (M+H) ⁺ =454.3.

Example 7 1-[5-(3-Fluoro-5-methylphenyl)-3-(6-methoxy-1H-indol-2-yl)pyridazin-4-yl]piperidin-4amine (compound 3-5).

Stage 7-1. Preparation of tert-butyl-N-[1-(5-chloro-3-hydroxypyridazin-4-yl)piperidin-4yl]carbamate. A mixture of 4,5-dichloropyridazin-3-ol (10.00 g, 60.61 mmol) and tert-butyl-N-(piperidine-4

- 49 043353 yl)carbamate (14.57 g, 72.73 mmol) dioxane (200 ml) and NaHCO3 (7.64 g, 90.92 mmol) were added under nitrogen. The mixture was refluxed for 1 day. The mixture was concentrated in vacuo and the residue (slurry) was triturated with DCM. The first solid was collected by vacuum filtration to yield the more polar undesired tert-butyl-N-[1-(5-chloro-6-hydroxypyridazin-4-yl)piperidin4-yl]carbamate. The filtrate was concentrated to dryness in vacuo and triturated with MeOH. The second solid was collected by vacuum filtration to provide the less polar desired product. The above trituration procedure with DCM or MeOH was repeated with the filtrate to obtain more product. Overall, the reaction gave the desired product (9.81 g, 49.2% yield) as a light yellow solid. MS (M+H)+=329.3.

Stage 7-2. Preparation of tert-butyl-M-{1-[5-(3-fluoro-5-methylphenyl)-3-hydroxypyridazin-4yl]piperidin-4-yl}carbamate. In a mixture of tert-butyl-N-[1-(5-chloro-3-hydroxypyridazin-4-yl)piperidin4-yl]carbamate (4.00 g, 12.17 mmol), (3-fluoro-5-methylphenyl) boric acid (3.748 g, 24.34 mmol), Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H4)] ₂ Cl ₂ ) (0.86 g, 1.22 mmol) and K ₂ cO ₃ ( 5.41 g, 39.12 mmol) dioxane (40 ml) and water (4.0 ml) were added to a stoppered test tube. The mixture was bubbled with N2 (gaseous) for 10 minutes and then heated at 100°C for 2 hours. The mixture was concentrated to dryness in vacuo and purified by silica gel column chromatography to give the title compound (2.81 g, 57.3% yield) as an off-white solid. MS (M+H)+=403.5.

Stage 7-3. Preparation of tert-butyl-N-{1-[3-chloro-5-(3-fluoro-5-methylphenyl)pyridazin-4yl]piperidin-4-yl}carbamate. To tert-butyl-M-{1-[5-(3-fluoro-5-methylphenyl)-3-hydroxypyridazin-4yl]piperidin-4-yl}carbamate (2.81 g, 6.97 mmol) was added POCl ₃ (20 ml, 0.214 mol) and the mixture was refluxed for 2 hours. The mixture was carefully poured onto ice and shaken overnight. The mixture was then made alkaline with NaOH (approximately 45 g) in an ice bath, followed by the addition of MeOH (20 ml) and Boc ₂ O (3 ml). After shaking at room temperature for 30 minutes, the mixture was concentrated to dryness in vacuo and purified by silica gel column chromatography to give the title compound (1.36 g, 46.2% yield) as a light yellow solid. MS (M+H)+=421.3.

Stage 7-4. Preparation of tert-butyl-N-{1-[5-(3-fluoro-5-methylphenyl)-3-(6-methoxy-1H-indol-2yl)pyridazin-4-yl]piperidin-4-yl}carbamate. In a mixture of tert-butyl-N-{1-[3-chloro-5-(3-fluoro-5methylphenyl)pyridazin-4-yl]piperidin-4-yl}carbamate (100.0 mg, 0.24 mmol), 6-methoxy-2(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (130.0 mg, 0.48 mmol), Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H ₄ )] ₂ Cl ₂ ) (16.9 mg, 0.024 mmol) and K2CO3 (98.7 mg, 0.71 mmol) dioxane (5 ml) and water (0.5 ml) were added to a stoppered test tube. The mixture was bubbled with N2 for 10 minutes and then heated at 100°C for 1 hour. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (59.2 mg, 46.6% yield) as a yellow solid. MS (M+H) ⁺ =532.3.

Stage 7-5. Preparation of 1-[5-(3-fluoro-5-methylphenyl)-3-(6-methoxy-1H-indol-2-yl)pyridazin-4yl]piperidin-4-amine dihydrochloride. Into a solution of tert-butyl-N-{1-[5-(3-fluoro-5-methylphenyl)-3-(6methoxy-1H-indol-2-yl)pyridazin-4-yl]piperidin-4-yl}carbamate (59.2 mg, 0.111 mmol) in DCM (0.8 ml) was added TFA (0.2 ml). The mixture was shaken at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography on a C18 column. The pure fractions were pooled, made basic with saturated NaHCO3 (aq) and concentrated to remove MeCN. The aqueous residue was extracted with DCM (3 times) and the combined organics were dried over anhydrous Na ₂ SO ₄ and concentrated to give a neutral product, which was triturated with 2N. HCl in ether (0.2 mL) to give 2 HCl salts of the title compound (47.1 mg, 0.0934 mmol, 84.1% yield) as a golden yellow solid. MS (M+H)+=432.4.

The following compounds were prepared similarly to Example 7 with appropriate substitution reagents and substrates at various stages.

- 50 043353

Connection no. MS (M+N) ⁺ 3-1 436.4 3-2 436.3 3-4 420.4 3-6 436.1 3-7 435.8 3-8 420.3 3-9 431.9 3-11 466.1 3-12 427.1 3-15 470.5 3-16 415.9 3-17 427.4 3-18 460.1 3-19 445.3 3-20 475.2 3-23 427.2

Example 8. 1-[3-(5-Chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin4-amine (compound 3- 3).

Stage 8-1. Preparation of tert-butyl-N-{1-[5-(3-fluoro-5-methylphenyl)-3-[(E)-2phenylethenyl]pyridazin-4-yl]piperidin-4-yl}carbamate. The title compound was obtained as a yellow solid using a method similar to that described in Example 7, Step 7-3. MS (M+H)+=489.4.

Stage 8-2. Preparation of tert-butyl-N-{1-[5-(3-fluoro-5-methylphenyl)-3-formylpyridazin-4yl]piperidin-4-yl}carbamate. In a solution of tert-butyl-N-{1-[5-(3-fluoro-5-methylphenyl)-3-[(E)-2phenylethenyl]pyridazin-4-yl]piperidin-4-yl}carbamate (161.9 mg, 0.33 mmol) in a mixed solvent of dioxane (5 ml) and water (1 ml), a solution of OsO ₄ (8.4 mg, 0.03 mmol) in t-BuOH (0.4 ml) was added, followed by periodate sodium (389.4 mg, 1.82 mmol). The mixture was shaken at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (2 times). The combined organics were concentrated to dryness in vacuo and the residue was purified by silica gel column chromatography to give the title compound (120.0 mg, 87.6% yield) as a brown gum.

Stage 8-3. Preparation of tert-butyl-N-{1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5(3-fluoro-5methylphenyl)pyridazin-4-yl]piperidin-4-yl }carbamate. Into a solution of tert-butyl-N-{1-[5-(3-fluoro-5methylphenyl)-3-formylpyridazin-4-yl]piperidin-4-yl}carbamate (120.0 mg, 0.29 mmol) in mixed 4-chlorobenzene-1,2-diamine (62.0 mg, 0.435 mmol) was added to a solvent of DMF (6 ml) and water (0.6 ml). The mixture was heated at 80°C over the weekend. The mixture was concentrated to half volume and purified by reverse phase chromatography on a C18 column. The pure fractions were combined, made basic with saturated NaHCO ₃ (aq) and concentrated to remove MeCN. The aqueous residue was extracted with DCM (3 times), the combined organics were dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound (86.4 mg, 55.5% yield) as a light brown solid. MS (M+H)+=537.5.

Stage 8-4. Preparation of 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin4-yl]piperidin-4-amine dihydrochloride. The title compound was obtained as a yellow solid using a method similar to that described in Example 7, Step 7-5. MS (M+H)+=437.3.

The following compounds were prepared similarly to Example 8 with appropriate substitution reagents and substrates at various stages.

- 51 043353

Example 9 1-[3-(3-Chloro-6-methoxy-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-4yl]piperidin-4-amine (compound 3- 21).

Stage 9-1. Preparation of tert-butyl-N-{1-[3-(3-chloro-6-methoxy-1H-indol-2-yl)-5-(3-fluoro-5methylphenyl)pyridazin-4-yl]piperidin-4- il}carbamate. Into a solution of tert-butyl-N-{1-[5-(3-fluoro-5methylphenyl)-3-(6-methoxy-1H-indol-2-yl)pyridazin-4-yl]piperidin4-yl}carbamate (from example 6, step 6-4) (126.0 mg, 0.24 mmol) to DMF (4 ml) was added NCS (63.3 mg, 0.47 mmol). The mixture was shaken for 10 minutes. Very little product was shown, so more NCS (31.6 mg, 0.24 mmol) was added and the reaction mixture continued to shake at room temperature for 10 minutes. Unreacted starting material still remained, but the reaction was stopped by quenching with water and saturated Na ₂ S ₂ O ₃ (aq). The mixture was extracted with EtOAc (2X) and the combined organics were concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography to give the title compound (69.5 mg, 51.9% yield). MS (M+H)+=566.5.

Stage 9-2. Preparation of 1-[3-(3-chloro-6-methoxy-1H-indol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridazin4-yl]piperidin-4-amine dihydrochloride. The title compound was obtained as a yellow solid using a method similar to that described in Example 7, Step 7-5. MS (M+H) ⁺ =466.2.

The following compounds were prepared similarly to Example 9 with appropriate substitution reagents and substrates at various stages.

Example 10 ).

Stage 10-1. Preparation of 2-[1-(5-chloro-3-hydroxypyridazin-4-yl)piperidin-4-yl]-2,3-dihydro-1Nisoindole-1,3-dione. The title compound was obtained as a light yellow solid using a method similar to that described in Example 6, Step 6-1. MS (M+H) ⁺ =358.8.

Stage 10-2. Preparation of 2-{1-[5-(3-fluoro-5-methylphenyl)-3-hydroxypyridazin-4-yl]piperidin-4yl}-2,3-dihydro-1H-isoindole-1,3-dione. The title compound was obtained as a light yellow solid using a method similar to that described in Example 7, Step 7-2. MS (M+H) ⁺ =433.2.

Stage 10-3. Preparation of 2-{1-[3-chloro-5-(3-fluoro-5-methylphenyl)pyridazin-4-yl]piperidin-4-yl}2,3-dihydro-1H-isoindol-1,3-dione. To 2-{1-[5-(3-fluoro-5-methylphenyl)-3-hydroxypyridazin-4yl]piperidin-4-yl}-2,3-dihydro-1H-isoindole-1,3-dione (325 mg , 0.91 mmol) POCl ₃ (3 ml) was added and the mixture was refluxed for 1 hour. The mixture was carefully poured onto ice, the solid was collected by vacuum filtration and washed with water to give the title compound (379.4 mg, 92.8%) as a yellow solid. MS (M+H) ⁺ =451.1.

Stage 10-4. Preparation of 2-{1-[5-(3-fluoro-5-methylphenyl)-3-(6-methoxy-1H-indol-2-yl)pyridazin-4yl]piperidin-4-yl}-2,3-dihydro -1H-isoindole-1,3-dione. The title compound was obtained as a brown solid using a method similar to that described in Example 7.

- 52 043353 stage 7-4. MS (M+H)+=562.4.

Stage 10-5. Preparation of 2-{4-[4-(1,3-dioxo-2.3-dihydro-1H-isoindol-2-yl)piperidin-1-yl]-5-(3fluoro-5-methylphenyl)pyridazin-3-yl} -6-methoxy-1H-indole-3-carbonitrile. Into a suspension of 2-{1-[5-(3-fluoro5-methylphenyl)-3-(6-methoxy-III-indol-2-yl)pyridazin-4-yl]piperidin-4-yl}-2,3- Dihydro-III-isoindole1,3-dione (48.0 mg, 0.09 mmol) in a mixed solvent of DMF (0.5 ml) and MeCN (5 ml) at 0°C was added a solution of chlorosulfonylisocyanate (0.020 ml) in MeCN ( 0.2 ml). The mixture was shaken at room temperature for 30 minutes. The mixture was poured into ice water, made basic with saturated NaHCO ₃ (aq) and extracted with EtOAc (2X). The combined organics were concentrated in vacuo and the residue was purified by silica gel column chromatography to give the title compound (21.8 mg, 43.5%) as a brown solid. MS (m+H) ⁺ =586.6.

Stage 10-6. Preparation of 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridazin-3-yl]-6methoxy-1H-indole-3-carbonitrile dihydrochloride. Into a suspension of 2-{1-[5-(3-fluoro-5-methylphenyl)-3-(6methoxy-1H-indol-2-yl)pyridazin-4-yl]piperidin-4-yl}-2,3 -dihydro-1H-isoindole-1,3-dione (21.8 g, 0.0372 mmol) in EtOH (2 ml) in a stoppered tube was added hydrazine monohydrate (5 drops) and the mixture was heated at 80°C for 30 minutes. The mixture was cooled to room temperature and concentrated. The residue was purified by reverse phase chromatography on a C18 column. The pure fractions were combined, made basic with saturated NaHCO ₃ (aq) and concentrated to remove MeCN. The aqueous residue was extracted with DCM (3 times), the combined organics were dried over anhydrous Na ₂ SO ₄ and concentrated to give a neutral compound, which was triturated with 2N. HCl in ether (0.2 ml) to obtain 2 HCl salts of the title compound (9.0 mg, 45.7%) as a yellow solid. MS (M+H)+=457.4.

The following compounds were prepared similarly to Example 10 with appropriate substitution reagents and substrates at various stages.

E# of MS connection (M+H) ⁺

3-26 452.3

Example 11 4-(4-Aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5methylphenyl)-N-methylpyridine -2-amine (compound 1-48).

Stage 11-1. Preparation of tert-butyl-N-[1-[5-(3-fluoro-5-methylphenyl)-3-formyl-2(methylamino)pyridin-4-yl]piperidin-4-yl]carbamate. Tert-butyl-N-[1-[2-amino5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl]carbamate (500 mg, 1.17 mmol, 1.00 eq.), sodium hydroxide (140 mg, 3.50 mmol, 3.00 eq.), N,N-dimethylformamide (5 ml), CH ₃ I (200 mg, 1.41 mmol, 1.20 eq.). The resulting solution was shaken for 30 minutes at 50°C. The crude product was further purified by preparative HPLC under the following conditions (Waters I): X bridge Prep C18 OBD column, 5 µm, 19x150 mm; mobile phase: water with 0.1% NH ₄ OH and CH ₃ CN (45% CH3CN to 85% for 13 minutes); detector UV 220 and 254 nm, which gave 165 mg (32%) of the title compound as a light yellow solid. MS (M+H)+=443.2. The methylation position was confirmed using NOE NMR experiment.

Stage 11-2. Preparation of tert-butyl-N-[1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5methylphenyl)-2-(methylamino)pyridin- 4-yl]piperidin-4-yl]carbamate. Tert-butyl-N-[1-[5-(3-fluoro-5-methylphenyl)-3-formyl-2-(methylamino)pyridin-4yl]piperidin-4-yl]carbamate ( 165 mg, 0.37 mmol, 1.00 eq.), Na ₂ S ₂ O ₅ (142 mg, 2.00 eq.), NMP (3 ml), water (0.3 ml), 3.5- difluorobenzene-1,2-diamine (165 mg, 1.14 mmol, 3.00 eq.). The resulting solution was shaken for 8 hours at 100°C. The crude product was further purified by preparative HPLC under the following conditions (Waters I): X bridge Prep C18 OBD column, 5 µm, 19x150 mm; mobile phase: water (0.05% TFA) and _CH3CN (5% CH3CN to 55% for 12 minutes); detector UV 220 and 254 nm to obtain 60 mg (28%) of the title compound as a brown solid. MS (M+H)+=567.5.

Stage 11-3. Preparation of 4-(4-aminoniperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3fluoro-5-methylphenyl)-N-methylpyridin-2 -amine hydrochloride. Tert-butyl-N-[1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2- was placed in a 50 ml round bottom flask. (methylamino)pyridin-4yl]piperidin-4-yl]carbamate (60 mg, 0.11 mmol, 1.00 eq.), dichloromethane (1.5 ml), trifluoroacetic acid (0.5 ml). The resulting solution was shaken for 1 hour at 25°C and then concentrated

- 53 043353 under vacuum. 5 ml of 1 M HCl was added to the residue and the mixture was freeze dried to give 49.0 mg (92%) of the title compound as a brown solid. MS (M+H) ⁺ =467.2. ΉNMR (300 MHz, CD ₃ OD, ppm): δ 7.64 (s, 1H), 7.37 (d, 1H), 7.18 (s, 1H), 7.14-7.06 ( m, 3H), 3.373.34 (m, 1H), 3.28-3.24 (m, 1H), 3.03 (m, 4H), 2.61-2.52 (m, 2H), 2 .48 (s, 3H), 1.64-1.57 (m, 2H), 1.25-1.18 (m,

2H).

The following compounds were prepared similarly to Example 11 with appropriate substitution reagents and substrates at various stages.___________________________

Connection no. MS (M+N) ⁺ 1-28 465.2 1-30 479.2 1-49 481.3 1-50 481.3 1-55 467.2 1-70 456.2 1-71 461.2 1-72 465.1 1-75 483.2 1-89 474.2 4-1 479.2

Example 12 methylphenyl)pyridin-2-amine (compound 1-5).

Stage 12-1. Preparation of tert-butyl-M-(4-chloro-3-formylpyridin-2-yl)carbamate. Tert-Butyl-N-(4-chloropyridin-2-yl)carbamate (15.0 g, 65.60 mmol, 1.00 eq.) was placed in a 500 mL 3-neck round bottom flask, purged and kept under an inert nitrogen atmosphere. , anhydrous tetrahydrofuran (300 ml). Then η-BuLi (2.5 M, 55.1 ml, 2.00 eq.) was added dropwise with shaking at -78°C for 30 minutes, followed by the addition of Ν,N-dimethylformamide (15.1 ml, 3.00 eq.) drops with shaking at -78°C for 5 minutes. The resulting solution was shaken for another 1 hour at -78°C, and then carefully quenched with 300 ml of saturated ammonium chloride solution. The mixture was extracted with 3x300 ml ethyl acetate, the combined organics were washed with 3x300 ml water and dried over anhydrous sodium sulfate. After filtering to remove solid, the solution was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether to give 12.0 g (71%) of the title compound as a light yellow solid. MS (M+H) =257.1.

Stage 12-2. Preparation of benzyl-K-[1-(2-amino-3-formylpyridin-4-yl)piperidin-4-yl]carbamate. Place tert-butyl-M-(4-chloro-3-formylpyridin-2-yl)carbamate (8.1 g, 31.56 mmol, 1.00 eq.), benzyl-M(piperidine) into a 250 mL round bottom flask -4-yl)carbamate (8.1 g, 34.57 mmol, 1.10 eq), DIEA (12.2 g, 94.40 mmol, 3.00 eq), ACN (100 ml). The resulting solution was shaken for 16 hours at 85°C and then concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether (1:3) to give 4.6 g (41%) of the title compound as a yellow solid. MS (M+H) ⁺ =355.2.

Stage 12-3. Preparation of bsnzyl^-[1-(2-amino-5-bromo-3-formylpyridin-4-yl)pipsridin-4yl]carbamate. Benzyl M-[1-(2-amino-3-formylpyridin-4yl)piperidin-4-yl]carbamate (4.5 g, 12.70 mmol, 1.00 eq.) was placed in a 100 mL round bottom flask. , NBS (2.9 g, 16.29 mmol, 1.30 eq.), DCE (50 ml). The resulting solution was shaken for 40 minutes at 85°C and then concentrated. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether to give 3.9 g (71%) of the title compound as a yellow solid. MS (M+H) ⁺ =433.1/435.1.

Stage 12-4. Preparation of benzyl-K-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4yl] piper idin-4-yl] carbamate. Benzyl-N-[1-(2-amino-5-bromo-3-formylpyridin-4-yl)piperidin-4-54043353 yl]carbamate ( 3.9 g, 9.00 mmol, 1.00 eq.), (3-fluoro-5-methylphenyl)boric acid (2.8 g, 18.19 mmol, 2.00 eq.), Pd2(dba) 3 (200 mg, 0.22 mmol, 0.02 eq.), t-Bu3P (400 mg), K3PO4 (5.7 g, 3.00 eq.), THF (50 ml), water (10 ml) . The resulting solution was shaken for 2 hours at 30°C, diluted with 200 ml H2O and then extracted with 3x200 ml ethyl acetate. Organic products were dried over anhydrous sodium sulfate. After filtering to remove solids, the solution was concentrated in vacuo and the resulting crude product was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (3:1) to yield 3.1 g (74%) of the title compound as light. yellow solid. MS (M+H)+=463.2.

Stage 12-5. Preparation of benzyl-N-[1-[2-amino-3 -(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5 methylphenyl)pyridin-4-yl ]piperidin-4-yl]carbamate. Benzyl-N-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl]carbamate ( 2.0 g, 4.32 mmol, 1.00 eq.), 4,5-difluorobenzene-1,2-diamine (3.1 g, 21.51 mmol, 5.00 eq.), N,Ndimethylformamide ( 50 ml), water (5 ml). The resulting solution was shaken for 48 hours at 100°C. The resulting solution was diluted with 200 ml H2O, extracted with 3x200 ml ethyl acetate, the ethyl acetate layer was washed with 3x100 ml brine and dried over anhydrous sodium sulfate. Solids were filtered off and the resulting solution was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether to give 1.8 g (71%) of the title compound as a brown solid. MS (M+H) ⁺ =587.1.

Stage 12-6. Preparation of benzyl-N-[1-[2-amino-3-(1-ethyl-5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3fluoro-5-methylphenyl)pyridin- 4-yl]piperidin-4-yl]carbamate. Benzyl-N-[1-[2-amino-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl) was placed in an 8 ml sealed tube )pyridin-4yl]piperidin-4-yl]carbamate (180 mg, 0.31 mmol, 1.00 eq.), sodium hydroxide (37 mg, 0.93 mmol, 3.00 eq.), N,N- dimethylformamide (2 ml), iodoethane (96 mg, 0.62 mmol, 2.00 eq.). The resulting solution was shaken for 1 hour at 50°C, then diluted with 100 ml of H2O. The mixture was extracted with 3x100 ml ethyl acetate and the ethyl acetate layer was washed with 3x100 ml brine, then dried over anhydrous sodium sulfate. The resulting mixture, after filtration to remove solids, was concentrated in vacuo and purified by preparative TLC (PE:EA=1:1) to obtain 120 mg (64%) of the title compound as a brown solid. MS (M+H) ⁺ =615.3.

Stage 12-7. Preparation of 4-(4-aminopiperidin-1-yl)-3-(1-ethyl-5,6-difluoro-1H-1,3-benzodiazol-2yl)-5-(3-fluoro-5-methylphenyl)pyridin- 2-amine dihydrochloride. Benzyl-N-[1-[2-amino-3-(1-ethyl-5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-) was placed in a 50 ml round bottom flask. fluoro-5-methylphenyl)pyridin4-yl]piperidin-4-yl]carbamate (120 mg, 0.20 mmol, 1.00 eq.), trifluoroacetic acid (5 ml). The resulting solution was shaken for 2 hours at 50°C. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC to provide 65 mg (60%) of the title compound as an off-white solid. MS (M+H) ⁺ =481.2. H-NMR (300 MHz, DMSO-d6, ppm): δ 8.23 (m, 3H), 8.11-7.81 (m, 3H), 7.42 (m, 2H), 7. 10 (m, 3H), 4.55 (m, 1H), 3.98 (m, 1H), 3.24 (m, 1H), 3.00 (m, 1H), 2.84 (m, 1H ), 2.57 (m, 1H), 2.40 (s, 3H), 2.21 (t, J=12.1 Hz, 1H), 1.52 (m, 1H), 1.41-0 .98 (m, 6H), 0.59 (m, J=12.9 Hz, 1H).

The position of ethyl was confirmed by NOE NMR experiment.

The following compounds were prepared similarly to Example 12 with appropriate substitution reagents and substrates at various stages.__________________________

Connection no. MS (M+N) ⁺ 1-29 465.2 1-57 467.2

Example 13 1-yl)pyridin-2-amine (compound 1-56).

Stage 13-1. Preparation of tert-butyl-N-[1-(2-chloro-3-formylpyridin-4-yl)piperidin-4yl]carbamate. 2,4-Dichloropyridin-3-carbaldehyde (2.0 g, 11.36 mmol, 1.00 eq), tert-butyl-N-(piperidin4-yl)carbamate (2.3 g, 11.48 mmol, 1.00 eq.), TEA (3.5 g, 34.59 mmol, 3.00 eq.), N,N-dimethylformamide (10 ml). The resulting solution was shaken for 1 hour at 40°C and then quenched with 50 ml of water. The crude product was extracted with 3x20 ml

- 55 043353 ethyl acetate and the ethyl acetate layer was washed with 4x20 ml saline solution, then dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated and purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:3) to obtain 3.2 g (83%) of the title compound as a yellow solid. MS (m+H) ⁺ =340.1/342.1.

Stage 13-2. Preparation of tert-butyl-N-[1-[3-formyl-2-(methylsulfanyl)pyridin4-yl]piperidin-4yl]carbamate. Tert-Butyl N-[1(2-chloro-3-formylniridin-4yl)piperidin-4-yl]carbamate (2.0 g, 5.89 mmol, 1.00 eq.) was placed in a 40 mL round bottom flask. , tetrahydrofuran (20 ml), (methylsulfanyl) sodium (500 mg, 7.13 mmol, 1.20 eq.). The resulting solution was shaken for 4 hours at 70°C, then cooled to room temperature, and quenched with 20 ml of water. The crude product was extracted with 3x20 ml ethyl acetate and the ethyl acetate was washed with 3x20 ml brine, then dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.6 g (77%) of the title compound as a yellow solid. MS (M+H)+=352.2.

Stage 13-3. Preparation of tert-butylF-[1-[5-bromo-3-formyl-2-(methylsulfanyl)pyridin-4yl]piperidin-4-yl]carbamate. Place tert-butyl-N-[1-[3-formyl-2(methylsulfanyl)pyridin-4-yl]piperidin-4-yl]carbamate (1.5 g, 4.27 mmol, 1) in a 40 mL round bottom flask. .00 eq.), DCE (20 ml), NBS (1.2 g, 6.74 mmol, 1.50 eq.). The resulting solution was shaken for 1 hour at 80°C, then cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether to give 1.2 g (65%) of the title compound as a yellow solid. MS (M+H) ⁺ =429.9/431.9.

Stage 13-4. Preparation of tert-butyl-N-[1-[5-(3-fluoro-5-methylphenyl)-3-formyl-2(methylsulfanyl)pyridin-4-yl]piperidin-4-yl]carbamate. Tert-butyl-N-[1-[5-bromo-3-formyl-2(methylsulfanyl)pyridin-4-yl]piperidin-4-yl] was placed in a 50 mL round bottom flask, purged and kept under an inert nitrogen atmosphere. carbamate (1.0 g, 2.32 mmol, 1.00 eq.), (3-fluoro-5methylphenyl)boric acid (546 mg, 3.55 mmol, 1.50 eq.), K ₃ PO ₄ (1 .5 g, 7.07 mmol, 3.00 eq.), Pd ₂ (dba) ₃ .CHCl ₃ (240 mg, 0.10 eq.), P(t-Bu) ₃ .BHF ₄ (135 mg, 0.20 equiv.), toluene (15 ml), water (1.5 ml). The resulting solution was shaken for 2 hours at 80°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column of ethyl acetate/petroleum ether to give 700 mg (66%) of the title compound as a yellow solid. MS (M+H)+=460.2.

Stage 13-5. Preparation of tert-butyl-N-[1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5methylphenyl)-2-(methylsulfanyl)pyridin- 4-yl]piperidin-4-yl]carbamate. Tert-butyl-N-[1-[5-(3-fluoro-5-methylphenyl)-3-formyl-2-(methylsulfanyl)pyridin-4yl]piperidin-4-yl]carbamate ( 200 mg, 0.44 mmol, 1.00 eq.), 3,5-difluorobenzene-1,2-diamine (184 mg, 1.28 mmol, 3.00 eq.), Na ₂ S ₂ O ₅ (166 mg, 2.00 eq.), NMP (3 ml). The resulting solution was shaken for 48 hours at 120°C. The reaction mixture was then quenched with 10 ml water and extracted with 3x10 ml ethyl acetate. The combined organics were washed with 3x10 ml water and dried over anhydrous sodium sulfate. Solids were filtered off and the resulting solution was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1:4) to yield 200 mg (79%) of the title compound as a yellow solid. MS (M+H)+=584.3.

Stage 13-6. Preparation of tert-butyl-N-[1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5methylphenyl)-2-methanesulfinylpyridin-4-yl ]piperidin-4-yl]carbamate. Tert-butyl-N-[1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl) was placed in a 50 ml round bottom flask. -2(methylsulfanyl)pyridin-4-yl]piperidin-4-yl]carbamate (200 mg, 0.34 mmol, 1.00 eq.), dichloromethane (10 ml), mCPBA (73.3 mg, 0.42 mmol, 1.20 eq.). The resulting solution was shaken for 1 hour at room temperature and then diluted with 10 ml of water. The crude product was extracted with 3x10 ml ethyl acetate and the ethyl acetate was washed with 3x 10 ml brine and dried over anhydrous sodium sulfate. The solids were filtered and the resulting mixture was concentrated in vacuo to provide 200 mg (97%) of the title compound as a gray solid. MS (M+H)+=600.3.

Stage 13-7. Preparation of tert-butyl-N-[1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5methylphenyl)-2-[(2-methoxyethyl) )amino]pyridin-4-yl]piperidin-4-yl]carbamate. Tert-butyl-N-[1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl) was placed in an 8-ml round bottom flask. -2methanesulfinylpyridin-4-yl]piperidin-4-yl]carbamate (80 mg, 0.13 mmol, 1.00 eq.), 2-methoxyethane-1amine (1 ml). The resulting solution was shaken for 12 hours at 100°C. After concentration, the crude product was purified by preparative TLC with ethyl acetate/petroleum ether (1:20) to obtain 50 mg (61%) of the title compound as a light yellow solid. MS (M+H)+=611.4.

Stage 13-8. Preparation of 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro5-methylphenyl)-N-(2- methoxyethyl)pyridin-2-amine. Tert-butyl-SH was placed in a 50-ml round-bottomed flask.

- 56 043353

[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-[(2-methoxyethyl)amino]pyridin-4yl]piperidine -4-yl]carbamate (50 mg, 0.08 mmol, 1.00 eq.), dichloromethane (5 ml), trifluoroacetic acid (1 ml). The resulting solution was shaken for 1 hour at room temperature. The mixture was then concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions (Prep-HPLC-013): SunFire Prep C18 OBD Column, 19x150 mm, 5 µm, 10 nm; mobile phase: water (0.05% TFA) and ACN (11.0% ACN to 23.0% in 6 minutes, 95.0% retention in 1 minute, 11.0% retention in 1 minute) ; detector 220 nm, obtaining 33.8 mg (66%) of the title compound as an off-white solid of the trifluoroacetic acid salt. MS (M+H) ⁺ =511.3. 1H NMR (300 MHz, DMSO-d6, ppm): δ, 7.77 (s, 1H), 7.72 (s, 3H), 7.32-7.29 (m, 1H), 7. 23-7.00 (m, 4H), 3.50 (s, 2H), 3.453.43 (m 2H), 3.23 (s, 3H), 3.03-2.99 (m, 2H), 2.90-2.88 (s, 1H), 2.41 (s, 3H), 2.36-2.28 (m, 2H), 1.47-1.43 (m, 2H), 1. 03-1.06 (m, 2H).

Example 14 4-(4-Aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)-3-{6-[(methoxyimino)methyl]-1 H1,3-benzodiazol-2-yl} pyridine-2-amine (1-40).

Stage 14-1. Preparation of methyl-2-[2-amino-4-(4-[[(benzyloxy)carbonyl]amino]piperidin-1-yl)-5(3-fluoro-5-methylphenyl)pyridin-3-yl]-1P- 1,3-benzodiazole-6-carboxylate. Benzyl N-[1[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4yl]carbamate (400 mg, 0.86) was placed in a 40 ml round bottom flask. mmol, 1.00 eq.), methyl 3,4-diaminobenzoate (575 mg, 3.46 mmol, 4.00 eq.), Na ₂ S ₂ O ₅ (329 mg, 2.00 eq.), NMP ( 10 ml). The resulting solution was shaken for 48 hours at 120°C. The resulting solution was diluted with 20 ml of water. The resulting solution was extracted with 3x20 ml ethyl acetate and the organic layers were combined. The resulting mixture was washed with 3x20 ml water. The resulting mixture was washed with 3x20 ml saline and dried over anhydrous sodium sulfate. The solids were then filtered off, the solution concentrated in vacuo and the crude product chromatographed on a silica gel column, eluting with ethyl acetate/petroleum ether (4:1) to give 240 mg (46%) of the title compound as a brown solid. MS [M+H] ⁺ =609.0.

Stage 14-2. Preparation of benzyl-N-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-[6(hydroxymethyl)-1H1,3-benzodiazol-2-yl]pyridin-4-yl]piperidine -4-yl]carbamate. Methyl 2-[2-amino-4-(4[[(benzyloxy)carbonyl]amino]piperidin-1-yl)5-(3 -fluoro-5-methylphenyl)pyridin-3-yl]-1H-1,3benzodiazol-6-carboxylate (120 mg, 0.20 mmol, 1.00 eq.), tetrahydrofuran (20 ml). LiAlH ₄ (27 mg, 0.71 mmol, 3.00 eq) was then added in portions at 0°C. The resulting solution was shaken for 1 hour at room temperature and then quenched with 10 ml of water. The mixture was extracted with 2x20 ml ethyl acetate and the combined organic layer was washed with 3x20 ml water and then dried over anhydrous sodium sulfate. After filtration to remove solids, the resulting solution was concentrated and the residue was applied to a dichloromethane/methanol silica gel column to provide 35.0 mg (31%) of the title compound as a light yellow solid. MS: [M+H] ⁺ =581.3.

Stage 14-3. Preparation of benzyl-N-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-(6-formyl-1H-1,3benzodiazol-2-yl)pyridin-4-yl]piperidin- 4-yl]carbamate. Benzyl-N-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-[6(hydroxymethyl)-1H-1,3-benzodiazol-2-yl was placed in an 8-ml round bottom flask. ]pyridin-4yl]piperidin-4-yl]carbamate (35 mg, 0.06 mmol, 1.00 eq.), CH3CN (5 ml), IBX (34 mg, 0.12 mmol, 2.00 eq.) . The resulting solution was shaken for 24 hours at room temperature and then 10 ml of water was added, the mixture was extracted with 3x10 ml of ethyl acetate and the combined ethyl acetate was washed with 3x10 ml of water, then dried over anhydrous sodium sulfate. After filtration to remove solids, the resulting solution was concentrated in vacuo to yield 30 mg (86%) of the title compound as a yellow solid. MS: [M+H] ⁺ =579.2.

Stage 14-4. Preparation of benzyl-N-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-[6-[(methoxyimino)methyl]-1H-1,3-benzodiazol-2-yl]pyridine -4-yl]piperidin-4-yl]carbamate. Benzyl-N-[1-[2-amino-5-(3-fluoro-5 methylphenyl)-3-(6-formyl-5,6-dihydro-1H-1,3benzodiazol-2) was placed in an 8-ml round bottom flask -yl)pyridin-4-yl]piperidin-4-yl]carbamate (30 mg, 0.05 mmol, 1.00 eq.), Omethylhydroxylamine hydrochloride (13 mg, 0.16 mmol, 3.00 eq.), methanol (2 ml), pyridine (8.2 mg, 0.10 mmol, 2.00 eq.). The resulting solution was shaken for 5 hours at room temperature and then concentrated in vacuo to yield 35 mg of the title compound as a crude yellow solid. MS: [M+H] ⁺ =608.3.

Stage 14-5. Preparation of 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3[6

- 57 043353

[(methoxyimino)methyl]-III-1,3-benzodiazol-2-yl]pyridin-2-amine. Benzyl-N-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-[6[(methoxyimino)methyl]-1H-1,3-benzodiazol- 2yl]pyridin-4-yl]piperidin-4-yl]carbamate (35 mg, 0.06 mmol, 1.00 eq.), trifluoroacetic acid (2 ml). The resulting solution was shaken for 1 hour at 50°C and then concentrated in vacuo. The crude product was purified by preparative HPLC to provide 2.5 mg (7%) of the title compound as a white solid of the trifluoroacetic acid salt. MS: [M+H]+=474.2. NMR (300 MHz, CD ₃ OD, ppm): δ 8.27 (s, 1H), 7.94 (s, 1H), 7.84-7.81 (m, 2H), 7.69 ( s, 1H), 7.19-7.00 (m, 3H), 3.98 (s, 3H), 3.05-2.95 (m, 1H), 2.612.53 (m, 3H), 2 .47 (s, 3H), 1.60-1.56 (m, 2H), 1.35-1.31 (m, 2H), 1.27-1.11 (m, 2H).

The following compounds were prepared similarly to Example 14 with appropriate substitution reagents and substrates at various stages.__________________________

Connection no. MS (M+N) ⁺ 1-22 460.2 1-44 474.3 1-47 459.2

Example 15 -yl]piperidin-4-amine (compound 4-8).

Stage 15-1. Preparation of tert-butyl-N-[1-[3-formyl-2-(morpholin-4-yl)pyridin4-yl]piperidin-4yl]carbamate. A mixture of tert-butyl-N-[1-(2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate obtained in step 13-1 (500 mg, 1.47 mmol) and morpholine ( 5 ml) was heated at 100°C in a stoppered tube for 5 hours and then cooled to room temperature. It was then diluted with water and the crude product was extracted with ethyl acetate (3x100 ml). The combined extracts were dried over Na ₂ SO ₄ then concentrated after filtering off the solid to give the desired product, tert-butyl-N-[1-[3-formul-2-(morpholin-4-yl)pyridin4-yl]pineridin-4yl ]carbamate, as a yellow solid (530 mg). MS: [M+H]+=391.2.

Stage 15-2. Preparation of tert-butyl-N-[1-[5-bromo-3-formyl-2-(morpholin-4-yl)pyridin-4yl]piperidin-4-yl]carbamate. Into a shaken solution of DCM (5 ml) containing tert-butyl-N-[1-[3formyl-2-(morpholin-4-yl)pyridin-4-yl]piperidin-4-yl]carbamate (300 mg, 0. 77 mmol, 1.00 eq.), NBS (138 mg, 0.78 mmol, 1.00 eq.) was added. The resulting solution was shaken for 30 minutes at room temperature and concentrated. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether to give the title compound as a yellow solid (290 mg). MS: [M+H]+=469.2, 471.2.

Stage 15-3. Preparation of tert-butyl-N-[1-[5-(3-fluoro-5-methylphenyl)-3-formul-2(morpholin-4yl)pyridin-4-yl]piperidin-4-yl]carbamate. Under N2 in toluene (10 ml), tert-butyl-N-[1-[5bromo-3-formyl-2-(morpholin-4-yl)pyridin-4-yl]piperidin-4-yl]carbamate (280 mg) was mixed , 0.60 mmol, 1.00 eq.), (3-fluoro-5-methylphenyl)boric acid (275 mg, 1.79 mmol, 3.00 eq.), Pd ₂ (dba) ₃ (30 mg, 0.03 mmol, 0.05 eq.), P(t-Bu) ₃ (60 mg), water (1 ml) and K3PO4 (379 mg, 3.00 eq.) and shaken for 2 hours at 70° C and then cooled to room temperature. The crude product was extracted with ethyl acetate, dried and concentrated. The residue was purified by silica gel chromatography, eluted with ethyl acetate/petroleum ether to give the title compound as a light yellow solid (240 mg). MS: [M+H]+=449.3.

Stage 15-4. Preparation of 1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2(morpholin-4-yl)pyridin-4- yl]piperidin-4-amine. Mixture of tert-butyl-N[1-[5-(3-fluoro-5-methylphenyl)-3formyl-2-(morpholin-4-yl)pyridin-4-yl]piperidin-4-yl]carbamate (100 mg, 0.20 mmol, 1.00 eq.), 3,5difluorobenzene-1,2-diamine (58 mg, 0.40 mmol, 2.00 eq.) and Na ₂ S ₂ O ₅ (76 mg, 2.00 eq.) in DMSO (2 ml) was heated with shaking in a stoppered tube for 16 hours at 120°C. The reaction mixture was then cooled to room temperature. Solids were filtered off. The crude product was purified by preparative HPLC under the following conditions: SunFire Prep C18 OBD Column, 19x150 mm, 5 µm; mobile phases: A=water (0.05% TFA), B=ACN (0.05% TFA), B from 10.0% to 33.0% over 6 minutes; UV detector 220 nm. Fractions containing pure product were combined and freeze-dried to obtain the title compound as an off-white solid.

- 58 043353 (46.1 mg). MS: [M+N]+=523.3. 1H NMR (300 MHz, CD3OD): δ 8.04 (s, 2H), 7.28 (dd, J=8.4, 1.8 Hz, 1H), 7.08 (s, 1H), 7. 05-6.89 (m, 3H), 3.48-3.46 (m, 4H), 3.40 (m, 2H), 3.27-3.22 (m, 4H), 2.93- 2.85 (m, 1H), 2.56-2.52 (m, 2H), 2.47 (s, 3H), 1.62-1.58 (m, 2H), 1.07-0, 95 (m, 2H).

The following compounds were prepared similarly to Example 15 with appropriate substitution reagents and substrates at various stages.___________________________

Connection no. MS (M+N) ⁺ 4-4 475.3 4-5 481.3 4-6 493.2 4-7 523.3 4-9 509.5 4-11 520.3

Example 16 2-amine (1-58).

Stage 16-1. Preparation of 5-fluoro-3-methoxy-2-nitroaniline. 3,5-difluoro-2-nitroaniline (2 g, 11.5 mmol, 1.0 equiv.), methanol (20 ml), potassium hydroxide (2 g, 35.6 mmol, 3 ,0 eq.). The resulting solution was shaken for 2 hours at room temperature, diluted with 100 ml H2O, extracted with 3x100 ml ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtering off the solids, the resulting solution was concentrated in vacuo and the residue was purified using a silica gel column, eluted with ethyl acetate/petroleum ether to obtain the desired 5-fluoro-3-methoxy-2-nitroaniline (1.1 g) as a yellow solid and the more polar minor isomer 3-fluoro-5-methoxy2-nitroaniline (300 mg) as a yellow solid. For the title compound: 1H NMR (300 MHz, DMSO- _d6 , ppm): δ, 6.50 (s, 2H), 6.27 (m, 1H), 6.23 (m, 1H) , 3.80 (s, 3H).

Stage 16-2. Preparation of 5-fluoro-3-methoxybenzene-1,2-diamine. A mixture of 5-fluoro-3-methoxy-2nitroaniline (1 g, 5.4 mmol, 1.0 eq.), palladium on carbon (50 mg) in propan-2-ol (50 ml) was shaken for 4 hours at room temperature in the presence of hydrogen gas. Solids were filtered off. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether to give the title compound (700 mg) as a brown solid. MS: bones ⁺ =157.1.

Stage 16-3. Preparation of benzyl-N-[1-(2-amino-3-formylpyridin-4-yl)piperidin-4-yl]carbamate. Mixture of tert-butyl-N-(4-chloro-3-formylπpyridin-2-yl)carbamate (8.1 g, 31.6 mmol, 1.0 eq.), benzyl-N(piperidin-4-yl)carbamate (8.1 g, 34.6 mmol, 1.1 eq.), DIEA (12.2 g, 94.4 mmol, 3.0 eq.), ACN (100 ml) shaken for 16 hours at 85° C. The resulting mixture was then cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether to give the title compound as a yellow solid (4.6 g). MS: [M+N] ⁺ =355.2.

Stage 16-4. Preparation of benzyl-N-[1-(2-amino-5-bromo-3-formylpyridin-4-yl)piperidin-4yl]carbamate. Mixture of benzyl-N-[1-(2-amino-3-formylpyridin-4-yl)piperidin-4-yl]carbamate (4.5 g, 12.7 mmol, 1.0 eq.), NBS (2, 9 g, 16.3 mmol, 1.3 eq.), DCE (50 ml). The resulting solution was shaken for 40 minutes at 85°C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether to give the title compound as a yellow solid (3.9 g). [M+H]+=433.1, 435.1.

Stage 16-4. Preparation of benzyl-N-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4yl]piperidin-4-yl]carbamate. Benzyl N-[1-(2-amino-5-bromo-3-formylpyridin-4-yl)piperidin-4yl]carbamate (3.9 g) was placed in a 100 mL round bottom flask, purged and kept under an inert nitrogen atmosphere. , 9.0 mmol, 1.0 eq.), (3-fluoro-5-methylphenyl)boric acid (2.8 g, 18.2 mmol, 2.0 eq.), Pd ₂ (dba) ₃ (200 mg, 0.2 mmol, 0.02 eq.), t-Bu ₃ P (400 mg), K ₃ PO ₄ (5.7 g, 3.0 eq.), THF (50 ml), water (10 ml). The resulting solution was shaken for 2 hours at 30°C. The resulting solution was diluted with 200 ml H2O, extracted with 3x200 ml ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solids were filtered off and the resulting solution was concentrated under vacuum. The remaining residue was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether to give the title compound as a light yellow solid (3.1g). [M+H] ⁺ =463.2.

Stage 16-5. Preparation of benzyl-N-{1-[2-amino-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3fluoro-5-methylphenyl)pyridin-4- yl]piperidin-4-yl}carbamate.

Mixture of benzyl-N-[1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4yl]carbamate (250 mg, 0.54 mmol, 1.0 eq.), 5-fluoro-3-methoxybenzene-1,2-diamine (245 mg, 1.6 mmol, 3.0 eq.), Na ₂ S ₂ O ₅ (207 mg, 2.0 eq.) in NMP (3 ml) and water (0.3 ml) were shaken for 16 hours at 120°C. The resulting solution was diluted with 100 ml H2O, extracted with 3x100 ml ethyl acetate. The organic layers were combined and washed with 3x100 ml brine, then dried over anhydrous sodium sulfate. The solids were then filtered off. The solution was concentrated under vacuum. The remainder was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to obtain the title compound as a light yellow solid (200 mg). [M+H] ⁺ =599.5.

Stage 16-6. Preparation of 4-(4-aminopiperudin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5(3-fluoro-5-methylphenyl)pyridin-2 -amine. Benzyl-N-{1-[2-amino-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl ]piperidin-4-yl}carbamate (200 mg, 0.33 mmol, 1.0 eq.) in trifluoroacetic acid (5 ml) was shaken for 2 hours at 50°C and then concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 column, 19x150 mm; Mobile phase A: water (0.05% TFA); mobile phase B: ACN; gradient: B from 15% to 38% over 6 minutes; flow rate: 20 ml/minute; detector 220 nm. Fractions of the pooled pure product were combined and lyophilized to give the title compound as the trifluoroacetic acid salt (off-white solid, 188 mg). [M+N] ⁺ =465.2. 1H NMR (300 MHz, DMSO- _d6 , ppm): δ, 8.16 (s, 3H), 7.79 (s, 1H), 7.61 (s, 2H), 7.13-7 .10 (m, 4H), 6.88 (d, J=11.1 Hz, 1H), 3.99 (s, 3H), 3.05 (d, J=12.6 Hz, 1H), 2 .89 (s, 1H), 2.43 (s, 3H), 1.53-1.49 (m, 2H), 1.17-1.13 (m, 2H).

Example 17 4-amine (compound 2-15).

Stage 17-1. Preparation of tert-butyl-N-[1-(3-formyl-2-methylpyridin-4-yl)piperidin-4yl]carbamate. A mixture of tert-butyl-N-[1-(2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate obtained in example 13, step 13-1 (340 mg, 1.0 mmol), methylboric acid (300 mg, 5.0 mmol), Pd(DTBPF)Cl ₂ (34 mg, 0.05 mmol), Cs ₂ CO3 (650 mg, 2.0 mmol), dioxane (5 ml), H2O (0 .5 ml) was shaken for 1 hour at 100°C in an inert atmosphere. The mixture was then concentrated in vacuo and the residue was directly loaded onto a silica gel column, eluted with ethyl acetate/petroleum ether to give tert-butyl-N-[1-(3-formyl-2-methylpyridin-4-yl)piperidin-4-yl ]carbamate as a brown solid (110 mg). MS: [M+N] ⁺ =320.2.

Stage 17-2. Preparation of tert-butyl-N-[1-(5-bromo-3-formyl-2-methylpyridin-4-yl)piperudin-4yl]carbamate. NBS (73 mg, 0.41 mmol), DMF (5 ml). The mixture was shaken for 16 hours at room temperature and the resulting solution was diluted with 100 ml of water. The product was extracted with ethyl acetate (3x100 ml). The ethyl acetate solution was washed with saline (3x100 ml) and then dried over anhydrous sodium sulfate. The solids were then filtered off, the solution concentrated and purified on a silica gel column, eluted with ethyl acetate/petroleum ether to give tert-butyl-N-[1-(5-bromo-3-formul-2-methylpyridin-4yl)piperidin-4 -yl]carbamate as a yellow solid (60 mg). MS: [M+N] ⁺ =398.2.

Stage 17-3. Preparation of tert-butyl-N-[1-[5-(3-fluoro-5-methylphenyl)-3-formyl-2-methylpyridin-4yl]piperidin-4-yl]carbamate. Mixture of tert-butyl-N-[1-(5-bromo-3-formyl-2-methylpyridin-4yl)piperidin-4-yl]carbamate (50 mg, 0.13 mmol), (3-fluoro-5-methylphenyl )boric acid (58 mg, 0.38 mmol), Pd(dppf)Cl ₂ (10 mg, 0.01 mmol), K2CO3 (52 mg, 0.38 mmol, 3.00 eq.), toluene (1 ml ), H2O (0.1 ml) was shaken for 2 hours at 80°C in an inert atmosphere. The resulting mixture was concentrated and purified on a silica gel column, eluted with ethyl acetate/petroleum ether to give tert-butyl-N-[1-[5-(3-fluoro-5-methylphenyl)-3-formyl-2-methylpyridinium-4- yl]piperidin-4yl]carbamate as a yellow solid (30 mg). MS: [M+N] ⁺ =428.6.

Stage 17-4. Preparation of 1-[3-(5-fluoro-7-methokCu-1H-1,3-benzodiazol-2-ul)-5-(3-fluoro-5methylphenyl)-2-methylpyridin-4-yl]piperidin-4- amine. Tert-butyl-N-{1-[3-(5-fluoro-7-methCu-1H-1,3benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methylpyridin-4- yl]piperidin-4-yl}carbamate (18 mg),

- 60 043353 prepared according to step 15-4, with tert-butyl-K[1-[5-(3-fluoro-5-methylphenyl)-3-formyl-2methylpyridin-4-yl]piperidin-4-yl]carbamate ( 30 mg, 0.07 mmol) and 5-fluoro-3-methoxybenzene-1,2diamine (step 17-2, 22 mg, 0.14 mmol) were shaken with TFA (1 ml) in DCM (5 ml) for 1 hours at room temperature. The mixture was concentrated and re-diluted with water (5 ml) and acetonitrile (1 ml) and then lyophilized to give 1-[3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5 -(3-fluoro5-methylphenyl)-2-methylpyridin-4-yl]piperidin-4-amine as trifluoroacetic acid (off-white solid, 6.9 mg). MS: [M+N] ⁺ =464.2. ^1H NMR (300 MHz, CD ₃ OD): δ 8.33 (s, 1H), 7.23-7.11 (m, 3H), 7.08-7.00 (m, 1H), 6.804- 6.80 (m, 1H), 4.05 (s, 3H), 3.10-2.93 (m, 1H), 2.68-2.52 (m, 2H), 2.49 (s, 3H), 2.41 (s, 3H), 1.69-1.52 (m, 2H), 1.30-1.12 (m, 2H).

Example A-1. Parenteral pharmaceutical composition.

To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-100 mg of a water-soluble salt of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof was dissolved in sterile water and then mixed with 10 ml of 0. 9% sterile saline solution. Optionally, a suitable buffer was added, as well as the optimal acid or base to adjust the pH. The mixture was included in a unit dosage form suitable for administration by injection.

Example A-2. Oral solution.

To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is added to water (with optimal solvent(s), optimal buffer(s) and taste-masking auxiliaries) to obtain a 20 mg/ml solution.

A-3. Oral tablet.

A tablet was prepared by mixing 20-50% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 20-50% by weight microcrystalline cellulose, 1-10% by weight low-substituted hydroxypropylcellulose and 1-10% by weight magnesium stearate or other appropriate auxiliary means. The tablets were obtained by direct compression. The total weight of the compressed tablets was maintained at 100-500 mg.

Example A-4. Oral capsule.

To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is mixed with starch or other suitable powder mixture. The mixture is included in an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is placed in a size 4 capsule or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.

Example A-5. Gel composition for local administration.

To prepare a pharmaceutical gel composition for topical administration, a compound of formula (I) or a pharmaceutically acceptable salt thereof was mixed with hydroxypropylcellulose, propylene glycol, isopropyl myristate and purified alcohol USP. The resulting gel mixture is then included in containers, such as tubes, that are suitable for topical administration.

Example B-1. SSTR assays.

Preparation of membranes.

Crude membrane fractions were prepared from Chinese hamster ovary (CHO) cells stably expressing one of five human or rodent somatostatin receptor subtypes. Cells were grown to 85-100% confluence in standard tissue culture plates in DM-MEM growth medium (Gibco) with the following supplements: 10% fetal bovine serum (Gibco), 100 U/ml penicillin (Gibco), 100 μg/ml streptomycin (Gibco), 10 mM HEPES (Gibco), 0.5 mg/ml G-418 (Gibco). To obtain membranes, cells were washed once with 1× Dulbecco's phosphate buffered saline (Gibco) containing 10 mM HEPES (Gibco), then once with sodium-free binding buffer (50 mM Tris base, 5 mM MgCl ₂ -6H ₂ O and 1 mM EGTA adjusted to pH 7.8). Cells were then scraped into binding buffer containing a protease inhibitor cocktail (100 μg/ml pepstatin A (Sigma), 50 μg/ml leupeptin (Sigma), 25 μg/ml aprotinin (Sigma), and 10 mg/ml bacitracin (USB Corporation) ). Cells were centrifuged at 43,500xg, homogenized, and the resulting membranes were collected by centrifugation at 67,000xg. The membranes were then resuspended in binding buffer containing a protease inhibitor cocktail using a glass Dounce homogenizer.

Functional analysis of SSTR2 agonists.

General review. All five SSTR subtypes are Gi coupled to G protein-coupled receptors (GPCRs), which result in a decrease in intracellular cyclic AMP (cAMP) when activated by an agonist. Therefore, measurement of intracellular cAMP levels can be used to assess whether the compounds of the present invention are agonists of SSTR subtypes (John Kelly, Troy Stevens, W. Joseph Thompson, and Roland Seifert, Current Protocols

- 61 043353 in Pharmacology, 2005, 2.2.1-2.2). One example of an intracellular cAMP assay is described below.

Protocol for cAMP analysis.

Four days before analysis, 5000 Chinese hamster ovary cells (CHO-K1, ATCC accession no. CCL61), stably expressing human somatostatin receptor subtype 2, were seeded into each well of a 96-well tissue culture plate in Ham's growth medium F12 (ThermoFisher accession no. 10080 -CM), supplemented with 10% donor bovine serum (Gemini Bio-Products No. 100-506), 100 units/ml penicillin; 100 µg/ml streptomycin; 2 mM L-glutamine (Gemini Bio-Products no. 400-110) and 0.2 mg/ml hygromycin B (GoldBio no. 31282-04-9). Cells were cultured at 37°C, 5% CO ₂ and 95% humidity. One day before analysis, the medium was aspirated and the cells were treated with 50 μl of 1.6 μM NKH477 (Sigma no. N3290) with various dilutions of compounds according to the present invention in assay buffer [1x Hank's balanced salt solution (ThermoFisher no. SH3058802), 0 .5 mM HEPES, pH 7.4, 0.1% bovine serum albumin, 0.2 mM 3-isobutyl-1methylxanthine (IBMX No., VWR 200002-790)]. The cells were incubated for 20 minutes at 37°C (the final concentration of compounds in accordance with the present invention was typically 0.10000 nM). Cells were treated with 50 μl of lysis buffer (HRTF cAMP kit, Cisbio). The lysate was transferred to 384-well plates, antibodies were added to detect and visualize cAMP, and incubated for 1-24 hours at room temperature. The time-resolved fluorescence signal was read using a Tecan M1000Pro multiplate reader. Intracellular cAMP concentrations were calculated by regression to a standard curve and plotted against the concentration of the compounds of the present invention, and the EC ₅₀ of the compounds were calculated using standard methods. All data manipulations were carried out using GraphPad Prism v6.

Exemplary biological activities of the compounds are shown in the following table by assessing the inhibition of cAMP activities on the human SST2 receptor (SSTR2).

Table A

- 62 043353

Connection no. 1-1 1-2 1-3 1-4 1-5 1-6 1-7 1-8 1-9 1-10 1-11 1-12 1-13 1-14 1-15 1-16 1-17 1-18 1-19 1-20 1-21 1-22 1-23 1-24 1-25 1-26 1-27

EU50 A A A A A A A A A A A A A A A A IN IN A A A A IN A A A A

- 63 043353

- 64 043353

- 65 043353

- 66 043353

A=EC ₅₀ below 10 nM; B=EC ₅₀ from 10 nM to 100 nM; C=EC ₅₀ above 100 nM.

The following table demonstrates the improved selectivity of typical cAMP inhibitory compounds for hSSTR2 compared to hSSTR4.

- 67 043353

Table B

R ¹ R ⁵ R ⁶ R ⁷ hSST4/hSST2 (ratio) Η H 5-C1 H e nh ₂ H 5-C1 H b CH3NH- H 5-C1 H a ch ₃ ch ₂ nh- H 5-C1 H a -OSNZ H 5-C1 H a H H 5-F 7-F d nh ₂ H 5-F 7-F b CH3NH- H 5-F 7-F a ch ₃ ch ₂ nh- H 5-F 7-F a ch ₃ o-ch ₂ ch ₂ nh- H 5-F 7-F a ABOUT H 5-F 7-F a -OSNZ H 5-F 7-F a H H 5-F 6-F e nh ₂ H 5-F 6-F b CH3NH- H 5-F 6-F a ch ₃ ch ₂ nh- H 5-F 6-F a H -CH3 5-F 6-F c nh ₂ -CH3 5-F 6-F a H -CH ₂ CH ₃ 5-F 6-F c nh ₂ -CH ₂ CH ₃ 5-F 6-F b H H 5-F H e nh ₂ H 5-F H b -OSNZ H 5-F H a H H 5-OCH3 H d nh ₂ H 5-OCH3 H b -OSNZ H 5-OSNZ H a H H H 7-CH3 e nh ₂ H H 7-СНз c

- 68 043353

n Η Η 7-F e nh ₂ Η Η 7-F c n Η 5-CN H c nh ₂ Η 5-CN H a n Η Η 7-OCH ₃ e nh ₂ Η Η 7-OCH ₃ d CH _-3NH- Η Η 7-OCH ₃ c n Η 5-OCF ₃ H c nh ₂ Η 5-OCF ₃ H a n Η 6-F 7-F e nh ₂ Η 6-F 7-F c n Η 6-F 4-OCH ₃ e nh ₂ Η 6-F 4-OCH ₃ c (CH- ₃ ) _2N- Η 6-F 4-OCH ₃ b ^F % ^N + Η 6-F 4-OCH ₃ a dn ₃ Η 6-F 4-OCH ₃ c Η Η 5-C1 7-F d νη ₂ Η 5-C1 7-F a CH _-3NH- Η 5-C1 7-F a Η Η 5-F 7-OCH _2CN e νη ₂ Η 5-F 7-OCH _2CN c Η Η 4-F 6-OMe d νη ₂ Η 4-F 6-OMe b

a=above 50, b=from 15 to 50; c=from 2.5 to 15; d=om 1 to 2.5; e=below 1

Example B-2. CYP2D6 assay protocol.

One day prior to analysis, various dilutions of the test articles of the present invention were prepared in assay buffer (CYP2D6 Blue Screening Kit Vivid®, ThermoFisher Scientific P2972) and the dilutions were added to a preparation of CYP450 microsomes expressing the functional human CYP2D6 isozyme (supplied in the kit). ) and incubated for 15 minutes at 37°C to ensure interactions between the test article in accordance with the present invention and the enzyme in the absence of enzyme turnover. The enzymatic reaction was initiated by adding the cofactor NADPH in the presence of a fluorogenic substrate. Under normal conditions, this substrate (which is not fluorescent) is cleaved by active CYP2D6 to produce a fluorescent product. In the presence of the test article, the absence of fluorescent product is evidence of inhibition of the CYP2D6 enzyme by the test article. The enzymatic reaction was allowed to proceed for 30 minutes at 37°C and then terminated by adding 0.5 M Tris, pH 10.8. The concentration of the digested fluorescent product was measured using the spectroscopic parameters prescribed in the Tecan M1000Pro Multiplate Reader Kit. Percentage inhibition was calculated based on the fluorescence intensity observed in the presence of the positive control inhibitor quinidine (Sigma Part No. Q3625) included in each assay. The percentage of inhibition was plotted against the concentration of the test article and the IC ₅₀ for CYP2D6 inhibition was calculated using standard methods. All data manipulations were performed using GraphPad Prism v6.

Example B-3. hERG assay protocol.

One day prior to analysis, various dilutions of the test articles of the present invention were prepared in assay buffer (hERG Fluorescence Polarization Assay Kit Predictor™, ThermoFisher Scientific Part No. PV5365) and the dilutions were added to the membrane fractions that contained the functional hERG ion channel (supplied in the kit). ). High affinity fluorescent ligand or hERG ion channel tag was added and incubated for 2 hours at room temperature. Under normal conditions, the label bound to the hERG channel and the measured fluorescent polarization was high. Replacement of the label with a test article in accordance with the present invention gave lower fluorescent polarization and indicated the affinity of the test article for the hERG channel. Free label concentration was measured by fluorescence polarization using the parameters prescribed in the Tecan M1000Pro Multiplate Reader Kit. The potent hERG channel ligand E4031, supplied in a kit that replaced 100% of the tag, was included in all assays and used to establish the window

-

Claims (15)

analysis for the purpose of data analysis. Fluorescence polarization was plotted against test article concentration and the IC50 for hERG inhibition was calculated using standard methods. All data manipulations were performed using GraphPad Prism v6. Inhibitions of CYP2D6 and hERG for representative compounds are shown in Table 1. C. Table C R ⁶ R ⁷ R1 hSST2 (EC ₅ o, nM) hSST4 (EC50, nM) Inhibition of CYP2D6 Inhibition of hERG 5-S1 N n 0.06 0.06 + + 5-С1 Н nh ₂ 0.03 0.70 ++ ++ 5-F 7-F n 0.08 0.15 + + 5-F 7-F nh ₂ 0.05 1.3 ++ ++ 5-F 7-F CH ₃ NH- 0.18 15 ++ ++ 5-F N Η 0.18 0.12 + + 5-F N νη ₂ 0.06 0.92 ++ ++ 7-F n Η 0.43 0.09 + ++ 7-F n νη ₂ 0.27 0.71 ++ ++ 5-CN n Η 0.13 1.2 ++ + 5-CN n νη ₂ 0.06 14 ++ ++ +=IC ₅₀ below 5 µM; ++=IC ₅₀ above 5 µM The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested by those skilled in the art are intended to be included within the spirit and scope of the present invention and within the scope of the appended claims. CLAIM 1. A compound of formula (III) or a pharmaceutically acceptable salt thereof Where R ¹ is -NR2R ³ , -OR ² or R ⁴ ; R ² represents hydrogen, substituted or unsubstituted C ₁ -C ₄ -alkyl, substituted or unsubstituted C ₁ -C ₄ -heteroalkyl or substituted or unsubstituted C ₃ -C ₆ -cycloalkyl; R ³ represents hydrogen, substituted or unsubstituted C ₁ -C ₄ -alkyl, substituted or unsubstituted C ₁ -C ₄ -heteroalkyl or substituted or unsubstituted C ₃ -C ₆ -cycloalkyl; or R ² and R ³ are taken together with the N atom to which they are attached to form substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl; - 70 043353 R ⁴ represents F, Cl, Br, -CN, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2CF3, -S(=O)2CH3, -CO2CH3, -CO2CH2CH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3E R ⁵ represents hydrogen or C ₁ -C ₄ -alkyl; each R ⁶ and R ⁷ independently represents hydrogen, halogen, substituted or unsubstituted Cl-C ₄ -alkyl, substituted or unsubstituted C ₂ -C ₄ -alkenyl, substituted or unsubstituted C ₂ -C ₄ -alkynyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted monocyclic C ₃ -C ₅ -heterocycloalkyl, which has 1 N atom, substituted or unsubstituted monocyclic C1-C5-heteroaryl, -CN, -OR ¹⁵ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -C(=O)N(R ¹⁵ )OR ¹⁵ , -N(R ¹⁵ )2, -NR ¹⁵ C (=O)R ¹⁵ , -NR ¹⁵ C(=O)OR ¹⁵ , -OC(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -NR ¹⁵ C (=O)NR ¹⁵ OR ¹⁵ , -C(R ¹⁵ )=N-OR ¹⁵ , -SR ¹⁵ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2; R ⁸ is hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -NH2, azetidinyl or pyrrolidinyl; R ⁹ is hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ; X ¹ represents N or CR ¹⁰ ; R ¹⁰ represents hydrogen, F, Cl, Br, -CN, -N(R ¹⁵ ) ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ fluoroalkyl or C ₁ -C ₄ -fluoroalkoxy; X ² represents CR ⁷ or N; X ³ represents CR ⁷ or N; R ^{1 1} represents hydrogen; R ^{1 2} represents hydrogen, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -heteroalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C ₃ -C ₅ -heterocycloalkyl , which has 1 O atom; R ¹³ is hydrogen, -OR ¹⁵ , -N(R ¹⁵ )2, -CN, -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, C ₁ -C ₆ -alkyl or CiC ₆ -fluoroalkyl ; or R ¹² and R ¹³ are taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted monocyclic 4-7 membered heterocyclic ring selected from substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperazinyl or substituted or unsubstituted azepanil; each R ¹⁴ is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; each R ¹⁵ is independently selected from hydrogen, substituted or unsubstituted C1- _C6 alkyl, substituted or unsubstituted _C1 - _C6 heteroalkyl, substituted or unsubstituted _C3 - _C7 cycloalkyl, substituted or unsubstituted monocyclic C ₂ -C ₆ -heterocycloalkyl, which has 1 O atom, substituted or unsubstituted phenyl and substituted or unsubstituted monocyclic heteroaryl; where substituted means that the group in question is optionally substituted by one or more added group(s), individually and independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3 )2, -CH3, -CH2CH3, -CF3, -OCH3 and -OCF3, where the term heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from oxygen, -NH-, -H(alkyl)- or sulfur where the term monocyclic heteroaryl refers to a C ₁ -C ₅ -heteroaryl that contains 1-4 N atoms, 0-1 O atom and 0-1 S atom in the ring. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ¹ is -NR ² R ³ ; R ² represents hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -heteroalkyl or C ₃ -C ₆ -cycloalkyl; R ³ represents hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, C ₁ -C ₄ -heteroalkyl or C ₃ -C ₆ -cycloalkyl; or R ² and R ³ are taken together with the N atom to which they are attached to form a substituted or unsubstituted azetidinyl, a substituted or unsubstituted pyrrolidinyl, a substituted or unsubstituted piperidinyl, a substituted or unsubstituted thiomorpholinyl, or a substituted or unsubstituted piperazinyl. 3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, where R ² represents hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2OH -CH2CH2OCH3 or -CH2CN; R ³ represents hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2CH2OH, -CH2CH2OCH3, -CH2CN or -CH2CF3; or R ² and R ³ are taken together with the N atom to which they are attached to form a substituted or unsubstituted azetidinyl, a substituted or unsubstituted pyrrolidinyl, a substituted or unsubstituted piperidinyl, a substituted or unsubstituted thiomorpholinyl, or a substituted or unsubstituted piperazinyl. - 71 043353 4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ¹ represents -NR2R ³ , -OR ² , F, Cl, Br, -CN, -CH2CH3, -CH ₂ CH ₂ CH3, CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH ₂ F, -CHF2, CF3 or -CH2CF3. 5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, where R ¹¹ hydrogen; R ¹² represents hydrogen or -CH ₃ . 6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (V) or is a pharmaceutically acceptable salt thereof: Formula (V) 7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (VI) or formula (VII) or is a pharmaceutically acceptable salt thereof: Formula (VI) Formula (VII), where R ² represents hydrogen, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH _{3 ) 2} , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH2CH(CH 3 )2, - CH(CH3)(CH2CH3), -C(CH3)3, -CH ₂ CH ₂ OH, -SYUSSHOSН3, -CH ₂ CN or -CH2CF3. 8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, where R ⁵ represents hydrogen or C ₁ -C ₄ -alkyl; X ¹ represents N or CR ¹⁰ ; X ² represents CR ⁷ ; and X ³ is CR ⁷ ; or X ² represents N and X ³ represents CR ⁷ ; or X ² represents CR ⁷ and X ³ represents N; R ¹⁰ represents hydrogen, F, Cl, Br, -CN, -N(R ¹⁵ ) ₂ , C1- _C4 alkyl, C1- _C4 alkoxy, C1- _C4 fluoroalkyl or C1- _C4 fluoroalkoxy . 9. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, where X ¹ represents N; And X ² represents CR ⁷ ; and X ³ is CR ⁷ . 10. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, where R ⁶ represents hydrogen, F, Cl, -CH ₃ , -CF ₃ , -C=CH, -CN, -OH, -OCH ₃ , -OCF ₃ , azetidinyl, pyrrolidinyl, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -CO2H, -CO2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH ₃ ) ₂ , -C(=O)NHOCH ₃ , -C(=O) N(CH ₃ )OCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHC(=O)CH ₃ , -NCH3C(=O)CH3, -NHC(=O)OCH3, - ЖНзС(=О)ОСНз, -OC(=O)NH2, -OC(=O)NHCH3, -OC(=O)N(CH3)2, -NHC(=O)NH ₂ , -NHC(=O) NHCH ₃ , -NCH ₃ C(=O)N(CH ₃ ) ₂ , -NHC(=O)NHOCH ₃ , -NHC(=O)NCH ₃ OCH ₃ , -NCH ₃ C(=O)NCH ₃ OCH ₃ , -CH=N-OH, -CH=N-OCH ₃ , -SO ₂ CH ₃ or -SO ₂ NH ₂ ; each R ⁷ independently represents hydrogen, F, Cl, Br, -CN, -CH3, -CF3, -CN, -OH, -OCH3 or -OCF3. 11. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, where R ⁶ is hydrogen, F, Cl, Br, -CN, -CH3, -CF3, -OH, -OCH3 or -OCF3; each R ⁷ independently represents hydrogen, F, Cl, -CH ₃ , -CF ₃ , -C^CH, -CN, -OH, -OCH ₃ , -OCF3, azetidinyl, pyrrolidinyl, tetrazolyl, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -CO2H, -CO2CH3, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)NHOCH ₃ , - C(=O)N(CH ₃ )OCH ₃ , -nh ₂ , -nhch ₃ , -N(CH3)2, -NHC(=O)CH3, -NCH3C(=O)CH3, -NHC(=O) OCH3, -NCHC( O)OCIh, -OC(=O)NH2, -OC(=O)NHCH3, -OC(=O)N(CH3)2, -NHC(=O)NH2, -NHC(=O )NHCH3, -NCH3C(=O)N(CH3)2, NHC(=O)NHOCH ₃ , NHC(=O)NCH ₃ OCH ₃ , -NCH ₃ C(=O)NCH ₃ OCH ₃ , -CH=N -OH, -CH=NOCH ₃ , -SO ₂ CH ₃ or -SO2NH2. 12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, where R ⁸ is hydrogen, F, Cl, Br, -CH ₃ , -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ; R ⁹ is hydrogen, F, Cl, Br, -CH ₃ , -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ . - 72 043353 13. The connection according to claim 1, wherein the connection is 1-1: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-III-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin2-amine ; 1-2: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine -2-amine; 1-3: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine -2-amine; 1-4: 4-(4-aminopiperidin-1-yl)-3-(1-ethenyl-5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5 -methylphenyl)pyridin-2-amine; 1 -5: 4-(4-aminopiperidin-1-yl)-3-(1-ethyl-5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5 -methylphenyl)pyridin-2-amine; 1-6: 4-(4-aminopiperidin-1-yl)-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2 -amine; 1-7: 4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5methylphenyl )pyridin-2-amine; 1-8: 4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)-3 -(5-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-2 -amine; 1 -9: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3 -yl]-1H-1,3-benzodiazol-5 -sulfonamide; 1-10: 4-(4-aminopiperidin-1-yl)-5 -(3-fluoro-5-methylphenyl)-3 -(7-methyl-1H-1,3-benzodiazol-2-yl)pyridin-2 -amine; 1-11: 4-(4-aminopiperidin-1-yl)-3-(7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin- 2-amine; 1-12: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3 -yl]-1H-1,3-benzodiazol-5 -carbonitrile; 1-13: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3 -(7-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-2 -amine; 1-14: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[5-(trifluoromethoxy)-1H-1,3-benzodiazol-2-yl]pyridine -2-amine; 1-15: 4-(4-aminopiperidin-1-ul)-3-(6,7-difluoro-1H-1,3-benzodiazol-2-ul)-5-(3-fluoro-5-methylphenyl)pyridine -2-amine; 1-16: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[5-(oxetan-3-yloxy)-1H-1,3-benzodiazol-2 -yl]pyridin-2-amine; 1-17: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3 -yl]-N-methoxy-1H1,3-benzodiazole -7-carboxamide; 1-18: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-N-methoxy-Nmethyl-1H-1 ,3-benzodiazole-7-carboxamide; 1-19: 4-(4-aminopiperidin-1-yl)-3-(5-cyclobutoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2 -amine; 1 -20: 4-(4-aminopiperidin-1 -yl)-3 -(5-cyclopropoxy-1 H-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyridin- 2-amine; 1-21: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3 -yl]-1H-1,3-benzodiazol-7 -carbonitrile; 1 -22: 4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)-3 -{7-[(hydroxyimino)methyl]-1H-1,3benzodiazol-2-yl} pyridine-2-amine; 1-23: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-Nmethoxy1H-1,3-benzodiazol- 5-carboxamide; 1-24: 2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-N-methoxy-Nmethyl-1H-1 ,3-benzodiazole-5-carboxamide; 1-25: 3-[6-amino-4-(4-aminopiperidin-1 -yl)-5-(5-chloro-1 H-1,3-benzodiazol-2-yl)pyridin-3 -yl]- 5methylbenzonitrile; 1-26: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[5-(3-fluoroazetidin-1-yl)-1H-1,3-benzodiazole -2-yl]pyridin-2-amine; 1-27: methyl-N - {2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl] -1H1,3- benzodiazol-7-yl}carbamate; 1-28: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-Nmethylpyridin- 2-amine; 1-29: 4-(4-aminopiperidin-1-yl)-3-(6-chloro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl )pyridin-2-amine; 1-30: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-N-ethyl-5-(3-fluoro-5-methylphenyl) )pyridin-2-amine; 1-31: 4-(4-aminopiperidin-1-yl)-3-{5,5-difluoro-4,6-dioxa-10,12-diazatricyclo[7.3.0.0 ³ , ⁷ ]dodeca- 73 043353 1,3(7),8,10-tetraen-11-yl}-5-(3-fluoro-5-methylphenyl)pyridin-2-amine; 1-32: 3-[6-amino-4-(4-aminopiperidin-1-yl)-5-(5-chloro-III-1,3-benzodiazol-2-yl)pyridin-3-yl]-5fluorobenzonitrile ; 1-33: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-1 H-indol-6carbonitrile; 1-34: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-[(propan-2-yloxy)imino]methyl]pyridin-2-amine; 1-35: 4-(4-aminopiperidin-1 -yl)-3-[(tert-butoxy)imino]methyl]-5 -(3-fluoro-5-methylphenyl)pyridin2-amine; 1-36: 4-(4-aminopiperidin-1 -yl)-3 -[(tert-butoxy)imino]methyl]-5 -(3,5-dimethylphenyl)pyridin-2amine; 1-37: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-[(propan-2-yloxy)imino]methyl]pyridin-2-amine; 1-38: 4-(4-aminopiperidin-1-yl)-3-[(tert-butoxy)imino]methyl]-5-(3-chloro-5-methylphenyl)pyridin2-amine; 1-39: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-[(hydroxyimino)methyl]pyridin-2-amine; 1-40: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{5-[(methoxyimino)methyl]-1H-1,3-benzodiazol-2- yl}pyridin-2-amine; 1-41: trans-4-amino-1-[2-amino-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3,5-dimethylphenyl)pyridin4-yl] piperidine-3-carbonitrile; 1-42: trans-4-amino-1-[2-amino-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin- 4-yl]piperidine-3-carbonitrile; 1-43: 4-(4-aminopiperidin-1-yl)-3-[5-(azetidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-5-(3 -fluoro5-methylphenyl)pyridin-2-amine; 1 -44: 4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)-3 - {4-[(methoxyimino)methyl]-1H-1,3benzodiazol-2-yl} pyridine-2-amine; 1-45: methyl-N - {2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl] -1H1,3- benzodiazol-5-yl}carbamate; 1-46: 1-{2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3 -yl]-1H-1,3benzodiazol- 5-yl}-3-methoxyurea; 1-47: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{5-[(hydroxyimino)methyl]-1H-1,3benzodiazol-2-yl} pyridine-2-amine; 1-48: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)- N-methylpyridin-2-amine; 1-49: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-N-ethyl-5-(3-fluoro-5 -methylphenyl)pyridin-2-amine; 1-50: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-N-ethyl-5-(3-fluoro-5 -methylphenyl)pyridin-2-amine; 1-51: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{1H-imidazo[4,5-c]pyridin-2yl}pyridin-2-amine ; 1-52: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{1H-imidazo[4,5-b]pyridin-2yl}pyridin-2-amine ; 1-53: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(5-methanesulfonyl-1H-1,3-benzodiazol-2-yl)pyridin-2 -amine; 1-54: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl) )pyridin-2-amine; 1-55: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-III-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)- N-methylpyridin-2-amine; 1-56: 3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-phor-5-methylphenyl)-N-(2-methoxyethyl)-4-(4 -methylpiperidin-1-yl)pyridin-2-amine; 1-57: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1-methyl-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5 -methylphenyl)pyridin-2-amine; 1-58: 4-(4-aminopiperidin-1-yl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl) )pyridin-2-amine; 1-59: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(4-fluoro-6-methoxy-1H-1,3-benzodiazol-2-yl )pyridine-2-amine. 1-60: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-4-fluoro1H-1 ,3-benzodiazol-6-yl} oxy)acetonitrile; 1-61: 4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)-3-{7-fluoro-5[(methoxyimino)methyl]-1H1,3-benzodiazol-2 -yl} pyridin-2-amine; 1 -62: 4-(4-aminopiperidin-1-yl)-3 -{6-fluoro-4-[(hydroxyimino)methyl]-1H-1,3-benzodiazol-2-yl} -5(3-fluoro -5-methylphenyl)pyridin-2-amine; - 74 043353 1-63: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{4-[(hydroxyimino)methyl]-III-imidazo[4,5-c] pyridin-2-yl}pyridin-2-amine; 1-64: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7-[(hydroxyimino)methyl]-3H-imidazo[4,5-b] pyridin-2-yl}pyridin-2-amine; 1-65: 4-(4-aminopiperidin-1-yl)-3-(5-ethynyl-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2 -amine; 1-66: 4-(4-aminopiperidin-1-yl)-3-(5-ethynyl-7-fluoro-1 H-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5- methylphenyl)pyridin-2-amine; 1-67: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)pyridine -2-amine; 1-68: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-III-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methoxyphenyl) )pyridin-2-amine; 1-69: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)pyridin-3 -yl]-7-fluoro-1H1,3-benzodiazole -5-carbonitrile; 1-70: 2-[4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)-2-(methylamino)pyridin-3 -yl]-1H1,3-benzodiazol-6 -carbonitrile; 1-71: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methoxy-1H-1,3-benzodiazol-2-yl)K- methylpyridin-2-amine; 1-72: 4-(4-aminopiperidin-1-yl)-3-(7-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-Nmethylpyridin- 2-amine; 1-73: 4-(4-aminopiperidin-1-yl)-3-(7-chloro-III-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2 -amine; 1-74: 2-({2-[2-amino-4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)pyridin-3-yl]-5-fluoro1H-1 ,3-benzodiazol-7-yl} oxy)acetonitrile; 1-75: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl) )-K-methylpyridin-2-amine; 1-76: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-{7-methoxy-5[(methoxyimino)methyl]1H-1,3-benzodiazol- 2-yl}pyridin-2-amine; 1-77: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2yl)pyridin-2 -amine; 1-78: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3,5-dimethylphenyl)pyridine-2 -amine; 1-79: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-methylphenyl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2yl)pyridin-2 -amine; 1-80: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-methoxy-5-methylphenyl)pyridine -2-amine; 1-81: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-III-1,3-benzodiazol-2-yl)-5-(3,5-difluorophenyl)pyridin2-amine; 1-82: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-7-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3,5-difluorophenyl)pyridine -2-amine; 1-83: 4-(4-aminopiperidin-1-yl)-5-(3,5-dimethylphenyl)-3-(6-fluoro-4-methoxy-1H-1,3-benzodiazol-2yl)pyridin-2 -amine; 1-84: 4-(4-aminopiperidin-1-yl)-5-(3,5-dimethylphenyl)-3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2yl)pyridin-2 -amine; 1-85: 2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-chloro-5-fluorophenyl)pyridin-3-yl]-7-fluoro-III-1,3benzodiazole -5-carbonitrile; 1-86: 4-(4-aminopiperidin-1-yl)-5-(3,5-difluorophenyl)-3-[5-(trifluoromethoxy)-1H-1,3-benzodiazol2-yl]pyridin-2-amine ; 1-87: 2-( {2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-chloro-5-fluorophenyl)pyridin-3 -yl]-5-fluoro-III ,3-benzodiazol-7-yl} oxy)acetonitrile; 1-88: 2-( {2-[2-amino-4-(4-aminopiperidin-1 -yl)-5-(3-chloro-5-fluorophenyl)pyridin-3 -yl]-7-fluoro-III ,3-benzodiazol-5-yl} oxy)acetonitrile; 1-89: 2-[4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-2-(methylamino)pyridin-3-yl]-7-fluoro1H-1,3 -benzodiazole-5-carbonitrile; 1 -90: 4-(4-aminopiperidin-1-yl)-5-(3-chloro-5-fluorophenyl)-3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol2-yl)pyridine -2-amine; 1-91: 4-(4-aminopiperidin-1-yl)-5-(4-fluoro-3-methylphenyl)-3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl )pyridin-2-amine; 1 -92: 4-(4-aminopiperidin-1-yl)-5-(3-chlorophenyl)-3 -(5-fluoro-7-methoxy-III-1,3-benzodiazol-2-yl)pyridin-2 -amine; 1-93: 4-(4-aminopiperidin-1-yl)-3-(5-fluoro-7-methoxy-1H-1,3-benzodiazol-2-yl)-5-(3-methylphenyl)pyridin-2 -amine; - 75 043353 1 -94: 4-(4-amino piperidin-1 -yl)-3-(5-chloro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5 -methylphenyl)pyridin-2-amine; 2-1: 1-[3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4-yl]piperidium-4 -amine; 2-2: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4-yl]piperidin-4 -amine; 2-3: 1-[5-(3-fluoro-5-methylphenyl)-2-methoxy-3-(5-methoxy-1H-1,3-benzodiazol-2-yl)pyridin-4-yl]piperidin- 4-amine; 2-4: 4-(4-aminopiperidin-1-yl)-3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin- 2-ol; 2-5: 1-[3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4-yl]piperidine -4-amine; 2-6: 3-[4-(4-aminopiperidin-1-yl)-5-(5-chloro-1H-1,3-benzodiazol-2-yl)-6-methoxypyridin-3-yl]-5methylbenzonitrile ; 2-7: 4-(4-aminopiperidin-1-yl)-3-(5,6-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl) pyridin-2-ol; 2-8: 2-[4-(4-aminopiperidin-1 -yl)-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-3 -yl]-1 Η-1,3-benzodiazol-5 -carbonitrile; 2-9: 1-(3-{6-chloro-3H-imidazo[4,5-c]pyridin-2-yl}-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4yl)piperidine -4-amine; 2-10: 4-(4-aminopiperidin-1-yl)-3 -(5-fluoro-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)pyridine -2-ol; 2-11: 1-[2-chloro-3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin- 4-amine; 2-13: 1-(3-{5-chloro-1H-imidazo[4,5-b]pyridin-2-yl}-5-(3-fluoro-5-methylphenyl)-2-methoxypyridin-4yl)piperidine -4-amine; 2-14: 1-[3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3,5-difluorophenyl)-2-methoxypyridin-4-yl]piperidin-4-amine ; 4-1: 3-(5-chloro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)-I-methyl-4-[4(methylamino)piperidine-1 -yl]pyridin-2-amine; 4-2: 2-[2-amino-5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)piperidin-1 -yl]pyridin-3 -yl] -1 Η-1,3 benzodiazole-6-carbonitrile; 4-3: 2-[2-amino-5-(3-fluoro-5-methylphenyl)-4-[4-(methylamino)piperidin-1-yl]pyridin-3-yl]-7-fluoro1H-1, 3-benzodiazole-5-carbonitrile; 4-4: 4-(4-aminopiperidin-1-yl)-5-(3-fluoro-5-methylphenyl)-3-(7-methoxy-1H-1,3-benzodiazol-2-yl)M, M-dimethylpyridin-2-amine; 4-5: 4-(4-aminopiperidin-1-yl)-3-(5,7-difluoro-1H-1,3-benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)M ,M-dimethylpyridin-2-amine; 4-6: 4-(4-aminopiperidin-1-yl)-3 -(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5- methylphenyl)-I,M-dimethylpyridin-2-amine; 4-7: 1 -[3 -(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)-2-(3-fluoroazetidine1 -yl)pyridin-4-yl]piperidin-4-amine; 4-9: 1 -[3 -(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-2-(3-fluoroazetidin-1 -yl)-5-(3-fluorophenyl )pyridin-4-yl]piperidin-4-amine; 4-10: 3 -(5-fluoro-7-methoxy-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)-4-[4(methylamino)piperidin- 1-yl]pyridin-2-amine; 4-11: 1 -[3 -(5-chloro-1 Η-1,3-benzodiazol-2-yl)-5 -(3-fluoro-5-methylphenyl)-2-(piperazin-1 -yl) pyridin4-yl]piperidin-4-amine; or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical composition for the treatment of acromegaly, neuroendocrine tumor, neuropathy, nephropathy, malignancy, pain or combinations thereof, containing a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary agent. 15. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the treatment of acromegaly, neuroendocrine tumor, neuropathy, nephropathy, malignancy, pain or combinations thereof. ^gj) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2