RU2785126C2 - New compounds and their pharmaceutical compositions for treatment of inflammatory diseases - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions relates to pharmaceutical chemistry and includes a compound of the formula I or its pharmaceutically acceptable salt, as well as a pharmaceutical composition based on them. In the formula I, Cy is phenyl or 5-6-element heteroaryl containing one or two N atoms; L₁ is a simple bond, -O-, -C(=O)-, -S(O)₂-, -NR^6a-, -C(=O)NR^6b-, or -S(O)₂NR^6c-; R¹ is H; C_1-6 alkyl optionally substituted with one-four substitutes specified in the claims; C_3-7 cycloalkyl optionally substituted with one OH or C_1-4 alkoxy, octadeuteriomorpholine-4-yl, or 4-9-element monocyclic, or spirobicyclic, or bridged, or condensed bicyclic heterocycloalkyl containing one, or two, or three heteroatoms independently selected from N, S, and O; where heterocycloalkyl is optionally substituted with one-three independently selected R¹¹ groups; R¹¹ is independently: OH, CN, halogen, -NR^8aR^8b, C_3-7 cycloalkyl, C_1-4 alkyl optionally substituted with one-three substitutes independently selected from halogen, OH, C_1-4 alkoxy, or R^9aR^9b, C_1-4 alkoxy optionally substituted with one C_1-4 alkoxy, 4-6-element monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, -C(=O)OC_1-4alkyl, or -NR^8cC(=O)OC_1-4 alkyl; R² is halogen or C_1-4 alkyl; n is equal to 0 or 1; L₂ is O or -NR⁴-; R³ is C_1-6 alkyl optionally substituted with one-four substitutes independently selected from halogen or C_3-7 cycloalkyl, phenyl substituted with one R^5a group and one or two independently selected R^5b groups, 6-element heteroaryl containing one or two N atoms, substituted with one R^5a group and one or two independently selected R^5b groups, 4-9-element monocyclic or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, optionally substituted with one, two, or three groups independently selected from R^5a and R^5b, or 4-10-element monocyclic or bridged cycloalkyl optionally substituted with one, two, or three groups independently selected from R^5a and R^5b; R⁴ is H, C_1-4 alkyl optionally substituted with one or two substitutes independently selected from OH or C_1-4 alkoxy, or C_3-7 cycloalkyl; R^5a is -CN, -SO₂-C_1-4 alkyl, or -CF₃; each R^5b is independently selected from halogen, C_1-4 alkyl, and C_3-7 cycloalkyl; each R^7a and R^7b is independently selected from H or C_1-4 alkyl optionally substituted with one -NR^10aR^10b; each R^6a, R^6b, R^6c, R^7c, R^7d, R^8a, R^8b, R^8c, R^9a, R^9b, R^10a, and R^10b is independently selected from H or C_1-4 alkyl.

EFFECT: compound of the formula I having inhibitory activity against JAK1, JAK2, JAK3, and TYK2.

14 cl, 1 dwg, 13 tbl, 1 ex

Description

Field of invention

The present invention relates to compounds that may be useful in the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23. In particular, the compound of the invention inhibits JAK, the tyrosine kinase family, and in particular TYK2. The present invention also relates to methods for preparing a compound of the invention, pharmaceutical compositions comprising a compound of the invention, methods for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23 by administering a compound of the invention.

State of the art invention

Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to the STAT transcription factors. Four members of the JAK family, JAK1, JAK2, JAK3 and TYK2 are described. Upon binding of a cytokine to its receptor, members of the JAK family auto- and/or transphosphorylate each other, followed by phosphorylation of STATs, which then migrate to the nucleus to modulate transcription. Interferons, most interleukins, as well as a number of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL are involved in JAK-STAT intracellular signal transduction. (Vainchenker et al., 2008)

A study of the combination of genetic models and small molecule JAK inhibitors revealed the therapeutic potential of JAK inhibitors (JAKinibs) (Babon et al., 2014). In the last decade, JAKinib has been developed with varying degrees of selectivity over members of the JAK family. In particular, while targeting multiple JAKs may not be detrimental (Broekman et al., 2011), the development of selective JAKinib would be highly desirable in order to design a treatment tailored to the needs of the patient despite the difficulties it presents (Fabian et al., 2005). For example, while JAK2 inhibition has proven beneficial in the treatment of polycythemia and myelofibrosis, an undesirable effect associated with JAK2 inhibition has been observed (O'Shea and Plenge, 2012), making compounds with JAK2 inhibition components unsuitable for the treatment of non-JAK2 mediated disease.

Using TYK2 knockout mice, IL-6, IL-10, IL-11, IL12, IL-13, IL-19, IL-20, IL-22, IL-23, IL-27, IL-28, IL-29, IL-31, IL-35 and/or type 1 interferons are TYK2 dependent (Schwartz et al., 2016). However, it has recently been shown that while JAK1 is a key factor in IFNα, IL6, IL10, and IL22 signaling, TYK2 is involved in type I interferon signaling (including IFNα, INFβ), IL23, and IL12 (Gillooly et al., 2016; Sohn et al., 2013). Because IL12 and IL23 activity is particularly elevated in patients with autoimmune diseases (O'Shea and Plenge, 2012) such as psoriasis and/or inflammatory bowel disease, selective inhibition of TYK2 may be particularly beneficial in the treatment of these diseases by avoiding JAK2-dependent signaling. erythropoietin (EPO) and thrombopoietin (TPO) (Neubauer et al., 1998; Parganas et al., 1998).

In addition, TYK2 has been reported to be a target for a variety of autoimmune disorders, providing protection against inflammatory diseases as well as type 2 diabetes with limited effects on the immune system. (Dendrou et al., 2016)

Accordingly, there remains a need for new compounds that can effectively and selectively inhibit JAK enzymes, in particular TYK2, which would allow the development of specific treatments and doses adapted to the pathology.

The essence of the invention

The present invention relates to compounds useful for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23. In particular, the compound of the invention inhibits JAK, the tyrosine kinase family, and in particular TYK2. The present invention also relates to methods for preparing a compound of the invention, pharmaceutical compositions comprising a compound of the invention, methods for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23 by administering a compound of the invention.

Accordingly, in a first aspect of the invention, compounds of the invention are provided having the formula (I):

where

Cy is phenyl or 5-6 membered heteroaryl containing one, two or three N atoms;

L ₁ is a single bond, -O-, -C(=O)-, -C(=O)O-, -S(O) ₂ -, -NR ^6a -, -C(=O)NR ^6b - , -S(O) ₂ NR ^6c - or -C(=O)NR ^6d S(O) ₂ -;

R ¹ is:

-H,

- C _1-6 alkyl optionally substituted with one or more independently selected

Oh,

halogen

C _1-4 alkoxy,

-NR ^7a R ^7b ,

-C(=O)OH-,

-C(=O)NR ^7c R ^7d ,

-C(=O)OC _1-4 alkyl or

4-8-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O;

- C _3-7 cycloalkyl optionally substituted with one or more OH, C _1-4 alkoxy, or

- 4-9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is optionally substituted with one or more independently selected R ¹¹ groups;

each R ¹¹ is independently:

-OH,

- CN,

- halogen,

- oxo,

- -NR ^8a R ^8b ,

- C _3-7 cycloalkyl,

- C _1-4 alkyl optionally substituted with one or more independently selected halogen, OH, C _1-4 alkoxy, -NR ^9a R ^9b ,

- C _1-4 alkoxy, optionally substituted with one C _1-4 alkoxy,

- 4-7-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O,

- -C(=O)OC _1-4 alkyl or

- -NR ^8c C(=O)OC _1-4 alkyl;

R ² is

- halogen,

- CN, or

- C _1-4 alkyl;

index n is 0 or 1;

L ₂ is O or -NR ⁴ -,

R ³ is

- C _1-6 alkyl optionally substituted with one or more independently selected

halogen, or

C _3-7 cycloalkyl,

- Phenyl substituted with one R ^5a group and one or two independently selected R ^5b groups,

- 6-membered heteroaryl containing one or two N atoms, substituted by one R ^5a group and one or two independently selected R ^5b groups,

- 4-10-membered monocyclic or fused, bridged or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b , or

- 4-10-membered monocyclic or fused, bridged or spirobicyclic cycloalkyl optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b ;

R ⁴ is

-H,

- C _1-4 alkyl optionally substituted with one or more independently selected OH or C _1-4 alkoxy, or

- C _3-7 cycloalkyl;

R ^5a is -CN, -SO ₂ -C _1-4 alkyl or -CF ₃ ;

each R ^5b is independently selected from halogen, C _1-4 alkyl and C _3-7 cycloalkyl;

each R ^7a and R ^7b is independently selected from

- H, and

- C _1-4 alkyl, optionally substituted with one -NR ^10a R ^10b ; and

each R ^6a , R ^6b , R ^6c , R ^6d , R ^7c , R ^7d , R ^8a , R ^8b , R ^8c , R ^9a , R ^9b , R ^10a , and R ^10b is independently selected from

H and C _1-4 alkyl.

In a particular aspect, the compounds of the invention are provided for use in the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations, and /or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

In addition, it has also been unexpectedly demonstrated that the compounds of the invention exhibit improved selectivity for TYK2 over other members of the JAK family, which may be useful in the treatment of diseases associated with IFNα, IL12 and/or IL23, in particular autoimmune diseases. such as psoriasis and/or inflammatory bowel disease.

In addition, the compounds of the invention and their selectivity for TYK2 may be useful in developing patient-specific treatments and individual patient dosages.

In a further aspect, the present invention relates to pharmaceutical compositions containing a compound of the invention and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may further comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more specific aspect, the additional therapeutically active ingredient is an agent for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations. and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

In addition, the compounds of the invention used in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable as they are made and used.

In a further aspect of the invention, the present invention relates to a method of treating a mammal, in particular a human, suffering from a condition selected from those listed herein, and in particular allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases. , transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23, which comprises administering an effective amount of a pharmaceutical composition or compounds of the invention as described herein.

The present invention also relates to pharmaceutical compositions containing a compound of the invention and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a specific aspect, the pharmaceutical composition is intended for use in the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations and/ or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

In additional aspects, the present invention relates to methods for synthesizing the compounds of the invention with representative protocols and synthetic routes disclosed hereinafter.

Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description.

It is understood that the compounds of the invention may be metabolized to form biologically active metabolites.

Brief description of the figures

In FIG. 1 shows the effect of a test compound of the invention on day 1-5 in a mouse model of psoriasis-like epidermal hyperplasia compared to vehicle (solid diamonds) and controls (solid squares) at q.d. (once daily) at 3 mg/kg (crosses), 10 mg/kg (asterisks), and 30 mg/kg (solid circles).

Detailed description of the invention

Definitions

The following terms have the meanings given below and are useful in understanding the description and intended scope of the present invention.

When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, if present, have the following meanings, unless otherwise indicated. It should also be understood that as described herein, any of the moieties defined below may be substituted with various substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set forth below. Unless otherwise indicated, the term "substituted" shall be defined as follows. In addition, it should be understood that the terms "groups" and "radicals" can be considered interchangeable when used in the present description.

The singular forms may be used herein to refer to one or more than one (i.e., at least one) grammatical subject matter. By way of example, "analogue" means one analogue or more than one analogue.

"Alkyl" means a linear or branched aliphatic hydrocarbon having the indicated number of carbon atoms. Specific alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl are attached to a straight alkyl chain. Typical alkyl groups are methyl (-CH ₃ ), ethyl (-CH ₂ -CH ₃ ), n-propyl (-CH ₂ -CH ₂ -CH ₃ ), isopropyl (-CH(CH ₃ ) ₂ ), n- butyl (-CH _{2 -CH 2 -CH} 2 -CH ₃ ), tert-butyl (-CH ₂ -C(CH ₃ ) ₃ ), sec-butyl (-CH ₂ -CH(CH ₃ ) ₂ ), n- pentyl (-CH ₂ -CH ₂ -CH _{2 -CH} 2 -CH ₃ ), n-hexyl (-CH ₂ -CH ₂ -CH _{2 -CH 2 -CH 2 -CH 3} ), and 1,2-dimethylbutyl ( -CHCH ₃ )-C(CH ₃ )H ₂ -CH ₂ -CH ₃ ). Representative alkyl groups have 1 to 4 carbon atoms.

"Alkenyl" refers to monovalent olefinic (unsaturated) hydrocarbon groups with the specified number of carbon atoms. A representative alkenyl has 2 to 8 carbon atoms, and more particularly 2 to 6 carbon atoms, which may be linear or branched and have at least 1 and especially 1 to 2 centers of olefinic unsaturation. Representative alkenyl groups include ethenyl (-CH=CH ₂ ), n-propenyl (-CH ₂ CH=CH ₂ ), isopropenyl (-C(CH ₃ )=CH ₂ ) and the like.

"Alkylene" refers to divalent alkene radical groups having the indicated number of carbon atoms, in particular having from 1 to 6 carbon atoms, and more specifically from 1 to 4 carbon atoms, which may be straight or branched. This term is illustrated by groups such as methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ -) or -CH(CH ₃ )- and the like.

"Alkynylene" refers to divalent alkynyl radical groups having the indicated number of carbon atoms and the number of triple bonds, in particular from 2 to 6 carbon atoms, and more specifically from 2 to 4 carbon atoms, which may be straight or branched. This term is exemplified by groups such as -C≡C-, -CH ₂ -C≡C- and -C(CH ₃ )HC≡CH-.

"Alkoxy" refers to an O-alkyl group, where the alkyl group has the indicated number of carbon atoms. In particular, the term refers to the group -OC _1-6 alkyl. Representative alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Characteristic alkoxy groups are lower alkoxy, i.e. with 1-6 carbon atoms. Other characteristic alkoxy groups have 1 to 4 carbon atoms.

"Amino" refers to the -NH ₂ radical.

"Aryl" refers to a monovalent aromatic hydrocarbon group obtained by removing one hydrogen atom from one carbon atom of the original aromatic ring system. In particular, aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the specified number of ring atoms. In particular, the term includes groups that include 6 to 10 ring members. Representative aryl groups include phenyl and naphthyl.

"Cycloalkyl" refers to a non-aromatic hydrocarbon ring structure, monocyclic, fused polycyclic, bridged polycyclic or spirocyclic, with the specified number of ring atoms. Cycloalkyl may have 3 to 12 carbon atoms, in particular 3 to 10, and more particularly 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single chain structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

"Cyano" refers to the -CN radical.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Typical halogen groups are fluorine or chlorine.

"Hetero" when used to describe a compound or group present in a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can be applied to any of the hydrocarbyl groups described above such as alkyl, eg heteroalkyl, cycloalkyl, eg heterocycloalkyl, aryl, eg heteroaryl, and the like, having 1 to 4 and especially 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, eg one heteroatom.

"Heteroaryl" means an aromatic ring structure, monocyclic or fused polycyclic, which includes one or more heteroatoms independently selected from O, N and S, and the specified number of ring atoms. In particular, an aromatic ring structure may have 5 to 9 ring members. The heteroaryl group may be, for example, a five-membered or six-membered monocyclic ring or a fused bicyclic structure formed from fused five- and six-membered rings or two fused six-membered rings or, as a further example, two fused five-membered rings. Each ring may contain up to about four heteroatoms, typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring contains up to 4 heteroatoms, more typically up to 3 heteroatoms, generally up to 2, eg one heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings may be basic, as in the case of imidazole or pyridine, or substantially nonbasic, as in the case of the indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any substituents on the amino group of the ring, should be less than five.

Examples of five-membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl.

Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g., adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl and pyrazolopyridinyl.

Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl. Specific heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

Exemplary heteroaryls include the following:

where each Y is selected from >C=O, NH, O and S.

"Heterocycloalkyl" means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic or bridged polycyclic, which includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms indicated. The heterocycloalkyl ring structure may have 4 to 12 ring members, in particular 4 to 10 ring members, and more particularly 4 to 7 ring members. Each ring may contain up to four heteroatoms, usually selected from nitrogen, sulfur and oxygen. Typically, the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, eg one heteroatom. Examples of heterocyclic rings include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (for example, 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothiophenyl (eg 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (eg 4-tetrahydropyranyl), tetrahydrothiopyranyl (eg , 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanil or piperazinyl.

As used herein, the term "heterocycloalkenyl" means "heterocycloalkyl" which contains at least one double bond. Specific examples of heterocycloalkenyl groups are shown in the following illustrative examples:

where each W is selected from CH ₂ , NH, O and S; each Y is selected from NH, O, C(=O), SO ₂ and S; and each Z is selected from N and CH.

Specific examples of monocyclic rings are shown in the following illustrative examples:

where each W and Y is independently selected from -CH ₂ -, -NH-, -O- and -S-.

Specific examples of fused bicyclic rings are shown in the following illustrative examples:

where each W and Y is independently selected from -CH ₂ -, -NH-, -O- and -S-.

Specific examples of bridged bicyclic rings are shown in the following illustrative examples:

where each W and Y is independently selected from -CH ₂ -, -NH-, -O- and -S- and each Z is selected from N and CH.

Specific examples of spirocyclic rings are shown in the following illustrative examples:

where each Y is selected from -CH ₂ -, -NH-, -O- and -S-.

"Hydroxy" refers to the -OH radical.

"Oxo" refers to the =O radical.

"Substituted" refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituent(s).

"Sulfo" or "sulfonic acid" refers to a radical such as -SO ₃ H.

"thiol" refers to the -SH group.

As used herein, the term "substituted with one or more" refers to one to four substituents. In one embodiment, this refers to one to three substituents. In additional embodiments, this refers to one or two substituents. In yet another embodiment, this refers to one substituent.

"Thioalkoxy" refers to the group -S-alkyl, where the alkyl group has the specified number of carbon atoms. In particular, the term refers to the group -SC _1-6 alkyl. Specific thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, t-thiobutoxy, sec-thiobutoxy, n-thiopentoxy, n-thiohexoxy and 1,2-dimethylthiobutoxy. Specific thioalkoxy groups are lower thioalkoxy, ie. with 1-6 carbon atoms. Other specific alkoxy groups have from 1 to 4 carbon atoms.

One skilled in the art of organic synthesis will appreciate that the maximum number of heteroatoms in a stable, chemically real heterocyclic ring, whether aromatic or non-aromatic, is determined by ring size, degree of unsaturation, and valency of the heteroatoms. In general, a heterocyclic ring may have from one to four heteroatoms, provided that the heteroaromatic ring is chemically real and stable.

"Pharmaceutical acceptable" means approved or approved by a federal or state government regulatory agency or an appropriate authority in countries other than the United States, or listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in animals, and in particular in humans.

A "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic, may be inorganic or organic acid addition salts and base addition salts. In particular, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton is present in the parent compound or is substituted with a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethinolamine, N-methylglucamine and the like. In addition, salts include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like and, if the compound contains a basic functionality, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acid functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like.

A "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

"Prodrugs" refers to compounds comprising derivatives of compounds of the invention which have leaving groups and upon solvolysis or under physiological conditions become compounds of the invention which are pharmaceutically active in vivo . Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

The term "solvate" refers to the forms of the compound associated with the solvent, usually obtained by the reaction of solvolysis. This physical interaction includes hydrogen bonding. Common solvents include water, EtOH, acetic acid, and the like. The compounds of the invention may be obtained, for example, in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates such as hydrates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are included in the crystal lattice of the crystalline solid. "Solvate" includes both the liquid phase and recoverable solvates. Representative solvates include hydrates, ethanolates and methanolates.

"Subject" includes people. The terms "human", "patient", and "subject" are used interchangeably herein.

An "effective amount" means an amount of a compound of the invention which, when administered to a subject for the treatment of a disease, is sufficient to effect such treatment for the disease. The "effective amount" may vary depending on the compound, the disease and its severity, and age, weight, etc. the subject to be treated.

"Prevention" or "prevention" refers to reducing the risk of occurrence or development of a disease or disorder (i.e., causing the non-development of at least one of the clinical symptoms of a disease in a subject who is exposed to the agent that causes the disease or is predisposed to the disease before the onset of the disease.

The term "prevention" is related to the term "prevention" and refers to a measure or procedure whose purpose is prevention rather than cure or cure. Non-limiting examples of preventive measures may include the administration of vaccines; administration of low molecular weight heparin to clinical patients at risk of thrombosis due to, for example, immobilization; and administering an antimalarial such as chloroquine before visiting a geographic region where malaria is epidemic or at high risk of contracting malaria.

The term "therapy" or "treatment" of any disease or disorder, in one embodiment, refers to the improvement of the disease or disorder (i.e., delaying the disease or reducing the manifestation, extent, or severity of at least one of its clinical symptoms). In another embodiment, "therapy" or "treatment" refers to an improvement in at least one physical parameter that may not be noticeable to the subject. In yet another embodiment, "therapy" or "treatment" refers to modulating a disease or disorder, physical (eg, stabilizing a noticeable symptom), physiological (eg, stabilizing a physical parameter), or both. In another embodiment, "therapy" or "treatment" refers to slowing the progression of a disease.

As used herein, the term "allergic disease(s)" refers to a group of conditions characterized by impaired hypersensitivity of the immune system, including allergic respiratory disease (eg, asthma, rhinitis), sinusitis, eczema, and urticaria, as well as food or food allergies. for insect venom.

As used herein, the term "asthma" as used herein refers to any lung disease characterized by changes in gas flow in the lungs associated with airway constriction from any cause (intrinsic, extrinsic, or both; allergic or non-allergic). The term asthma can be used with one or more adjectives to indicate the cause.

As used herein, the term "inflammatory disease(s)" refers to a group of conditions including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (eg, asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory liver diseases (eg, primary biliary cholangitis (PBC) and/or primary sclerosing cholangitis (PSC)), inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), endotoxin-mediated disease states (eg, complications after bypass surgery or chronic endotoxin conditions contributing to, for example, chronic heart failure), and related diseases affecting cartilage such as joint disease. Specifically, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (eg, asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. More specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. Even more specifically, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

As used herein, the term "metabolic disease(s)" refers to a group of conditions associated with the body's ability to process certain nutrients and vitamins. Metabolic disorders include phenylketonuria (PKU), type II diabetes, hyperlipidemia, gout, and rickets. A specific example of metabolic disorders is type II diabetes and/or obesity.

As used herein, the term "autoinflammatory disease(s)" refers to a group of diseases including cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a disease Behcet, systemic-onset juvenile idiopathic arthritis (SJIA), or Still's disease.

As used herein, the term "autoimmune disease(s)" refers to a group of diseases including obstructive airway disease, including conditions such as COPD, asthma (e.g., hereditary asthma, acquired asthma, dust-induced asthma, infantile asthma ), in particular, chronic or advanced asthma (eg, late asthma and airway hyperresponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye syndrome, type 1 diabetes mellitus and related complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's thyroiditis and autoimmune thyroiditis), contact dermatitis and in addition pruritic dermatitis, inflammatory bowel disease ( eg, Crohn's disease and ulcerative colitis) , interferonopathy, atherosclerosis and amyotrophic lateral sclerosis. In particular, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.

As used herein, the term "proliferative disease(s)" refers to conditions such as cancer (eg, uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (eg, polycythemia, essential thrombocytosis, and myelofibrosis), leukemia (eg, acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

As used herein, the term "cancer" refers to a malignant or benign growth of cells in the skin or organs of the body, such as, but not limited to, the breast, prostate, lung, kidney, pancreas, stomach, or intestines. Cancer tends to invade adjacent tissue and spread (metastasize) to distant organs, such as the bones, liver, lungs, or brain. As used herein, the term "cancer" includes both types of metastatic tumor cells (such as, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and tissue carcinoma types (such as, but not limited to them, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma) . In particular, the term "cancer" refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, brain tumors, tumors of the brain and spinal cord, breast cancer, bronchial tumors, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma , cutaneous T-cell lymphoma, fetal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing's sarcoma family tumors, eye cancer, retinoblastoma, gallbladder cancer, gastrointestinal (gastric) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastroin testinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma (liver cancer), Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, insulinomas (pancreatic endocrine tumors), Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma , non-Hodgkin's lymphoma, lymphoma, Waldenström's macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, p oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, epithelial ovarian cancer, embryonic cell ovarian tumor, low potential ovarian cancer, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumor moderately differentiated glands, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumors, plasma cell tumor/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma (kidney), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family tumors, sarcoma, Kaposi's, Cesari's syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer (gastrointestinal tract), supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymus cancer, thyroid cancer, urethra cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumors

As used herein, the term "leukemia" refers to neoplastic diseases of the blood and blood-forming organs. Such diseases can cause bone marrow and immune system dysfunction, making the host very susceptible to infection and bleeding. In particular, the term "leukemia" refers to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphoblastic leukemia (CLL).

As used herein, the term "transplant rejection" refers to the acute or chronic rejection of allo- or xenografts of cells, tissues, or solid organs, e.g., islets of Langerhans, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease.

As used herein, the term "disorders associated with impaired cartilage renewal" includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, sympathetic reflex dystrophy, aldodystrophy, Tiondze's syndrome, or cost Tietze's syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemic, Mseleni's disease and Handigodu's disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. In a specific embodiment, the term refers to ankylosing spondylitis.

As used herein, the term "congenital cartilage malformation(s)" includes conditions such as hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia, in particular, but not limited to, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.

As used herein, the term "disease(s) associated with hypersecretion of IFNα, IL12 and/or IL23 includes conditions such as systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis , multiple sclerosis, trisomy 21 and/or Crohn's disease.

"Compound(s) of the present invention" and equivalent expressions are intended to encompass compounds of formula(s) as described herein, which expression includes pharmaceutically acceptable salts and solvates, e.g., hydrates and solvates of pharmaceutically acceptable salts, where the context so permits. . Likewise, reference to intermediates, whether self-claimed or not, is intended to cover their salts and solvates where the context so permits.

When ranges are specified herein, for example (but not limited to) C ₁ - ₈ alkyl, when referring to a range, the representation of each member of the specified range must be justified.

Other derivatives of the compounds of the present invention are active in both acid and acid derivative forms, but the acid sensitive form often offers the advantage of solubility, tissue compatibility, or sustained release in the mammalian body (Bundgard, H, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters obtained by reacting the parent acid with a suitable alcohol, or amides obtained by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Particularly useful prodrugs are aliphatic or aromatic esters, amides and anhydrides derived from acid groups suspended from the compounds of the invention. In some cases, it is desirable to form prodrugs of the double ester type, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Specific such prodrugs are esters of C ₁ - ₈ alkyl, C ₂ - ₈ alkenyl, C ₆ - ₁₀ optionally substituted aryl, and (C ₆ - ₁₀ aryl)-(C _1-4 alkyl) compounds of the invention.

The present invention includes all isotopic forms of the compounds of the invention provided herein, whether in the form (i) where all atoms with a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as " natural isotopic form"), or (ii) where one or more atoms are replaced by atoms having the same atomic number but a mass number different from the mass number of atoms that predominates in nature (referred to herein as the "non-natural variant isotopic form") . It is clear that an atom can occur in nature as a mixture of mass numbers. The term "unnatural isotopic form variant" also includes embodiments in which the proportion of an atom of a given atomic number having a mass number that is less naturally occurring (referred to herein as "unnatural isotope") has been increased relative to that naturally occurring, e.g. , to levels of >20%, >50%, >75%, >90%, >95%, or >99% in terms of the number of atoms of that atomic number (the latter embodiment is referred to as the "isotopically enriched variant form"). The term "unnatural variant isotopic form" also includes embodiments in which the proportion of the unusual isotope has been reduced relative to that found in nature. Isotopic forms may include radioactive forms (ie, they include radioisotopes) and non-radioactive forms. The radioactive forms are typically isotopically enriched variant forms.

Thus, a non-natural variant of the isotopic form of a compound may contain one or more artificial or unusual isotopes, such as deuterium ( ² H or D), carbon-11 ( ¹¹ C), carbon-13 ( ¹³ C), carbon-14 ( ¹⁴ C ), nitrogen-13 ( ¹³ N), nitrogen-15 ( ¹⁵ N), oxygen-15 ( ¹⁵ O), oxygen-17 ( ¹⁷ O), oxygen-18 ( ¹⁸ O), phosphorus-32 ( ³² P), sulfur-35 ( ³⁵ S), chlorine-36 ( ³⁶ Cl), chlorine-37 ( ³⁷ Cl), fluorine-18 ( ¹⁸ F) iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), in one or several atoms or may include an increased proportion of these isotopes compared to the proportion that prevails in nature in one or more atoms.

Non-natural variants of isotopic forms containing radioisotopes can, for example, be used for tissue distribution studies of the drug and/or substrate. Radioactive isotopes of tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C are particularly useful for this purpose in terms of their ease of incorporation and ease of detection. Non-natural variants of isotopic forms that include deuterium, i.e. ² H or D may confer certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. In addition, non-natural variants of isotopic forms can be produced that include positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N and will be useful in Positron Emission Topography (PET) studies to investigate the degree of occupancy substrate receptors.

It is also understood that compounds that have the same molecular formulas but differ in the nature or sequence of the binding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers".

Stereoisomers that are not mirror images of each other are called "diastereomers", and those stereomers that are mirror images that do not overlap when superimposed are called "enantiomers". If a compound has an asymmetric center, such as one associated with four different groups, then a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described according to the R- and S-sequence rules of Kahn and Prelog, or the way in which the molecule rotates the plane of polarized light, and is denoted as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers, respectively). A chiral compound may exist as an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

"Tautomers" refers to compounds that are interchangeable forms of a specific compound structure and that differ in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium with the motion of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they rapidly interconvert when treated with acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, which are also formed upon treatment with acid or base.

Tautomeric forms may be essential to achieve optimal chemical reactivity and biological activity of the compound of interest.

The compounds of the invention may have one or more asymmetric centers; therefore, such compounds can be obtained as single (R)- or (S)-stereoisomers or as mixtures thereof.

Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

It is understood that the compounds of the invention may be metabolized to form biologically active metabolites.

Invention

The present invention relates to compounds that may be useful in the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23. In particular, the compound of the invention inhibits JAK, the tyrosine kinase family, and in particular TYK2. The present invention also relates to methods for preparing a compound of the invention, pharmaceutical compositions comprising a compound of the invention, methods for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23 by administering a compound of the invention.

Accordingly, in a first aspect of the invention, compounds of the invention are provided having the formula (I):

where

Cy is phenyl or 5-6 membered heteroaryl containing one, two or three N atoms;

L ₁ is a single bond, -O-, -C(=O)-, -C(=O)O-, -S(O) ₂ -, -NR ^6a -, -C(=O)NR ^6b - , -S(O) ₂ NR ^6c - or -C(=O)NR ^6d S(O) ₂ -;

R ¹ is:

-H,

- C _1-6 alkyl optionally substituted with one or more independently selected

Oh,

halogen

C _1-4 alkoxy,

-NR ^7a R ^7b ,

-C(=O)OH-,

-C(=O)NR ^7c R ^7d ,

-C(=O)OC _1-4 alkyl, or

4-8-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O;

- C _3-7 cycloalkyl optionally substituted with one or more OH, C _1-4 alkoxy, or

- 4-9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is optionally substituted with one or more independently selected R ¹¹ groups;

each R ¹¹ is independently:

-OH,

- CN,

- halogen,

- oxo,

- -NR ^8a R ^8b ,

- C _3-7 cycloalkyl,

- C _1-4 alkyl optionally substituted with one or more independently selected halogen, OH, C _1-4 alkoxy, -NR ^9a R ^9b ,

- C _1-4 alkoxy, optionally substituted with one C _1-4 alkoxy,

- 4-7-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O,

- -C(=O)OC _1-4 alkyl or

- -NR ^8c C(=O)OC _1-4 alkyl;

R ² is

- halogen,

- CN, or

- C _1-4 alkyl;

index n is 0 or 1;

L ₂ is O or -NR ⁴ -,

R ³ is

- C _1-6 alkyl optionally substituted with one or more independently selected

halogen, or

C _3-7 cycloalkyl,

- Phenyl substituted with one R ^5a group and one or two independently selected R ^5b groups,

- 6-membered heteroaryl containing one or two N atoms, substituted by one R ^5a group and one or two independently selected R ^5b groups,

- 4-10-membered monocyclic or fused, bridged or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b , or

- 4-10-membered monocyclic or fused, bridged or spirobicyclic cycloalkyl optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b ;

R ⁴ is

-H,

- C _1-4 alkyl optionally substituted with one or more independently selected OH or C _1-4 alkoxy, or

- C _3-7 cycloalkyl;

R ^5a is -CN, -SO ₂ -C _1-4 alkyl or -CF ₃ ;

each R ^5b is independently selected from halogen, C _1-4 alkyl and C _3-7 cycloalkyl;

each R ^7a and R ^7b is independently selected from

- H, and

- C _1-4 alkyl, optionally substituted with one -NR ^10a R ^10b ; and

each R ^6a , R ^6b , R ^6c , R ^6d , R ^7c , R ^7d , R ^8a , R ^8b , R ^8c , R ^9a , R ^9b , R ^10a , and R ^10b is independently selected from

H and C _1-4 alkyl.

In another embodiment, the compound of the invention corresponds to formula I, wherein L ₂ is -NR ⁴ , where R ⁴ is as previously described. In a specific embodiment, R ⁴ is H. In another specific embodiment, R ⁴ is -CH ₃ , -CH ₂ -CH ₂ -CH ₂ -OH, -CH ₂ -CHOH-CH ₃ , -CH ₂ -CH ₂ -CH ₂ -OCH ₃ or cyclopropyl.

In one embodiment, the compound of the invention corresponds to formula I, where L ₂ is O.

In one embodiment, the compound according to the invention corresponds to formula I, where R ³ represents C _1-6 alkyl. In a particular embodiment, R ³ is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , or -CH(CH ₃ )C(CH ₃ ) ₃ .

In one embodiment, the compound of the invention corresponds to formula I, wherein R ³ is C _1-6 alkyl substituted with one or more independently selected halogen or C _3-7 cycloalkyl. In a specific embodiment, R ³ is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH(CH ₃ )C(CH ₃ ) ₃ , each of which is optionally substituted with one or several independently selected halo or C _3-7 cycloalkyl. In another specific embodiment, R ³ is C _1-6 alkyl optionally substituted with one or more independently F, cyclopropyl, or cyclobutyl. In a more specific embodiment, R ³ is selected from:

и

.

and

.

In another embodiment, the compound of the invention corresponds to formula I, wherein R ³ is phenyl substituted with one R ^5a and one or two independently selected R ^5b groups. In a specific embodiment, R ³ is phenyl substituted with one R ^5a and two independently selected R ^5b groups.

In another embodiment, the compound of the invention corresponds to formula I, wherein R ³ is a 6-membered heteroaryl substituted with one R ^5a group and one or two independently selected R ^5b groups. In one embodiment, R ³ is pyridinyl or pyridazinyl, each of which is substituted with one R ^5a group and one R ^5b group.

In one embodiment, the compound of the invention corresponds to formula I, where R ³ is

или

or

where R ^5a and R ^5b have the meanings as described above.

In one embodiment, the compound of the invention corresponds to formula I, wherein R ³ is as defined above and R ^5a is -CN, -SO ₂ -C _1-4 alkyl, or -CF ₃ . In a particular embodiment, R ^5a is -CN, -SO ₂ CH ₃ or -CF ₃ . In a more specific embodiment, R ^5a is -CN.

In one embodiment, the compound of the invention corresponds to formula I, wherein R ³ is as defined above and each R ^5b is independently selected from halo, C _1-4 alkyl, and C _3-7 cycloalkyl. In a specific embodiment, each R ^5b is independently selected from F, -CH ₃ , -CH ₂ CH ₃ and cyclopropyl.

In one embodiment, the compound of the invention corresponds to formula I, where R ³ is a 4-10 membered monocyclic or fused, bridged or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O. In a specific embodiment, R ³ is tetrahydropyranyl or oxa-spiro[3.5]nonane.

In one embodiment, the compound of the invention corresponds to formula I, where R ³ is a 4-10 membered monocyclic or fused, bridged or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b . In a specific embodiment, R ³ is tetrahydropyranyl or oxa-spiro[3.5]nonane, each of which is optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b . In another specific embodiment, R ³ is a 4-10 membered monocyclic or fused, bridged or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b where R ^5a is -CN, -SO ₂ CH ₃ or -CF ₃ and R ^5b is selected from F, -CH ₃ , -CH ₂ CH ₃ and cyclopropyl.

In one embodiment, the compound of the invention corresponds to formula I, where R ³ is a 4-10 membered monocyclic or fused, bridged or spirobicyclic cycloalkyl. In a particular embodiment, R ³ is cyclohexyl or bicyclo[1.1.1]pentane.

In one embodiment, the compound of the invention corresponds to formula I, where R ³ is a 4-10 membered monocyclic or fused, bridged or spirobicyclic cycloalkyl optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b . In a specific embodiment, R ³ is cyclohexyl or bicyclo[1.1.1]pentane, each of which is optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b . In another specific embodiment, R ³ is a 4-10 membered monocyclic or fused, bridged or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b where R ^5a is -CN, -SO ₂ CH ₃ or -CF ₃ and R ^5b is selected from F, -CH ₃ , -CH ₂ CH ₃ and cyclopropyl.

In one embodiment, the compound of the invention corresponds to any of formulas II:

where R ¹ , L ₁ , R ² , Cy and subscript n have the meanings as previously described.

In one embodiment, the compound of the invention corresponds to formula I, or II, where Cy is phenyl.

In one embodiment, the compound of the invention is of formula I or II, wherein Cy is a 5-6 membered heteroaryl containing one, two, or three N atoms. In a specific embodiment, Cy is pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl. In a more specific embodiment, Cy is pyridinyl, pyrimidinyl, or pyridazinyl. In the most specific embodiment, Cy is pyridazinyl.

In one embodiment, the compound of the invention corresponds to formula I or II, where the index n is 1 and R ² is as described previously. In a particular embodiment, R ² is F, CN or -CH ₃ .

In one embodiment, the compound of the invention corresponds to formula I, or II, where the index n is 0.

In one embodiment, a compound of the invention is of formula IIIa, IIIb, IIIc, or IIId:

where L ₁ and R ¹ have the meanings as previously described.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where L ₁ represents a single bond.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where L ₁ is -O-

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where L ₁ represents -C(=O)-.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where L ₁ represents -S(O) ₂ -.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, wherein L ₁ is -NR ^6a - and R ^6a is selected from H and C _1-4 alkyl. In a specific embodiment, R ^6a is selected from H and -CH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where L ₁ is -C(=O)NR ^6b - and R ^6b is selected from H and C _1-4 alkyl. In a specific embodiment, R ^6b is selected from H and -CH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where L ₁ is -S(O) ₂ NR ^6c - and R ^6c is selected from H, and C _1-4 alkyl. In a particular embodiment, R ^6c is selected from H and -CH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where L ₁ is -C(=O)NR ^6d S(O) ₂ - and R ^6d is selected from H and C _1-4 alkyl. In a specific embodiment, R ^6d is selected from H and -CH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is H.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is C _1-6 alkyl. In a particular embodiment, R ¹ is -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is C _1-6 alkyl substituted with one or more independently selected OH, halogen, C _1-4 alkoxy, -NR ^7a R ^7b , -C (=O)OH-, -C(=O)NR ^7c R ^7d , -C(=O)OC _1-4 alkyl or 4-8-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N , S and O, and where each R ^7a , R ^7b , R ^7c and R ^7d have the meanings as described previously. In a particular embodiment, R ¹ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH _{3 ,} or -CH ₂ CH ₂ CH(CH ₃ ) ₂ each substituted with one or more independently selected OH, halogen, C _1-4 alkoxy, -NR ^7a R ^7b , -C(=O)OH-, -C(=O)NR ^7c R ^7d , -C(=O)OC _1-4 alkyl, 4-8 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O, and where each R ^7a , R ^7b , R ^7c and R ^7d have the meanings as previously described. In a specific embodiment, each R ^7a and R ^7b is independently H, or C _1-4 alkyl optionally substituted with one -NR ^10a R ^10b , where each R ^10a and R ^10b is independently selected from H, -CH ₃ or -CH _{2CH3 .} In a more specific embodiment, each R ^7a and R ^7b is independently H, or -CH ₃ or -CH ₂ CH ₃ , each of which is optionally substituted with one -NR ^10a R ^10b , where each R ^10a and R ^10b is independently selected from H, -CH ₃ or -CH ₂ CH ₃ . In another specific embodiment, each R ^7c and R ^7d is independently H, -CH ₃ or -CH ₂ CH ₃ .

In another specific embodiment, R ¹ is C _1-6 alkyl substituted with one or more OH, F, -OCH ₃ , -OCH ₂ CH ₃ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₂ -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -C(=O)OH-, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)NHCH ₂ CH ₃ , -C (=O)N(CH ₃ ) ₂ , -C(=O)OC _1-4 alkyl, dioxanil, morpholinyl. In a more specific embodiment, R ¹ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH _{3 ,} or -CH ₂ CH ₂ CH(CH ₃ ) ₂ , each of which is substituted by one or more OH, F, -OCH ₃ , -OCH ₂ CH ₃ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₂ -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -C(=O)OH-, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)NHCH ₂ CH ₃ , -C(=O )N(CH ₃ ) ₂ , -C(=O)OC _1-4 alkyl, dioxanil, morpholinyl.

In the most specific embodiment, R ¹ is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ NH ₂ , -CH ₂ CH(OH)CH ₃ , -CH ₂ -CH ₂ OCH ₃ , -CH ₂ CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ CH(CH ₃ )OCH ₃ , -CH ₂ CH ₂ C(CH ₃ )OH, -CH ₂ -C (= O)NHCH ₂ CH ₃ , -CH ₂ -morpholinyl, -CH ₂ -dioxanyl, or -CH ₂ N(CH ₃ )CH ₂ CH ₂ N(CH ₃ ) ₂ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is C _3-7 cycloalkyl. In a particular embodiment, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, wherein R ¹ is C _3-7 cycloalkyl substituted with one or more independently selected OH or C _1-4 alkoxy. In a specific embodiment, R ¹ is C _3-7 cycloalkyl substituted with one, two or three independently selected OH, C _1-4 alkoxy. In a more specific embodiment, R ¹ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two or three independently selected OH, C _1-4 alkoxy. In another more specific embodiment, R ¹ is C _3-7 cycloalkyl substituted with one, two or three independently selected OH, -OCH ₃ or -OCH ₂ CH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O. In a specific embodiment, R ¹ is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, tetrahydropyranyl, piperazinyl, dioxanyl, [1,4]oxazepanyl, 2-oxa-5-aza-bicyclo[2.2.1 ]heptanyl, 1-oxa-6-aza-spiro[3.3]heptanyl, octahydropyrrolo[3,4-b]pyrrolyl, 2-oxa-6-aza-spiro[3.4]octanyl, 2-oxa-7-aza-spiro [4.4] nonanil, 2,6-diaza-spiro[3.3]heptanyl or 2,5-diaza-bicyclo[2.2.1]heptanyl. In a more specific embodiment, R ¹ is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, tetrahydropyranyl, piperazinyl, or dioxanyl.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups. In a specific embodiment, R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted with one, two or three independently selected R ¹¹ groups. In a more specific embodiment, R ¹ is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, piperidinyl, tetrahydropyranyl, piperazinyl, dioxanyl, [1,4]oxazepanyl, 2-oxa-5-aza-bicyclo[2.2. 1]heptanyl, 1-oxa-6-aza-spiro[3.3]heptanyl, octahydropyrrolo[3,4-b]pyrrolyl, 2-oxa-6-aza-spiro[3.4]octanyl, 2-oxa-7-aza- spiro[4.4]nonanyl, 2,6-diaza-spiro[3.3]heptanyl, or 2,5-diaza-bicyclo[2.2.1]heptanyl, each substituted with one, two or three independently selected R ¹¹ groups. In a most specific embodiment, R ¹ is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, tetrahydropyranyl, piperazinyl or dioxanyl, each of which is substituted with one, two or three independently selected R ¹¹ groups.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is OH.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is -CN.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted with one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is halogen. In a specific embodiment, R ¹¹ is F or Cl

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is oxo.

, In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is -NR ^8a R ^8b and each R ^8a and R ^8b is as previously defined. In a particular embodiment, each R ^8a and R ^8b is independently H or C _1-4 alkyl. In a more specific embodiment, each R ^8a and R ^8b is independently H, -CH ₃ or -CH ₂ CH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is C _3-7 cycloalkyl. In a particular embodiment, R ¹¹ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups. where one or more R ¹¹ groups is C _1-4 alkyl optionally substituted with one or more independently selected halo, OH, C _1-4 alkoxy, -NR ^9a R ^9b , where each R ^9a and R ^9b is as defined previously. In a particular embodiment, R ¹¹ is -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , each of which is optionally substituted with one or more independently selected halo, OH, C _1-4 alkoxy, -NR ^9a R ^9b where each R ^9a and R ^9b has a meaning as previously defined. In another specific embodiment, R ¹¹ is C _1-4 alkyl optionally substituted with one or more independently selected F, -OCH ₃ , -OCH ₂ CH ₃ , -NH ₂ , -NHCH _{3 ,} or -N(CH ₃ ) ₂ . In a more specific embodiment, R ¹¹ is -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) _{2 ,} or -CH ₂ CH ₂ CH ₃ , each of which is optionally substituted with one or more independently selected F, -OCH ₃ , -OCH ₂ CH ₃ , -NH ₂ , -NHCH ₃ or -N(CH ₃ ) ₂ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted with one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is C _1-4 alkoxy optionally substituted with one C _1-4 alkoxy. In a particular embodiment, R ¹¹ is -OCH ₃ , -OCH ₂ CH ₃ , or -OCH ₂ CH ₂ CH ₃ , each of which is optionally substituted with one or more independently selected C _1-4 alkoxy. In another specific embodiment, R ¹¹ is C _1-4 alkoxy optionally substituted with one or more independently selected -OCH ₃ , -OCH ₂ CH ₃ , or -OCH ₂ CH ₂ CH ₃ . In a more specific embodiment, R ¹¹ is -OCH ₃ , -OCH ₂ CH ₃ or -OCH ₂ CH ₂ CH ₃ , each of which is optionally substituted with one or more independently selected -OCH ₃ , -OCH ₂ CH ₃ or -OCH ₂ CH ₂ CH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups. where one or more R ¹¹ groups is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O. In a particular embodiment, R ¹¹ is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl or morpholinyl.

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is -C(=O)OC _1-4 alkyl. In a particular embodiment, R ¹¹ is -C(=O)OCH ₃ .

In one embodiment, the compound of the invention corresponds to any of formulas I-IIId, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups, where one or more R ¹¹ groups is -NR ^8c C(=O)OC _1-4 alkyl, where R ^8c is as previously defined. In a particular embodiment, R ¹¹ is -NHC(=O)OCH ₃ , -NCH ₃ C(=O)OCH ₃ , or -NHC(=O)OCH ₂ CH ₃ .

In one embodiment, the compound of the invention is selected from:

4-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-3-ethyl-5-fluoro- benzonitrile,

5-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-4-methyl-pyridin-2- carbonitrile

4-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-cyclohexanecarbonitrile,

N7-(6-aminopyrimidin-4-yl)-N5-(3,3-dimethyl-tetrahydropyran-4-yl)-3,N5-dimethyl-3H-imidazo[4,5-b]pyridine-5,7- diamine,

N7-(6-aminopyrimidin-4-yl)-N5,3-dimethyl-N5-[(1S)-1,2,2-trimethylpropyl]imidazo[4,5-b]pyridine-5,7-diamine,

(±)-(1R,3R)-3-{[7-(6-aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino }-cyclohexanecarbonitrile,

4-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-3-cyclopropyl-5-fluoro- benzonitrile,

5-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-4-ethyl-pyridin-2- carbonitrile,

N7-(6-aminopyrimidin-4-yl)-N5-[(1R)-1-cyclopropylethyl]-N5,3-dimethyl-imidazo[4,5-b]pyridine-5,7-diamine,

N7-(6-aminopyrimidin-4-yl)-3,N5-dimethyl-N5-((3R,4S)-3-methyl-tetrahydropyran-4-yl)-3H-imidazo[4,5-b]pyridine- 5,7-diamine,

N7-(6-aminopyrimidin-4-yl)-N5-bicyclo[1.1.1]pent-1-yl-3,N5-dimethyl-3H-imidazo[4,5-b]pyridine-5,7-diamine,

N7-(6-aminopyrimidin-4-yl)-3,N5-dimethyl-N5-(3-methyl-tetrahydropyran-4-yl)-3H-imidazo[4,5-b]pyridine-5,7-diamine,

N7-(6-aminopyrimidin-4-yl)-N5-(1-cyclopropyl-2,2,2-trifluoroethyl)-3,N5-dimethyl-3H-imidazo[4,5-b]pyridine-5,7- diamine,

N7-(6-aminopyrimidin-4-yl)-3,N5-dimethyl-N5-(5-oxa-spiro[3.5]non-8-yl)-3H-imidazo[4,5-b]pyridine-5, 7-diamine,

5-(1-cyclopropyl-2,2,2-trifluoro-ethoxy)-3-methyl-N-(5-methylsulfonyl-2-pyridyl)imidazo[4,5-b]pyridine-7-amine,

6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridazine-3-carboxylic acid of ethylamide,

6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-N-(2-hydroxy-propyl )-nicotinamide,

6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridazine-3-carboxylic acid (2 -hydroxy-propyl)-amide,

5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridine-2-carboxylic acid of ethylamide,

2-{4-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-phenyl}-N- ethyl acetate,

4-methyl-5-{3-methyl-7-[6-(morpholin-4-carbonyl)-pyridin-3-ylamino]-3H-imidazo[4,5-b]pyridin-5-yloxy}-pyridine- 2-carbonitrile,

5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridine-2-carboxylic acid of methylamide,

5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridine-2-carboxylic acid (2 -hydroxy-propyl)-amide,

5-{7-[6-(2-Methoxy-ethylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridine- 2-carbonitrile,

5-{7-[6-(3-Methoxy-propylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridine- 2-carbonitrile,

5-{7-[6-(3-Hydroxy-3-methyl-butylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4- methyl-pyridine-2-carbonitrile,

5-{7-[6-(3-hydroxy-propylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridin- 2-carbonitrile,

5-(7-{6-[([1,4]Dioxan-2-ylmethyl)-amino]-pyrimidin-4-ylamino}-3-methyl-3H-imidazo[4,5-b]pyridine-5- yloxy)-4-methyl-pyridine-2-carbonitrile,

5-{7-[6-(3-Methoxy-cyclobutylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridine- 2-carbonitrile,

5-{7-[6-(3-Methoxy-butylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridine- 2-carbonitrile,

4-methyl-5-[3-methyl-7-(6-morpholin-4-yl-pyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridin-5-yloxy]-pyridin-2- carbonitrile,

4-methyl-5-{3-methyl-7-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-3H-imidazo[4,5-b]pyridin-5-yloxy }-pyridine-2-carbonitrile,

5-{7-[6-(3-Dimethylaminomethyl-azetidin-1-yl)-pyridazin-3-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4- methyl-pyridine-2-carbonitrile,

(±)-4-methyl-5-{3-methyl-7-[6-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-pyridazin-3-ylamino]-3H -imidazo[4,5-b]pyridin-5-yloxy}-pyridine-2-carbonitrile,

4-methyl-5-(3-methyl-7-{6-[4-(2,2,2-trifluoroethyl)-piperazin-1--yl]-pyridazin-3-ylamino}-3H-imidazo[4, 5-b]pyridin-5-yloxy)-pyridine-2-carbonitrile,

(±)-5-{7-[6-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-pyridazin-3-ylamino]-3-methyl-3H-imidazo[4,5 -b]pyridin-5-yloxy}-4-methyl-pyridine-2-carbonitrile,

4-methyl-5-{3-methyl-7-[6-((S)-2-methyl-morpholin-4-yl)-pyridazin-3-ylamino]-3H-imidazo[4,5-b]pyridine -5-yloxy}-pyridine-2-carbonitrile,

5-{7-[6-(4-Cyano-piperidin-1-yl)-pyridazin-3-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4- methyl-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(4-propan-2-ylpiperazin-1-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile,

5-[7-[[5-(4-cyclobutylpiperazin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 - carbonitrile,

5-[7-[[5-(4-cyclopropylpiperazin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 - carbonitrile,

4-methyl-5-[3-methyl-7-[(5-morpholin-4-ylpyridin-2-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile,

4-methyl-5-[7-[[5-(4-methylpiperazin-1-carbonyl)pyridin-2-yl]amino]-3-(trideuteriomethyl)imidazo[4,5-b]pyridin-5-yl] oxypyridine-2-carbonitrile,

5-[7-[(6-Aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrile,

4-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-ethyl-benzenesulfonamide,

N4-[5-(1-cyclopropyl-2,2,2-trifluoro-ethoxy)-3-methyl-imidazo[4,5-b]pyridin-7-yl]pyrimidin-4,6-diamine,

5-[[7-[(6-Aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]amino]-4-methyl-pyridine-2-carbonitrile,

5-[7-[4-(aminomethyl)anilino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile formate salt,

4-methyl-5-[3-methyl-7-[(5-methylsulfonyl-2-pyridyl)amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(trifluoromethyl)-2-pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-(4-methylsulfonylanilino)imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[(1-methylpyrazol-4-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

4-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- benzamide,

4-methyl-5-[3-methyl-7-(4-morpholinosulfonylanilino)imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-ethyl-4- methyl pyridine-3-carboxamide,

3-methyl-N7-(5-methylsulfonyl-2-pyridyl)-N5-[2-methyl-1-(trifluoromethyl)propyl]imidazo[4,5-b]pyridine-5,7-diamine,

4-[[5-[(6-Cyano-4-methyl-3-pyridyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- benzamide,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- pyridine-3-carboxamide,

5-[7-[4-(difluoromethylsulfonyl)anilino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile,

5-[7-(4-cyclopropylsulfonylanilino)-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile,

5-[7-[(1,1-dimethyl-3-oxo-isoindolin-5-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl- pyridine-2-carbonitrile,

5-[7-[4-(3-methoxypropylsulfonyl)anilino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile,

N4-[5-(1-cyclopropylethoxy)-3-methyl-imidazo[4,5-b]pyridin-7-yl]pyrimidin-4,6-diamine,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- pyridazine-3-carboxamide,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- pyridine-3-carboxamide,

4-methyl-5-[3-methyl-7-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2 - carbonitrile,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- pyridazine-3-carboxamide,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N,2- trimethyl-pyridine-3-carboxamide,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-ethyl-2- methyl pyridine-3-carboxamide,

5-[7-[[5-[(dimethylamino)methyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile formate salt,

4-methyl-5-[3-methyl-7-[[5-(morpholin-4-ylmethyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile formate salt,

5-[7-[[5-[[2-(dimethylamino)ethyl-methylamino]methyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4 -methylpyridine-2-carbonitrile formate salt,

5-[7-[(5-methoxypyridin-2-yl)amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[(3S)-3-methylmorpholin-4-yl]pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5- yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(1-methylpiperidin-4-yl)oxypyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(oxan-4-yl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile,

5-[[7-[(6-aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]-cyclopropyl-amino]-4-methyl-pyridin-2 - carbonitrile,

5-[7-[4-(3-hydroxyoxetan-3-yl)anilino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-(1-methylazetidin-3-yl)oxypyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile,

5-[[5-[(1-cyclopropyl-2,2,2-trifluoroethyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-ethyl-pyridine- 2-carboxamide,

N5-(1-cyclopropyl-2,2,2-trifluoroethyl)-3-methyl-N7-(5-methylsulfonyl-2-pyridyl)imidazo[4,5-b]pyridine-5,7-diamine,

N7-(6-aminopyrimidin-4-yl)-3-methyl-N5-[2-methyl-1-(trifluoromethyl)propyl]imidazo[4,5-b]pyridin-5,7-diamine,

N7-(6-aminopyrimidin-4-yl)-N5-(1-cyclobutylethyl)-3-methyl-imidazo[4,5-b]pyridine-5,7-diamine,

N7-(6-aminopyrimidin-4-yl)-N5-(cyclopropylmethyl)-3-methyl-imidazo[4,5-b]pyridine-5,7-diamine,

5-[7-[[5-(3-Hydroxyazetidine-1-carbonyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl- pyridine-2-carbonitrile,

N,N-dimethyl-6-[[3-methyl-5-[[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino]imidazo[4,5-b]pyridin-7-yl]amino ]pyridine-3-carboxamide,

N7-(6-aminopyrimidin-4-yl)-3-methyl-N5-[(1R)-2-methyl-1-(trifluoromethyl)propyl]imidazo[4,5-b]pyridine-5,7-diamine,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-(2-dimethylaminoethyl )pyridine-3-carboxamide,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-(3-methoxypropyl )pyridine-3-carboxamide,

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-(3-hydroxypropyl )pyridine-3-carboxamide,

5-[7-[[5-[3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carbonyl]-2-pyridyl]amino]-3-methylimidazo[4,5-b]pyridine -5-yl]oxy-4-methyl-pyridine-2-carbonitrile,

5-[7-[[5-(3-Methoxyazetidine-1-carbonyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl- pyridine-2-carbonitrile,

5-[7-[[5-[3-(methoxymethyl)azetidine-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4 -methyl-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(4-methylpiperazin-1-carbonyl)-2-pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine -2-carbonitrile,

5-[7-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4 -methyl-pyridine-2-carbonitrile,

5-[7-[[5-[(3R)-3-(dimethylamino)pyrrolidin-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methylpyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-(morpholine-4-carbonyl)pyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile,

4-methyl-5-[3-methyl-7-(4-morpholinoanilino)imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[4-(4-methylpiperazin-1-yl)anilino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

5-[7-[[6-[3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carbonyl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b] pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile,

5-[7-[[5-[(3S)-3-hydroxypyrrolidin-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy- 4-methyl-pyridine-2-carbonitrile,

5-[7-[[5-(3-cyclopropyl-3-hydroxy-azetidine-1-carbonyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl] hydroxy-4-methyl-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(8-oxa-3-azaspiro[4.4]nonane-3-carbonyl)-2-pyridyl]amino]imidazo[4,5-b]pyridine -5-yl]oxy-pyridine-2-carbonitrile,

5-[7-[[6-(3-hydroxyazetidin-1-carbonyl)pyridazin-3-yl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl -pyridine-2-carbonitrile,

5-[7-[[6-(3-Methoxyazetidin-1-carbonyl)pyridazin-3-yl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl -pyridine-2-carbonitrile,

5-[7-[[6-[3-(methoxymethyl)azetidine-1-carbonyl]pyridazin-3-yl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy- 4-methyl-pyridine-2-carbonitrile,

5-[7-[[5-[3-(hydroxymethyl)azetidine-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4 -methyl-pyridine-2-carbonitrile,

5-[7-[[5-(3-Hydroxy-3-methyl-azetidine-1-carbonyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl] hydroxy-4-methyl-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(3-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-pyridyl]amino]imidazo[4,5-b]pyridine -5-yl]oxy-pyridine-2-carbonitrile,

5-[7-[[5-(3-Methoxy-3-methyl-azetidine-1-carbonyl)-2-pyridyl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methyl-pyridine-2-carbonitrile,

tert-Butyl 1-[6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]pyridine -3-carbonyl]azetidine-3-carboxylate,

4-methyl-5-[3-methyl-7-[[5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridyl]amino]imidazo[4,5-b ]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

5-[7-[[5-(4-hydroxypiperidin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 - carbonitrile,

5-[7-[[5-(4-Methoxypiperidin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 - carbonitrile,

5-[7-[[5-[4-(dimethylamino)piperidine-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4- methylpyridine-2-carbonitrile,

5-[7-[[5-[(3R)-3-hydroxypyrrolidin-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4 -methylpyridine-2-carbonitrile,

4-{6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridine-3-carbonyl }-piperazine-1-carboxylic acid tert-butyl ester,

5-[7-[[5-[(3R)-3-(2-methoxyethoxy)pyrrolidine-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridine-5- yl]oxy-4-methylpyridine-2-carbonitrile,

(1-{6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridin-3- carbonyl}-pyrrolidin-3-yl)-methyl-carbamic acid tert-butyl ester,

4-methyl-5-[3-methyl-7-[[5-(2-oxa-7-azaspiro[3.4]octane-7-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile,

5-[7-[[5-[3-[(dimethylamino)methyl]azetidine-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy -4-methylpyridine-2-carbonitrile,

5-[7-[[5-[(3S)-3-(dimethylamino)pyrrolidin-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methylpyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(2-oxa-6-azaspiro[3.3]heptan-6-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile,

5-[7-[[5-[3,3-bis(hydroxymethyl)azetidine-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy -4-methylpyridine-2-carbonitrile,

6-[[5-(6-Cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]-N-(2-hydroxyethyl)-N- methylpyridine-3-carboxamide,

4-methyl-5-[3-methyl-7-[[5-(3-propan-2-yloxyazetidine-1-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile,

5-[7-[[5-(4-Hydroxy-4-methylpiperidin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4 -methylpyridine-2-carbonitrile,

6-[[5-(6-Cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]-N-[rac-(1R,3R) -3-hydroxycyclopentyl]pyridine-3-carboxamide,

4-methyl-5-[3-methyl-7-[[5-[rac-(3R,4R)-3-fluoro-4-hydroxypyrrolidine-1-carbonyl]pyridin-2-yl]amino]imidazo[4, 5-b]pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[rac-(3R,4R)-3,4-dihydroxypiperidine-1-carbonyl]pyridin-2-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[rac-(3R,4R)-3-fluoro-4-methoxypyrrolidine-1-carbonyl]pyridin-2-yl]amino]imidazo[4, 5-b]pyridin-5-yl]oxypyridine-2-carbonitrile,

5-[7-[[6-[3-(dimethylamino)azetidin-1-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4- methylpyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[(2S)-2-methylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[(2R)-2-methylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[(3R)-3-methylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[(3S)-3-methylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[rac-(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[rac-(2R,6R)-2,6-dimethylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-(4-methylpiperazin-1-carbonyl)pyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile,

3,5-difluoro-4-[3-methyl-7-[[5-(4-methylpiperazin-1-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl] hydroxybenzonitrile,

4-methyl-5-[3-methyl-7-[[6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridazin-3-yl] amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile,

5-{7-[5-((3R,4R)-3-Dimethylamino-4-hydroxy-pyrrolidine-1-carbonyl)-pyridin-2-ylamino]-3-methyl-3H-imidazo[4,5-b ]pyridin-5-yloxy}-4-methyl-pyridine-2-carbonitrile,

5-{7-[5-((3S,4S)-3-hydroxy-4-morpholin-4-yl-pyrrolidin-1-carbonyl)-pyridine-2-ylamino]-3-methyl-3H-imidazo[4 ,5-b]pyridin-5-yloxy}-4-methyl-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[2-(trifluoromethyl)morpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl ]oxypyridine-2-carbonitrile,

5-[7-[[5-(2-cyclopropylmorpholin-4-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 - carbonitrile,

4-methyl-5-[3-methyl-7-[[5-[(3R)-3-propan-2-ylmorpholin-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(2-oxa-5-azabicyclo[2.2.1]heptan-5-carbonyl)pyridin-2-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile,

5-[7-[[5-(3-cyclopropylmorpholin-4-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 - carbonitrile,

4-[6-[[5-(6-cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]pyridine-3-carbonyl]morpholin- 2-carbonitrile,

4-methyl-5-{3-methyl-7-[5-((3aS,6aS)-1-methyl-hexahydro-pyrrolo[3,4-b]pyrrole-5-carbonyl)-pyridine-2-ylamino] -3H-imidazo[4,5-b]pyridin-5-yloxy}-pyridine-2-carbonitrile,

4-[6-[[5-(6-cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]pyridine-3-carbonyl]morpholin- 3-carbonitrile,

5-[7-[[6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methylpyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)pyridazin-3-yl]amino]imidazo[ 4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

5-[7-[[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methylpyridine-2-carbonitrile,

5-[7-[[6-[(2S,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl ]hydroxy-4-methylpyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-(1,4-oxazepan-4-yl)pyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5-yl] oxypyridine-2-carbonitrile,

5-[7-[[6-[(2R,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl ]hydroxy-4-methylpyridine-2-carbonitrile,

5-[7-[[6-[2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4- methylpyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile,

4-[6-[[5-(6-cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]pyridazin-3-yl]morpholin- 2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-[(2R)-2-methylmorpholin-4-yl]pyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5- yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-[(2R)-2-propan-2-ylmorpholin-4-yl]pyridazin-3-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridazin-3-yl]amino] imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile,

5-[7-[[6-(2,2-dimethylmorpholin-4-yl)pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridine -2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-[rac-(2R,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[6-[(2S)-2-propan-2-ylmorpholin-4-yl]pyridazin-3-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(piperazin-1-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile,

N7-(6-aminopyrimidin-4-yl)-N5-(1-cyclopropyl-2,2,2-trifluoroethyl)-3-methyl-imidazo[4,5-b]pyridine-5,7-diamine,

4-methyl-5-[3-methyl-7-[(5-piperazin-1-yl-2-pyridyl)amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile ,

5-[7-[[5-[4-(dimethylamino)-1-piperidyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4- methyl-pyridine-2-carbonitrile,

5-[7-[[5-[3-(dimethylamino)pyrrolidin-1-yl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4 -methyl-pyridine-2-carbonitrile,

5-[7-[[5-[2-methoxyethyl(methyl)amino]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl- pyridine-2-carbonitrile,

5-[7-[[5-[4-(hydroxymethyl)-1-piperidyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4- methyl-pyridine-2-carbonitrile,

5-[7-[[5-(dimethylamino)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[1-(2-morpholinoethyl)pyrazol-4-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridin-2- carbonitrile,

5-[[7-[(6-aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]-(2-hydroxypropyl)amino]-4-methyl- pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(2,2,3,3,5,5,6,6-octadeuterio-4-methyl-piperazine-1-carbonyl)-2-pyridyl ]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile,

4-methyl-5-[3-methyl-7-[[5-(2,2,6,6-tetradeuterio-4-methyl-piperazine-1-carbonyl)-2-pyridyl]amino]imidazo[4,5 -b]pyridin-5-yl]oxy-pyridine-2-carbonitrile, and

4-methyl-5-[3-methyl-7-[[5-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteriomethyl)piperazine-1-carbonyl]-2- pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile.

In one embodiment, the compound of the invention is 4-ethyl-5-{3-methyl-7-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-3H-imidazo[4,5-b] pyridin-5-yloxy}-pyridine-2-carbonitrile.

In another embodiment, the compound of the invention is not 4-ethyl-5-{3-methyl-7-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-3H-imidazo[4,5-b ]pyridin-5-yloxy}-pyridine-2-carbonitrile.

In one embodiment, the compound of the invention is 4-methyl-5-[3-methyl-7-(6-morpholin-4-yl-pyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridine- 5-yloxy]-pyridine-2-carbonitrile.

In another embodiment, the compound of the invention is not 4-methyl-5-[3-methyl-7-(6-morpholin-4-yl-pyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridine -5-yloxy]-pyridine-2-carbonitrile.

In one embodiment, the present invention relates to a compound for obtaining compounds of formula A:

where

R ^5a is -CN, -SO ₂ C _1-4 alkyl or -CF ₃ ;

R ^5b is selected from halo, C _1-4 alkyl and C _3-7 cycloalkyl.

In an additional embodiment, the present invention relates to a compound for obtaining compounds of formula A, where R ^5a represents -CN, -SO ₂ CH ₃ or -CF ₃ . In a particular embodiment, R ^5a is -CN.

In a further embodiment, the present invention relates to a compound for preparing compounds of formula A, wherein R ^5b is selected from halo, C _1-4 alkyl, and C _3-7 cycloalkyl. In a particular embodiment, R ^5b is F, -CH ₃ , -CH ₂ CH ₃ or cyclopropyl. In a more specific embodiment, R ^5b is -CH ₃ .

In one embodiment, the present invention relates to a compound for obtaining compounds of formula A, where R ^5a represents -CN and R ^5b represents -CH ₃ .

In one embodiment, the compounds of the invention are in their naturally occurring isotopic form.

In one embodiment, the compounds of the invention are in a non-natural isotopic form. In a particular embodiment, the non-natural isotopic form is one in which deuterium (ie ² H or D) is included, where hydrogen is defined in the chemical structure at one or more atoms of the compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form that is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form that is radioactive. Suitable radioactive isotopes are stable isotopes. Accordingly, the non-natural isotopic form is a pharmaceutically acceptable form.

In one embodiment, a compound of the invention is provided wherein one atom of the compound is in a non-naturally occurring isotopic form. In another embodiment, a compound of the invention is provided wherein two or more atoms are in a non-natural isotopic form.

Non-natural variants of isotopic forms, as a rule, can be obtained by conventional methods known to those skilled in the art, or by the methods described here, for example, by methods similar to those described in the attached examples, to obtain natural isotopic forms. Thus, non-natural variants of isotopic forms can be obtained using appropriate isotopically variant (or labeled) reagents instead of the usual reagents used in the examples.

In one embodiment, the compound of the invention is not an isotopic variant.

In one aspect, the compound of the invention according to any of the embodiments described herein is present as the free base.

In one aspect, a compound of the invention according to any of the embodiments described herein is a pharmaceutically acceptable salt.

In one aspect, a compound of the invention according to any of the embodiments described herein is a solvate of the compound.

In one aspect, a compound of the invention according to any of the embodiments described herein is a solvate of a pharmaceutically acceptable salt of the compound.

While the groups specifically listed above for each embodiment are generally listed above, a compound of the invention includes a compound wherein any or all of the variants in the above formula, as well as other formulas present herein, are selected from one or more specific members or groups. , respectively specified, for each variable. Thus, the present invention is intended to include within its scope all combinations of such embodiments.

While the groups listed for each embodiment are generally listed above separately, a compound of the invention may be a compound for which one or more variables (e.g., R groups) are selected from one or more embodiments according to any formula ( ami) above. Thus, the present invention is intended to include within its scope all combinations of variables of any of the disclosed embodiments.

Alternatively, the exclusion of one or more of these variables from a group or embodiment, or combinations thereof, is also contemplated by the present invention.

In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulas above. Prodrugs are derivatives of the compounds of the invention which have metabolically cleavable groups and are converted by solvolysis or under physiological conditions into the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

Other derivatives of the compounds of the present invention are active in both acid and acid derivative forms, but the acid sensitive form often offers the advantage of solubility, tissue compatibility, or sustained release in the mammalian body (Bundgard, H, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters obtained by reacting the parent acid with a suitable alcohol, or amides obtained by reacting the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups, which can be included in the compounds of this invention, are the preferred prodrugs. In some cases, it is desirable to form prodrugs of the double ester type, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly useful are C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, aryl, C ₇ -C ₁₂ substituted aryl, and C ₇ -C ₁₂ arylalkyl esters of the compounds of the invention.

Declared:

one). Compound according to formula (I):

where

Cy is phenyl or 5-6 membered heteroaryl containing one, two or three N atoms;

L ₁ is a single bond, -O-, -C(=O)-, -C(=O)O-, -S(O) ₂ -, -NR ^6a -, -C(=O)NR ^6b - , -S(O) ₂ NR ^6c - or -C(=O)NR ^6d S(O) ₂ -;

R ¹ is:

-H,

- C _1-6 alkyl optionally substituted with one or more independently selected

Oh,

halogen

C _1-4 alkoxy,

-NR ^7a R ^7b ,

-C(=O)OH-,

-C(=O)NR ^7c R ^7d ,

-C(=O)OC _1-4 alkyl or

4-8-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O;

- C _3-7 cycloalkyl optionally substituted with one or more OH, C _1-4 alkoxy, or

- 4-9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is optionally substituted with one or more independently selected R ¹¹ groups;

each R ¹¹ is independently:

-OH,

- CN,

- halogen,

- oxo,

- -NR ^8a R ^8b ,

- C _3-7 cycloalkyl,

- C _1-4 alkyl optionally substituted with one or more independently selected halo, OH, C _1-4 alkoxy, -NR ^9a R ^9b ,

- C _1-4 alkoxy, optionally substituted with one C _1-4 alkoxy,

- 4-7-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O,

- -C(=O)OC _1-4 alkyl or

- -NR ^8c C(=O)OC _1-4 alkyl;

R ² is

- halogen,

- CN, or

- C _1-4 alkyl;

index n is 0 or 1;

L ₂ is O or -NR ⁴ -,

R ³ is

- C _1-6 alkyl optionally substituted with one or more independently selected

halogen, or

C _3-7 cycloalkyl,

- Phenyl substituted with one R ^5a group and one or two independently selected R ^5b groups,

- 6-membered heteroaryl containing one or two N atoms, substituted by one R ^5a group and one or two independently selected R ^5b groups,

- 4-10-membered monocyclic or fused, bridged or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b , or

- 4-10-membered monocyclic or fused, bridged or spirobicyclic cycloalkyl optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b ;

R ⁴ is

-H,

- C _1-4 alkyl optionally substituted with one or more independently selected OH or C _1-4 alkoxy, or

- C _3-7 cycloalkyl;

R ^5a is -CN, -SO ₂ -C _1-4 alkyl or -CF ₃ ;

each R ^5b is independently selected from halogen, C _1-4 alkyl and C _3-7 cycloalkyl;

each R ^7a and R ^7b is independently selected from

- H, and

- C _1-4 alkyl, optionally substituted with one -NR ^10a R ^10b ; and

each R ^6a , R ^6b , R ^6c , R ^6d , R ^7c , R ^7d , R ^8a , R ^8b , R ^8c , R ^9a , R ^9b , R ^10a , and R ^10b is independently selected from

H and C _1-4 alkyl;

or a pharmaceutically acceptable salt thereof, or a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

2). The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L ₂ is -NR ⁴ .

3). The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein ^R4 is H.

four). The compound or pharmaceutically acceptable salt thereof according to paragraph 2, where R ⁴ represents -CH ₃ , -CH ₂ -CH ₂ -CH ₂ -OH, -CH ₂ -CHOH-CH ₃ , -CH ₂ -CH ₂ -CH ₂ - OCH ₃ or cyclopropyl.

5). The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein L ₂ is O.

6). The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is C ₁₆ alkyl optionally substituted with one or more independently selected halo or C _3-7 cycloalkyl.

7). The compound or pharmaceutically acceptable salt thereof according to paragraph 1, where R ³ represents -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ )CH(CH ₃ ) ₂ , -CH(CH ₃ )C(CH ₃ ) ₃ , each of which is optionally substituted with one or more independently selected halogen or C _3-7 cycloalkyl.

eight). A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is C _1-6 alkyl optionally substituted with one or more independently F, cyclopropyl, or cyclobutyl.

9). The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is selected from:

и

and

ten). A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is phenyl substituted with one R ^5a group and one or two independently selected R ^5b groups.

eleven). A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is phenyl substituted with one R ^5a group and two independently selected R ^5b groups.

12). A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is a 6-membered heteroaryl substituted with one R ^5a group and one or two independently selected R ^5b groups.

13). The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is pyridinyl or pyridazinyl, each of which is substituted with one R ^5a group and one R ^5b group.

fourteen). A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is

или

.

or

.

fifteen). The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-14, where R ^5a represents -CN, -SO ₂ -C _1-4 alkyl or -CF ₃ .

16). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-14, wherein R ^5a is -CN, -SO ₂ CH ₃ , or -CF ₃ .

17). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-14, wherein R ^5a is -CN.

eighteen). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-17, wherein R ^5b is independently selected from halogen, C _1-4 alkyl, and C _3-7 cycloalkyl.

19). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-17, wherein R ^5b is independently selected from F, -CH ₃ , -CH ₂ CH ₃ and cyclopropyl.

twenty). A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is a 4-10 membered monocyclic or fused, bridged or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b .

21). The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is tetrahydropyranyl or oxa-spiro[3.5]nonane, each of which is optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b .

22). A compound or pharmaceutically acceptable salt thereof according to 1-9, 20 or 21, wherein R ^5a is -CN, -SO ₂ CH ₃ or -CF ₃ .

23). A compound or pharmaceutically acceptable salt thereof according to paragraph 1-9, 20, 21 or 22, where R ^5b is selected from F, -CH ₃ , -CH ₂ CH ₃ and cyclopropyl.

24). The compound or pharmaceutically acceptable salt thereof according to claim 20, wherein R ³ is a 4-10 membered monocyclic or fused, bridged or spirobicyclic cycloalkyl optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b .

25). The compound or pharmaceutically acceptable salt thereof according to item 24, wherein R ³ is cyclohexyl or bicyclo[1.1.1]pentane, each of which is optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b .

26). A compound or a pharmaceutically acceptable salt thereof according to paragraph 1-9, 24 or 25, where where R ^5a represents -CN, -SO ₂ CH ₃ or -CF ₃ .

27). A compound or pharmaceutically acceptable salt thereof according to 1-9 or 24-26 wherein R ^5b is selected from F, -CH ₃ , -CH ₂ CH ₃ and cyclopropyl.

28). A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound corresponds to formula II:

29). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-28, wherein Cy is phenyl.

thirty). A compound or pharmaceutically acceptable salt thereof according to any one of 1-28, wherein Cy is a 5-6 membered heteroaryl containing one, two or three N atoms.

31). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-28, wherein Cy is pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl.

32). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-28, wherein Cy is pyridinyl, pyrimidinyl, or pyridazinyl.

33). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-28, wherein Cy is pyridazinyl.

34). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-33, wherein the index n is 1.

35). The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-34, where R ² represents F, CN or -CH ₃ .

36). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-33, wherein the index n is 0.

37). A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is of formula IIIa, IIIb, IIIc, or IIId:

38). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-37, wherein L ₁ is a single bond.

39). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-37, wherein L ₁ is -O-

40). The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, where L ₁ represents -C(=O)-.

41). The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, where L ₁ represents -S(O) ₂ -.

42). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-37, wherein L ₁ is -NR ^6a -.

43). The compound or pharmaceutically acceptable salt thereof according to item 42, wherein R ^6a is H or C _1-4 alkyl.

44). The compound or pharmaceutically acceptable salt thereof according to item 42, where R ^6a represents H or -CH ₃ .

45). The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, where L ₁ represents -C(=O)NR ^6b -.

46). The compound or pharmaceutically acceptable salt thereof according to item 45, wherein R ^6b is H or C _1-4 alkyl.

47). The compound or pharmaceutically acceptable salt thereof according to item 45, where R ^6b represents H or -CH ₃ .

48). The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, where L ₁ represents -S(O) ₂ NR ^6c -.

49). The compound or pharmaceutically acceptable salt thereof according to item 48, wherein R ^6c is H or C _1-4 alkyl.

fifty). The compound or pharmaceutically acceptable salt thereof according to item 48, where R ^6c represents H or -CH ₃ .

51). The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, where L ₁ represents -C(=O)NR ^6d S(O) ₂ -.

52). The compound or pharmaceutically acceptable salt thereof according to item 51, wherein R ^6d is H or C _1-4 alkyl.

53). The compound or pharmaceutically acceptable salt thereof according to item 51, where R ^6d represents H or -CH ₃ .

54). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-53, wherein R ¹ is H.

55). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, wherein R ¹ is C _1-6 alkyl.

56). The compound or pharmaceutically acceptable salt thereof according to item 55, where R ¹ represents -CH ₃ or -CH ₂ CH ₃ .

57). A compound or pharmaceutically acceptable salt thereof according to any one of 1-37, wherein R ¹ is C _1-6 alkyl substituted with one or more independently selected OH, halogen, C _1-4 alkoxy, -NR ^7a R ^7b , -C( =O)OH-, -C(=O)NR ^7c R ^7d , -C(=O)OC _1-4 alkyl or 4-8-membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O

58). The compound or pharmaceutically acceptable salt thereof according to item 57, where R ¹ represents -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ )2, -CH ₂ CH ₂ CH ₂ CH ₃ or -CH ₂ CH ₂ CH(CH ₃ ) ₂ each substituted with one or more independently selected OH, halogen, C _1-4 alkoxy, -NR ^7a R ^7b , -C(=O)OH-, - C(=O)NR ^7c R ^7d , -C(=O)OC _1-4 alkyl, 4-8 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O.

59). A compound or pharmaceutically acceptable salt thereof according to item 57 or 58, wherein R ^7a is H, or C _1-4 alkyl optionally substituted with one -NR ^10a R ^10b .

60). A compound or pharmaceutically acceptable salt thereof according to item 57 or 58, wherein R ^7a is H.

61). The compound or pharmaceutically acceptable salt thereof according to item 59, wherein R ^7a is -CH ₃ or -CH ₂ CH ₃ , each of which is optionally substituted with one -NR ^10a R ^10b .

62). The compound or pharmaceutically acceptable salt thereof according to item 61, where each R ^10a and R ^10b is independently selected from H, -CH ₃ or -CH ₂ CH ₃ .

63). A compound or pharmaceutically acceptable salt thereof according to item 57 or 58, wherein R ^7b is H or C _1-4 alkyl optionally substituted with one -NR ^10a R ^10b .

64). A compound or pharmaceutically acceptable salt thereof according to item 57 or 58, wherein R ^7b is H.

65). The compound or pharmaceutically acceptable salt thereof according to item 63, wherein R ^7b is -CH ₃ or -CH ₂ CH ₃ , each of which is optionally substituted with one -NR ^10a R ^10b .

66). The compound or pharmaceutically acceptable salt thereof according to item 65, where each R ^10a and R ^10b is independently selected from H, -CH ₃ or -CH ₂ CH ₃ .

67). A compound or pharmaceutically acceptable salt thereof according to item 57 or 58, wherein R ^7c is H.

68). A compound or pharmaceutically acceptable salt thereof according to item 57 or 58, wherein R ^7c is -CH ₃ or -CH ₂ CH ₃ .

69). A compound or pharmaceutically acceptable salt thereof according to item 57 or 58, wherein R ^7d is H.

70). The compound or pharmaceutically acceptable salt thereof according to item 57 or 58, where R ^7d represents -CH ₃ or -CH ₂ CH ₃ .

71). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, wherein R ¹ is C _1-6 alkyl substituted with one or more OH, F, -OCH ₃ , -OCH ₂ CH ₃ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₂ -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -C(=O)OH-, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C( =O)NHCH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)OC _1-4 alkyl, dioxanil or morpholinyl.

72). The compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, where R ¹ represents -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ or -CH ₂ CH ₂ CH(CH ₃ ) ₂ , each of which is substituted by one or more OH, F, -OCH ₃ , -OCH ₂ CH ₃ , -NH ₂ , -NHCH ₃ , -NHCH ₂ CH ₂ -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -C(=O)OH-, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O) NHCH ₂ CH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)OC _1-4 alkyl, dioxanil, morpholinyl.

73). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, wherein R ¹ is C _3-7 cycloalkyl.

74). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-37, wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

75). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, wherein R ¹ is C _3-7 cycloalkyl substituted with one or more independently selected OH or C _1-4 alkoxy.

76). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, wherein R ¹ is C _3-7 cycloalkyl substituted with one, two or three independently selected OH or C _1-4 alkoxy.

77). A compound or pharmaceutically acceptable salt thereof according to any one of 1-37, wherein R ¹ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each substituted with one, two or three independently selected OH or C _1-4 alkoxy.

78). A compound or pharmaceutically acceptable salt thereof according to any one of paragraphs 1-37, wherein R ¹ is C _3-7 cycloalkyl substituted with one, two or three independently selected OH, -OCH ₃ or -OCH ₂ CH ₃ .

79). A compound or pharmaceutically acceptable salt thereof according to any one of 1-37, wherein R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O .

80). A compound or pharmaceutically acceptable salt thereof according to any one of 1-37, wherein R ¹ is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, piperidinyl, tetrahydropyranyl, piperazinyl, dioxanyl, [1,4]oxazepanyl, 2- oxa-5-aza-bicyclo[2.2.1]heptanyl, 1-oxa-6-aza-spiro[3.3]heptanyl, octahydropyrrolo[3,4-b]pyrrolyl, 2-oxa-6-aza-spiro[3.4] octanyl, 2-oxa-7-aza-spiro[4.4]nonanyl, 2,6-diaza-spiro[3.3]heptanyl or 2,5-diaza-bicyclo[2.2.1]heptanyl.

81). A compound or pharmaceutically acceptable salt thereof according to any one of 1-37, wherein R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O ; where heterocycloalkyl is substituted by one or more independently selected R ¹¹ groups.

82). A compound or pharmaceutically acceptable salt thereof according to any one of 1-37, wherein R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O ; where heterocycloalkyl is substituted with one, two or three independently selected R ¹¹ groups.

83). A compound or pharmaceutically acceptable salt thereof according to any one of 1-37, wherein R ¹ is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, piperidinyl, tetrahydropyranyl, piperazinyl, dioxanyl, [1,4]oxazepanyl, 2- oxa-5-aza-bicyclo[2.2.1]heptanyl, 1-oxa-6-aza-spiro[3.3]heptanyl, octahydropyrrolo[3,4-b]pyrrolyl, 2-oxa-6-aza-spiro[3.4] octanyl, 2-oxa-7-aza-spiro[4.4]nonanyl, 2,6-diaza-spiro[3.3]heptanyl, or 2,5-diaza-bicyclo[2.2.1]heptanyl, each of which is substituted with one, two or three independently selected R ¹¹ groups.

84). The compound according to item 81, 82 or 83, where R ¹¹ represents OH.

85). The connection according to item 81, 82 or 83, where R ¹¹ represents CN.

86). The compound according to item 81, 82 or 83, where R ¹¹ represents halogen.

87). The compound according to item 81, 82 or 83, where R ¹¹ represents F or Cl

88). The compound according to item 81, 82 or 83, where R ¹¹ represents oxo.

89). The compound according to item 81, 82 or 83, where R ¹¹ represents -NR ^8a R ^8b and each R ^8a and R ^8b independently represents H or C _1-4 alkyl.

90). The compound according to item 81, 82 or 83, where R ¹¹ represents -NR ^8a R ^8b and each R ^8a and R ^8b H, -CH ₃ or -CH ₂ CH ₃ .

91). The compound according to item 81, 82 or 83, where R ¹¹ represents C _3-7 cycloalkyl.

92). The compound according to item 81, 82 or 83, where R ¹¹ represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

93). A compound according to item 81, 82, or 83, wherein R ¹¹ is C _1-4 alkyl optionally substituted with one or more independently selected halogen, OH, C _1-4 alkoxy, or -NR ^9a R ^9b , where each R ^9a and R ^9b is independently H, or C _1-4 alkyl.

94). The compound according to item 81, 82 or 83, where R ¹¹ represents -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -CH ₂ CH ₂ CH ₃ , each of which is optionally substituted by one or more independently selected halogen, OH, C _1-4 alkoxy, -NR ^9a R ^9b where each R ^9a and R ^9b is independently H or C _1-4 alkyl.

95). The compound of claim 81, 82, or 83 wherein R ¹¹ is C _1-4 alkyl optionally substituted with one or more independently selected F, -OCH ₃ , OCH ₂ CH ₃ , -NH ₂ , -NHCH _{3 ,} or -N(CH ₃ ) ₂ .

96). The compound according to item 81, 82 or 83, where R ¹¹ represents -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -CH ₂ CH ₂ CH ₃ , each of which is optionally substituted with one or more independently F , -OCH ₃ , -OCH ₂ CH ₃ , -NH ₂ , -NHCH ₃ or -N(CH ₃ ) ₂ .

97). The compound according to item 81, 82 or 83, where R ¹¹ represents C _1-4 alkoxy, optionally substituted with one C _1-4 alkoxy.

98). The compound according to item 81, 82 or 83, where R ¹¹ represents -OCH ₃ , -OCH ₂ CH ₃ , or -OCH ₂ CH ₂ CH ₃ , optionally substituted with one C _1-4 alkoxy.

99). The compound according to item 81, 82 or 83, where R ¹¹ represents C _1-4 alkoxy, optionally substituted with one -OCH ₃ , -OCH ₂ CH ₃ or -OCH ₂ CH ₂ CH ₃ .

100). The compound according to item 81, 82 or 83, where R ¹¹ represents -OCH ₃ , -OCH ₂ CH ₃ , or -OCH ₂ CH ₂ CH ₃ , optionally substituted with one -OCH ₃ , -OCH ₂ CH ₃ or -OCH ₂ CH _{2CH3 .}

101). The compound according to item 81, 82 or 83, where R ¹¹ represents -OCH ₃ or -OCH ₂ CH ₂ OCH ₃ .

102). The compound according to item 81, 82 or 83, where R ¹¹ is a 4-7 membered monocyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O.

103). The compound according to item 81, 82 or 83, where R ¹¹ represents azetidinyl, oxetanyl, pyrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl or morpholinyl.

104). The compound according to item 81, 82 or 83, where R ¹¹ represents -C(=O)OC _1-4 alkyl.

105). The compound according to item 81, 82 or 83, where R ¹¹ represents -C(=O)OCH ₃ .

106). The compound according to item 81, 82 or 83, where R ¹¹ represents -NR ^8c C(=O)OC _1-4 alkyl.

107). The compound according to item 81, 82 or 83, where R ¹¹ represents -NHC(=O)OCH ₃ , -NCH ₃ C(=O)OCH ₃ or -NHC(=O)OCH ₂ CH ₃ .

108). A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of paragraphs 1-107.

109). Pharmaceutical composition according to claim 108, including an additional therapeutic agent.

110). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-107 or a pharmaceutical composition according to any one of items 108-109 for use in medicine.

111). A compound according to any one of items 1-107 or a pharmaceutical composition according to any one of items 108-109 for use in the treatment or prevention of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

112). A compound or pharmaceutically acceptable salt thereof according to any one of items 1-107, or a pharmaceutical composition according to any one of items 108-109 is administered in combination with an additional therapeutic agent.

113). The pharmaceutical composition according to item 109 or the method according to item 112, where the additional therapeutic agent is an agent for the treatment or prevention of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired renewal cartilage, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

114). The compound for obtaining compounds or its pharmaceutically acceptable salt according to paragraph 1, where the compound for obtaining corresponds to formula A:

where

R ^5a is -CN, -SO ₂ C _1-4 alkyl or -CF ₃ ;

R ^5b is selected from halo, C _1-4 alkyl and C _3-7 cycloalkyl.

115). Connection to obtain according to paragraph 114, where R ^5a represents -CN, -SO ₂ CH ₃ or -CF ₃ .

116). The compound to be obtained according to item 114, where R ^5a represents -CN.

117). Connection to obtain according to any one of items 114-116, where R ^5b represents F, -CH ₃ , -CH ₂ CH ₃ or cyclopropyl.

118). Connection to obtain according to any one of paragraphs 114-116, where R ^5b represents-CH ₃ .

Pharmaceutical compositions

Dosage form 1 - Tablets

The compound according to the invention of formula I in the form of a dry powder can be mixed with dry binder gelatin at a weight ratio of about 1:2. You can add a small amount of magnesium stearate as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg active compound of the invention of formula I per tablet) on a tablet press.

Dosage Form 2 - Capsules

The compound according to the invention of formula I in the form of a dry powder can be mixed with a starch diluent in a weight ratio of about 1:1. The mixture can be filled into 250 mg capsules (125 mg active compound of the invention of formula I per capsule).

Dosage Form 3 - Liquid

The compound of the invention of formula I (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be mixed, passed through a No. 10 mesh US sieve and then mixed with a pre-prepared microcrystalline cellulose solution and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Sufficient water is then added with stirring. Water is then added in an amount sufficient to obtain a total volume of 5 ml.

Dosage Form 4 - Tablets

The compound according to the invention of formula I in the form of a dry powder can be mixed with dry binder gelatin at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of the active compound of the invention of formula I) on a tablet press.

Dosage form 5 - for injection

The compound of the invention of formula I can be dissolved or suspended in an aqueous injectable medium, sterile buffered saline, to a concentration of about 5 mg/ml.

Dosage form 6 - for local application

Stearyl alcohol (250 g) and petroleum jelly (250 g) can be melted at about 75°C, and then mixture A of the compound of the invention of formula I (50 g), methyl paraben (0.25 g), propyl paraben (0.15 g), sodium lauryl sulfate (10 g) and propylene glycol (120 g) dissolved in water (about 370 g), and the resulting mixture is stirred until solidified.

Methods of treatment

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in the manufacture of a medicament for the prevention and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

In additional aspects of the method of treatment, the present invention provides methods for the prevention and/or treatment of a mammal suffering from allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital malformations cartilage and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein for the treatment or prevention of said condition.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage renewal, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the prevention and/or treatment of allergic diseases. In a specific embodiment, the allergic disease is asthma.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the manufacture of a medicament for the prevention and/or treatment of allergic diseases. In a specific embodiment, the allergic disease is asthma.

In additional aspects of the method of treatment, the present invention provides methods for the prevention and/or treatment of a mammal suffering from allergic diseases, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein for the treatment or prevention of said condition. In a specific embodiment, the allergic disease is asthma.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of allergic diseases. In a specific embodiment, the allergic disease is asthma.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the prevention and/or treatment of inflammatory diseases. In a specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In a more specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the manufacture of a medicament for the prevention and/or treatment of inflammatory diseases. In a specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In a more specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

In additional aspects of the method of treatment, the present invention provides methods for preventing and/or treating a mammal suffering from inflammatory diseases, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein to treat or prevent said condition. In a specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In a more specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of inflammatory diseases. In a specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel disease. In a more specific embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the prevention and/or treatment of metabolic diseases. In a specific embodiment, the metabolic disease is type II diabetes and/or obesity.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the manufacture of a medicament for the prevention and/or treatment of metabolic diseases. In a specific embodiment, the metabolic disease is type II diabetes and/or obesity.

In additional aspects of the method of treatment, the present invention provides methods for preventing and/or treating a mammal suffering from metabolic diseases, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein to treat or prevent said condition. In a specific embodiment, the metabolic disease is type II diabetes and/or obesity.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of metabolic diseases. In a specific embodiment, the metabolic disease is type II diabetes and/or obesity.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the prevention and/or treatment of autoimmune diseases. In a specific embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the manufacture of a medicament for the prevention and/or treatment of autoimmune diseases. In a specific embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.

In additional aspects of the method of treatment, the present invention provides methods for preventing and/or treating a mammal suffering from autoimmune diseases, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein to treat or prevent said condition. In a specific embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of autoimmune diseases. In a specific embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the prevention and/or treatment of autoinflammatory diseases. In a specific embodiment, the autoimmune disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcet's disease, systemic-onset juvenile idiopathic arthritis (SJIA), or Still's disease.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the manufacture of a medicament for the prevention and/or treatment of autoinflammatory diseases. In a specific embodiment, the autoimmune disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcet's disease, systemic-onset juvenile idiopathic arthritis (SJIA), or Still's disease.

In additional aspects of the method of treatment, the present invention provides methods for preventing and/or treating a mammal suffering from autoinflammatory diseases, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein to treat or prevent said condition. In a specific embodiment, the autoimmune disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcet's disease, systemic-onset juvenile idiopathic arthritis (SJIA), or Still's disease.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of autoinflammatory diseases. In a specific embodiment, the autoimmune disease is cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcet's disease, systemic-onset juvenile idiopathic arthritis (SJIA), or Still's disease.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the prevention and/or treatment of proliferative diseases. In a specific embodiment, the proliferative disease is cancer, leukemia, multiple myeloma, and psoriasis.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the manufacture of a medicament for the prevention and/or treatment of proliferative diseases. In a specific embodiment, the proliferative disease is cancer, leukemia, multiple myeloma, and psoriasis.

In additional aspects of the method of treatment, the present invention provides methods for preventing and/or treating a mammal suffering from proliferative diseases, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein to treat or prevent said condition. In a specific embodiment, the proliferative disease is cancer, leukemia, multiple myeloma, and psoriasis.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of proliferative diseases. In a specific embodiment, the proliferative disease is cancer, leukemia, multiple myeloma, and psoriasis.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the prevention and/or treatment of transplant rejection. In a specific embodiment, transplant rejection is graft versus host.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the manufacture of a medicament for the prevention and/or treatment of transplant rejection. In a specific embodiment, transplant rejection is graft versus host.

In additional aspects of the method of treatment, the present invention provides methods for preventing and/or treating a mammal suffering from transplant rejection, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein to treat or prevent said condition. In a specific embodiment, transplant rejection is graft versus host.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of transplant rejection. In a specific embodiment, transplant rejection is graft versus host.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in the prevention and/or treatment of diseases associated with impaired cartilage renewal. In a specific embodiment, the disease associated with impaired cartilage renewal is ankylosing spondylitis.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in the manufacture of a medicament for the prevention and/or treatment of diseases associated with impaired cartilage renewal. In a specific embodiment, the disease associated with impaired cartilage renewal is ankylosing spondylitis.

In additional aspects of the method of treatment, the present invention provides methods for the prevention and/or treatment of a mammal suffering from a disease associated with impaired cartilage turnover, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein for the treatment or prevention of said condition. . In a specific embodiment, the disease associated with impaired cartilage renewal is ankylosing spondylitis.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of a disease associated with impaired cartilage renewal. In a specific embodiment, the disease associated with impaired cartilage renewal is ankylosing spondylitis.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention, for use in the prevention and/or treatment of congenital cartilage malformations. In a specific embodiment, the congenital cartilage malformations are selected from microtia, anotia, and/or metaphyseal chondrodysplasia.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in the manufacture of a medicament for the prevention and/or treatment of congenital cartilage malformations. In a specific embodiment, congenital cartilage malformations, cartilage malformations are selected from microtia, anotia, and/or metaphyseal chondrodysplasia.

In additional aspects of the method of treatment, the present invention provides methods for the prevention and/or treatment of a mammal suffering from congenital cartilage malformations, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein to treat or prevent said condition. In a specific embodiment, congenital cartilage malformations, cartilage malformations are selected from microtia, anotia, and/or metaphyseal chondrodysplasia.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of congenital cartilage malformations. In a specific embodiment, congenital cartilage malformations, cartilage malformations are selected from microtia, anotia, and/or metaphyseal chondrodysplasia.

In one embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in medicine. In a specific embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in the prevention and/or treatment of diseases associated with hypersecretion of IFNα, IL12 and/or IL23. In a specific embodiment, the disease associated with hypersecretion of IFNα, IL12 and/or IL23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and/or Crohn's disease.

In another embodiment, the present invention relates to compounds of the invention or pharmaceutical compositions containing a compound of the invention for use in the manufacture of a medicament for the prevention and/or treatment of diseases associated with hypersecretion of IFNα, IL12 and/or IL23. In a specific embodiment, the disease associated with hypersecretion of IFNα, IL12 and/or IL23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and/or Crohn's disease.

In additional aspects of the method of treatment, the present invention provides methods for the prevention and/or treatment of a mammal suffering from diseases associated with hypersecretion of IFNα, IL12 and/or IL23, comprising administering an effective amount of a compound of the invention or one or more pharmaceutical compositions described herein, for treatment or prevention of said condition. In a specific embodiment, the disease associated with hypersecretion of IFNα, IL12 and/or IL23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and/or Crohn's disease.

In one embodiment, the present invention provides pharmaceutical compositions containing a compound of the invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is an agent for the treatment of diseases associated with hypersecretion of IFNα, IL12 and/or IL23. In a specific embodiment, the disease associated with hypersecretion of IFNα, IL12 and/or IL23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and/or Crohn's disease.

Dose levels for injection range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all over about 1 to about 120 hours, especially 24 to 96 hours. To achieve adequate steady state levels a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered. The maximum total dose is not expected to exceed 1 g/day for a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions such as degenerative diseases, the treatment regimen is typically extended over many months or years, so oral dosing is preferred for patient convenience and tolerability. When taken orally, one to four (1-4) regular doses per day, especially one to three (1-3) regular doses per day, usually one to two (1-2) regular doses per day and most typically one (1) regular dose daily are representative treatment regimens. Alternatively for long acting drugs, oral, once every two weeks, once a week and once a day are representative treatment regimens. In particular, the dosage regimen may be every 1-14 days, more specifically 1-10 days, even more specifically 1-7 days, and most specifically 1-3 days.

Using these dosing regimens, each dose provides from about 1 to about 1000 mg of a compound of the invention, with specific doses each providing from about 10 to about 500 mg, and especially from about 30 to about 250 mg.

Transdermal doses are generally chosen to provide similar or lower blood levels than those achieved using injection doses.

When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk of developing a disease, usually under the advice and supervision of a physician, at the dosage levels described above. Patients at risk of developing a particular condition typically include those who have a family history of the disease or who have been identified by genetic testing or screening as particularly susceptible to developing the condition.

The compound of the invention may be administered as the sole active agent, or it may be administered in combination with other therapeutic agents, including other compounds of the invention that exhibit the same or similar therapeutic activity and have been found to be safe and effective when administered in combination. In a specific embodiment, the co-administration of two (or more) agents allows the use of significantly lower doses of each, thereby reducing the observed side effects.

In one embodiment, a compound of the invention or a pharmaceutical composition containing a compound of the invention is administered as a drug. In a particular embodiment, said pharmaceutical composition further comprises an additional active ingredient.

In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of a disease involving inflammation, specific agents include, but are not limited to, immunoregulatory agents such as azathioprine, corticosteroids (eg, prednisolone or dexamethasone), cyclophosphamide , cyclosporin A, tacrolimus, mycophenolate, mofetil, muromonab-CD3 (OKT3, eg Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of arthritis (e.g., rheumatoid arthritis), specific agents include, but are not limited to, analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDs (e.g., but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporine) and biological DMARDs (e.g., but not limited to, infliximab, etanercept, adalimumab, rituximab and abatacept).

In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of proliferative disorders, specific agents include, but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel , vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (eg, Herceptin ^TM ), capecitabine, raloxifene hydrochloride, EGFR inhibitors (eg, lressa®, tarceva™, erbitux™) , VEGF inhibitors (eg Avastin™), proteasome inhibitors (eg Velcade™), Glivec® and hsp90 inhibitors (eg 17-AAG). In addition, the compound of the invention according to formula I can be administered in combination with other therapies, including, but not limited to, radiation therapy or surgery. In a specific embodiment, the proliferative disorder is selected from cancer, myeloproliferative disease, or leukemia.

In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of autoimmune diseases, specific agents include, but are not limited to: glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards) (cyclophosphamide), nitrosoureas, platinum compounds of the present invention and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin and mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (eg, IFN-β), TNF-binding proteins (eg, infliximab, etanercept, or adalimumab ), mycophenolate, fingolimod and myriocin.

In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of transplant rejection, specific agents include, but are not limited to: calcineurin inhibitors (eg, cyclosporine or tacrolimus (FK506)), mTOR inhibitors (eg, sirolimus , everolimus), antiproliferatives (eg, azathioprine, mycophenolic acid), corticosteroids (eg, prednisolone, hydrocortisone), antibodies (eg, anti-IL-2Rα receptor monoclonal antibodies, basiliximab, daclizumab), anti-T cell polyclonal antibodies (eg, antithymocyte globulin (ATG), antilymphocyte globulin (ALG)).

In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of asthma and/or rhinitis and/or COPD, specific agents include, but are not limited to: beta2-adrenergic agonists (e.g., salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (eg, ipratropium bromide), glucocorticoids (oral or inhaled). Long-acting Β2-agonists (eg, salmeterol, formoterol, bambuterol, and extended-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (eg, fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and inhibitors (eg, montelukast, zafirlukast and zileuton), inhibitors of mediator release (eg, cromoglycate and ketotifen), biological regulators of the IgE response (eg, omalizumab), antihistamines (eg, ceterizine, cinnarizine, fexofenadine), and vasoconstrictors (eg, oxymetazoline, xylometazoline, naphazoline, and tramazolin) .

Additionally, a compound of the invention may be administered in conjunction with asthma and/or COPD rescue therapy, such treatments include oxygen or heliox, nebulized salbutamol or terbutaline (optionally in combination with anticholinergics (e.g., ipratropium), systemic steroids ( oral or intravenous, eg, prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, nonspecific beta-agonists, injectable or inhaled (eg, epinephrine, isoetarine, isoproterenol, metaproterenol), anticholinergics (IV or nebulizers, eg , glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamiphylline), inhalational anesthetics that have a bronchodilator effect (eg, isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of inflammatory bowel disease (IBD), specific agents include, but are not limited to: glucocorticoids (eg, prednisone, budesonide), synthetic disease-modifying, immunomodulatory agents (eg, methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine) and biological disease-modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).

In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prevention of SLE, specific agents include, but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), disease-modifying antirheumatic drugs (DMARDs), such as antimalarials (eg, plaquenil, hydroxychloroquine), immunosuppressants (eg, methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics such as nonsteroidal anti-inflammatory drugs, opiates (eg, dextropropoxyphene and co-codamol), opioids (eg, hydrocodone, oxycodone, MS Contin, or methadone) and durogesic fentanyl transdermal patch.

In one embodiment, a compound of the invention is administered in conjunction with another therapeutic agent for the treatment and/or prevention of psoriasis, specific agents include, but are not limited to: topical preparations such as bath solutions, moisturizers, tar-containing medicated creams and ointments. , dithranol (anthralin), corticosteroids such as deoxymethasone (Topicort™), fluocinonide, vitamin D3 analogs (eg calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic drugs such as methotrexate, cyclosporine, retinoids, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologics such as Amevive™, Enbrel™, Humira™, Remicade™, Raptiva™ and ustekinumab (an IL-12 and IL-12 blocker). In addition, the compound of the invention may be administered in combination with other therapies including, but not limited to, phototherapy or photochemotherapy (eg, psoralen ultraviolet A (PUVA) phototherapy).

In one embodiment, a compound of the invention is co-administered with another therapeutic agent to treat and/or prevent an allergic reaction, specific agents include, but are not limited to: antihistamines (e.g., cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g., prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or antileukotrienes (eg montelukast or zafirlukast), anticholinergics and decongestants.

As will be apparent to those skilled in the art, any means of delivering two or more therapeutic agents to a patient as part of the treatment regimen mentioned above may be used in co-administration. As long as two or more agents can be administered simultaneously in the same dosage form, ie in the form of a single pharmaceutical composition, this is not essential. Means can be entered in the form of different dosage forms and at different times.

CHEMICAL METHODS OF SYNTHESIS

General information

The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It is understood that if typical or preferred process conditions (ie, reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by one skilled in the art through routine optimization techniques.

In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent unwanted interactions of certain functional groups. The choice of an appropriate protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, is well known in the art (Greene, T W; Wuts, P G M;, 1991).

The following methods detail methods for preparing the compound of the invention as defined above and comparative examples. The compound of the invention can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis.

All reagents are commercial grade products and were used as received without further purification unless otherwise noted. Commercially available anhydrous solvents were used for reactions carried out under an inert atmosphere. In all other cases, reactive grade solvents were used unless otherwise noted. Column chromatography was carried out on silica gel 60 (35-70 μm). Thin layer chromatography was performed using plates pre-coated with F-254 silica gel (0.25 mm thick). ¹ H NMR spectra were recorded on a Bruker Advance 300 NMR spectrometer (300 MHz). Chemical shifts (δ) for ¹ H-NMR spectra are expressed in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the corresponding residual solvent proton peak, i.e. CHCl ₃ (δ 7.27) as internal standard. Multiplicity is expressed as singlet (s), doublet (d), triplet (t), quartet (q), quintuplet (quin), multiplet (m) and wide signal (broad). Electrospray mass spectra were obtained on a Waters platform LC/MS spectrometer or using a Waters Acquity H-Class UPLC connected to a Waters Mass Detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 µm, 2.1 mm in .d. x 50 mm length, Waters Acquity UPLC BEH C18 1.7 µm, 2.1 mm id. x 30 mm length, or Waters Xterra MS 5 µm C18, 100 x 4.6 mm. The methods used either MeCN/H ₂ O gradients (H ₂ O contains 0.1% TFA or 0.1% NH ₃ ) or MeOH/H ₂ O gradients (H ₂ O contains 0.05% TFA). Microwave heating was performed using a Biotage Initiator.

Racemic mixtures were separated on an Agilent HP1100 system with UV detection. Columns used: Chiralpak 1A (10×250 mm, 5 µm). Solvents used: i PrOH and t BME. Enantiomeric purity was determined on an Agilent HP1100 system with UV detection. Columns used: Chiralpak IA (4.6×250 mm, 5 µm). Solvents used: i PrOH and t BME.

Table I. List of abbreviations used in the experimental section:

Reduction Definition DCM dichloromethane MeCN Acetonitrile DMF N,N-dimethylformamide Cat. Catalytic amount TFA Trifluoroacetic acid THF tetrahydrofuran NMR nuclear magnetic resonance DMSO Dimethyl sulfoxide LC-MS liquid chromatography combined with mass spectrometry EtOAc ethyl acetate APCI atmospheric pressure chemical ionization Rt retention time With singlet lat. With wide singlet d doublet dd double doublet m multiplet min minute ml milliliter µl microliter G gram mg milligram TEA triethylamine mmol millimole HPLC high performance liquid chromatography NMP N-methylpyrrolidone AcCl acetyl chloride ppm parts per million Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium(0) Pd(OAc) ₂ Palladium(II) acetate XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Comm. Compound Sp. Way Prov.s. intermediate connection MM Molecular mass Meas.MM Measured molecular weight NA not involved Pd(dppf)CL _2. DCM 1,1'-Bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride micron micrometer t BME tert-butyl methyl ether i PrOH isopropanol DMA dimethylacetamide TFA Trifluoroacetic acid DBU 1,8-Diazabicycloundec-7-ene DiPPF 1,1'-Bis(di-isopropylphosphino)ferrocene HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate NIS N-iodosuccinimide Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XantPhos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate MorDALPhos Di(1-adamantyl)-2-morpholinophenylphosphine MorDALPhos Pd G3 (2-(Di-1-adamantylphosphino)morpholinobenzene)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate BrettPhos 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate methanesulfonate Phos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl SPhos Pd G2 Chlorine(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (II) RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuBrettPhos Pd G3 [(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl) ]palladium(II) methanesulfonate TMHD 2,2,6,6-Tetramethyl heptanedione T3P Propylphosphonic anhydride

Obtaining by synthesis of the compound according to the invention

General synthesis methods

Compounds of the invention and comparative examples can be obtained in accordance with the following schemes.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

General methods used to synthesize compounds and intermediates

Method A1-a

A solution of acid (1 equiv.), HATU (1.3 equiv.) and Et ₃ N (2.5 equiv.) in NMP is stirred for 1 min, after which the amine (1 equiv.) is added. Upon completion, the mixture is filtered and the filtrate is purified by preparative chromatography to give the desired product.

Method A1-b

To a suspension of acid (1 eq.), Et ₃ N (5 eq.) and amine (1-3 eq.) in DMF, a 50% solution of T3P in AcOEt (2 eq.) was slowly added at room temperature. The reaction mixture is stirred at room temperature until the process is complete. The reaction mixture was poured onto ice/water and extracted with DCM. The organic layer is concentrated to dryness to give the desired product.

Method A2:

Step 1: To a solution of acid (1 eq.) and EDCI.HCl (1.5 eq.) in dry DCM at room temperature, add amine (1.1 eq.), then DIPEA (2.0 eq.). The mixture was stirred at room temperature for 18 hours. It was then quenched with aqueous NaHCO ₃ followed by extraction with DCM. The organic layer was concentrated to dryness and the crude material was either used as such or purified by column chromatography using EtOAc/DCM or MeOH/DCM as eluent to give the desired amide.

Step 2: A solution of Boc-protected amide (1.0 eq.) in DCM/TFA (1:1) is heated at 45° C. for 18 hours. Then concentrated to dryness to remove excess TFA. The compound was purified through an SCX column using MeOH followed by 2N NH ₃ in MeOH as eluent to give the desired product as the free base.

Method A3:

Step 1: To a solution of acid (1 eq.) and HATU (1.1 eq.) in dry DMF at room temperature, add amine (1.5 eq.), then DIPEA (1.5 eq.). The mixture was stirred at room temperature for 18 hours. It was then diluted with water, followed by extraction with EtAOc. The organic layer is concentrated to dryness and the crude material is either used as such or purified by column chromatography using EtOAc/DCM or MeOH/DCM as eluent to give the desired amide.

Method B1

Aryl halide (1.0 eq.), amine or aniline (1.0 eq.), Pd ₂ CL ₂ (allyl) ₂ (0.02 eq.), MorDALPhos (0.04 eq.) and Cs ₂ CO ₃ ( 1.2 eq.) is mixed under N ₂ at room temperature, after which 1,4-dioxane is added. The resulting mixture is stirred at 110°C. The mixture is then allowed to cool to room temperature, then diluted in DMSO and filtered. The filtrate is purified by preparative HPLC to give the desired product.

Method B2-a

Aniline (1.0 eq.), aryl halide (1.2 eq.), XantPhos Pd G3 (0.04 eq.) and Cs ₂ CO ₃ (1.2 eq.) are mixed under N2 atmosphere at room temperature, after which add 1,4-dioxane. The resulting mixture is stirred at 80°C. The mixture is then allowed to cool to room temperature, then diluted in DMSO and filtered. The filtrate is purified by preparative HPLC to give the desired product. Alternatively, the mixture is poured into water and then filtered. The resulting solid is washed with water and dried to give the desired product.

Method B2-b

A suspension of aniline (1.0 eq.), aryl halide (1.1 eq.) and K ₃ PO ₄ (3.0 eq.) in degassed dioxane was heated to reflux. To this solution was added dropwise (over 7 hours) a solution of Pd(OAc) ₂ (0.14 eq.) and Xantphos (0.28 eq.) in degassed dioxane. Upon completion, the reaction mixture was filtered while hot on a pad of dicalite (Carlo Erba, ref P8880014) and the filter agent washed with THF and CHCl ₃ . The solvent was evaporated and the solid was triturated in acetonitrile. The solid was filtered off, washed with acetonitrile. The crude product was purified by column chromatography using CHCl ₃ /MeOH: 98/2 as eluent to give the desired product.

Method B3

Intermediate 1 (1.0 eq.), aniline or amine (2.0 eq.), XantPhos Pd G3 (0.03 eq.), XantPhos (0.03 eq.) and Cs ₂ CO ₃ (1.3 equiv.) are mixed under N ₂ atmosphere at room temperature, after which 1,4-dioxane is added. The resulting mixture is stirred at 110°C. Upon completion, the mixture is cooled to room temperature and applied to silica. The crude material is purified by column chromatography using EtOAc/petroleum ether or MeOH/DCM as eluent.

Method C1

Step 1: To a solution of dry THF containing aniline (1 eq.) is added NaH (60% dispersion in mineral oil, 2.2 eq.) under N ₂ atmosphere. The mixture is stirred for 5 minutes at room temperature before the addition of iodomethane (2 eq.). The reaction mixture is then stirred at room temperature overnight. The reaction conversion is monitored by LCMS. The reaction is quenched with MeOH, then concentrated to dryness. The crude residue is purified by column chromatography using MeOH/DCM, 7N NH ₃ in MeOH/DCM or EtOAc/petroleum ether as eluent.

Step 2: To a solution of the dibenyl-protected amine (1 eq.) in dry DCM (0.25 M) at 0° C., Tf ₂ O (8 eq.) is added dropwise. The mixture is then stirred at room temperature for 18 hours. The conversion of the reaction is monitored by LCMS. The reaction is quenched with NaHCO ₃ and the mixture is extracted with DCM. The organic layer was concentrated to dryness to give the desired crude material, which was used as such or purified by chromatography.

Stage 3: Aniline (1 eq.), 2-chloro-4-aminopyrimidine (2.0 eq.), BrettPhos Pd G3 (0.1 eq.), BrettPhos (0.1 eq.), Cs ₂ CO ₃ ( 2.0 equiv.) mixed in an inert atmosphere. Add a solvent, usually 1,4-dioxane and the mixture is stirred at 110°C for 18 hours Then the reaction mixture is cooled to room temperature and quenched with water H ₂ O and the connection was extracted with DCM. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by chromatography to give the desired compound.

Method C2

Step 1: To a solution of aniline (1.0 eq.) in dry THF under N ₂ at 0°C was added NaH (60% dispersion in mineral oil, 1.5 eq.). After 10 minutes, iodomethane (2.0 eq.) is added and the mixture is stirred at 40°C. Upon completion of the reaction (monitored by LCMS), the mixture was allowed to cool to room temperature and quenched with saturated aqueous NaHCO ₃ . Then, the mixture is extracted with DCM, dried over MgSO ₄ , filtered and concentrated to dryness. The crude material is purified by column chromatography using EtOAc/petroleum ether or MeOH/DCM as eluent to give the desired product.

Stage 2: Aryl chloride (1.0 eq.), Aniline (2.0 eq.), MorDALPhos Pd G3 (0.03 eq.), MorDALPhos (0.03 eq.) and Cs ₂ CO ₃ (1.3 equiv.) is mixed under N ₂ atmosphere at room temperature, after which 1,4-dioxane is added and the mixture is stirred at 110°C. Upon completion, the mixture is cooled to room temperature and diluted in DMSO. After filtration, the filtrate is purified by preparative HPLC to obtain the desired product.

Method D1

The Boc-protected amine (1.0 eq.) was dissolved in anhydrous 1,4-dioxane under N ₂ atmosphere. HCl (4.0 M in dioxane, 10 eq.) was added dropwise and the reaction mixture was stirred at room temperature. After 2 hours, all volatiles are evaporated in vacuo. The crude product is dissolved in DCM, washed with saturated aqueous NaHCO ₃ , dried and evaporated in vacuo. The crude material was either used as such or purified by column chromatography to give the desired product.

Method P1

TEA ( _1.3 eq.) . The mixture is stirred at 160° C. overnight. Then cooled to room temperature and diluted with H ₂ O. The reaction was made basic using saturated aqueous NaHCO ₃ . This mixture is extracted with EtOAc. The organic layer was washed with brine (3x), dried over MgSO ₄ , filtered and concentrated to dryness to give the crude product. The crude material is used as such or purified by chromatography.

Method P2

6-Iodopyridazine-3-amine (CAS [187973-60-0], 1.0 eq.), Amine (2.0 eq.), CuI (0.1 eq.), L-hydroxyproline (CAS [51- 35-4], 0.2 eq.) and K ₃ PO ₄ (3.0 eq.) are mixed together under N2 atmosphere. Add DMSO and the mixture is stirred at 60°C. After two nights, the mixture is cooled to room temperature and DMSO is removed under reduced pressure. The residue is diluted in MeOH and filtered. The filtrate was purified by column chromatography using 7N NH3 in MeOH/DCM as eluent to give the desired product.

Method P3

To a solution of the amine (1 eq.) in anhydrous dioxane (10 ml) was added DIPEA (4 eq.) and 3,6-dichloropyridazine (CAS [141-30-0], 1.0 eq.) and the mixture was stirred for 24 h at 100°C. The mixture is then diluted with DCM and washed with brine. The reaction mixture is extracted with DCM. The combined organic extracts are dried and evaporated in vacuo to give a crude material which is used as such or purified by chromatography.

Synthesis of intermediates

Intermediate 1: 7-chloro-5-iodo-3-methyl-3H-imidazo[4,5-b]pyridine

Step 1: 2,4-dichloro-6-iodo-pyridin-3-ylamine: To a solution of 2,4-dichloro-3-aminopyridine (250 g, 1.54 mmol, 1 eq.) in dry MeCN (1.2 k) NIS (382 g, 1.70 mmol, 1.1 eq.) and TFA (35.45 ml, 0.46 mmol, 0.3 eq.) were added under N ₂ at room temperature. The mixture was stirred at 40° C. for 18 hours in a 3 L round bottom flask. The reaction mixture was then quenched with saturated Na ₂ S ₂ O ₃ (500 ml) and NaHCO ₃ (700 ml). The organic layer was washed with saturated NaHCO ₃ and the aqueous layers were washed twice with EtOAc (2×700 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to dryness to give the crude product. It was purified by column chromatography using cyclohexane and EtOAc (10%) to give the desired LCMS product: m/z=289 [M+H].

Stage 2: 4-chloro-6-iodo-N2-methyl-pyridine-2,3-diamine

2,4-dichloro-6-iodo-pyridine-3-amine (20 g, 0.07 mmol, 1 eq.) was dissolved in n-butanol (300 ml) in an autoclave (600 ml). Methylamine (33% in EtOH, 28.72 ml, 0.28 mmol, 4 eq) was added under N ₂ at room temperature. The mixture was stirred at 180°C for 18 hours and then cooled to room temperature. This step was repeated twice and at the end all reactions were combined and concentrated to give 60 g of the title compound, which was used as such in the next step. LCMS: m/z=284 [M+H].

Step 3: 7-chloro-5-iodo-3-methyl-3H-imidazo[4,5-b]pyridine To a solution of 4-chloro-6-iodo-N-2-methyl-pyridine-2,3-diamine ( 60 g, 021 mmol, 1 eq.) in formic acid (30 ml) was added trimethylorthoformate (69.5 ml, 0.64 mmol, 3 eq.). The mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to dryness, after which the residue was diluted with DCM and quenched with saturated aqueous NaHCO ₃ . After extraction with DCM, the organic layer was dried over Na ₂ SO 4 , filtered and concentrated to dryness to give the crude material. It was purified by column chromatography using cyclohexane/EtOAc 10 to 60% EtOAc as eluent to give the desired product. LCMS: m/z=294 [M+H]. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm: 8.46 (s, 1H), 7.83 (s, 1H), 3.81 (s, 3H).

Intermediate 2: 5-(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile

Intermediate 1 (68.51 g, 233.83 mmol, 1.0 eq.), Intermediate 21 (47.00 g, 350.75 mmol, 1.5 eq.), CuI (8.89 g, 46 .77 mmol, 0.2 eq.), TMHD (97.45 ml, 467.66 mmol, 2 eq.) and Cs ₂ CO ₃ (152 g, 467.66 mmol, 2 eq.) were mixed together under air, was added, DMF (234 ml) and the mixture was stirred at 85°C for 2 nights. If complete conversion was not achieved, additional CuI (0.1 eq.) and TMHD (1 eq.) were added, after which the mixture was further stirred at 85° C. for another night. Then, the mixture was cooled to 0°C. The resulting thick paste was then filtered and the filter cake (cake) was washed with ice-cold DMF (2×20 ml). It was then washed with ice-cold MTBE (3×150 ml). After drying the precipitate, it was suspended in 500 ml of 10% TMEDA aqueous solution. Stirred for 2 hours, filtered and the filter cake was washed with H ₂ O to obtain the desired product. LCMS: m/z=300 [M+H] ⁺ .

Intermediate 3: 5-(7-Amino-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile

To a mixture of intermediate 2 (5.0 g, 16.72 mmol, 1.0 eq.), benzophenone imine (CAS [1013-88-3], 2.81 ml, 16.72 mmol, 1.0 eq.), Pd₂CL₂(allyl)₂ (122 mg, 0.33 mmol, 0.02 eq.), XantPhos (387 mg, 0.67 mmol, 0.04 eq.) and Cs₂CO₃ (6.54 g, 20.07 mmol, 1.2 eq) under N atmosphere₂, was added 1,4-dioxane (100 ml) and the mixture was stirred at 110°C for 24 hours After cooling to room temperature, the mixture was diluted with EtOAc and filtered through celite. The filter cake was washed with EtOAc (100 mL) and the filtrate was poured into 2N HCl. aqueous HCl solution (200 ml), stirring it for 10 min. After extraction with EtOAc, the aqueous phase was neutralized to pH=7 using NaHCO₃. This was followed by extraction with EtOAc (5x 100 ml) after which the combined organic layers were dried over MgSO_four, filtered and concentrated to dryness to give the crude which was triturated with DCM to give the desired product. LCMS: m/z=281 [M+H]⁺.

Alternative Synthesis of Intermediate 3: 5-(7-Amino-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile

Step 1: 2,6-dichloro-4-amino-5-nitropyridine (520 g, 2.5 mol, 1.0 eq.) was added to acetonitrile (5.2 L) at room temperature. To the mixture was added with stirring at room temperature, Boc ₂ O (710 g, 3.25 mol, 1.3 eq.) and K ₃ PO ₄ (1000 g, 4.71 mol, 1.9 eq.). The reaction mixture was heated under reflux for 1-2 hours. Then a solution of Boc ₂ O (110 g, 0.5 mol, 0.2 eq.) in acetonitrile (100 ml) was added and the reaction mixture was heated under reflux for another hour. The reaction mixture was cooled to room temperature and filtered through a pad of Na ₂ SO ₄ . Na ₂ SO ₄ was washed with acetonitrile (2 l). The filtrate was evaporated under reduced pressure and redissolved in DCM (5 L). The DCM layer was washed with water. The organic layer was extracted with DCM (5 L) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give the desired product. LCMS: m/z=306/308 [M+H].

Step 2: 2,6-dichloro-4 Boc-amino-5-nitropyridine (770 g, 2.5 mol, 1.0 eq.) was added to isopropanol (11 L) at room temperature. To the mixture was added, with stirring at room temperature, methylamine 33% in EtOH (800 mL, 3.0 eq.) over 1 h 30. The reaction mixture was stirred at room temperature for 1 h 30 min. The suspension was filtered, washed with isopropanol (1 L) then water (4 L). After drying, the desired product was obtained. LCMS: m/z=302.9/304.8 [M+H].

Step 3: tert-butyl N-[6-chloro-2-(methylamino)-3-nitro-4-pyridyl]carbamate (788 g, 2.6 mol, 1.0 eq) was added to acetonitrile (5, 5 l) at room temperature. To the mixture was added with stirring at room temperature, 5-hydroxy-4-methyl-pyridine-2-carbonitrile (384 g, 2.86 mol 1.1 eq.) and Na ₂ CO ₃ (414 g, 3.9 mol, 1.5 eq.). The reaction mixture was heated under reflux for 48 hours. The reaction mixture was cooled to room temperature and the insoluble was filtered off and washed with acetonitrile (2 L). The combined organic layers were evaporated. The crude material was washed with water (5 L), collected and dried to give the desired product. LCMS: m/z=401.1 [M+H] ; m/z=399.2 [MH]. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.70 (s, 1H), 9.05 (q, 1H), 8.62 (s, 1H), 8.13 (s, 1H), 7 .23 (s, 1H), 2.59 (d, 3H), 2.24 (s, 3H), 1.50 (s, 9H).

Stage 4: tert-butyl N-[6-[(6-cyano-4-methyl-3-pyridyl)oxy]-2-(methylamino)-3-nitro-4-pyridyl]carbamate (150 g, 375 mmol, 1 0 eq.) was added a mixture of acetic acid (750 ml, 35 eq.) and trimethylorthoformate (750 ml, 18 eq.) at room temperature. To the mixture was added in portions with vigorous stirring at 20-21°C, Zn dust <10 μm (total 120 g, 4.9 eq., added portionwise 15 g). Each addition was carried out after the reaction mixture had cooled to 20-21°C. The reaction mixture was stirred for one hour after the last addition. The suspension was filtered on Dicalite 4158 (Carlo Erba, ref P8880014), washed with THF (1 L) and the combined organic layers were evaporated. The residue was slowly poured into a cold mixture of 20% ammonia solution (100 ml) and water (2 l). The resulting solid was filtered, washed with water (2 L) and dried to give the desired product. LCMS: m/z=381.0 [M+H]; m/z=379.2 [MH]. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.32 (br s, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H) , 7.54 (s, 1H), 3.60 (s, 3H), 2.27 (s, 3H), 1.49 (s, 9H).

Stage 5: tert-butyl N-[6-[(6-cyano-4-methyl-3-pyridyl)oxy]-2-(methylamino)-3-nitro-4-pyridyl]carbamate (197 g, 0.518 mol, 1.0 eq.) was suspended in a mixture of hydrochloric acid, 4N. solution in water (1 L) and THF (1 L). The reaction mixture was heated at 60°C for 5 hours. The reaction mixture was cooled to room temperature and the solid was filtered off, washed with THF (1 L) and dried to give the desired product as the hydrochloride salt. LCMS: m/z=281.4 [M+H]. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.28 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7.57 (br s, 2-3H), 6.33 (s, 1H), 3.67 (s, 3H), 2.25 (s, 3H).

Intermediate 4: 5-(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-ylamino)-4-methyl-pyridine-2-carbonitrile

7-chloro-5-iodine-3-methyl-3H-imidazo[4,5-b]pyridine (intermediate 1, 50 mg, 0.171 mmol, 1.0 eq.), 5-amino-4-methylpyridine-2 -carbonitrile (intermediate 17, 24 mg, 0.205 mmol, 1.2 eq.), XantPhos Pd G3 (5 mg, 0.005 mmol, 0.03 eq.), XantPhos (3 mg, 0.005 mmol, 0.03 eq. ) and K ₃ PO ₄ (72 mg, 0.342 mmol, 2.0 eq.) were mixed under N ₂ at room temperature. Added diglyme (1 ml) and the mixture was stirred at 80°C. After one night the mixture was cooled to room temperature, quenched with water and the mixture was extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude material was purified using column chromatography (EtOAc/petroleum ether, 7:3-1:0) to obtain the desired product. LCMS: m/z=299 [M+H] ⁺ .

Intermediate 5: 5-[(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-methyl-amino]-4-methyl-pyridine-2-carbonitrile

7-chloro-5-iodine-3-methyl-3H-imidazo[4,5-b]pyridine (intermediate 1, 50 mg, 0.171 mmol, 1.0 eq.), 5-amino-4-methylpyridine-2 -carbonitrile (intermediate 18, 30 mg, 0.205 mmol, 1.2 eq.), RuPhos Pd G3 (4 mg, 0.005 mmol, 0.03 eq.), RuPhos (2 mg, 0.005 mmol, 0.03 eq. ) and K ₃ PO ₄ (72 mg, 0.342, 2.0 eq.) were mixed under N ₂ at room temperature. Added diglyme (1 ml) and the mixture was stirred at 80°C. After one night, the mixture was cooled to room temperature, quenched with water and the compound was extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude material was purified using column chromatography (EtOAc/petroleum ether, 1:1-1:0) to obtain the desired product. LCMS: m/z=313 [M+H] ⁺ .

intermediate connection 8: (7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-methyl-((S)-1,2,2-trimethyl-propyl)-amine

To a solution of intermediate 67 (130 mg, 0.49 mmol, 1 eq.) in dry THF (2 ml) was added sodium hydride (60% in oil, 39 mg, 0.98 mmol, 2.0 eq.) under atmospheric _N2 . After 5 minutes, methyl iodide (46 μl, 0.73 mmol, 1.5 eq.) was added. The reaction mixture was heated at 40°C for 18 hours. Then, the reaction mixture was diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The crude material obtained was purified by column chromatography (PE/EtOAc gradient elution from 20% to 80% EtOAc) to give the desired product. LCMS: m/z=281 [M+H] ⁺ .

intermediate connection 12: (7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-((R)-1-cyclopropyl-ethyl)-methyl-amine

To a solution of intermediate 65 (220 mg, 0.88 mmol, 1 eq.) in dry THF (2 ml) was added sodium hydride (60% in oil, 71 mg, 1.76 mmol, 2 eq.) under N ₂ . After 5 minutes, methyl iodide (82 μl, 1.32 mmol, 1.5 eq.) was added. The reaction mixture was heated at 40°C for 18 hours Then, the reaction mixture was diluted with EtOAc and washed with saturated saline. The combined organic extracts were dried and evaporated in vacuo. The resulting crude material was purified by column chromatography (PE/EtOAc gradient elution from 20% to 80% EtOAc) to give the desired product. LCMS: m/z=265 [M+H] ⁺ .

intermediate connection 14: Dibenzyl-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-amine

Stage 1: 2,6-dichloro-3-nitro-pyridin-4-ylamine

To 25 ml conc. H ₂ SO ₄ in a round bottom flask at -5°C was added 2,6-dichloro-pyridin-4-ylamine (3.0 g, 18.5 mmol). The mixture was stirred at -5°C until a homogeneous solution was obtained. 1.4 ml (22.5 mmol, 1.2 eq.) of a solution of nitric acid in 5 ml of H ₂ SO ₄ was added slowly, keeping the internal temperature T below 10°C. the mixture was stirred at 0-10°C for 30 min. the mixture was then heated to 80°C for 30 min. The mixture was cooled to room temperature and the mixture was poured onto ice. The resulting yellow suspension was neutralized by slow addition of aqueous NH ₃ until pH ~4. The product was filtered and washed with ice water to give the desired product. LCMS:m/z=209 [M+H] ⁺ .

Step 2: Dibenzyl-(2,6-dichloro-3-nitro-pyridin-4-yl)-amine

To a solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (5.0 g, 24.1 mmol) in dry DMF (200 ml) was added benzyl bromide (8.6 ml, 72.5 mmol, 3, 0 eq.) and K ₂ CO ₃ (16.6g, 120.5 mmol, 5.0 eq.) and the mixture was stirred at 80°C. After 1 h, complete conversion was observed by LCMS. The mixture was diluted with EtOAc and quenched with water. The compound was extracted with EtOAc. The combined organic layers were washed with sat. NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (petroleum ether/EtOAc: 100/0-80/20) to give the desired product. LCMS: m/z=388 [M+H] ⁺ .

Stage 3: N4,N4-Dibenzyl-6-chloro-N2-methyl-3-nitro-pyridine-2,4-diamine

To a mixture of dibenzyl-(2,6-dichloro-3-nitro-pyridin-4-yl)-amine (6.9 g, 17.8 mmol) and Cs ₂ CO ₃ (5.8 g, 17.8 mmol, 1.0 eq.) in THF (100 ml) was added MeNH ₂ (2N in THF, 8.9 ml, 17.8 mmol, 1 eq.) at 0°C and the mixture was stirred at room temperature for 24 hours. conversion was monitored by LCMS. Volatiles were removed in vacuo. The residue was dissolved in DCM and washed twice with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the desired product, which was used as such in the next step. LCMS: m/z=383 [M+H] ⁺

Stage 4: N4,N4-Dibenzyl-6-chloro-N2-methyl-pyridine-2,3,4-triamine

To a solution of N4,N4-dibenzyl-6-chloro-N2-methyl-3-nitro-pyridine-2,4-diamine (crude mixture, 15.5 mmol) in MeOH/THF (1:1) (100 ml) was added zinc (5.0 g, 77.5 mmol 5 eq.) and NH ₄ Cl (170 mg, 3.0 mmol, 0.2 eq.). The resulting mixture was stirred at room temperature. After one night, the reaction mixture was heated to 50° C. until LCMS indicated completion of the reaction. The reaction mixture was then cooled to room temperature, then filtered through celite. The filtrate was evaporated. The residue was dissolved in DCM and washed with sat. _NaHC03 . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the desired product, which was used as such in the next step. LCMS: m/z=353[M+H] ⁺ .

Step 5: Dibenzyl-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-amine (intermediate 14)

Triethyl orthoformate (5.1 ml, 31 mmol , 2 eq.) and the mixture was stirred at 80°C. After 18 hours LCMS showed complete conversion to the desired product. Acetonitrile was removed in vacuo. The residue was dissolved in DCM and washed with sat. NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel chromatography (petroleum ether/EtOAc: 100/0-70/30) to give the desired product. LCMS: m/z=363 [M+H] ⁺ .

Intermediate 15: 4-Amino-3-ethyl-5-fluorobenzonitrile

Starting from commercially available 4-amino3-fluorobenzonitrile [63069-50-1], 4-amino-3-ethyl-5-fluorobenzonitrile was prepared in 2 steps according to WO2017012647 (intermediate 13, page 61). LCMS: m/z=165 [M+H] ⁺ .

Intermediate 16: 4-(7-Dibenzylamino-3-methyl-3H-imidazo[4,5-b]pyridin-5-ylamino)-3-ethyl-5-fluoro-benzonitrile

Step 3: 4-(7-Dibenzylamino-3-methyl-3H-imidazo[4,5-b]pyridin-5-ylamino)-3-ethyl-5-fluoro-benzonitrile

Dibenzyl-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-amine (Intermediate 14, 200 mg, 0.552 mmol, 1.0 eq.), 4-amino -3-ethyl-5-fluorobenzonitrile (Intermediate 15, 181 mg, 1.104 mmol, 2.0 eq.), XantPhos Pd G3 (52 mg, 0.055 mmol, 0.1 eq.), XantPhos (30 mg, 0.055 mmol , 0.1 eq.), Cs ₂ CO ₃ (360 mg, 1.104 mmol, 2.0 eq.), were mixed together under N ₂ atmosphere. Dry 1,4-dioxane (3 ml) was added and the mixture was stirred at 110° C. for 18 hours. The reaction mixture was cooled to room temperature and quenched with H ₂ O. Extraction was carried out with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give the desired product, which was used as such in the next step. LCMS: m/z=491 [M+H] ⁺ .

Intermediate 17: 5-Amino-4-methylpyridine-2-carbonitrile

5-Amino-2-bromo-4-methyl-pyridine (1.0 g, 5 mmol, 1 eq.), Zn(CN) ₂ (640 mg, 5.5 mmol, 1.1 eq.) and Pd( PPh ₃ ) ₄ (580 mg, 0.5 mmol, 0.1 eq.) was mixed in dry DMF (10 ml) under N ₂ and heated in a closed microwave tube at 150° C. for 5 min under microwave irradiation . The reaction mixture was cooled to room temperature and poured into an aqueous sat. _NaHC03 . Extraction was carried out with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The resulting crude residue was triturated with Et ₂ O to give the desired product. LCMS: m/z=134 [M+H] ⁺ .

Intermediate 18: 3-methyl-4-methylamino-benzonitrile

A solution of 5-amino-4-methylpyridine-2-carbonitrile (intermediate 17, 1.0 g, 7.52 mmol, 1.0 eq.) in dry THF (25 ml) under N ₂ was cooled to -78°C . Then, LiHMDS (1M in THF, 7.52 ml, 7.52 mmol, 1.0 eq.) was added slowly. The resulting mixture was stirred at room temperature for 3 hours, after which iodomethane (940 μl, 15.04 mmol, 2.0 eq.) was added dropwise. The mixture was stirred at room temperature for 18 hours. It was then quenched with 1 ml of water and concentrated to dryness. The resulting crude material was purified by column chromatography (acetone/petroleum ether, 1:3) to give the desired product. LCMS: m/z=148 [M+H] ⁺ .

Intermediate 19: 4-Amino-3-cyclopropyl-5-fluoro-benzonitrile

Step 1: 4-Amino-3-fluoro-5-iodo-benzonitrile

To a solution of 4-amino-3-fluoro-benzonitrile (4.00 g, 29.4 mmol, 1.0 eq.) and NIS (6.64 g, 29.4 mmol, 1.0 eq.) in dry THF (90 ml) was added TFA (680 μl, 8.84 mmol, 0.3 eq.). The reaction mixture was stirred at room temperature for 24 hours Then quenched with saturated NaHCO ₃ solution, followed by extraction with DCM. The resulting organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give the desired product. Used as such in the next step. LCMS: m/z=263 [M+H] ⁺ .

Stage 2: 4-Amino-3-cyclopropyl-5-fluoro-benzonitrile

4-Amino-3-fluoro-5-iodo-benzonitrile (2.00 g, 7.64 mmol, 1.0 eq) and SPhos Pd G2 (165 mg, 0.24 mmol, 0.03 eq) were dissolved in dry THF (30 ml) under N ₂ at room temperature and cyclopropyl zinc bromide (0.5M in THF, 24.45 ml, 12.23 mmol, 1.6 eq.) was added slowly. The mixture was stirred at room temperature for 2 h, then quenched with MeOH, concentrated to dryness, dissolved in DCM, loaded onto silica gel and purified by column chromatography (EtOAc/petroleum ether, gradient elution from 15% EtOAc to 30% EtOAC) to give the desired LCMS product: m/z=177 [M+H] ⁺ .

Intermediate 20: 5-Amino-4-ethyl-pyridine-2-carbonitrile

5-Amino-4-methylpyridine-2-carbonitrile was prepared from 6-bromo-4-ethyl-pyridin-3-ylamine (CAS [929617-29-8]) as described in WO2017012647 (page 55). LCMS: m/z=148 [M+H] ⁺ .

Intermediate 21: 5-hydroxy-4-methylpyridine-2-carbonitrile

5-Bromo-2-cyano-4-methylpyridine mixture (CAS [886364-86-9], 26.8 g mg, 136 mmol, 1 eq.), 4,4,4',4',5,5, 5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (CAS [73183-34-3], 48.4 g, 190 mmol, 1.4 eq.), Pd( dppf)CL ₂ .CH ₂ CL ₂ (5.55 g, 6.80 mmol, 0.05 eq.), potassium acetate (40 g, 408 mmol, 3 eq.) was stirred under N ₂ in 1.4- dioxane (500 ml) for 2 hours at 110°C. Then the reaction mixture was cooled to 0°C before adding dropwise hydrogen peroxide (30% aqueous solution, 83 ml, 816 mmol, 6.0 eq.). After 2 hours, the reaction mixture was diluted with DCM and washed with water. The aqueous phase was acidified to pH 4-5 and extracted three times with DCM. The combined organic extracts were dried and evaporated in vacuo. The resulting crude material was purified by column chromatography (PE/EtOAc gradient elution 30% to 50% EtOAc). The resulting material was triturated with pentane and diethyl ether to give the desired product.

Intermediate 22: 5-Amino-pyridine-2-carboxylic acid (2-hydroxy-propyl)-amide

Stage 1: 5-nitro-pyridine-2-carboxylic acid (2-hydroxy-propyl)-amide

A solution of 5-nitro-pyridine-2-carboxylic acid methyl ester (CAS [29682-14-2], 1.0 g, 5.49 mmol, 1.0 eq) and 1-amino-propan-2-ol ( CAS [78-96-6], 472 μl, 6.04 mmol, 1.1 eq.) in dry EtOH (15 ml) under N ₂ was stirred at 110°C in a in a sealed tube. After one night the mixture was cooled to room temperature and concentrated to dryness and the crude residue was purified by column chromatography (EtOAc/petroleum ether, 50% to 80% EtOAc gradient) to give the desired product. LCMS: m/z=226 [M+H] ⁺ .

Stage 2: 5-Amino-pyridine-2-carboxylic acid (2-hydroxy-propyl)-amide

A suspension of 5-nitro-pyridine-2-carboxylic acid (2-hydroxy-propyl)-amide and Pd/C in MeOH under N ₂ was placed under an H ₂ atmosphere. Then stirred at room temperature. After 3 hours the reaction was stopped and filtered through thick Pall-Seitz filter paper. The resulting filter cake was washed with MeOH and the filtrate was concentrated to dryness to give 1.08 g of a colorless oil. Suspended in H ₂ O and lyophilized to obtain the desired product. LCMS: m/z=196 [M+H] ⁺ .

Intermediate 23: 2-fluoro-6-methyl-4-methylsulfonyl-phenol

Stage 1: 2-bromo-6-fluoro-4-methylsulfonyl-phenol

A mixture of 2-fluoro-4-methylsulfonylphenol (CAS [398456-87-6], 3 g, 15.7 mmol, 1 eq) and KOAc (1.55 g, 15.7 mmol, 1 eq) in AcOH (40 ml) was stirred at room temperature. The mixture was cooled to 0° C. and BR ² (0.812 ml, 15.7 mmol, 1 eq.) was added dropwise. The mixture was stirred for 30 min at 0° C., then concentrated and the precipitate was filtered off to give the desired product. LCMS: m/z=269.18 [M+H].

Stage 2: 1-fluoro-2-(methoxymethoxy)-3-bromo-5-methylsulfonylbenzene.

Chloromethyl methyl ether (107-30-2, 0.87 ml, 11.45 mmol, 1.1 eq.) was added dropwise to a solution of 2-bromo-6-fluoro-4-methylsulfonyl-phenol (2.8 g, 10 .41 mmol, 1 eq.) and DIPEA in DCM (20 ml) at 0°C. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was washed with water and the separated organic layer was dried and evaporated to give the crude product. The crude product was purified by column chromatography using a gradient elution ranging from 0% to 100% EtOac in cyclohexane. Evaporation of the solvent gave the desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.02-7.98 (m, 1H), 7.91 (dd, J ₁ =10.7 Hz, J ₂ =2.1 Hz, 1H ), 5.31 (s, 2H), 3.52 (s, 3H), 3.30 (s, 3H).

Stage 3: 1-fluoro-2-(methoxymethoxy)-3-methyl-5-methylsulfonyl-benzene

The reaction was carried out on a scale of 2 x 1.4 g in microwave vessels, in parallel. 1-fluoro-2-(methoxymethoxy)-3-bromo-5-methylsulfonylbenzene (2.8 g, 8.9 mmol, 1 eq.) and Cs ₂ CO ₃ (8.74 g, 26.8 mmol, 3 eq.) was suspended in dioxane (34 ml) and the reaction mixture was purged with argon for 10 minutes in a microwave vessel. Catalyst Pd(dppf)CL ₂ .DCM (1.638 g, 1.8 mmol, 0.2 eq.) and methylboronic acid (CAS [13061-96-6], 803 mg, 13.4 mmol, 1.5 eq. ) was added to the reaction mixture and the reaction mixture was sealed. The reaction mixture was stirred at 100°C for 2 hours. After 2 hours, the reaction mixture was diluted with EtOAc (50 ml) and filtered. The filtrate was evaporated to give 5.8 g of crude product. The crude product was purified by column chromatography using a gradient of MeOH in DCM (0% to 5% MeOOH) to give the desired product. LC-MS: m/z=249 [M+H].

Stage 4: 2-fluoro-6-methyl-4-methylsulfonyl-phenol

1-fluoro-2-(methoxymethoxy)-3-methyl-5-methylsulfonyl-benzene (1.9 g, 7.65 mmol, 1 eq) was dissolved in DCM (12 ml) and TFA (12 ml) and water were added (2 ml). The reaction mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was evaporated to dryness to give the crude product. The crude product was dissolved in EtOAc and precipitated with cyclohexane. The precipitate was filtered and dried to give the desired product. LCMS: m/z=205.33 [M+H]. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 7.55-7.50 (m, 2H), 5.74 (d, J =5.4 Hz, 1H), 3.01 (s, 3H), 2.33 (s, 3H).

Intermediate 28: (7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-(1-cyclopropyl-2,2,2-trifluoroethyl)-amine

Intermediate 1 (450 mg, 1.53 mmol, 1.0 eq.), CuI (29 mg, 0.15 mmol, 0.1 eq.), 3,4,7,8-tetramethyl-1,10- phenanthroline (72 mg, 0.3 mmol, 0.2 eq.), cesium carbonate (72 mg, 0.3 mmol, 0.2 eq.) were mixed together in dimethylformamide (2 ml), then 1-cyclopropyl-2 was added ,2,2-trifluoroethan-1-ol (CAS [1993-77-7], 858 mg, 6.13 mmol, 4.0 eq.) and the mixture was heated at 80°C. The reaction mixture was diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The resulting crude material was purified by column chromatography (PE/EtOAc gradient elution from 20% to 80% EtOAc) to give the desired product. LCMS: m/z=306 [M+H] ⁺ .

Intermediate 32: Amino-pyridine-2-carboxylic acid ethylamide

Suspension of 5-nitro-pyridine-2-carboxylic acid ethylamide (CAS [1437794-42-7], 3.0 g, 15.38 mmol, 1.0 eq) and Pd/C (10% loading, 163 mg, 1.54 mmol, 0.1 eq.) was stirred in MeOH (15 ml) under N ₂ atmosphere. The mixture was placed under an H ₂ atmosphere. Then stirred at room temperature. After 3 h, the mixture was filtered. The resulting precipitate was washed with MeOH and the filtrate was concentrated to dryness to give the desired product. LCMS: m/z=166 [M+H] ⁺ .

Intermediate 48: 7-Chloro-5-(1-cyclopropylethoxy)-3-methyl-3H-imidazo[4,5-b]pyridine

Ice-cold solution of intermediate 57 (225 mg, 1.23 mmol, 1.0 eq.), tri-n-butylphosphine (460 µl, 1.84 mmol, 1.5 eq.) and 1-cyclopropylethanol (CAS [765 -42-4], 225 mg, 1.23 mmol, 1.0 eq.) in THF (10 ml) was within 10 minutes. Then, azodicarboxylic dimorpholide (CAS [10465-82-4], 472 mg, 1.84 mmol, 1.5 eq.) was added at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was diluted with EtOAC and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The resulting crude material was purified by column chromatography (PE/EtOAc gradient elution from 20% to 80% EtOAc) to give the desired product. LCMS: m/z=252 [M+H] ⁺ .

Intermediate 50: N-ethyl-4-methyl-pyridine-3-carboxamide

2-Amino-4-methyl-5-pyridinecarboxylic acid (CAS 179555-11-4, 250 mg, 1.64 mmol, 1.0 eq.) was mixed with HATU (686 mg, 1.80 mmol, 1.1 eq. .), DIPEA (857 μl, 4.92 mmol, 3.0 eq.) and DMF (1.0 M). The mixture was stirred for 5 minutes at room temperature, EtNH ₃ Cl (201 mg, 2.5 mmol, 1.5 eq.) was added and stirring continued overnight. Then, the reaction mixture was diluted with water (10 ml) and was extracted with EtOAc (3×10 ml). The combined organic extracts were washed with brine (10 ml), saturated aqueous NaHCO ₃ (10 ml) and again with brine (10 ml). Then, the organic layer was dried and evaporated in vacuo to give the desired product, which was used as such in the next step. LCMS: m/z=180 [M+H] ⁺ .

Intermediate 52: 6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-2- methyl-pyridine-3-carboxylic acid

Intermediate 51 (550 mg, 1.1 mmol, 1.0 eq.) and LiI (573 mg, 4.3 mmol, 4.0 eq.) were suspended in anhydrous pyridine (5 ml) under N ₂ and heated to 115°C for 48 hours. Then, the reaction mixture was evaporated in vacuo and the residue was suspended in a saturated aqueous solution of Na ₂ CO ₃ and EtOAc. The EtOAc phase was discarded and the pH of the aqueous phase was adjusted to 5-6. The resulting precipitate was filtered and dried overnight under vacuum at 50° C. to give the desired product. LCMS: m/z=416 [M+H] ⁺ .

Intermediate 53: 5-((S)-3-methyl-4-morpholinyl)-2-pyridinamine

The reaction vial was loaded with 2-amino-5-bromopyridine (CAS [1072-97-5], 250 mg, 1.45 mmol, 1.0 eq.), (S)-3-methylmorpholine (CAS [350595-57-2 ], 246 µl, 2.17 mmol, 1.5 eq.) and RuPhos Pd G3 (61 mg, 0.073 mmol, 0.05 eq.). The mixture was purged with N ₂ and LiHMDS (3.5 ml, 3.48 mmol, 2.4 eq., 1.0 M in THF) was added dropwise. After stirring for 20 minutes at 60° C., the mixture was allowed to cool to room temperature and quenched with a few drops of MeOH. Then, the crude material was purified by chromatography (isocratic elution) to obtain the desired product. LCMS: m/z=194 [M+H] ⁺ .

Intermediate 54: 5-((S)-3-methyl-4-morpholinyl)-2-pyridinamine

NiCL ₂ .dme (21 mg, 0.09 mmol, 0.12 eq.) and dtbbpy (24 mg, 0.09 mmol, 0.12 eq.) were mixed in DMA (3 ml) at room temperature under nitrogen and stirred for 5 minutes. Then, 2-(Boc-amino)-5-bromopyridine (CAS [159451-66-8], 204 mg, 0.75 mmol, 1.0 eq.), potassium (tetrahydro -2H- pyran-4-yl) trifluoroborate (CAS [1279123-50-0], 152 mg, 0.79 mmol, 1.05 eq.), 2,6-lutidine (140 µl, 1.2 mmol, 1.6 eq.) and [Ir{ dFCF ₃ ppy} ₂ (bpy)]PF ₆ (24 mg, 0.023 mmol, 0.03 eq.) was added sequentially. The mixture was stirred until all solids dissolved, after which anhydrous 1,4-dioxane (12 ml) was added and stirred overnight at room temperature under blue light (Kessil KSH150B LED Grow Light 150, Blue, 34W). Notes: The vial was placed in a crystallizer containing water. Air flow was applied to keep the reaction below 20°C. The distance between vial and lamp was approx. 5 cm. The distance between the funnel (air flow) and the vial was approx. 5 cm. The mixture was concentrated and partitioned between DCM and water. The aqueous layer was discarded. The organic phase was dried and evaporated in vacuo. The crude material obtained was purified by column chromatography (petroleum ether/EtOAc 8/2-1/1) to give the desired product. LCMS: m/z=279 [M+H] ⁺ .

Intermediate 56: 3-Chloro-6-(1-methylazetidin-3-yl)oxypyridazine

NaH (101 mg, 2.52 mmol , 4.5 eq., 60% in mineral oil). The mixture was stirred at room temperature for 10 minutes and then heated to 50°C for another 10 minutes. The mixture was then cooled to room temperature, after which 3,6-dichloropyridazine (CAS [141-30-0], 161 mg, 1.85 mmol, 1.1 eq) was added and the mixture was stirred for 2 h at room temperature. Then, the mixture was added dropwise to a stirred solution of NaHCO ₃ (10 ml saturated solution+10 ml water) and was extracted with DCM (3×10 ml). The combined organic extracts were dried and evaporated in vacuo to give the desired product. LCMS: m/z=200 [M+H] ⁺ .

Intermediate 57: 7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-ol

Intermediate 1 (6.0 g, 20.48 mmol, 1 eq), tBuBrettPhos Pd G3 (348 mg, 0.410 mmol, 0.02 eq) and CsOH monohydrate (10.08 g, 61.44 mmol, 3 equiv.) was mixed in 1,4-dioxane (40 ml), after which H ₂ O (3.68 ml, 204.80 mmol, 10 equiv.) was added. The mixture was stirred at room temperature. After one night, the reaction mixture was quenched with H ₂ O and impurities were extracted with EtOAc. The aqueous layer was acidified to pH=5 and the compound was extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated to dryness to give the desired product. LCMS: m/z=184 [M+H] ⁺ .

Intermediate 61: 6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]nicotinic acid

Intermediate 60 (1.24 g, 3.0 mmol, 1.0 eq.) and LiI (1.20 g, 9.0 mmol, 3.0 eq.) were suspended in anhydrous pyridine (10 ml, 0.3 M) under N ₂ atmosphere and heated to 115°C for 2 days. Then, the reaction mixture was evaporated in vacuo and the residue was suspended in a saturated aqueous solution of Na ₂ CO ₃ and EtOAc. The EtOAc phase was discarded and the pH of the aqueous phase was adjusted to 5-6. The resulting precipitate was filtered and dried overnight under vacuum at 50° C. to give the desired product. LCMS: m/z=402 [M+H] ⁺ .

Intermediate 63: 6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridazin-3- carboxylic acid

Intermediate 62 (1.24 g, 3.0 mmol, 1.0 eq.) and LiI (1.20 g, 9.0 mmol, 3.0 eq.) were suspended in anhydrous pyridine (10 ml) under N ₂ and heated to 115°C for 48 hours. Then, the reaction mixture was evaporated in vacuo and the residue was suspended in a saturated aqueous solution of Na ₂ CO ₃ and EtOAc. The EtOAc phase was discarded and the pH of the aqueous phase was adjusted to pH 5-6. The resulting precipitate was filtered and dried overnight under vacuum at 50° C. to give the desired product. LCMS: m/z=403 [M+H] ⁺ .

Intermediate 83: 2-(4-Amino-phenyl)-N-ethyl-acetamide

To a solution of 4-aminophenylacetic acid (CAS [1197-55-3], 1.0 g, 6.61 mmol, 1.0 eq.), EDCI (1.52 g, 7.94 mmol, 1.2 eq. ) and HOBt (1.21 g, 7.94 mmol, 1.2 eq.) in dichloromethane (30 ml) was added ethylamine (CAS [75-04-7], 3.63 ml, 7.27 mmol, 1, 0 eq.) and DIPEA (2.30 ml, 13.2 mmol, 2.0 eq.). The mixture was stirred at room temperature for 18 h. Then, the reaction mixture was diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo to give the desired product. LCMS: m/z=179 [M+H] ⁺ .

Intermediate 84: 6-Amino-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone

6-Amino-nicotinic acid (CAS [3167-49-5], 19.6 g, 142 mmol, 1.0 eq.), N-methyl-piperazine (CAS [109-01-3], 19 ml, 170 mmol, 1.2 eq) and DIPEA (54 ml, 313 mmol, 2.2 eq) were stirred in dry EtOH (250 ml) until HATU (81 g, 213 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 18 hours then concentrated. The solid that appeared was filtered off and discarded. The filtrate was purified by column chromatography using DCM/EtOH/25% aqueous NH ₃ (7/1/0.1 ratio) as eluent to give the desired product. LCMS: m/z=221 [M+H] ⁺ .

Intermediate 85: 7-chloro-5-iodo-3-(trideuteriomethyl)imidazo[4,5-b]pyridine

Step 1 and Step 2 were the same as for Intermediate 1.

Step 3: 4-chloro-6-iodo-N2-(trideuteriomethyl)pyridine-2,3-diamine

2,4-dichloro-6-iodo-pyridine-3-amine (10 g, 0.03 mmol, 1 eq.) was dissolved in n-butanol (150 ml) in an autoclave (300 ml). Methyl-d3-amine hydrochloride (CAS [74326-22-8], 5 g, 0.07 mmol, 2.3 eq.) and TEA (9.69 ml, 0.07 mmol, 1 eq.) were added under atmosphere N ₂ at room temperature. The mixture was stirred at 180°C for 48 h and then cooled to room temperature. The reaction mixture was concentrated to give the desired product, which was used as such in the next step. LCMS: m/z=287 [M+H].

Step 4: 7-chloro-5-iodo-3-(trideuteriomethyl)imidazo[4,5-b]pyridine

To a solution of 4-chloro-6-iodine-N2-(trideuteriomethyl)pyridine-2,3-diamine (10 g, 0.03 mmol, 1 eq.) in formic acid (5 ml) was added trimethylorthoformate (10 ml, 0.09 mmol, 3 eq.). The mixture was stirred at 60°C for 1 h. The reaction mixture was concentrated to dryness, the residue was diluted with DCM and quenched with saturated aqueous NaHCO₃. After DCM extraction, the organic layer was dried over Na₂SO_four, filtered and concentrated to dryness to give the crude material. It was purified by column chromatography using cyclohexane/EtOAc eluent, 0 to 70% EtOAc gradient to give the desired product. LCMS: m/z=297 [M+H].

Intermediate 86: 5-[(7-Chloro-3-methyl-imidazo[4,5-b]pyridin-5-yl)-cyclopropyl-amino]-4-methyl-pyridine-2-carbonitrile

Intermediate 4 (150 mg, 0.50 mmol, 1 eq.), cyclopropylboronic acid (CAS [411235-57-9], 86.26 mg ml, 1.0 mmol, 2 eq.) and Cs ₂ CO ₃ ( 106.44 mg, 1.0 mmol, 2 eq) were suspended in DMF (5 ml) in a round bottom flask equipped with a drying tube and 4Å molecular sieves. The resulting suspension was stirred at room temperature. In a separate flask, 2,2'-bipyridine (78.42 mg, 0.05 mmol, 0.1 eq.) and copper(II) acetate (91.20 mg, 1.00 mmol, 2 eq.) were suspended in acetonitrile (2.5 ml) and the mixture was heated at 80°C for 10 minutes. After 10 minutes, the hot solution was added to a suspension of the compound in DMF. The reaction mixture was stirred overnight at room temperature. After stirring overnight at room temperature, the temperature of the reaction mixture was raised to 55°C. The reaction mixture was stirred overnight at 55°C. The reaction mixture was cooled, water was added and the resulting suspension was extracted with DCM. The organic layers were combined, dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product. The crude product was purified by separation chromatography using 0-25% (10% MeOH/DCM) in DCM to give the desired product. LCMS: m/z=340 [M+H].

Intermediate 87: 4-ethyl-5-hydroxy-pyridine-2-carbonitrile

Stage 1: 4-ethyl-5-iodo-pyridine-2-carbonitrile

To an ice-cold suspension of intermediate 20 (1 g, 6.8 mmol, 1 eq.) in water (20 ml) was added hydrochloric acid (3.5 ml, 7.5 mmol, 1.1 eq.) and an aqueous solution ( 3 ml) sodium nitrite (0.518 g, 7.5 mmol, 1.1 eq.). The reaction mixture was allowed to stir at 0° C. for 15 min after which an aqueous solution (5 ml) of potassium iodide (1.24 g, 7.5 mmol, 1.1 eq.) was added. The reaction mixture continued to stir at ambient temperature for 1 hour Then, the reaction mixture was diluted with EtOAc (100 ml). The organic phase was isolated and the remaining aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were concentrated under reduced pressure and the resulting crude material was purified by column chromatography (cyclohexane as solvent A and cyclohexane:ethyl acetate=5:1 as solvent B, gradient 0-100% solvent B). Fractions containing product were combined and evaporated to give the desired product. LCMS: m/z=259 [M+H].

Stage 2: 4-ethyl-5-hydroxy-pyridine-2-carbonitrile

The reaction was carried out in 2 microwave treatment vessels. Bis(pinacolato)diborone (1.9 g, 7.49 mmol, 1.4 eq.) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (0.441 g, 0.54 mmol, 0.1 eq.) and potassium acetate (1.58 g, 16.1 mmol, 3 eq.). The reaction mixture was purged with argon and then heated in a microwave reactor for 30 min at 150°C. The reaction mixtures were cooled to 0°C, after which a solution of hydrogen peroxide (30% wt./mass. 3.28 ml, 32.1 mmol, 6 eq.) was slowly added. The reaction mixture was stirred at ambient temperature for 18 hours. The combined mixtures were filtered and the residue was washed with ethyl acetate (100 ml). The mother liquor was washed with water (50 ml) and evaporated under reduced pressure to give a crude substance. Purification was carried out by column chromatography using cyclohexane as solvent A and cyclohexane:ethyl acetate=1:1 as solvent B (gradient from 0 to 100% solvent B) to obtain the desired product. LCMS: m/z=149.05 [M+H].

Intermediate 89: 5-[7-Chloro-3-(trideuteriomethyl)imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile

Intermediate 85 (2.1 g, 7.1 mmol, 1.0 eq.), Intermediate 21 (1.43 g, 10.6 mmol, 1.5 eq.), CuI (270 mg, 1.42 mmol, 0.2 eq.), TMHD (3.0 ml, 14.2 mmol, 2 eq.) and Cs ₂ CO ₃ (4.61 g, 14.2 mmol, 2 eq.) were mixed together under air, was added DMF (12 ml) and the mixture was stirred at 85°C for 72 hours Then, the mixture was cooled to 0°C. The resulting thick paste was then filtered and the filter cake washed with ice-cold DMF. Then washed with ice-cold MTBE. After drying the filter cake, it was suspended in 25 ml of 10% TMEDA aqueous solution. Stirred for 2 hours, filtered and washed the filter cake with water to give the desired product. LCMS: m/z=303 [M+H] ⁺ .

Intermediate 92: 4-(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-3,5-difluoro-benzonitrile

A mixture of intermediate 57 (300 mg, 1.63 mmol, 1 eq.), 3,4,5-trifluorobenzonitrile ([134227-45-5], 300 mg, 1.63 mmol, 1 eq.), K ₂ CO ₃ (452 mg, 3.26 mmol, 2 eq.) in NMP (3 ml) was heated for 18 h at 100°C. Then, the reaction mixture was diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The crude material obtained was purified by column chromatography (PE/EtOAc 50/50 to 0/100) to give the desired product. LCMS: m/z=321 [M+H] ⁺ .

Intermediate 93: (6-bromo-3-pyridyl)-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteriomethyl)piperazin-1-yl]methanone

Stage 1: tert-butyl-4-(6-bromopyridine-3-carbonyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazine-1-carboxylate

6-bromonicotinic acid mixture ([6311-35-9], 745 mg, 3.69 mmol, 1.1 eq.), piperazine-d8-NT-Boc ([1126621-86-0], 650 mg, 3, 35 mmol, 1 eq.), HATU (1.4 g, 3.69 mmol, 1.1 mmol) and Et ₃ N (0.93 ml, 6.7 mmol, 2 eq.) in DCM (15 ml) stirred overnight at room temperature. Then, the mixture was diluted with DCM and extracted twice with saturated aqueous NH ₄ Cl. The resulting organic layer was evaporated to give an oil. The resulting oil was purified using column chromatography (DCM/MeOH 100/0 till 98/2) to obtain the desired product.

Step 2: (6-bromo-3-pyridyl)-(2,2,3,3,5,5,6,6-octadeuteriopiperazin-1-yl) methanone

tert-Butyl-4-(6-bromopyridine-3-carbonyl)-2,2,3,3,5,5,6,6-octadeuterio-piperazine-1-carboxylate (1.1 g, 2.9 mmol, 1 eq.) was mixed with 4 M HCl in a solution of dioxane (7 ml, 29 mmol, 10 eq.) in dioxane (20 ml). A small amount of water was added to improve overall solubility. After completion of the reaction, the mixture was concentrated to dryness to give the HCl salt of the desired product.

Step 3: (6-bromo-3-pyridyl)-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteriomethyl)piperazin-1-yl]methanone

The HCl salt of (6-bromo-3-pyridyl)-(2,2,3,3,5,5,6,6-octadeuteriopiperazin-1-yl)methanone (300 mg, 0.96 mmol, 1 eq.) was mixed with NaH (115 mg, 2.88 mmol, 3 equiv.) in THF (6 ml). The resulting mixture was stirred at room temperature for 30 minutes. Then, iodomethane-d ₃ (60 μl, 0.96 mmol, 1 eq.) was added dropwise to the mixture. The mixture was stirred at 40°C. After cooling to 0°C, the mixture was diluted with water and extracted with DCM. The organic layer was concentrated to give the crude desired product, which was used as such.

Table II. Intermediates to exemplary compounds of the invention

Prov.s. Structure Name SM Way MM Meas.MM one

7-chloro-5-iodine-3-methyl-3H-imidazo[4,5-b]pyridine CAS[2587-02-2] as an example 293 294 2

5-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile Prov.s. one as an example 300 300 3

5-(7-Amino-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridine-2-carbonitrile Ex.c.2 as an example 280 281 four

5-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-ylamino)-4-methyl-pyridine-2-carbonitrile Prov.s. 1, Ex.s. 17 as an example 299 299 5

5-[(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-methyl-amino]-4-methyl-pyridine-2-carbonitrile Prov.s. 1, Ex.s. eighteen as an example 313 313 6

(±)-4-[(7-chloro-3-methyl-imidazo[4,5-b]pyridin-5-yl)amino]cyclohexanecarbonitrile Prov.s. 1, [873537-33-8] B3 290 290 7

7-chloro-N-(3,3-dimethyltetrahydropyran-4-yl)-3-methyl-imidazo[4,5-b]pyridine-5-amine Prov.s. 1, [1400580-54-2] B3 295 295 eight

(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-methyl-((S)-1,2,2-trimethyl-propyl)-amine Prov.s. 67 as an example 280 281 9

(±)-(1R,3R)-3-[(7-chloro-3-methyl-imidazo[4,5-b]pyridin-5-yl)amino]cyclohexanecarbonitrile Prov.s. 1, [920966-30-9] B3 290 290 ten

4-[(7-Chloro-3-methyl-imidazo[4,5-b]pyridin-5-yl)amino]-3-cyclopropyl-5-fluoro-benzonitrile Prov.s. 1, Ex.s. 19 B3 342 342 eleven

5-[(7-Chloro-3-methyl-imidazo[4,5-b]pyridin-5-yl)amino]-4-ethyl-pyridine-2-carbonitrile Prov.s. 1, Ex.s. twenty B3 313 313 12

(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-((R)-1-cyclopropyl-ethyl)-methyl-amine Prov.s. 65, [6240-96-6] as an example 264 265 13

(±)-7-chloro-3-methyl-N-[(3R,4S)-3-methyltetrahydropyran-4-yl]imidazo[4,5-b]pyridine-5-amine Prov.s. 1, [1682655-57-7] B3 281 281 fourteen

Dibenzyl-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-amine [2587-02-2] as an example 362 363 fifteen

4-Amino-3-ethyl-5-fluorobenzonitrile [63069-50-1] As an example 164 165 16

4-(7-Dibenzylamino-3-methyl-3H-imidazo[4,5-b]pyridin-5-ylamino)-3-ethyl-5-fluoro-benzonitrile Prov.s. 15, R.s. 16 As an example 490 491 17

5-Amino-4-methylpyridine-2-carbonitrile [156118-16-0] As an example 133 134 eighteen

3-methyl-4-methylamino-benzonitrile Prov.s. 17 As an example 147 148 19

4-Amino-3-cyclopropyl-5-fluoro-benzonitrile [63069-50-1] As an example 176 177 twenty

5-Amino-4-ethyl-pyridine-2-carbonitrile [929617-29-8] As an example 147 148 21

5-hydroxy-4-methylpyridine-2-carbonitrile [886364-86-9] As an example 134 135 22

5-Amino-pyridine-2-carboxylic acid (2-hydroxy-propyl)-amide [29682-14-2], [78-96-6] As an example 195 226 23

2-fluoro-6-methyl-4-methylsulfonylphenol [398456-87-6] As an example 204 205 24

N-(3-bicyclo[1.1.1]pentanyl)-7-chloro-3-methylimidazo[4,5-b]pyridine-5-amine Exc.1, [2287-35-0] B3 249 249 25

7-chloro-3-methyl-N-(3-methyltetrahydropyran-4-yl)imidazo[4,5-b]pyridine-5-amine Exc.1, [1787906-12-0] B3 281 281 26

7-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-3-methyl-imidazo[4,5-b]pyridine-5-amine Exc.1, [75702-99-7] B3 305 305 27

7-chloro-3-methyl-N-(5-oxaspiro[3.5]nonan-8-yl)imidazo[4,5-b]pyridine-5-amine Prov.s. 1, [1309434-30-7] B3 307 307 28

7-chloro-5-(1-cyclopropyl-2,2,2-trifluoroethoxy)-3-methyl-3H-imidazo[4,5-b]pyridine Prov.s. 1, [1993-77-7] As an example 305 306 29

6-Amino-pyridazine-3-carboxylic acid ethylamide [301548-08-3] and [75-04-7] A2 166 167 thirty

6-Amino-N-(2-hydroxy-propyl)-nicotinamide [231958-14-8] and [78-96-6] A2 195 196 31

6-Amino-pyridazine-3-carboxylic acid (2-hydroxy-propyl)-amide [301548-08-3] and [78-96-6] A2 167 168 32

5-Amino-pyridine-2-carboxylic acid ethylamide [1437794-42-7] As an example 165 166 33

N-(2-Methoxy-ethyl)-pyrimidine-4,6-diamine [5305-59-9] and [109-85-3] P1 168 169 34

N-(3-Methoxy-propyl)-pyrimidine-4,6-diamine [5305-59-9] and [5332-73-0] P1 182 183 35

4-(6-aminopyrimidin-4-ylamino)-2-methyl-butan-2-ol [5305-59-9] and [26734-08-7] P1 196 197 36

3-(6-aminopyrimidin-4-ylamino)-propan-1-ol [5305-59-9] and [156-87-6] P1 168 169 37

N-[1,4]Dioxan-2-ylmethyl-pyrimidin-4,6-diamine [5305-59-9] and [88277-83-2] P1 210 211 38

N-(3-Methoxy-cyclobutyl)-pyrimidine-4,6-diamine [5305-59-9] and [1234615-98-5] P1 194 195 39

4-(6-aminopyrimidin-4-ylamino)-butan-2-ol [5305-59-9] and [39884-48-5] P1 182 183 40

6-(3-Dimethylaminomethyl-azetidin-1-yl)-pyridazin-3-ylamine [187973-60-0] and [321890-22-6] P2 207 208 41

(±)-6-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-pyridazin-3-ylamine [187973-60-0] and [147539-61-5] P2 221 222 42

6-[4-(2,2,2-Trifluoroethyl)-piperazin-1-yl]-pyridazin-3-ylamine [187973-60-0] and [13349-90-1] P2 261 262 43

(±)-6-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-pyridazin-3-ylamine [187973-60-0] and [6485-55-8] P2 208 209 44

6-((S)-2-methyl-morpholin-4-yl)-pyridazin-3-ylamine [187973-60-0] and [74572-13-7] P2 194 195 45

1-(6-Amino-pyridazin-3-yl)-piperidine-4-carbonitrile [187973-60-0] and [4395-98-6] P2 203 204 46

(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-(2-methyl-1-trifluoromethyl-propyl)-amine Prov.s. 1, [1582-18-9] B3 307 307 47

5-[7-[4-(N-Boc-aminomethyl)anilino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile Prov.s. 1, [94838-55-8] B1 485 486 48

7-chloro-5-(1-cyclopropyl-ethoxy)-3-methyl-3H-imidazo[4,5-b]pyridine Prov.s. 57 As an example 251 252 49

4-methyl-5-[3-methyl-7-[[5-(2,2,2-trifluoro-1-hydroxy-ethyl)-2-pyridyl]amino]imidazo[4,5-b]pyridine-5 -yl]oxy-pyridine-2-carbonitrile Prov.s. 3, [1188477-81-7] B3 455 456 fifty

N -ethyl-4-methyl-pyridine-3-carboxamide [179555-11-4] As an example 179 180 51

Methyl 6-[[5-[(6-cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-2-methyl-pyridine -3-carboxylate Pr.s.2, [872355-52-7] B1 429 430 52

6-[[5-[(6-cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-2-methyl-pyridine- 3-carboxylic acid Prov.s. 51 As an example 415 416 53

5-(( S )-3-methyl-4-morpholinyl)-2-pyridinamine [1072-97-5], [350595-57-2] As an example 193 194 54

N -Boc-5-(tetrahydro -2H -pyran-4-yl)pyridine-2-amine [159451-66-8], [1279123-50-0] As an example 278 279 55

5-(tetrahydro- 2H- pyran-4-yl)pyridine-2-amine Prov.s. 54 D1 178 179 56

3-chloro-6-(1-methylazetidin-3-yl)oxypyridazine [111043-48-2], [141-30-0] As an example 200 200 57

7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-ol Prov.s. one As an example 184 184 58

(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-(1-cyclobutyl-ethyl)-amine Prov.s. 1, [60637-96-9] B3 264 265 59

(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-cyclopropylmethyl-amine Prov.s. 1, [13375-29-6] B3 276 277 60

6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-nicotinic acid methyl ester Prov.s. 2, [36052-24-1] B1 415 416 61

6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-nicotinic acid Prov.s. 60 As an example 401 402 62

6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridazine-3-carboxylic acid methyl ester Prov.s. 2, [98140-96-6] B1 416 417 63

6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridazine-3-carboxylic acid Prov.s. 62 As an example 402 403 64

(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-((R)-2-methyl-1-trifluoromethyl-propyl)-amine Prov.s. 1, [1032181-63-7] B3 306 307 65

(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-((R)-1-cyclopropyl-ethyl)-amine Prov.s. 1, [6240-96-6] B3 251 251 66

(6-aminopyridazin-3-yl)-(4-methylpiperazin-1-yl) methanone [301548-08-3] and [109-01-3] A3 221 222 67

(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-((S)-1,2,2-trimethyl-propyl)-amine Prov.s. 1, [22526-47-2] B1 267 267 68

[(R)-4-(6-chloro-pyridazin-3-yl)-morpholin-2-yl]-methanol [141-30-0], [1436436-17-7] P3 229 230 69

4-(6-chloropyridazin-3-yl)-2,2,3,3,5,5,6,6-octadeuterio-morpholine [141-30-0], [342611-02-3] P3 207 208 70

[(S)-4-(6-chloro-pyridazin-3-yl)-morpholin-2-yl]-methanol [141-30-0], [1313584-92-7] P3 229 230 71

(2S,6S)-4-(6-chloro-pyridazin-3-yl)-2,6-dimethyl-morpholine [141-30-0], [276252-76-4] P3 227 228 72

4-(6-chloro-pyridazin-3-yl)-[1,4]oxazepane [141-30-0], [5638-60-8] P3 213 214 73

(2R,6R)-4-(6-chloro-pyridazin-3-yl)-2,6-dimethyl-morpholine [141-30-0], [171753-74-5] P3 227 228 74

[4-(6-chloro-pyridazin-3-yl)-morpholin-2-yl]-methanol [141-30-0], [103003-01-6] P3 229 230 75

3-(6-chloro-pyridazin-3-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane [141-30-0], [54745-74-3] P3 225 226 76

4-(6-chloro-pyridazin-3-yl)-morpholine-2-carbonitrile [141-30-0], [1205751-07-0] P3 224 225 77

(R)-4-(6-chloro-pyridazin-3-yl)-2-methyl-morpholine [141-30-0], [168038-14-0] P3 213 214 78

(R)-4-(6-chloro-pyridazin-3-yl)-2-isopropyl-morpholine [141-30-0], [792886-64-7] P3 241 242 79

(1S,4S)-5-(6-chloro-pyridazin-3-yl)-2-oxa-5-aza-bicyclo[2.2.1]heptane [141-30-0], [547716-11-0 ] P3 211 212 80

4-(6-chloro-pyridazin-3-yl)-2,2-dimethyl-morpholine [141-30-0], [147688-58-2] P3 227 228 81

( rel )-(2S,6S)-4-(6-chloro-pyridazin-3-yl)-2,6-dimethyl-morpholine [141-30-0], [6485-45-6] P3 227 228 82

(S)-4-(6-chloro-pyridazin-3-yl)-2-isopropyl-morpholine [141-30-0], [1286768-31-7] P3 241 242 83

2-(4-Amino-phenyl)-N-ethyl-acetamide [1197-55-3], [75-04-7] As an example 178 179 84

6-Amino-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone [3167-49-5], [109-01-3] As an example 220 221 85

7-chloro-5-iodine-3-(trideuteriomethyl)imidazo[4,5-b]pyridine [2587-02-2] As an example 297 297 86

5-[(7-chloro-3-methyl-imidazo[4,5-b]pyridin-5-yl)-cyclopropyl-amino]-4-methyl-pyridine-2-carbonitrile Prov.s. 4, [411235-57-9] As an example 339 340 87

4-ethyl-5-hydroxy-pyridine-2-carbonitrile Prov.s. twenty As an example 148 149 88

tert-butyl 4-[6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]- 3-pyridyl]piperazine-1-carboxylate Prov.s. 2, [571188-59-5] B1 542 543 89

5-[7-chloro-3-(trideuteriomethyl)imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile Prov.s. 85, R.s. 21 As an example 303 303 90

1-(6-chloropyridazin-3-yl)-N, N-dimethyl-azetidine-3-amine [141-30-0], [935670-07-8] P3 213 213 91

(1R,4R)-2-(6-chloro-pyridazin-3-yl)-5-methyl-2,5-diaza-bicyclo[2.2.1]heptane [141-30-0], [125224-64-8] P3 224 225 92

4-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-3,5-difluorobenzonitrile Prov.s. 57, [134227-45-5] As an example 321 321 93

(6-bromo-3-pyridyl)-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteriomethyl)piperazin-1-yl]methanone [1126621-86-0], [6311-35-9] and [865-50-9] as an example 295 295-297

Illustrative examples

Compound 1: N-[3-methyl-5-(4-methyl-6-trifluoromethyl-pyridin-3-yloxy)-3H-imidazo[4,5-b]pyridin-7-yl]-pyrimidin-4,6 -diamine

Stage 1: 7-chloro-3-methyl-5-(4-methyl-6-trifluoromethyl-pyridin-3-yloxy)-3H-imidazo[4,5-b]pyridine

Intermediate 1 (110 mg, 0.377 mmol, 1.0 eq.), 4-methyl-6-trifluoromethyl-pyridin-3-ol (CAS [1253790-72-5], 100 mg, 0.565 mmol, 1.5 eq. .), CuI (7 mg, 0.038 mmol, 0.1 eq.), TMHD [1118-71-4] (78 μl, 0.377, 1.0 eq.) and Cs ₂ CO ₃ (246 mg, 0.754 mmol, 2.0 eq.) was mixed together under air, dry DMF (1 ml) was added and the mixture was stirred at 85° C. overnight. After cooling to room temperature, the mixture was filtered through thick pall-seitz filter paper. The resulting precipitate was washed with EtOAc. The resulting filtrate was washed with H ₂ O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The crude material was purified using column chromatography (EtOAc/DCM, gradient 20% - 60% EtOAc) to obtain the desired product. LCMS: m/z=343 [M+H] ⁺ .

Stage 2: N-[3-methyl-5-(4-methyl-6-trifluoromethyl-pyridin-3-yloxy)-3H-imidazo[4,5-b]pyridin-7-yl]-pyrimidin-4,6 -diamine

7-chloro-3-methyl-5-(4-methyl-6-trifluoromethyl-pyridin-3-yloxy)-3H-imidazo[4,5-b]pyridine

(40 mg, 0.117 mmol, 1.0 eq.), pyrimidine-4,6-diamine (CAS [79364-63-9], 26 mg, 0.234 mmol, 2.0 eq.), MorDALPhos Pd G3 (2 mg , 0.002 mmol, 0.02 eq.), MorDALPhos (1 mg, 0.002 mmol, 0.02 eq.), Cs ₂ CO ₃ (46 mg, 0.140 mmol, 1.2 eq.) were mixed together under N ₂ atmosphere, after which 1,4-dioxane (1 ml) was added. The resulting mixture was stirred at 110°C. After one night the mixture was cooled to room temperature. The mixture was diluted with 2 ml DMSO and purified by prep-HPLC to give the desired product.

LCMS: m/z=417 [M+H] ⁺ .

Compound 2: N-[5-(2-fluoro-4-methanesulfonyl-6-methylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl]-pyrimidin-4,6 -diamine

Stage 1: 7-chloro-5-(2-fluoro-4-methanesulfonyl-6-methylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine

Intermediate 1 (957 mg, 3.27 mmol, 1.0 eq.), Intermediate 23 (1.0 g, 4.90 mmol, 1.5 eq.), CuI (62 mg, 0.327 mmol, 0, 1 eq.), TMHD (CAS [1118-71-4], 681 µl, 3.27, 1.0 eq.) and Cs ₂ CO ₃ (2.13 g, 6.54 mmol, 2.0 eq. ) was mixed together under air, dry DMF (10 ml) was added and the mixture was stirred at 85°C. After one week, the mixture was cooled to room temperature and filtered through thick pall-seitz filter paper. The resulting precipitate was washed with EtOAc. The resulting filtrate was washed with H ₂ O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The crude material was purified using column chromatography (EtOAc//DCM, 10% till 100% EtOAc) to obtain the desired product.

Stage 2: N-[5-(2-fluoro-4-methanesulfonyl-6-methylphenoxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl]-pyrimidin-4,6 -diamine

7-chloro-5-(2-fluoro-4-methanesulfonyl-6-methyl-phenoxy)-3-methyl-3H-imidazo[4,5-b]pyridine (50 mg, 0.136 mmol, 1.0 eq.) , pyrimidine-4,6-diamine (CAS [79364-63-9], 30 mg, 0.271 mmol, 2.0 eq.), MorDALPhos Pd G3 (2 mg, 0.002 mmol, 0.02 eq.), MorDALPhos ( 1 mg, 0.002 mmol, 0.02 eq.) and Cs ₂ CO ₃ (53 mg, 0.163 mmol, 1.2 eq.) were mixed together under N2 atmosphere, 1,4-dioxane (1 ml) was added. The resulting mixture was stirred at 110°C. After one night the mixture was cooled to room temperature. The mixture was diluted with 2 ml DMSO and purified by prep-HPLC to give the desired product. LCMS: m/z=444 [M+H] ⁺ .

Compound 3: 6-[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy]-5-methyl-pyridazin-3-carbonitrile

Stage 1: 7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-ol

Intermediate 1 (6.0 g, 20.48 mmol, 1.0 eq), tBuBrettPhos Pd G3 (348 mg, 0.410 mmol, 0.02 eq) and CsOH monohydrate (10.08 g, 61.44 mmol , 3.0 eq.) was mixed in 1,4-dioxane (40 ml) and H ₂ O (3.68 ml, 204.80 mmol, 10 eq.) was added. The mixture was stirred mechanically at room temperature. After one night, the reaction mixture was quenched with H ₂ O and impurities were extracted with EtOAc. The aqueous layer was acidified to pH=5 and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated to dryness to give the desired product. LCMS: m/z=184 [M+H] ⁺ .

Stage 2: 6-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-5-methyl-pyridazin-3-carbonitrile

7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-ol (500 mg, 2.73 mmol, 1.0 eq.), 6-chloro-5-methyl-pyridazin-3 -carbonitrile (627 mg, 4.10 mmol, 1.5 eq.) and K ₂ CO ₃ (566 mg, 4.10 mmol, 1.5 eq.) were mixed together under N ₂ atmosphere. Then, dry DMF (8 ml) was added and the mixture was stirred at 100°C. After 3 h, the mixture was cooled to room temperature and quenched with H ₂ O to obtain a suspension. Filtration gave a solid which was washed with H ₂ O then dried in a vacuum oven to give the desired product. LCMS: m/z=301 [M+H] ⁺ .

Step 3: 6-[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy]-5-methyl-pyridazine-3-carbonitrile

6-(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-5-methyl-pyridazine-3-carbonitrile (50 mg, 0.167 mmol, 1.0 eq.) , pyrimidine-4,6-diamine [79364-63-9] (37 mg, 0.333 mmol, 2.0 eq.), Pd ₂ (dba) ₃ (3 mg, 0.003 mmol, 0.02 eq.), MorDALPhos (3 mg, 0.006 mmol, 0.04 eq.) and Cs ₂ CO ₃ (65 mg, 0.200 mmol, 1.2 eq.) were mixed together under N ₂ atmosphere, dioxane (1 ml) was added and the mixture was stirred at 110° C. After one night the mixture was cooled to room temperature. The mixture was diluted with 2 ml DMSO and purified by prep-HPLC to give the desired product. LCMS: m/z=375 [M+H] ⁺ .

Compound 4: 5-[[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-(3-methoxy-propyl)-amino] -4-methyl-pyridine-2-carbonitrile

Stage 1: 5-[(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-(3-methoxy-propyl)-amino]-4-methyl-pyridine-2 -carbonitrile

To a solution of intermediate 4 (150 mg, 0.48 mmol, 1.0 eq.) and Cs ₂ CO ₃ (186 mg, 0.57 mmol, 1.2 eq.) in dry DMF (3 ml) under N ₂ 1-bromo-3-methoxypropane (CAS [36865-41-5], 147 mg, 0.96 mmol, 2.0 eq) was added. The mixture was stirred at 50° C. for 3 h. Then cooled to room temperature and quenched with H ₂ O. The compound was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The crude material was purified by column chromatography (MeOH/DCM, 2% MeOH) to give the desired product. LCMS: m/z=371 [M+H] ⁺ .

Stage 2: 5-[[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-(3-methoxy-propyl)-amino] -4-methyl-pyridine-2-carbonitrile

5-[(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-(3-methoxy-propyl)-amino]-4-methyl-pyridine-2-carbonitrile ( 113 mg, 0.30 mmol, 1.0 eq.), pyrimidine-4,6-diamine (CAS [79364-63-9], 66 mg, 0.60 mmol, 2.0 eq.), Pd ₂ ( dba) ₃ (5 mg, 0.006 mmol, 0.02 eq.), MorDALPhos (5 mg, 0.012 mmol, 0.04 eq.) and Cs ₂ CO ₃ (117 mg, 0.36 mmol, 1.2 eq. ) were mixed together under N ₂ atmosphere after which 1,4-dioxane (2 ml) was added and the mixture was stirred at 110°C. After one night the mixture was cooled to room temperature and DMSO (1 ml) was added. The mixture was filtered and purified by preparative HPLC to give the desired product. LCMS: m/z=445 [M+H] ⁺ .

Compound 5: 5-[[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-(3-hydroxy-propyl)-amino] -4-methyl-pyridine-2-carbonitrile

Stage 1: 5-[[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-amino] -4-methyl-pyridine-2-carbonitrile

To a solution of intermediate 4 (100 mg, 0.33 mmol, 1.0 eq.) in dry DMF (1 ml) under N ₂ was added LHMDS (1M in THF, 390 μl, 0.39 mmol, 1.2 eq. .). The mixture was stirred at room temperature for 5 minutes, then 3-bromopropoxy-tert-butyl-dimethylsilane (CAS [89031-84-5], 98 mg, 0.39 mmol, 1.2 eq) was added and the mixture was stirred at 50°C for 3 hours Then cooled to room temperature and extinguished H ₂ O. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The crude material was purified by column chromatography (EtOAc/petroleum ether, 6:4) to give the desired product. LCMS: m/z=471 [M+H] ⁺ .

Stage 2: 5-[[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-(3-hydroxy-propyl)-amino] -4-methyl-pyridine-2-carbonitrile

5-[[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-amino]-4- methyl pyridine-2-carbonitrile (102 mg, 0.217 mmol, 1.0 eq.), pyrimidine-4,6-diamine (CAS [79364-63-9], 48 mg, 0.434 mmol, 2.0 eq.) , Pd₂(dba)₃ (4 mg, 0.046 mmol, 0.02 eq.), MorDALPhos (4 mg, 0.08 mmol, 0.04 eq.) and Cs₂CO₃ (85 mg, 0.26 mmol, 1.2 eq.) were mixed together under N₂, after which 1,4-dioxane (2 ml) was added. Then, the mixture was stirred at 110°C overnight. After the mixture had cooled to room temperature, DMSO (1 ml) and TBAF (1M in THF, 0.6 ml, 0.6 mmol, 2.8 eq.) were added. The mixture was stirred for 10 minutes at room temperature. The reaction mixture was then filtered and purified by preparative HPLC to give the desired product. LCMS: m/z=431 [M+H]⁺.

Compound 6: 4-methyl-5-[3-methyl-7-[[5-[4-(trideuteriomethyl)piperazine-1-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine- 5-yl]oxypyridine-2-carbonitrile

Step 1: (6-Amino-pyridin-3-yl)-(4-trideuteriomethyl-piperazin-1-yl)-methanone

6-Amino-nicotinic acid (CAS [3167-49-5], 447 mg, 3.236 mmol, 1.0 eq.), N-methyl-D3-piperazine (CAS [1093380-08-5], 444 µl, 3.883 , 1.2 eq.) and DIPEA (1.24 ml, 7.119 mmol, 2.2 eq.) were stirred in dry EtOH (5 ml), after which HATU (1.844 g, 4.854 mmol, 1.5 eq.) was added. . The mixture was stirred at room temperature for 18 hours. It was then concentrated to dryness and redissolved in DCM. The precipitate formed was filtered off. The filtrate was purified by column chromatography using DCM/EtOH/25% aqueous NH3 (7/1/0.1) as eluent to give the desired product.

Stage 2: 4-methyl-5-[3-methyl-7-[[5-[4-(trideuteriomethyl)piperazine-1-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine- 5-yl]oxypyridine-2-carbonitrile

Intermediate 2 (201 mg, 0.673 mmol, 1.0 eq.), (6-amino-pyridin-3-yl)-(4-trideuteriomethyl-piperazin-1-yl)-methanone (150 mg, 0.673 mmol, 1 0 eq.), Pd ₂ Cl ₂ (allyl) ₂ (5 mg, 0.013 mmol, 0.02 eq.), MorDALPhos (12 mg, 0.026 mmol, 0.04 eq.) and Cs ₂ CO ₃ (263 mg , 0.808 mmol, 1.2 eq.) were mixed together under N, after which 1,4-dioxane (3 ml) was added. The mixture was stirred at 110°C. After one night the mixture was cooled to room temperature followed by the addition of 0.5 ml DMSO. The mixture was filtered and the filtrate was purified by preparative HPLC to give the desired product. LCMS: m/z=487 [M+H] ⁺ .

Compound 7: 4-ethyl-5-{3-methyl-7-[5-(morpholin-4-carbonyl)-pyridin-2-ylamino]-3H-imidazo[4,5-b]pyridin-5-yloxy} -pyridine-2-carbonitrile

Stage 1: 5-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-ethyl-pyridine-2-carbonitrile

Intermediate 1 (215 mg, 0.733 mmol, 1.0 eq.), 4-ethyl-5-hydroxy-pyridine-2-carbonitrile (intermediate 87, 141 mg, 0.953 mmol, 1.3 eq.), CuI ( 28 mg, 0.147 mmol, 0.2 eq.), TMHD (CAS [1118-71-4], 305 µl, 1.466 mmol, 2.0 eq.) and Cs ₂ CO ₃ (478 g, 1.466 mmol, 2, 0 eq.) was mixed together under air, the solvent was added and the mixture was stirred at 85°C. After 48 hours, the mixture was cooled to room temperature and quenched with 10% aq. TMEDA solution and the compound was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The crude material was purified using column chromatography (EtOAc/DCM, 7:3) to obtain the desired product. LCMS: m/z=314 [M+H]+.

Step 2: 4-ethyl-5-{3-methyl-7-[5-(morpholin-4-carbonyl)-pyridin-2-ylamino]-3H-imidazo[4,5-b]pyridin-5-yloxy} -pyridine-2-carbonitrile

5-(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-ethyl-pyridine-2-carbonitrile (82 mg, 0.263 mmol, 1.0 eq.) , 5-[(morpholin-4-yl)carbonyl]pyridine-2-amine (CAS [827587-90-6], 55 mg, 0.263 mmol, 1.0 eq.), MorDALPhos Pd G3 (CAS [6035-47 -8], 5 mg, 0.005 mmol, 0.02 eq.), MorDALPhos (CAS [1237588-12-3] (2 mg, 0.005 mmol, 0.02 eq.) and Cs ₂ CO ₃ (103 mg, 0.316 mmol, 1.2 eq.) were mixed together under N2, after which 1,4-dioxane (1 ml) was added and the mixture was stirred at 110° C. After one night, the mixture was allowed to cool to room temperature and then diluted with 2 ml DMSO The resulting mixture was filtered and the filtrate was purified by preparative HPLC to give the desired product LCMS: m/z=485 [M+H]+.

Compound 79 and 80: 5-[7-[[5-[1-(dimethylamino)-2,2,2-trifluoroethyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridine- 5-yl]oxy-4-methylpyridin-2-carbonitrile and 5-[7-[[5-[1-(ethylamino)-2,2,2-trifluoroethyl]pyridin-2-yl]amino]-3-methylimidazo [4,5-b]pyridin-5-yl]oxy-4-methylpyridine-2-carbonitrile

Step 1: Solution of intermediate 49 (75 mg, 0.16 mmol, 1.0 eq.) and Et ₃ N (46 μl, 0.33 mmol, 2.0 eq.) in anhydrous DCM (1 ml, 0.0 eq.) 2 M) was cooled to 0°C in an atmosphere of N ₂ . MsCl (CAS [124-63-0], 25 μl, 0.33 mmol, 2.0 eq.) in 0.1 ml anhydrous DCM was added dropwise and the mixture was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with DCM (5 ml) and quenched with saturated aqueous NaHCO ₃ (5 ml). The organic layer was washed with brine (5 ml), dried and evaporated in vacuo to give the desired product which was used as such. MS m/z 474/476 (75/25%).

Stage 2: 5-[7-[[5-(1-Chloro-2,2,2-trifluoroethyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl ]oxy-4-methyl-pyridine-2-carbonitrile (31 mg, 0.066 mmol, 1.0 eq.), Me ₂ NH ₂ Cl (53 mg, 0.66 mmol, 10 eq.) and K ₂ CO ₃ ( 182 mg, 1.32 mmol, 20 eq.) were mixed together in anhydrous DMF (0.3 ml). The mixture was stirred for 1 h at 80° C. under N ₂ . Then, the reaction mixture was diluted with water (5 ml) and was extracted with EtOAc (2×5 ml). The combined organic extracts were dried and evaporated in vacuo. The residue was dissolved in MeOH, filtered and purified by preparative HPLC to give the desired product. LCMS 79 : m/z=483 [M+H] ⁺ ; LCMS 80 : m/z=483 [M+H] ⁺ .

Compound 187: 5-[[7-[(6-Aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]-(2-hydroxypropyl)amino]-4 -methyl-pyridine-2-carbonitrile

Stage 1: 5-[2-[t-butyl(dimethyl)silyl]oxypropylamino]-4-methyl-pyridine-2-carbonitrile

In a 5 ml vial, 2-[tert-butyl(dimethyl)silyl]oxypropylamine (CAS [1789680-15-4], 380 mg, 2 mmol, 2.0 eq.), 2-cyano-4-methyl-5- Bromopyridine (CAS [886364-86-9], 200 mg, 1 mmol, 1.0 eq.), XantPhosPd G3 (CAS [1445085-97-1], 29 mg, 0.03 mmol, 0.03 eq.) , XantPhos (CAS [161265-03-8], 17.5 mg, 0.03 mmol, 0.03 eq.), and Cs ₂ CO ₃ (975 mg, 3.0 mmol, 3.0 eq.) were added . Dry 1,4-dioxane (3 ml) was added and the mixture was placed under N ₂ atmosphere and degassed. The mixture was stirred overnight at 70°C. Water and ethyl acetate were added, after shaking, the aqueous layer was separated. The organic layer was washed again with water. The precipitate in the organic layer was filtered off. The organic layer was dried over MgSO ₄ , filtered and evaporated. Purification by column chromatography with 5-25% EtOAc in PE gave the desired product (200 mg, 33% yield). LCMS: m/z=306 [M+H] ⁺ .

Step 2: 5-[2-[tert-Butyl(dimethyl)silyl]oxypropyl-(7-chloro-3-methylimidazo[4,5-b]pyridin-5-yl)amino]-4-methyl-pyridine -2-carbonitrile

In 5 ml vial, 5-[2-[tert-butyl(dimethyl)silyl]oxypropylamino]-4-methyl-pyridine-2-carbonitrile (50 mg, 0.16 mmol, 1.0 eq.), Exc. . 1 (48 mg, 0.16 mmol, 1.0 eq.), Pd2dba3 (15 mg, 0.016 mmol, 0.1 eq.), P(tBu) ₃ .HBF ₄ (9.3 mg, 0.032 mmol, 0 .2 eq.) and NaOtBu (16 mg, 0.192 mmol, 1.2 eq.) were added. Dry toluene was added and the mixture was placed under N ₂ atmosphere. Degassed and stirred for 5 hours at 110°C. Water and ethyl acetate were added and the mixture was filtered through celite. The layers were separated and the organic layer was dried over MgSO ₄ , filtered and evaporated. The crude product was purified by column chromatography using 5% EtOAc to 70% EtOAc in PE eluents to give the desired product. LCMS: m/z=471 [M+H] ⁺ .

Step 3: 5-[[7-[(6-aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]-[2-[tert-butyl(dimethyl )silyl]oxypropyl]amino]-4-methyl-pyridine-2-carbonitrile

In a 5 ml vial, 5-[2-[tert-butyl(dimethyl)silyl]oxypropyl-(7-chloro-3-methyl-imidazo[4,5-b]pyridin-5-yl)amino]-4-methyl -pyridine-2-carbonitrile (50 mg, 0.22 mmol, 1 eq.), 4,6-diaminopyrimidine (49 mg, 0.44 mmol, 2 eq.), MorDalPhos Pd G3 (18 mg, 0.022 mmol, 0 1 eq.), MorDalPhos (10 mg, 0.022 mmol, 0.1 eq.) and Cs ₂ CO ₃ (143 mg, 0.44 mmol, 2 eq.) were added. Anhydrous 1,4-dioxane was added and the mixture was placed under N ₂ atmosphere and degassed. Then stirred at 110° C. for 2 hours. The mixture was cooled to room temperature, water and ethyl acetate were added, the layers were separated and the aqueous layer was washed with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the desired product which was used as such. LCMS (M+1): 545.3

Stage 4: 5-[[7-[(6-Aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]-(2-hydroxypropyl)amino]-4 -methyl-pyridine-2-carbonitrile

A 1 M solution of TBAF in THF (0.2 ml, 0.2 mmol, 2 equiv.) was added to a solution of 5-[[7-[(6-aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4 ,5-b]pyridin-5-yl]-[2-[tert-butyl(dimethyl)silyl]oxypropyl]amino]-4-methyl-pyridine-2-carbonitrile (50 mg, 0.1 mmol, 1 eq. ) in anhydrous THF (10 ml) at room temperature and the mixture was stirred overnight. The volatiles were evaporated and the mixture was purified by preparative chromatography to give the desired product. LCMS: m/z=431 [M+H] ⁺ .

Compound 38: 4-methyl-5-[3-methyl-7-(6-morpholin-4-yl-pyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridin-5-yloxy]pyridine -2-carbonitrile

Path 1

Intermediate 3 (1.0 eq., 409 g, 1.459 mol) and 4-(6-bromopyridazin-3-yl)morpholine (CAS [66346-91-6], 1.1 eq., 392 g) were added to xylene mixture of isomers (8 l) at room temperature. Tribasic potassium phosphate (3.0 eq., 929 g) was added to the mixture with stirring at room temperature. The reaction mixture was heated from room temperature to 135°C for 2 hours 30 minutes. Then a suspension of Pd(OAc) ₂ (2 mol%, 6.6 g) and Xantphos (4 mol%, 33.8 g) in xylene (50 ml) was added to the hot mixture. The reaction mixture was heated at reflux for 1 h 30. Then a suspension of Pd(OAc) ₂ (2 mol%, 6.6 g) and Xantphos (4 mol%, 33.8 g) in xylene (50 ml) was added and the reaction the mixture was heated at reflux for an additional 1 h 30. Then a suspension of Pd(OAc) ₂ (2 mol%, 6.6 g) and Xantphos (4 mol%, 33.8 g) in xylene (50 ml) was added to the last once. The reaction mixture was refluxed for an additional 1 hour 30 minutes. The reaction mixture was cooled to room temperature and stirred overnight. The suspension was filtered, washed with acetonitrile (5 L). The solid was washed with water (15 L) until neutral pH, dried under vacuum, then suspended in acetonitrile (6.5 L) and stirred at room temperature for 1 hour. The suspension was filtered, washed with acetonitrile (2 L) and dried. Chromatography on SiO ₂ (1 g SiO ₂ per 1 g crude) using CHCl ₃ /acetone (70/30) and then CHCl ₃ /MeOH (96/4) as eluent gives the desired product.

Path 2

Intermediate 3 (280 mg, 1 mmol, 1.0 eq.), 4-(6-bromopyridazin-3-yl)morpholine (268 mg, 1.1 mmol, 1.1 eq.) and CsCO ₃ (977 mg , 3 mmol, 3 eq.) is mixed under argon atmosphere at room temperature and degassed tert-amyl alcohol or DMF (5 ml) is added. [Pd(cinnamyl)Cl] ₂ (5.18 mg, 0.010 mmol, 0.01 eq) and JosiPhos (CAS[1702311-34-9]) (13 mg, 0.024 mmol, 0.024 eq) are added under argon as a solid or as a pre-mixed solution in 1 ml of degassed tert-amyl alcohol or DMF. The mixture is heated to 100°C for at least 2 hours.

The reaction mixture is then cooled to room temperature and cetonitrile is added. The suspension is filtered, the solid triturated first with water, then with acetonitrile and dried to obtain the desired product.

Table III. Exemplary Compounds of the Invention

Conn.# Structure Name SM Spos. MM Calc.MM eight

4-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-3-ethyl-5-fluoro- benzonitrile Prov.s. 16 C1 417 418 9

5-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-4-methyl-pyridin-2- carbonitrile Prov.s. four C2 386 387 ten

4-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-cyclohexanecarbonitrile Prov.s. 6 C2 378 378 eleven

N7-(6-aminopyrimidin-4-yl)-N5-(3,3-dimethyl-tetrahydropyran-4-yl)-3,N5-dimethyl-3H-imidazo[4,5-b]pyridine-5,7- diamine Prov.s. 7 C2 383 383 12

N7-(6-aminopyrimidin-4-yl)-N5,3-dimethyl-N5-[(1S)-1,2,2-trimethylpropyl]imidazo[4,5-b]pyridine-5,7-diamine Prov.s. 33, [79364-63-9] B1 355 355 13

(±)-(1R,3R)-3-{[7-(6-aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino }-cyclohexanecarbonitrile Prov.s. 9 C2 378 378 fourteen

4-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-3-cyclopropyl-5-fluoro- benzonitrile Prov.s. ten C2 430 430 fifteen

5-{[7-(6-Aminopyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-amino}-4-ethyl-pyridin-2- carbonitrile Prov.s. eleven C2 400 401 16

N7-(6-aminopyrimidin-4-yl)-N5-[(1R)-1-cyclopropylethyl]-N5,3-dimethylimidazo[4,5-b]pyridine-5,7-diamine Prov.s. 34, [79364-63-9] B1 338 339 17

N7-(6-aminopyrimidin-4-yl)-3,N5-dimethyl-N5-((3R,4S)-3-methyl-tetrahydropyran-4-yl)-3H-imidazo[4,5-b]pyridine- 5,7-diamine Prov.s. 13 C2 368 369 eighteen

N7-(6-aminopyrimidin-4-yl)-N5-bicyclo[1.1.1]pent-1-yl-3,N5-dimethyl-3H-imidazo[4,5-b]pyridine-5,7-diamine Prov.s. 24 C2 336 337 19

N7-(6-aminopyrimidin-4-yl)-3,N5-dimethyl-N5-(3-methyl-tetrahydropyran-4-yl)-3H-imidazo[4,5-b]pyridine-5,7-diamine Prov.s. 25 C2 368 369 twenty

N7-(6-aminopyrimidin-4-yl)-N5-(1-cyclopropyl-2,2,2-trifluoroethyl)-3,N5-dimethyl-3H-imidazo[4,5-b]pyridine-5,7- diamine Prov.s. 26 C2 392 393 21

N7-(6-aminopyrimidin-4-yl)-3,N5-dimethyl-N5-(5-oxa-spiro[3.5]non-8-yl)-3H-imidazo[4,5-b]pyridine-5, 7-diamine Prov.s. 27 C2 395 395 22

5-(1-cyclopropyl-2,2,2-trifluoroethoxy)-3-methyl-N-(5-methylsulfonyl-2-pyridyl)imidazo[4,5-b]pyridine-7-amine Prov.s. 28, [35196-11-3] B1 441 442 23

6-[5-(6-cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridazine-3-carboxylic acid ethylamide Prov.s. 2, Ex.s. 29 B1 429 430 24

6-[5-(6-cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-N-(2-hydroxy-propyl )-nicotinamide Prov.s. 2, Ex.s. thirty B1 459 459 25

6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridazine-3-carboxylic acid (2 -hydroxy-propyl)-amide Prov.s. 2, Ex.s. 31 B1 460 460 26

5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridine-2-carboxylic acid ethylamide Prov.s. 2, Ex.s. 32 B1 429 429 27

2-{4-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-phenyl}-N- ethyl acetate Ex.s.3, Ex.s. 83 B1 442 442 28

4-methyl-5-{3-methyl-7-[6-(morpholin-4-carbonyl)-pyridin-3-ylamino]-3H-imidazo[4,5-b]pyridin-5-yloxy}-pyridine- 2-carbonitrile Prov.s. 2, [1180131-89-8] B1 471 471 29

5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridine-2-carboxylic acid methylamide Prov.s. 2, [941284-74-8] B1 414 415 thirty

5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridine-2-carboxylic acid (2 -hydroxy-propyl)-amide Prov.s. 2, Ex.s. 22 B1 459 459 31

5-{7-[6-(2-Methoxyethylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridin-2- carbonitrile Prov.s. 2, Ex.s. 33 B1 431 432 32

5-{7-[6-(3-Methoxy-propylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridine- 2-carbonitrile Prov.s. 2, Ex.s. 34 B1 445 446 33

5-{7-[6-(3-Hydroxy-3-methyl-butylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4- methyl-pyridine-2-carbonitrile Prov.s. 2, Ex.s. 35 B1 459 460 34

5-{7-[6-(3-hydroxy-propylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridin- 2-carbonitrile Prov.s. 2, Ex.s. 36 B1 431 432 35

5-(7-{6-[([1,4]Dioxan-2-ylmethyl)-amino]-pyrimidin-4-ylamino}-3-methyl-3H-imidazo[4,5-b]pyridine-5- yloxy)-4-methyl-pyridine-2-carbonitrile Prov.s. 2, Ex.s. 37 B1 473 474 36

5-{7-[6-(3-Methoxy-cyclobutylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridine- 2-carbonitrile Prov.s. 2, Ex.s. 38 B1 457 458 37

5-{7-[6-(3-Methoxy-butylamino)-pyrimidin-4-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridine- 2-carbonitrile Prov.s. 2, Ex.s. 39 B1 459 460 38

4-methyl-5-[3-methyl-7-(6-morpholin-4-yl-pyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridin-5-yloxy]-pyridin-2- carbonitrile Prov.s. 2, [66346-91-6] or Etc. 3, [66346-91-6] B1
or see above 443 444 39

4-methyl-5-{3-methyl-7-[6-(4-methyl-piperazin-1-yl)-pyridazin-3-ylamino]-3H-imidazo[4,5-b]pyridin-5-yloxy }-pyridine-2-carbonitrile Prov.s. 2, [66346-94-9] B1 456 457 40

5-{7-[6-(3-Dimethylaminomethyl-azetidin-1-yl)-pyridazin-3-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4- methyl-pyridine-2-carbonitrile Prov.s. 2, Ex.s. 40 B1 470 471 41

(±)-4-methyl-5-{3-methyl-7-[6-((3R,5S)-3,4,5-trimethyl-piperazin-1-yl)-pyridazin-3-ylamino]-3H -imidazo[4,5-b]pyridin-5-yloxy}-pyridine-2-carbonitrile Prov.s. 2, Ex.s. 41 B1 484 485 42

4-methyl-5-(3-methyl-7-{6-[4-(2,2,2-trifluoroethyl)-piperazin-1-yl]-pyridazin-3-ylamino}-3H-imidazo[4,5 -b]pyridin-5-yloxy)-pyridine-2-carbonitrile Prov.s. 2, Ex.s. 42 B1 524 525 43

(±)-5-{7-[6-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-pyridazin-3-ylamino]-3-methyl-3H-imidazo[4,5 -b]pyridin-5-yloxy}-4-methyl-pyridine-2-carbonitrile Prov.s. 2, Ex.s. 43 B1 471 472 44

4-methyl-5-{3-methyl-7-[6-((S)-2-methyl-morpholin-4-yl)-pyridazin-3-ylamino]-3H-imidazo[4,5-b]pyridine -5-yloxy}-pyridine-2-carbonitrile Prov.s. 2, Ex.s. 44 B1 457 458 45

5-{7-[6-(4-Cyano-piperidin-1-yl)-pyridazin-3-ylamino]-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4- methyl-pyridine-2-carbonitrile Prov.s. 2, Ex.s. 45 B1 466 467 46

4-methyl-5-[3-methyl-7-[[5-(4-propan-2-ylpiperazin-1-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile Prov.s. 61, [4318-42-7] A1-a 512 513 47

5-[7-[[5-(4-cyclobutylpiperazin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 -carbonitrile Prov.s. 61, [799557-65-6] A1-a 524 525 48

5-[7-[[5-(4-cyclopropylpiperazin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 -carbonitrile Prov.s. 61, [20327-23-5] A1-a 510 511 49

4-methyl-5-[3-methyl-7-[(5-morpholin-4-ylpyridin-2-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 2, [571189-78-1] B1 442 443 fifty

4-methyl-5-[3-methyl-7-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile Prov.s. 2, [571189-49-6] B1 456 457 51

4-methyl-5-[7-[[5-(4-methylpiperazin-1-carbonyl)pyridin-2-yl]amino]-3-(trideuteriomethyl)imidazo[4,5-b]pyridin-5-yl] oxypyridine-2-carbonitrile Prov.s. 84, R.s. 89 B1 487 487 52

5-[7-[(6-Aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrile Prov.s. 2, [79364-63-9] B1 373 374 53

4-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-ethyl-benzenesulfonamide Prov.s. 2, [1709-53-1] B1 464 464 54

N4-[5-(1-cyclopropyl-2,2,2-trifluoroethoxy)-3-methyl-imidazo[4,5-b]pyridin-7-yl]pyrimidin-4,6-diamine Prov.s. 28, [79364-63-9] B1 379 380 55

5-[[7-[(6-aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]amino]-4-methyl-pyridine-2-carbonitrile Prov.s. 4, [79364-63-9] B1 372 373 57

5-[7-[4-(Aminomethyl)anilino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile formate salt Ex.p.47 D1 385 369 (M-NH ₂ -) 58

4-methyl-5-[3-methyl-7-[(5-methylsulfonyl-2-pyridyl)amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 2, [35196-11-3] B1 436 436 59

4-methyl-5-[3-methyl-7-[[5-(trifluoromethyl)-2-pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 2, [74784-70-6] B1 425 426 60

4-methyl-5-[3-methyl-7-(4-methylsulfonylanilino)imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 2, [5470-49-5] B1 435 435 61

4-methyl-5-[3-methyl-7-[(1-methylpyrazol-4-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 2, [69843-13-6] B1 360 361 62

4-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- benzamide Prov.s. 2, [6331-71-1] B1 428 428 63

4-methyl-5-[3-methyl-7-(4-morpholinosulfonylanilino)imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 2, [21626-70-0] B1 506 506 64

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-ethyl-4- methyl pyridine-3-carboxamide Prov.s. 2, Ex.s. fifty B1 443 443 65

3-methyl-N7-(5-methylsulfonyl-2-pyridyl)-N5-[2-methyl-1-(trifluoromethyl)propyl]imidazo[4,5-b]pyridine-5,7-diamine Prov.s. 46, [35196-11-3] B1 443 443 66

4-[[5-[(6-Cyano-4-methyl-3-pyridyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- benzamide Prov.s. 4, [6331-71-1] B1 427 427 67

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- pyridine-3-carboxamide Prov.s. 4, [827588-33-0] B1 428 428 68

5-[7-[4-(Difluoromethylsulfonyl)anilino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile Prov.s. 2, [24906-77-2] B1 471 471 69

5-[7-(4-cyclopropylsulfonylanilino)-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile Prov.s. 2, [1147558-13-1] B1 461 461 71

5-[7-[4-(3-methoxypropylsulfonyl)anilino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile Prov.s. 2, [1247164-58-4] B1 493 493 72

N4-[5-(1-cyclopropylethoxy)-3-methylimidazo[4,5-b]pyridin-7-yl]pyrimidin-4,6-diamine Prov.s. 48, [79364-63-9] B1 325 326 73

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- pyridazine-3-carboxamide Prov.s. 2, [1250216-83-1] B1 429 429 74

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- pyridine-3-carboxamide Prov.s. 2, [827588-33-0] B1 429 429 75

4-methyl-5-[3-methyl-7-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2 -carbonitrile Prov.s. 2, [827587-90-6] B1 471 471 76

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N-dimethyl- pyridazine-3-carboxamide Prov.s. 4, [1250216-83-1] B1 429 429 77

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N, N,2- trimethyl-pyridine-3-carboxamide Prov.s. 52, [506-59-2] A1 443 443 78

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-ethyl-2- methyl pyridine-3-carboxamide Prov.s. 52, [557-66-4] A1 443 443 81

5-[7-[[5-[(dimethylamino)methyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile formate salt Prov.s. 2, [1384429-17-7] B1 415 415 82

4-methyl-5-[3-methyl-7-[[5-(morpholin-4-ylmethyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile formate salt Prov.s. 2, [400775-78-2] B1 457 457 83

5-[7-[[5-[[2-(dimethylamino)ethyl-methylamino]methyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4 -methylpyridine-2-carbonitrile formate salt Prov.s. 2, [1197332-20-9] B1 472 472 84

5-[7-[(5-methoxypyridin-2-yl)amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile Prov.s. 2, [10167-97-2] B1 387 388 85

4-methyl-5-[3-methyl-7-[[5-[(3S)-3-methylmorpholin-4-yl]pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5- yl]oxypyridine-2-carbonitrile Prov.s. 2, Ex.s. 53 B1 457 457 86

4-methyl-5-[3-methyl-7-[[5-(1-methylpiperidin-4-yl)oxypyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile Prov.s. 2, [1249322-37-9] B1 471 471 87

4-methyl-5-[3-methyl-7-[[5-(oxan-4-yl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile Prov.s. 2, Ex.s. 55 B1 442 442 88

5-[[7-[(6-aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]-cyclopropyl-amino]-4-methyl-pyridin-2 -carbonitrile Prov.s. 86, [156-81-0] B1 413 414 89

5-[7-[4-(3-Hydroxyoxetan-3-yl)anilino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile Prov.s. 2, [1111735-05-7] B1 429 429 90

4-methyl-5-[3-methyl-7-[[6-(1-methylazetidin-3-yl)oxypyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile Prov.s. 3, Ex.s. 56 B2-a 444 444 91

5-[[5-[(1-cyclopropyl-2,2,2-trifluoroethyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-ethyl-pyridine- 2-carboxamide Prov.s. 26, R.s. 32 B1 433 434 92

N5-(1-cyclopropyl-2,2,2-trifluoroethyl)-3-methyl-N7-(5-methylsulfonyl-2-pyridyl)imidazo[4,5-b]pyridine-5,7-diamine Prov.s. 26, [35196-11-3] B1 440 441 93

N7-(6-aminopyrimidin-4-yl)-3-methyl-N5-[2-methyl-1-(trifluoromethyl)propyl]imidazo[4,5-b]pyridine-5,7-diamine Prov.s. 46, [79364-63-9] B1 380 381 94

N7-(6-aminopyrimidin-4-yl)-N5-(1-cyclobutylethyl)-3-methyl-imidazo[4,5-b]pyridine-5,7-diamine Prov.s. 58, [79364-63-9] B1 338 339 95

N7-(6-aminopyrimidin-4-yl)-N5-(cyclopropylmethyl)-3-methylimidazo[4,5-b]pyridine-5,7-diamine Prov.s. 59, [79364-63-9] B1 350 351 96

5-[7-[[5-(3-Hydroxyazetidine-1-carbonyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl- pyridine-2-carbonitrile Prov.s. 2, [45347-82-8] A1-a 457 457 97

N,N-dimethyl-6-[[3-methyl-5-[[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino]imidazo[4,5-b]pyridin-7-yl]amino ]pyridine-3-carboxamide Prov.s. 64, [827588-33-0] B1 436 436 98

N7-(6-aminopyrimidin-4-yl)-3-methyl-N5-[(1R)-2-methyl-1-(trifluoromethyl)propyl]imidazo[4,5-b]pyridine-5,7-diamine Prov.s. 64, [79364-63-9] B1 380 381 99

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-(2-dimethylaminoethyl )pyridine-3-carboxamide Prov.s. 61, [108-00-9] A1-a 472 472 100

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-(3-methoxypropyl )pyridine-3-carboxamide Prov.s. 61, [5332-73-0] A1-a 473 473 101

6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]-N-(3-hydroxypropyl )pyridine-3-carboxamide Prov.s. 61, [156-87-6] A1-a 459 459 102

5-[7-[[5-[3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridine -5-yl]oxy-4-methyl-pyridine-2-carbonitrile Prov.s. 61, [1357923-33-1] A1-a 499 499 103

5-[7-[[5-(3-Methoxyazetidine-1-carbonyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl- pyridine-2-carbonitrile Prov.s. 61, [110925-17-2] A1-a 471 471 104

5-[7-[[5-[3-(methoxymethyl)azetidine-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4 -methyl-pyridine-2-carbonitrile Prov.s. 61, [942308-06-7] A1-a 485 485 105

4-methyl-5-[3-methyl-7-[[5-(4-methylpiperazin-1-carbonyl)-2-pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine -2-carbonitrile Prov.s. 61, [5332-73-0] A1-a 484 484 106

5-[7-[[5-[3-(dimethylamino)azetidine-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4 -methyl-pyridine-2-carbonitrile Prov.s. 61, [124668-49-1] A1-a 484 484 107

5-[7-[[5-[(3R)-3-(dimethylamino)pyrrolidin-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methylpyridine-2-carbonitrile Prov.s. 61, [132958-72-6] A1-a 498 498 108

4-methyl-5-[3-methyl-7-[[6-(morpholine-4-carbonyl)pyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile Prov.s. 63, [110-91-8] A1-a 472 472 109

4-methyl-5-[3-methyl-7-(4-morpholinoanilino)imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 2, [2524-67-6] B1 442 442 110

4-methyl-5-[3-methyl-7-[4-(4-methylpiperazin-1-yl)anilino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 2, [16153-81-4] B1 455 455 111

5-[7-[[6-[3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carbonyl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b] pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile Prov.s. 63, [1357923-33-1] A1-a 500 500 112

5-[7-[[5-[(3S)-3-hydroxypyrrolidin-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy- 4-methyl-pyridine-2-carbonitrile Prov.s. 61, [100243-39-8] A1-a 471 471 113

5-[7-[[5-(3-cyclopropyl-3-hydroxy-azetidine-1-carbonyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl] hydroxy-4-methyl-pyridine-2-carbonitrile Prov.s. 61, [848192-93-8] A1-a 497 497 114

4-methyl-5-[3-methyl-7-[[5-(8-oxa-3-azaspiro[4.4]nonane-3-carbonyl)-2-pyridyl]amino]imidazo[4,5-b]pyridine -5-yl]oxy-pyridine-2-carbonitrile Prov.s. 61, [175-97-3] A1-a 511 511 115

5-[7-[[6-(3-hydroxyazetidin-1-carbonyl)pyridazin-3-yl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl -pyridine-2-carbonitrile Prov.s. 63, [45347-82-8] A1-a 458 458 116

5-[7-[[6-(3-Methoxyazetidin-1-carbonyl)pyridazin-3-yl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl -pyridine-2-carbonitrile Prov.s. 63, [45347-82-8] A1-a 472 472 117

5-[7-[[6-[3-(methoxymethyl)azetidine-1-carbonyl]pyridazin-3-yl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy- 4-methyl-pyridine-2-carbonitrile Prov.s. 63, [942308-06-7] A1-a 486 486 118

5-[7-[[5-[3-(hydroxymethyl)azetidine-1-carbonyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4 -methyl-pyridine-2-carbonitrile Prov.s. 61, [928038-44-2] A1-a 471 471 119

5-[7-[[5-(3-Hydroxy-3-methyl-azetidine-1-carbonyl)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl] hydroxy-4-methyl-pyridine-2-carbonitrile Prov.s. 61, [124668-46-8] A1-a 471 471 120

4-methyl-5-[3-methyl-7-[[5-(3-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-2-pyridyl]amino]imidazo[4,5-b]pyridine -5-yl]oxy-pyridine-2-carbonitrile Prov.s. 61, [936947-34-1] A1-a 483 483 121

5-[7-[[5-(3-Methoxy-3-methyl-azetidine-1-carbonyl)-2-pyridyl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methyl-pyridine-2-carbonitrile Prov.s. 61, [905843-93-8] A1-a 485 485 122

tert-Butyl 1-[6-[[5-[(6-Cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-yl]amino]pyridine -3-carbonyl]azetidine-3-carboxylate Prov.s. 61, [53871-08-2] A1-a 541 541 123

4-methyl-5-[3-methyl-7-[[5-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-pyridyl]amino]imidazo[4,5-b ]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 61, [1203567-11-6] A1-a 496 496 124

5-[7-[[5-(4-hydroxypiperidin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 -carbonitrile Prov.s. 61, [5382-16-1] A1-a 485 485 125

5-[7-[[5-(4-Methoxypiperidin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 -carbonitrile Prov.s. 61, [4045-24-3] A1-a 499 499 126

5-[7-[[5-[4-(dimethylamino)piperidine-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4- methylpyridine-2-carbonitrile Prov.s. 61, [50533-97-6] A1-a 512 512 127

5-[7-[[5-[(3R)-3-hydroxypyrrolidin-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4 -methylpyridine-2-carbonitrile Prov.s. 61, [2799-21-5] A1-a 471 471 128

4-{6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridine-3-carbonyl }-piperazine-1-carboxylic acid tert-butyl ester Prov.s. 61, [57260-71-6] A1-a 570 570 129

5-[7-[[5-[(3R)-3-(2-methoxyethoxy)pyrrolidine-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridine-5- yl]oxy-4-methylpyridine-2-carbonitrile Prov.s. 61, [942618-26-0] A1-a 529 529 130

(1-{6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridin-3- carbonyl}-pyrrolidin-3-yl)-methyl-carbamic acid tert-butyl ester Prov.s. 61, [172478-00-1] A1-a 584 584 131

4-methyl-5-[3-methyl-7-[[5-(2-oxa-7-azaspiro[3.4]octane-7-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [39640-71-6] A1-a 497 497 132

5-[7-[[5-[3-[(dimethylamino)methyl]azetidine-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy -4-methylpyridine-2-carbonitrile Prov.s. 61, [321890-22-6] A1-a 498 498 133

5-[7-[[5-[(3S)-3-(dimethylamino)pyrrolidin-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methylpyridine-2-carbonitrile Prov.s. 61, [132883-44-4] A1-a 498 498 134

4-methyl-5-[3-methyl-7-[[5-(2-oxa-6-azaspiro[3.3]heptan-6-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [1045709-32-7] A1-a 483 483 135

5-[7-[[5-[3,3-bis(hydroxymethyl)azetidine-1-carbonyl]pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy -4-methylpyridine-2-carbonitrile Prov.s. 61, [1016232-92-0] A1-a 501 501 136

6-[[5-(6-Cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]-N-(2-hydroxyethyl)-N- methylpyridine-3-carboxamide Prov.s. 61, [109-83-1] A1-a 459 459 137

4-methyl-5-[3-methyl-7-[[5-(3-propan-2-yloxyazetidine-1-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile Prov.s. 61, [871657-49-7] A1-a 499 499 138

5-[7-[[5-(4-Hydroxy-4-methylpiperidin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4 -methylpyridine-2-carbonitrile Prov.s. 61, [3970-68-1] A1-a 499 499 139

6-[[5-(6-Cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]-N-[rac-(1R,3R) -3-hydroxycyclopentyl]pyridine-3-carboxamide Prov.s. 61, [124555-33-5] A1-a 485 485 140

4-methyl-5-[3-methyl-7-[[5-[rac-(3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-carbonyl]pyridin-2-yl]amino]imidazo[4, 5-b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [1334320-82-9] A1-a 489 489 141

4-methyl-5-[3-methyl-7-[[5-[rac-(3R,4R)-3,4-dihydroxypiperidine-1-carbonyl]pyridin-2-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [39640-71-6] A1-a 501 501 142

4-methyl-5-[3-methyl-7-[[5-[rac-(3R,4R)-3-fluoro-4-methoxypyrrolidine-1-carbonyl]pyridin-2-yl]amino]imidazo[4, 5-b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [1203566-98-6] A1-a 503 503 143

5-[7-[[6-[3-(dimethylamino)azetidin-1-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4- methylpyridine-2-carbonitrile Prov.s. 2, Ex.s. 90 B1 457 457 144

4-methyl-5-[3-methyl-7-[[5-[(2S)-2-methylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile Prov.s. 61, [74572-13-7] A1-a 485 485 145

4-methyl-5-[3-methyl-7-[[5-[(2R)-2-methylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile Prov.s. 61, [168038-14-0] A1-a 485 485 146

4-methyl-5-[3-methyl-7-[[5-[(3R)-3-methylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile Prov.s. 61, [74572-04-6] A1-a 485 485 147

4-methyl-5-[3-methyl-7-[[5-[(3S)-3-methylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridine-5- yl]oxypyridine-2-carbonitrile Prov.s. 61, [350595-57-2] A1-a 485 485 148

4-methyl-5-[3-methyl-7-[[5-[rac-(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [6485-55-8] A1-a 499 499 149

4-methyl-5-[3-methyl-7-[[5-[rac-(2R,6R)-2,6-dimethylmorpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [6485-45-6] A1-a 499 499 150

4-methyl-5-[3-methyl-7-[[6-(4-methylpiperazin-1-carbonyl)pyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile Prov.s. 66
Prov.s. 2 B1 485 485 151

3,5-difluoro-4-[3-methyl-7-[[5-(4-methylpiperazin-1-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl] oxybenzonitrile Prov.s. 92, R.s. 84 B1 505 505 152

4-methyl-5-[3-methyl-7-[[6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridazin-3-yl] amino]imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 3, Ex.s. 91 B2-a 469 469 153

5-{7-[5-((3R,4R)-3-Dimethylamino-4-hydroxy-pyrrolidine-1-carbonyl)-pyridin-2-ylamino]-3-methyl-3H-imidazo[4,5-b ]pyridin-5-yloxy}-4-methyl-pyridine-2-carbonitrile Prov.s. 61, [960289-61-6] A1-a 514 514 154

5-{7-[5-((3S,4S)-3-hydroxy-4-morpholin-4-yl-pyrrolidin-1-carbonyl)-pyridine-2-ylamino]-3-methyl-3H-imidazo[4 ,5-b]pyridin-5-yloxy}-4-methyl-pyridine-2-carbonitrile Prov.s. 61, [1187339-81-6] A1-a 556 556 155

4-methyl-5-[3-methyl-7-[[5-[2-(trifluoromethyl)morpholine-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl ]oxypyridine-2-carbonitrile Prov.s. 61, [1196152-51-8] A1-a 539 539 156

5-[7-[[5-(2-cyclopropylmorpholin-4-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 -carbonitrile Prov.s. 61, [1063734-79-1] A1-a 511 511 157

4-methyl-5-[3-methyl-7-[[5-[(3R)-3-propan-2-ylmorpholin-4-carbonyl]pyridin-2-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [74572-01-3] A1-a 513 513 158

4-methyl-5-[3-methyl-7-[[5-(2-oxa-5-azabicyclo[2.2.1]heptan-5-carbonyl)pyridin-2-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 61, [31560-06-2] A1-a 483 483 159

5-[7-[[5-(3-cyclopropylmorpholin-4-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2 -carbonitrile Prov.s. 61, [260667-05-7] A1-a 511 511 160

4-[6-[[5-(6-Cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]pyridine-3-carbonyl]morpholin- 2-carbonitrile Prov.s. 61, [1205751-07-0] A1-a 496 496 161

4-methyl-5-{3-methyl-7-[5-((3aS,6aS)-1-methyl-hexahydro-pyrrolo[3,4-b]pyrrole-5-carbonyl)-pyridine-2-ylamino] -3H-imidazo[4,5-b]pyridin-5-yloxy}-pyridine-2-carbonitrile Prov.s. 61, [877212-98-1] A1-a 510 510 162

4-[6-[[5-(6-Cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]pyridine-3-carbonyl]morpholin- 3-carbonitrile Prov.s. 61, [97039-63-9] A1-a 496 496 163

5-[7-[[6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methylpyridine-2-carbonitrile Prov.s. 3, Ex.s. 68 B2-a 474 474 164

4-methyl-5-[3-methyl-7-[[6-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)pyridazin-3-yl]amino]imidazo[ 4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 3, Ex.s. 69 B2-a 452 452 165

5-[7-[[6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl] hydroxy-4-methylpyridine-2-carbonitrile Prov.s. 3, Ex.s. 70 B2-a 474 474 166

5-[7-[[6-[(2S,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl ]hydroxy-4-methylpyridine-2-carbonitrile Prov.s. 3, Ex.s. 71 B2-a 472 472 167

4-methyl-5-[3-methyl-7-[[6-(1,4-oxazepan-4-yl)pyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5-yl] oxypyridine-2-carbonitrile Prov.s. 3, Ex.s. 72 B2-a 458 458 168

5-[7-[[6-[(2R,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl ]hydroxy-4-methylpyridine-2-carbonitrile Prov.s. 3, Ex.s. 73 B2-a 472 472 169

5-[7-[[6-[2-(hydroxymethyl)morpholin-4-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4- methylpyridine-2-carbonitrile Prov.s. 3, Ex.s. 74 B2-a 474 474 170

4-methyl-5-[3-methyl-7-[[6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 3, Ex.s. 75 B2-a 470 470 171

4-[6-[[5-(6-Cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]pyridazin-3-yl]morpholin- 2-carbonitrile Prov.s. 3, Ex.s. 76 B2-a 468 469 172

4-methyl-5-[3-methyl-7-[[6-[(2R)-2-methylmorpholin-4-yl]pyridazin-3-yl]amino]imidazo[4,5-b]pyridin-5- yl]oxypyridine-2-carbonitrile Prov.s. 3, Ex.s. 77 B2-a 458 458 173

4-methyl-5-[3-methyl-7-[[6-[(2R)-2-propan-2-ylmorpholin-4-yl]pyridazin-3-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 3, Ex.s. 78 B2-a 486 486 174

4-methyl-5-[3-methyl-7-[[6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridazin-3-yl]amino] imidazo[4,5-b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 3, Ex.s. 79 B2-a 455 456 175

5-[7-[[6-(2,2-dimethylmorpholin-4-yl)pyridazin-3-yl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridine -2-carbonitrile Prov.s. 3, Ex.s. 80 B2-a 472 472 176

4-methyl-5-[3-methyl-7-[[6-[rac-(2R,6R)-2,6-dimethylmorpholin-4-yl]pyridazin-3-yl]amino]imidazo[4,5- b]pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 3, Ex.s. 81 B2-a 472 472 177

4-methyl-5-[3-methyl-7-[[6-[(2S)-2-propan-2-ylmorpholin-4-yl]pyridazin-3-yl]amino]imidazo[4,5-b] pyridin-5-yl]oxypyridine-2-carbonitrile Prov.s. 3, Ex.s. 82 B2-a 486 486 178

4-methyl-5-[3-methyl-7-[[5-(piperazin-1-carbonyl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile Comm. 128 D1 470 470 179

N7-(6-aminopyrimidin-4-yl)-N5-(1-cyclopropyl-2,2,2-trifluoroethyl)-3-methylimidazo[4,5-b]pyridine-5,7-diamine Prov.s. 26, [156-81-0] B1 378 380 180

4-methyl-5-[3-methyl-7-[(5-piperazin-1-yl-2-pyridyl)amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 88 D1 442 443 181

5-[7-[[5-[4-(dimethylamino)-1-piperidyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4- methyl-pyridine-2-carbonitrile Prov.s. 2, [1002317-13-6] B1 484 485 182

5-[7-[[5-[3-(dimethylamino)pyrrolidin-1-yl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4 -methyl-pyridine-2-carbonitrile Prov.s. 2, [748183-23-5] B1 470 471 183

5-[7-[[5-[2-methoxyethyl(methyl)amino]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl- pyridine-2-carbonitrile Prov.s. 2, [866620-42-0] B1 445 446 184

5-[7-[[5-[4-(hydroxymethyl)-1-piperidyl]-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4- methyl-pyridine-2-carbonitrile Prov.s. 2, [1152501-47-7] B1 471 472 185

5-[7-[[5-(dimethylamino)-2-pyridyl]amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridine-2-carbonitrile Prov.s. 2, [39856-52-5] B1 400 402 186

4-methyl-5-[3-methyl-7-[[1-(2-morpholinoethyl)pyrazol-4-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridin-2- carbonitrile Prov.s. 2, [1152961-27-7] B1 460 461 187

5-[[7-[(6-aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]-(2-hydroxypropyl)amino]-4-methyl- pyridine-2-carbonitrile Examplified Examplified 430 431 188

4-methyl-5-[3-methyl-7-[[5-(2,2,3,3,5,5,6,6-octadeuterio-4-methyl-piperazine-1-carbonyl)-2-pyridyl ]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 61, [917358-65-7] A1-a 492 492 189

4-methyl-5-[3-methyl-7-[[5-(2,2,6,6-tetradeuterio-4-methyl-piperazine-1-carbonyl)-2-pyridyl]amino]imidazo[4,5 -b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 61, [343864-02-8] A1-a 488 488 190

4-methyl-5-[3-methyl-7-[[5-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteriomethyl)piperazine-1-carbonyl]-2- pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridine-2-carbonitrile Prov.s. 3, Ex.s. 93 B2-a 495 495

Table IV. 1H NMR of final compounds

Conn.# ¹ H NMR one ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.74 (s, 1H), 8.54 (s, 1H), 8.21 (d, J =0.9 Hz, 1H), 8, 17 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 6.63 (s, 2H), 6.34 (d, J = 1.1 Hz, 1H), 3.59 (s, 3H), 2.32 (s, 3H). 2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.71 (s, 1H), 8.22 (d, J =0.9 Hz, 1H), 8.16 (s, 1H), 8, 14 (s, 1H), 7.80 (d, J = 7.4 Hz, 2H), 6.63 (s, 2H), 6.34 (d, J = 1.0 Hz, 1H), 3, 54 (s, 3H), 3.32 (s, 3H), 2.30 (s, 3H). 3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.83 (s, 1H), 8.37 (d, J=1.0 Hz, 1H), 8.29 (s, 1H), 8, 23 (s, 1H), 8.16 (d, J=1.0 Hz, 1H), 6.64 (s, 2H), 6.35 (d, J=1.0 Hz, 1H), 3, 70 (s, 3H), 2.42 (d, J=1.0 Hz, 3H). four ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.36 (s, 1H), 8.70 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.93 (d, J =0.9 Hz, 1H), 7.41 (s, 1H), 6.52 (s, 2H), 6.22 (d, J =1.1 Hz, 1H), 4.08 (dd, J =8.2, 6.4 Hz, 2H), 3.72 (s, 3H), 3.47 (d, J=12.2 Hz, 2H), 3.26 (s , 3H), 2.21 (s, 3H), 1.98 (n, J = 6.3 Hz, 2H). 5 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7 .88 (d, J=0.9 Hz, 1H), 7.36 (s, 1H), 6.48 (s, 2H), 6.17 (d, J=1.0 Hz, 1H), 4 .62 (s, 1H), 4.08-4.02 (m, 2H), 3.67 (s, 3H), 3.51 (t, J=6.2 Hz, 2H), 2.16 ( s, 3H), 1.82 (kv, J=6.8, 6.3 Hz, 2H). 6 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.20 (s, 1H), 8.54 (s, 1H), 8.39 (dd, J =2.3, 0.7 Hz, 1H ), 8.29 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.77 (dd, J = 8.6, 2.4 Hz, 1H), 7 .51 (dd, J= 8.7, 0.8 Hz, 1H), 3.61 (s, 3H), 3.52 (s, 4H), 2.34 (s, 4H), 2.29 ( e, J = 0.7 Hz, 3H). 7 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.21 (s, 1H), 8.54 (s, 1H), 8.42 (dd, J =2.4, 0.7 Hz, 1H ), 8.29 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.80 (dd, J =8.6, 2.4 Hz, 1H), 7 .52 (dd, J = 8.6, 0.8 Hz, 1H), 3.67-3.61 (m, 4H), 3.61 (s, 3H), 3.55 (s, 4H), 2.68 (kv, J =7.5 Hz, 2H), 1.19 (t, J =7.5 Hz, 3H). eight ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.23 (s, 1H), 7.96 (s, 1H), 7.87-7.81 (m, J=15.66, 9, 85, 7.33 Hz, 3H), 7.36 (s, 1H), 6.45 (s, 2H), 6.16 (s, 1H), 3.68 (s, 3H), 3.35 ( s, 3H), 2.59 (q, J=7.45 Hz, 2H), 1.14 (t, J=7.58 Hz, 3H). 9 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.3 (s, 1H), 8.63 (s, 1H), 8.08 (t, J=0.7 Hz, 1H), 8, 0 (s, 1H), 7.92 (d, J=0.9 Hz, 1H), 7.43 (s, 1H), 6.48 (s, 2H), 6.18 (d, J=1 .0 Hz, 1H), 3.67 (s, 3H), 3.48 (s, 3H), 2.18 (s, 3H). ten ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.01 (s, 1H), 8.15 (d, J=0.73 Hz, 1H), 7.87 (s, 1H), 7, 61 (s, 1H), 6.46 (s, 2H), 6.21 (d, J=0.78 Hz, 1H), 4.42-4.36 (m, J=0.0 Hz, 1H ), 3.67 (s, 3H), 2.73-2.66 (m, J=0.0 Hz, 1H), 2.15 (td, J=3.03, 2.52 Hz, 2H) , 1.73-1.58 (m, J=0.0 Hz, 6H). eleven ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.01 (s, 1H), 8.14 (d, J=0.9 Hz, 1H), 7.87 (s, 1H), 7, 69 (s, 1H), 6.45 (s, 2H), 6.22 (d, J=0.9 Hz, 1H), 4.8 (dd, J=12.63, 3.79 Hz, 1H ), 4.01 (dd, J=11.12, 4.55 Hz, 1H), 3.67 (s, 3H), 3.46-3.4 (m, J=11.37, 11.37 Hz, 2H), 3.23 (d, J=11.12 Hz, 1H), 2.92 (s, 3H), 2.22 (dt, J=25.01, 7.58 Hz, 1H), 1.39-1.32 (m, J=7.71 Hz, 1H), 1.08 (s, 3H), 0.79 (s, 3H). 12 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.97 (s, 1H), 8.14 (d, J=0.72 Hz, 1H), 7.85 (s, 1H), 7, 61 (s, 1H), 6.45 (s, 2H), 6.22 (d, J=0.81 Hz, 1H), 4.87 (q, J=7.07 Hz, 1H), 3, 67 (s, 3H), 2.89 (s, 3H), 1.16 (d, J=7.07 Hz, 3H), 0.95 (s, 9H). 13 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.04 (s, 1H), 8.15 (d, J=1.0 Hz, 1H), 7.88 (s, 1H), 7, 67 (s, 1H), 6.45 (s, 1H), 6.22 (d, J=1.0 Hz, 1H), 3.68 (s, 3H), 3.35 (s, 1H), 2.87 (s, 3H), 2.01-1.44 (m, J=0.0 Hz, 8H). fifteen 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.29 (s, 1H), 8.61 (s, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7 .89 (d, J=1.0 Hz, 1H), 7.40 (s, 1H), 6.47 (s, 2H), 6.18 (d, J=1.0 Hz, 1H), 3 .67 (s, 3H), 3.47 (s, 3H), 2.53 (s, 2H), 1.14 (t, J=7.5 Hz, 3H). 16 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.95 (s, 1H), 8.13 (d, J=0.73 Hz, 1H), 7.84 p (s, 1H), 7 .53 (s, 1H), 6.45 (s, 2H), 6.21 (d, J=0.95 Hz, 1H), 4.15-4.08 (m, J=5.3 Hz, 1H), 3.65 (s, 3H), 2.95 (s, 3H), 1.19 ppm (d, J=6.79 Hz, 3H), 1.1-1.04 (m, 1H) , 0.58-0.51 (m, 1H), 0.4-0.29 (m, 2H), 0.27-0.21 (m, 1H). 17 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.02 (s, 1H), 8.16 (d, J=0.9 Hz, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 6.46 (s, 2H), 6.23 (d, J=1.0 Hz, 1H), 4.39 (td, J=11.2, 3.8 Hz, 1H) , 3.98 (dd, J=11.3, 4.5 Hz, 1H), 3.89 (dd, J=11.2, 4.4 Hz, 1H), 3.68 (s, 3H), 3.52-3.41 (m, 1H), 3.08 (t, J=11.0 Hz, 1H), 2.88 (s, 3H), 2.02-1.88 (m, 1H) , 1.78 (qvd, J=12.3, 4.7 Hz, 1H), 1.56 (d, J=9.0 Hz, 1H), 0.69 (d, J=6.6 Hz, 3H). eighteen 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.14 (s, 1H), 8.14 (d, J=0.76 Hz, 1H), 8.0 (s, 1H), 7.9 (s, 1H), 6.47 (s, 2H), 6.23 (d, J=0.76 Hz, 1H), 3.68 (s, 3H), 3.0 (s, 3H), 2 .49 (s, 1H), 2.23 (s, 6H). twenty 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.17 (s, 1H), 8.16 (d, J=0.9 Hz, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 6.49 (s, 2H), 6.25 (d, J=1.0 Hz, 1H), 4.99 (q, J=9.0 Hz, 1H), 3.64 (s, 3H), 3.06 (s, 3H), 1.48-1.35 (m, 1H), 0.87-0.69 (m, 1H), 0.64 (dt, J=9 .7, 4.7 Hz, 1H), 0.57 (dt, J=9.6, 4.8 Hz, 1H), 0.20 (dd, J=4.7, 1.3 Hz, 1H) . 21 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.05 (s, 1H), 8.10 (d, J=0.9 Hz, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 6.46 (s, 2H), 6.23 (d, J=1.0 Hz, 1H), 4.60 (t, J=12.3 Hz, 1H), 3.77 (dd, J=11.8, 3.8 Hz, 1H), 3.67 (s, 3H), 3.50 (dd, J=12.4, 10.2 Hz, 1H), 2.91 ( s, 3H), 2.36-2.21 (m, 2H), 2.11-1.47 (m, 9H). 22 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.4 (d, J=7.32 Hz, 1H), 8.82 (d, J=2.3 Hz, 1H), 8.2 ( s, 1H), 8.13 (dd, J=8.85, 2.53 Hz, 1H), 7.98 (s, 1H), 7.6 (d, J=8.85 Hz, 1H), 5.46 (ddd, J=24.49, 2.8, 2.02 Hz, 1H), 3.76 (d, J=8.1 Hz, 3H), 3.27 (dd, J=2, 53, 1.52 Hz, 3H), 1.34-1.25 (m, 1H), 0.77-0.59 ppm (m, 4H). 23 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.53 (s, 1H), 9.12 (t, J=6.0 Hz, 1H), 8.60 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.09 (d, J=9.2 Hz, 1H), 7.89 (d, J=9, 2 Hz, 1H), 3.64 (s, 3H), 3.33 (m, J=7.3 Hz, 2H), 2.31 (s, 3H), 1.16 (t, J=7, 2 Hz, 3H). 24 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.23 (s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.56 (s, 1H), 8.51 (dd, J=9.8, 4.1 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 8.19-8.04 (m, 2H), 7, 49 (d, J=8.7 Hz, 1H), 4.96-4.73 (m, 1H), 3.80 (dt, J=12.3, 6.0 Hz, 1H), 3.61 (s, 3H), 3.28-3.08 (m, 2H), 2.30 (s, 3H), 1.07 (s, 3H). 25 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.48 (s, 1H), 8.88 (t, J=5.9 Hz, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.89 (d, J=9, 2 Hz, 1H), 4.89 (s, 1H), 3.91-3.77 (m, 1H), 3.64 (s, 3H), 3.33-3.21 (m, 2H), 2.31 (s, 3H), 1.09 (d, J=6.2 Hz, 3H). 26 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.76 (s, 1H), 8.68 (dd, J=2.6, 0.8 Hz, 1H), 8.64 (t, J= 6.1 Hz, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 8.11 (d, J=0.8 Hz, 1H), 8.00 (dd, J= 8.6, 0.8 Hz, 1H), 7.95 (dd, J=8.5, 2.6 Hz, 1H), 6.70 (s, 1H), 3.60 (s, 3H), 3.38-3.27 (m, 2H), 2.28 (d, J=0.7 Hz, 3H), 1.13 (td, J=7.2, 3.5 Hz, 3H). 27 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.21 (s, 1H), 8.49 (s, 1H), 8.11 (s, 1H), 8.07 (d, J=0, 7 Hz, 1H), 8.01 (t, J=5.4 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz , 2H), 6.45 (s, 1H), 3.58 (s, 3H), 3.37 (s, 2H), 3.14-3.02 (m, 2H), 2.25 (d, J=0.7 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H). 28 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.69 (s, 1H), 8.64 (dd, J=2.7, 0.7 Hz, 1H), 8.53 (s, 1H) , 8.18 (s, 1H), 8.10 (t, J=0.8 Hz, 1H), 7.93 (dd, J=8.5, 2.7 Hz, 1H), 7.66 ( dd, J=8.5, 0.7 Hz, 1H), 6.68 (s, 1H), 3.63 (m, J=22.7 Hz, 11H), 2.28 (s, 3H). 29 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.68 (s, 1H), 8.67 (dd, J=2.6, 0.8 Hz, 1H), 8.61 (q, J= 4.9 Hz, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 8.04-7.97 (m, 1H), 7, 95 (dd, J=8.5, 2.6Hz, 1H), 6.70 (s, 1H), 3.60 (s, 3H), 2.83 (d, J=4.7Hz, 3H ), 2.28 (s, 3H). thirty 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.78 (s, 1H), 8.69 (dd, J=2.6, 0.8 Hz, 1H), 8.54 (s, 1H) , 8.47 (t, J=6.0 Hz, 1H), 8.18 (s, 1H), 8.10 (d, J=0.7 Hz, 1H), 8.01 (dd, J= 8.5, 0.7 Hz, 1H), 7.95 (dd, J=8.5, 2.6 Hz, 1H), 6.70 (s, 1H), 4.85 (s, 1H), 3.86-3.74(m, 1H), 3.60(s, 3H), 3.41-3.29(m, 1H), 3.24-3.14(m, 1H), 2, 28 (d, J=0.7 Hz, 3H), 1.07 (s, 3H). 32 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.73 (s, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 8.18 (s, 2H), 8 .11 (s, 1H), 7.17 (s, 1H), 6.41 (s, 1H), 3.59 (s, 3H), 3.41-3.38 (m, J=6.39 , 6.23 Hz, 4H), 3.25 (s, 3H), 2.28 (s, 3H), 1.8-1.73 (m, J=6.59 Hz, 2H), 33 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.72 (s, 1H), 8.52 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8 .18 (s, 1H), 8.11 (s, 1H), 7.07 (s, 1H), 6.38 (s, 1H), 4.35 (s, 1H), 3.31-3, 22 (m, 4H), 2.28 (s, 3H), 1.65 (dd, J=7.87, 5.86 Hz, 2H), 1.15 (s, 6H). 35 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.75 (s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 8.19 (s, 2H), 8 .18 (s, 2H), 8.12 (t, J=0.7 Hz, 1H), 7.28 (s, 1H), 6.44 (s, 1H), 3.76 (d, J= 11.3 Hz, 2H), 3.72-3.46 (m, 7H), 3.44 (s, 1H), 3.25 (dd, J=11.4, 9.8 Hz, 2H), 2.29 (d, J=0.7 Hz, 3H). 36 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.77 (s, 1H), 8.53 (s, 1H), 8.26 (s, 1H), 8.19 (s, 2H), 8 .11 (s, 1H), 7.44 (d, J=6.7 Hz, 1H), 6.37 (s, 1H), 3.59 (s, 4H), 3.29 (d, J= 1.7 Hz, 1H), 3.16 (d, J=6.8 Hz, 3H), 2.73-2.63 (m, 2H), 2.29 (d, J=0.7 Hz, 3H), 1.80 (dt, J=11.6, 8.8 Hz, 2H). 37 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.72 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8 .15-8.08 (m, 1H), 7.12 (s, 1H), 6.89 (s, 1H), 6.40 (s, 1H), 4.55 (d, J=4.8 Hz, 1H), 3.70 (s, 1H), 3.59 (s, 3H), 3.30 (d, J=16.8 Hz, 2H), 2.29 (d, J=0.7 Hz, 3H), 1.58 (dKV, J=13.7, 7.0, 6.6 Hz, 2H), 1.11 (s, 3H). 38 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.86 (s, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 8 .15-8.08 (m, 1H), 7.64 (d, J=9.7 Hz, 1H), 7.43 (d, J=9.7 Hz, 1H), 3.75 (t, J=4.8 Hz, 4H), 3.61 (s, 3H), 3.50-3.42 (m, 4H), 2.31 (d, J=0.7 Hz, 3H). 39 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.83 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.18 (s, 1H), 8 .11 (d, J=0.7 Hz, 1H), 7.60 (d, J=9.7 Hz, 1H), 7.42 (d, J=9.8 Hz, 1H), 3.61 (s, 3H), 3.50 (t, J=5.0 Hz, 4H), 2.44 (t, J=4.9 Hz, 4H), 2.31 (d, J=0.7 Hz , 3H), 2.24 (s, 3H), 41 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.81 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.18 (s, 1H), 8 .11 (s, 1H), 7.60 (d, J=9.7 Hz, 1H), 7.44 (d, J=9.8 Hz, 1H), 4.14-4.03 (m, 2H), 3.61 (s, 3H), 2.65-2.54 (m, 2H), 2.31 (s, 3H), 2.26-2.14 (m, 5H), 1.09 (d, J=6.1 Hz, 6H). 42 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.84 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.19 (s, 1H), 8 .11 (d, J=0.7 Hz, 1H), 7.62 (d, J=9.8 Hz, 1H), 7.43 (d, J=9.8 Hz, 1H), 3.61 (s, 3H), 3.52 (t, J=5.0 Hz, 4H), 3.26 (kv, J=10.2 Hz, 2H), 2.76 (t, J=5.0 Hz , 4H), 2.31 (d, J=0.7 Hz, 3H). 43 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.83 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.19 (s, 1H), 8 .11 (t, J=0.7 Hz, 1H), 7.62 (d, J=9.7 Hz, 1H), 7.42 (d, J=9.8 Hz, 1H), 4.21 -3.97 (m, 2H), 3.67 (ddd, J=10.5, 6.3, 2.4 Hz, 2H), 3.62 (s, 3H), 2.49-2.40 (m, 2H), 2.31 (d, J=0.7 Hz, 3H), 1.17 (d, J=6.2 Hz, 6H). 44 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.84 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.19 (s, 1H), 8 .12 (t, J=0.7 Hz, 1H), 7.63 (d, J=9.8 Hz, 1H), 7.43 (d, J=9.8 Hz, 1H), 4.10 (d, J=12.4 Hz, 1H), 3.99 (d, J=12.8 Hz, 1H), 3.94 (ddd, J=11.5, 3.7, 1.2 Hz, 1H), 3.71-3.53 (m, 4H), 2.87 (td, J=12.4, 3.5 Hz, 1H), 2.60-2.52 (m, 2H), 2 .31 (d, J=0.7 Hz, 3H), 1.17 (d, J=6.2 Hz, 3H). 45 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.84 (s, 1H), 8.53 (s, 1H), 8.19 (d, J=0.9 Hz, 2H), 8.12 (s, 1H), 7.62 (d, J=9.8 Hz, 1H), 7.45 (d, J=9.8 Hz, 1H), 3.81 (ddd, J=13.3, 6.5, 3.6 Hz, 2H), 3.61 (s, 3H), 3.40 (dd, J=9.0, 3.5 Hz, 2H), 3.20-3.09 (m , 1H), 2.37-2.25 (m, 3H), 2.06-1.89 (m, 2H), 1.78 (dtd, J=12.5, 8.6, 3.5 Hz , 2H). 49 1H NMR (400 MHz, (DMSO-d ₆ ) δ ppm: 9.69 (s, 1H), 8.5 (s, 1H), 8.14 (s, 1H), 8.11 (s, 1H) , 8.1 (s, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.46 (dd, J=9.1, 3.0 Hz, 1H), 7.37 ( e, J=9.1 Hz, 1H), 3.75 (m, 4H), 3.58 (s, 3H), 3.09 (m, 4H), 2.28 (s, 3H). fifty 1H NMR (400 MHz, (DMSO-d ₆ ) δ ppm : 9.66 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H) , 8.1 (s, 2H), 7.99 (d, J=3.0 Hz, 1H), 7.45 (dd, J=9.1, 3.0 Hz, 1H), 7.34 ( d, J=8.9 Hz, 1H), 3.58 (s, 3H), 3.11 (m, 4H), 2.47 (m, 4H), 2.27 (s, 3H), 2, 22 (s, 3H). 51 1H NMR (400 MHz, (DMSO-d ₆ ) δ ppm : 10.19 (s, 1H), 8.53 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8 .28 (s, 1H), 8.20 (s, 2H), 8.10 (s, 1H), 7.76 (dd, J=8.6, 2.5 Hz, 1H), 3.53 ( s br, 3H), 2.35 (s, 4H), 2.28 (s, 3H), 2.2 (s, 3H). 52 ¹ H NMR 400 MHz, (DMSO-d ₆ ) δ ppm): 9.71 (s, 1H), 8.52 (s, 1H), 8.2 (d, J=0.6 Hz, 1H), 8.17 (s, 1H), 8.16 (s, 1H), 8.1 (s, 1H), 6.6 (s, 2H), 6.34 (d, J=0.6 Hz, 1H ), 3.58 (s, 3H), 2.28 (s, 3H). 53 1H NMR (400 MHz, CDCl3) δ ppm: 8.49 (s, 1H), 8.01 (s, 1H), 7.90 (dd, J=6.8, 2.0 Hz, 2H), 7 .86 (s, 1H), 7.64 (s, 1H), 7.46 (dd, J=6.8, 2.0 Hz, 2H), 6.83 (s, 1H), 4.68 ( t, J=6.1 Hz, 1H), 3.69 (s, 3H), 3.06 (dkv, J=7.3, 6.8 Hz, 2H), 2.33 (s, 3H), 1.15 (t, J=7.3 Hz, 3H). 54 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm : 9.55 (s, 1H), 8.22 (s, 1H), 8.12 (d, J=5.11 Hz, 1H), 7, 85 (s, 1H), 6.60 (m, 2H), 6.3 (d, J=0.94 Hz, 1H), 5.43 (dt, J=15.42, 6.82 Hz, 1H ), 3.72 ppm (s, 3H), 1.32-1.23 ppm (m, 1H), 0.75-0.69 ppm (m, 1H), 0.67-0.57 ppm (m , 3H). 55 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.45 (s, 1H), 9.39 (s, 1H), 8.73 (s, 1H), 8.21 p (s, 1H ), 8.08 (s, 1H), 8.02 (s, 1H), 7.82 (s, 1H), 6.57 (s, 2H), 6.28 (d, J=0.8 Hz , 1H), 3.72 (s, 3H), 2.37 (s, 3H). 56 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.61 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.16 (s, 1H) , 8.09 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 7.49 (dd, J= 8.1, 1.6 Hz, 1H), 6.7 (s, 1H), 4.36 (s, 2H), 3.58 ppm (s, 3H), 2.25 ppm (s, 3H). 57 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.34 (s, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H) , 8.07 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.48 (s, 1H) , 4.32 (s, 3H), 3.90 (s, 2H), 3.57 (s, 3H), 2.24 (s, 3H). 58 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.55 (s, 1H), 8.79 (d, J=2.5 Hz, 1H), 8.57 (s, 1H), 8 .27 (s, 1H), 8.25 (s, 1H), 8.15 (dd, J=8.8, 2.5 Hz, 1H), 8.13 (s, 1H), 7.64 ( e, J=8.8 Hz, 1H), 3.62 (s, 3H), 3.26 (s, 3H), 2.30 (s, 3H). 59 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.43 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8 .28 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.07 (dd, J=9.0, 2.0 Hz, 1H), 7.64 ( e, J=9.0 Hz, 1H), 3.62 (s, 3H), 2.29 (s, 3H). 60 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.85 (s, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H) , 7.92 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 6.83 (s, 1H), 3.65 (s, 3H) , 3.37 (s, 3H), 2.33 (s, 3H). 61 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.81 (s, 1H), 8.39 (s, 1H), 8.0 (s, 1H), 7.99 (s, 1H) , 7.79 (s, 1H), 7.43 (s, 1H), 6.17 (s, 1H), 3.77 (s, 3H), 3.49 (s, 3H), 2.18 ( s, 3H). 62 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.46 (s, 1H), 8.51 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 6.63 (s, 1H), 3.58 (s, 3H), 2.98 (s, 6H), 2.26 (s, 3H). 63 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.81 (s, 1H), 8.54 (s, 1H), 8.19 (s, 1H), 8.1 (s, 1H) , 7.69 (d, J=8.9 Hz, 2H), 7.63 (d, J=8.9 Hz, 2H), 6.81 (s, 1H), 3.65 (t, J= 4.7 Hz, 4H), 3.60 (s, 3H), 2.88 (t, J=4.7 Hz, 4H), 2.28 (s, 3H). 64 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.94 (s, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.30 (t, J= 5.4 Hz, 1H), 8.23 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.32 (s, 1H), 3.6 (s, 3H), 3.25 (qvd, J=7.2, 5.4 Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H), 1.12 (t, J=7 .2 Hz, 3H). 65 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.0 (s, 1H), 8.71 (d, J=2.31 Hz, 1H), 8.08 (dd, J=8.97 , 2.54 Hz, 1H), 7.93 (s, 1H), 7.8 (s, 1H), 7.5 (d, J=8.85 Hz, 1H), 6.98 (d, J =9.83Hz, 1H), 5.01(td, J=9.1, 5.81Hz, 1H), 3.72-3.69(s, 3H), 3.25(s, 3H) , 2.17 (td, J=12.63, 6.81 Hz, 1H), 1.01 (t, J=7.7 Hz, 6H). 66 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.62 (s, 1H), 9.14 (s, 1H), 8.48 (s, 1H), 8.04 (s, 1H) , 7.79 (s, 1H), 7.45 (d, J=9.1 Hz, 2H), 7.42 (d, J=9.1 Hz, 2H), 6.92 (s, 1H) , 3.72 (s, 3H), 2.99 (s, 6H), 2.33 (s, 3H). 67 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.82 (s, 1H), 9.47 (s, 1H), 8.73 (s, 1H), 8.39 (dd, J= 2.4, 0.5 Hz, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.82 (s, 1H), 7.77 (dd, J=8.6 , 2.4 Hz, 1H), 7.43 (dd, J=8.6, 0.5 Hz, 1H), 3.72 (s, 3H), 3.0 (s, 6H), 2.37 (s, 3H). 68 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.09 (s, 1H), 8.56 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H) , 7.86 (d, J=9.0 Hz, 2H), 7.67 (d, J=9.0 Hz, 2H), 7.24 (t, JHF=52.4 Hz, 1H), 6 .87 (s, 1H), 3.60 (s, 3H), 2.27 (s, 3H). 69 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.83 (s, 1H), 8.54 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H) , 7.82 (dt, J=9.5, 2.4 Hz, 2H), 7.6 (dt, J=9.5, 2.4 Hz, 2H), 6.78 (s, 1H), 3.59 (s, 3H), 2.85-2.79 (m, 1H), 2.27 (s, 3H), 1.13-1.09 (m, 2H), 1.07-1, 01 (m, 2H). 70 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.33 (s, 1H), 9.29 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H) , 8.08 (s, 1H), 7.26 (d, J=8.1 Hz, 1H), 6.99 (dd, J=8.1, 2.0 Hz, 1H), 6.91 ( e, J=2.0 Hz, 1H), 6.52 (s, 1H), 3.57 (s, 3H), 2.24 (s, 3H), 1.25 (s, 6H). 71 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.85 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.09 (s, 1H) , 7.82 (dt, J=9.5, 2.6 Hz, 2H), 7.61 (dt, J=9.5, 2.6 Hz, 2H), 6.79 (s, 1H), 3.59 (s, 3H), 3.34 (t, J=6.7 Hz, 2H), 3.28-3.24 (m, 2H), 3.17 (s, 3H), 2.26 (s, 3H), 1.81-1.74 (m, 2H). 73 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.43 (s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.25 (s, 1H) , 8.11 (s, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.78 (d, J=9.2 Hz, 1H), 3.62 (s, 3H) , 3.08 (s, 3H), 3.06 (s, 3H), 2.30 (s, 3H). 74 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.19 (s, 1H), 8.54 (s, 1H), 8.42 (d, J=2.3 Hz, 1H), 8 .29 (s, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.79 (dd, J=8.6, 2.3 Hz, 1H), 7.5 ( dd, J=8.6, 0.5 Hz, 1H), 3.6 (s, 3H), 3.0 (s, 6H), 2.28 (s, 3H), 75 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.21 (s, 1H), 8.53 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8 .29 (s, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.79 (dd, J=8.6, 2.4 Hz, 1H), 7.51 ( dd, J=8.6, 0.5 Hz, 1H), 3.64-3.61 (m, 4H), 3.6 (s, 3H), 3.55-3.52 (m, 4H) , 2.28 (s, 3H). 76 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.08 (s, 1H), 9.48 (s, 1H), 8.91 (s, 1H), 8.29 (s, 1H) , 8.13 (s, 1H), 7.82 (s, 1H), 7.81(d, J=9.2 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H) , 3.73 (s, 3H), 3.10 (s, 3H), 3.06 (s, 3H), 2.37 (s, 3H). 77 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.04 (s, 1H), 8.59 (s, 1H), 8.3 (s, 1H), 8.21 (s, 1H) , 8.15 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.65 (s, 3H) , 3.0 (s, 3H), 2.82 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H). 78 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.04 (s, 1H, NH), 8.60 (s, 1H), 8.29 (s, 1H), 8.25 (t, J=5.4Hz, 1H, NH), 8.21(s, 1H), 8.16(s, 1H), 7.66(d, J=8.5Hz, 1H), 7.26( d, J=8.5 Hz, 1H), 3.65 (s, 3H), 3.25 (m, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 1, 11 (t, J=7.2 Hz, 3H). 79 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.09 (s, 1H), 8.54 (s, 1H), 8.33 (d, J=2.2 Hz, 1H), 8 .28 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.74 (dd, J=8.6, 2.2 Hz, 1H), 7.53 ( d, J=8.6Hz, 1H), 4.51(q, JHF=9.7Hz, 1H), 3.60(s, 3H) 2.29(s, 3H), 2.25(s , 6H). 80 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.01 (s, 1H), 8.54 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 8 .26 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.83 (dd, J=8.5, 2.0 Hz, 1H), 7.49 ( d, J=8.5 Hz, 1H), 4.47-4.35 (m, 1H), 3.60 (s, 3H), 2.53-2.46 (m, 2H), 2.83 -2.73 (m, 1H), 2.29 (s, 3H), 1.01 (t, J=7.1 Hz, 3H). 81 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.93 (s, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 8.23 (s, 2H) , 8.17 (s, 1H), 8.08 (s, 1H), 7.66 (dd, J=8.5, 2.3 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 4.81 (s, 1H), 3.59 (s, 3H), 3.53 (s, 2H), 2.27 (s, 3H), 2.25 (s, 6H). 82 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.89 (s, 1H), 8.52 (s, 1H), 8.24 (s, 2H), 8.21 (d, J= 2.0 Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.63 (dd, J=8.6, 2.3 Hz, 1H), 7.42 ( d, J=8.6 Hz, 1H), 4.51 (s, 1H), 3.59 (s, 3H), 3.56 (t, J=4.4 Hz, 4H), 3.42 ( s, 2H), 2.35 (t, J=4.0 Hz, 4H), 2.28 (s, 3H). 83 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.89 (s, 1H), 8.52 (s, 1H), 8.25 (s, 2H), 8.22 (d, J= 2.2 Hz, 1H), 8.17 (s, 1H), 8.1 (s, 1H), 7.65 (dd, J=8.5, 2.2 Hz, 1H), 7.43 ( d, J=8.5 Hz, 1H), 4.27-4.15 (m, 1H), 3.59 (s, 3H), 3.48 (s, 2H), 2.67 (t, J =6.8Hz, 2H), 2.52(t, J=6.8Hz, 2H), 2.35(s, 6H), 2.28(s, 3H), 2.14(s, 3H ). 84 ¹H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.76 (s, 1H), 8.51 (s, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 8.10 (s, 1H), 8.06 (t, J=1.9 Hz, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 3.80 (s, 3H ), 3.58 (s, 3H), 2.28 (s, 3H). 85 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.70 (s, 1H), 8.50 (s, 1H), 8.14 (s, 1H), 8.12 (s, 1H) , 8.10 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.44 (dd, J=9.0, 2.8 Hz, 1H), 7.38 ( d, J=9.0 Hz, 1H), 3.88-3.61 (m, 5H), 3.58 (s, 3H), 3.12-3.00 (m, 2H), 2.28 (s, 3H), 0.95 (d, J=6.3 Hz, 3H). 86 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.77 (s, 1H), 8.50 (s, 1H), 8.14 (s, 1H), 8.11 (s, 1H) , 8.10 (s, 1H), 8.06 (d, J=2.8 Hz, 1H), 7.45 (dd, J=8.9, 2.8 Hz, 1H), 7.41 ( e, J=8.9 Hz, 1H), 4.33 (septuplet, J=4.0 Hz, 1H), 3.58 (s, 3H), 2.69-2.61 (m, J=3 .8 Hz, 2H), 2.28 (s, 3H), 2.18 (s, 3H), 1.95-1.91 (m, 2H), 1.65-1.62 (m, 2H) , 1.67-1.59 (m, 2H). 87 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.84 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 8.22 (d, J= 2.5 Hz, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.65 (dd, J=8.7, 2.5 Hz, 1H), 7.41 ( d, J=8.7 Hz, 1H), 3.95 (td, J=5.8, 3.0 Hz, 2H), 3.59 (s, 3H), 3.47-3.40 (m , 2H), 2.81-2.74 (m, J=5.2 Hz, 1H), 2.28 (s, 3H), 1.72-1.66 (m, 4H). 88 1H NMR (300 MHz, DMSO-d6,) δ ppm 9.34 (s, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 8.16 (s, 1H), 7, 97 (s, 1H), 7.95 (s, 1H), 6.51 (br s, 2H), 6.25 (s, 1H), 3.46 (s, 3H), 3.22- 3.12 (m, 1H), 2.09 (s, 3H), 1.05-0.95 (m, 2H), 0.57-0.48 (m, 2H). 89 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.31 (s, 1H), 8.49 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H), 6.50 (s, 1H), 6.33 (s, 1H), 4.77 (d, J=6.6 Hz, 2H), 4.71 (d, J=6.6 Hz, 2H), 3.57 (s, 3H), 2.24 (s, 3H). 90 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.05 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 8.2 (s, 1H), 8.11 (s, 1H), 7.79 (d, J=9.5 Hz, 1H), 7.25 (d, J=9.5 Hz, 1H), 5.2 (quintuplet, J=5 .7 Hz, 1H), 3.76-3.72 (m, 2H), 3.60 (s, 3H), 3.06-3.02 ppm (m, 2H), 2.30 ppm (s, 6H). 94 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.89 (s, 1H), 8.14 (s, 1H), 7.79 (s, 1H), 7.31 (s, 1H) , 6.47 (s, 2H), 6.17 (d, J=0.79 Hz, 1H), 6.15 (d, J=8.34 Hz, 1H), 4.03-3.98 ( m, 1H), 3.65 (s, 3H), 2.41-2.33 (m, 1H), 1.98-1.9 (m, 2H), 1.86-1.69 (m, 4H), 1.02 (d, J=6.34 Hz, 3H). 96 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.29 (s, 1H), 8.6 (d, J=2.03 Hz, 1H), 8.55 (s, 1H), 8 .32 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.95 (dd, J=8.77, 2.45 Hz, 1H), 7.51 ( d, J=8.82 Hz, 1H), 5.8 (d, J=5.81 Hz, 1H), 4.58-4.5 (m, 2H), 4.28-4.24 (m , 1H), 4.15-4.12 (m, 1H), 3.82-3.78 (m, 1H), 3.61 (s, 3H), 2.29 (s, 3H). 97 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.54 (s, 1H), 8.37 (d, J=2.27 Hz, 1H), 7.89 (s, 1H), 7 .77 (d, J=2.73 Hz, 1H), 7.77 (s, 1H), 7.39 (d, J=8.61 Hz, 1H), 6.95 (d, J=9, 83 Hz, 1H), 5.07-4.96 (m, 1H), 3.69 (s, 3H), 2.99 (s, 6H), 2.21-2.13 (m, 1H), 1.02 (dd, J=16.67, 9.61 Hz, 6H). 98 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm : 9.05 ppm (s, 1H), 8.17 (d, J=0.5 Hz, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 6.92 (d, J=9.61 Hz, 1H), 6.5 (s, 2H), 6.21 (d, J=0.74 Hz, 1H), 5.02-4.95 (m, 1H), 3.66 (s, 3H), 2.16 (dq, J=19.47, 6.59 Hz, 1H), 1.0 (t, J= 6.83 Hz, 6H). 100 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.26 (s, 1H), 8.79 (d, J=2.28 Hz, 1H), 8.57 (s, 1H), 8 .46 (t, J=5.56 Hz, 1H), 8.27 (d, J=10.39 Hz, 2H), 8.14 (d, J=2.27 Hz, 1H), 8.1 (dd, J=8.8, 2.48 Hz, 1H), 7.48 (d, J=8.61 Hz, 1H), 3.62 (s, 3H), 3.41-3.29 ( m, 4H), 3.25 (s, 3H), 3.31 (s, 3H), 1.80-1.73 (m, 2H). 101 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.27-10.2 (m, 1H), 8.79 (d, J=2.04 Hz, 1H), 8.57 (s, 1H), 8.44 (t, J=5.56 Hz, 1H), 8.3 (d, J=3.45 Hz, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 8.1 (dd, J=8.8, 2.48 Hz, 1H), 7.5 (d, J=8.83 Hz, 1H), 4.55-4.47 (m, 1H ), 3.6 (s, 3H), 3.49-3.33 ppm (m, 4H), 2.3 ppm (s, 3H), 1.72-1.66 (m, 2H), 102 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.29 (s, 1H), 8.62 (d, J=2.28 Hz, 1H), 8.55 (s, 1H), 8 .31 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.96 (dd, J=8.78, 2.45 Hz, 1H), 7.51 ( d, J=8.82 Hz, 1H), 4.37-4.32 (m, 1H), 4.27-4.23 (m, 1H), 4.0-3.91 (m, 2H) , 3.61 (s, 3H), 2.65-2.57 (m, 1H), 2.29 (s, 3H), 1.05 (d, J=4.3 Hz, 6H). 103 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.31 (s, 1H), 8.63 (d, J=2.49 Hz, 1H), 8.55 (s, 1H), 8 .3 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.97 (dd, J=8.76, 2.45 Hz, 1H), 7.51 ( d, J=8.61 Hz, 1H), 4.60-4.54 ppm (m, 1H), 4.30-4.24 (m, 3H), 3.84-382 (m, 1H), 3.61 (s, 3H), 3.25 (s, 3H), 2.29 ppm (s, 3H). 105 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.19 (s, 1H), 8.53 (s, 1H), 8.38 (d, J=2.27 Hz, 1H), 8 .28 (s, 1H), 8.2 (s, 1H), 8.11 (s, 1H), 7.76 (dd, J=8.59, 2.33 Hz, 1H), 7.51- 7.49 (m, 1H), 3.6 (s, 3H), 3.52 (s, 4H), 2.34 (s, 4H), 2.28 (s, 3H), 2.2 (s , 3H) 107 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.23 (s, 1H), 8.55 (s, 2H), 8.31 (d, J=3.29 Hz, 1H), 8 .22 (s, 1H), 8.15 (s, 1H), 8.14 (d, J=5.5 Hz, 2H), 7.92-7.89 (m, 1H), 7.51 ( d, J=8.64 Hz, 1H), 3.85-3.52 (m, 6H), 2.96-2.66 (m, 2H), 2.3 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 2.15-2.02 (m, 1H), 1.84-1.7 (m, 1H). 108 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.58 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H) , 7.86 (dd, J=16.05, 9.2 Hz, 2H), 3.71 (s, 4H), 3.63 (s, 8H), 2.31 (s, 3H). 113 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.37 (d, J=2.06 Hz, 1H), 8.31 (s, 1H), 8.15-8.06 (m, 2H), 7.98 (s, 1H), 7.89 (s, 1H), 7.72 (dd, J=8.66, 2.34 Hz, 1H), 7.27 (d, J=8 .78 Hz, 1H), 3.99-3.84 (m, 2H), 3.66-3.53 (m, 2H), 3.36 ppm (s, 3H), 2.03 (s, 3H ), 0.96 (dkv, J=13.73, 5.35 Hz, 1H), 0.19-0.05 (m, 4H). 125 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.34 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.43 (d, J= 2.19 Hz, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.83 (dd, J=8.44, 2.21 Hz, 1H), 7.37 ( d, J=8.6 Hz, 1H), 4.00-3.77 (m, 2H), 3.67 (s, 3H), 3.51-3.33 (s, 1H), 3.33 -3.24(m, 5H), 2.28(s, 3H), 1.94-1.82(m, 2H), 1.53-1.45(m, 2H). 126 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.22 (s, 1H), 8.54 (s, 1H), 8.43 (d, J=2.19 Hz, 1H), 8 .3 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.79 ppm (dd, J=8.6, 2.37 Hz, 0H), 7.53 (d, J=8.6 Hz, 0H), 4.61-3.78 (m, 2H), 3.60 (s, 3H), 3.33-2.79 (m, 3H), 2, 69 (s, 6H), 2.32 (s, 3H), 2.08-1.81 (m, 2H), 1.69-1.5 (m, 2H). 134 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.28 (s, 1H), 8.59 (d, J=2.37 Hz, 1H), 8.55 (s, 1H), 8 .28 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.93 (dd, J=8.77, 2.37 Hz, 1H), 7.5 ( d, J=8.61 Hz, 1H), 4.73-4.66 (m, 4H), 4.57 (s, 2H), 4.22 (s, 2H), 3.61 (s, 3H ), 2.29 (s, 3H). 137 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.32 (s, 1H), 8.62 (d, J=2.37 Hz, 1H), 8.56 (s, 1H), 8, 38 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.97 (dd, J=8.77, 2.38 Hz, 1H), 7.46 (d , J=8.78 Hz, 1H), 4.62-4.53 (m, 1H), 4.43 (m, 1H), 4.35-4.21 (m, 2H), 3.88- 3.77 (m, 1H), 3.65-3.45 (m, 1H), 2.29 (s, 3H), 1.1 (d, J=6.04 Hz, 6H). 138 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm : 10.32 (s, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 8.42 (d, J=2 .19 Hz, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.82 (dd, J=8.59, 2.37 Hz, 1H), 7.37 (d , J=8.6 Hz, 1H), 3.67 (s, 3H), 3.55-3.17 (m, 4H), 2.28 (s, 3H), 1.59-1.42 ( m, 4H), 1.17 (s, 3H). 142 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.36 (s, 1H), 8.61-8.56 (m, 3H), 8.14 (s, 1H), 8.11 (s , 1H), 7.98 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 5.35-5.18 (m, 1H), 4 .17-3.56 (m, 8H), 3.34 (d, J=36.77 Hz, 3H), 2.29 (s, 3H). 143 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.79 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 7.6 (d, J=9.54 Hz, 1H), 6.94 (d, J=9.43 Hz, 1H), 4.07-4.03 (m , 2H), 3.8-3.77 (m, 2H), 3.64 (s, 3H), 3.28-3.17 (m, 1H), 2.3 (d, J=4.54 Hz, 3H), 2.13 (s, 6H). 144 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.24 (s, 1H), 8.55 (s, 1H), 8.42-8.4 (m, 1H), 8.29 (s , 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.81-7.78 (m, 1H), 7.5 (d, J=8.81 Hz, 1H) , 4.4-3.97 (m, , 2H), 3.61 (s, 3H), 3.69-3.38 ppm (m, 4H), 3.3-2.74 (m, 1H) , 2.29 (s, 3H), 1.19-1.0 (m, 3H). 145 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.24 (s, 1H), 8.55 (s, 1H), 8.42-8.4 (m, 1H), 8.29 (s , 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.81-7.78 (m, 1H), 7.5 (d, J=8.81 Hz, 1H) , 4.4-3.97 (m, , 2H), 3.61 (s, 3H), 3.69-3.38 ppm (m, 4H), 3.3-2.74 (m, 1H) , 2.29 (s, 3H), 1.19-1.0 (m, 3H). 146 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.21 (s, 1H), 8.54 (s, 1H), 8.4 (d, J=2.04 Hz, 1H), 8, 3 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.78 (dd, J=8.59, 2.33 Hz, 1H), 7.52 (dd , J=8.6, 0.46 Hz, 1H), 4.24-4.09 (m, 1H), 3.87-3.56 (m, 2H), 3.64-3.56 (m , 5H), 3.46-3.33 (m, 2H), 2.29 (s, 3H), 1.26 (s, 3H). 147 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.21 (s, 1H), 8.54 (s, 1H), 8.4 (d, J=2.04 Hz, 1H), 8, 3 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.78 (dd, J=8.59, 2.33 Hz, 1H), 7.52 (dd , J=8.6, 0.46 Hz, 1H), 4.24-4.09 (m, 1H), 3.87-3.56 (m, 2H), 3.64-3.56 (m , 5H), 3.46-3.33 (m, 2H), 2.29 (s, 3H), 1.26 (s, 3H). 148 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.24 (s, 1H), 8.55 (s, 1H), 8.41 (d, J=0.46 Hz, 1H), 8, 29 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.8 (dd, J=8.6, 2.33 Hz, 1H), 7.5 (d , J=8.36 Hz, 1H), 4.47-3.45 (m, 8H), 3.0-2.71 (m, 1H), 2.28 (s,, 3H), 1.26 -0.92 (m, 6H). 149 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.2 (s, 1H), 8.54 (d, J=5.32 Hz, 1H), 8.4 (d, J=2.73 Hz, 1H), 8.29 (s, 1H), 8.2 (s, 1H), 8.11 (s, 1H), 7.77 (dd, J=8.6, 2.33 Hz, 1H ), 7.51 (d, J=8.34 Hz, 1H), 4.0-3.9 (m, 2H), 3.66-3.53 (m, 5H), 3.32-3, 15 (m, 2H), 2.28 (s, 3H), 1.18-1.04 (m, 6H). 151 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.23 (s, 1H), 8.42 (d, J=2.27 Hz, 1H), 8.34 (s, 1H), 8, 21 (s, 1H), 8.06 (td, J=8.32, 3.0 Hz, 2H), 7.78 (dd, J=8.59, 2.44 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 3.65-3.44 (m, 7H), 2.39-2.3 (m, 4H), 2.21 (s, 3H). 152 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.73 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.11 (d, J=0.48 Hz, 1H), 7.57 (d, J=9.62 Hz, 1H), 7.09 (d, 1H), 4.61 (s, 1H), 3.61 (s, 3H), 3.54-3.48 (m, 2H), 3.39-3.31 (m, 2H), 2.83 (dd, J=9.6, 2.01 Hz, 1H), 2.31 (s, 3H), 2.30 (s, 3H), 1.92 (d, J=9.34 Hz, 1H), 1.79 (d, J=9.35 Hz, 1H). 153 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.21 (s, 1H), 8.53 (s, 1H), 8.52 (s, 1H), 8.3 (d, J=3 .54 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.89 (d, J=8.34 Hz, 1H), 7.5 (d, J=8 .6 Hz, 1H), 5.26-5.15 (m, 1H), 4.25-4.12 (m, 1H), 3.78-3.65 (m, 2H), 3.6 ( s, 3H), 3.5-3.33 (m, 2H), 2.66-2.57 (m, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 2 .15 (s, 3H). 154 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm : 10.2 ppm (s, 1H), 8.53 (s, 1H), 8.52 (s, 1H), 8.3 (d, J= 2.28 Hz, 1H), 8.2 (s, 1H), 8.11 (s, 1H), 7.88 (d, J=4.55 Hz, 1H), 7.49 (d, J= 8.6 Hz, 1H), 5.28-5.18 (m, 1H), 4.29-4.15 (m, 1H), 3.8-3.68 (m, 2H), 3.64 -3.48(m, 7H), 2.78-2.53(, 4H), 3.48-3.3(m, 2H), 2.28(s, 3H). 155 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm : 10.26 (s, 1H), 8.55 (s, 1H), 8.47 (d, J=2.26 Hz, 1H), 8, 28 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.83 (dd, J=8.6, 2.29 Hz, 1H), 7.53 (dd , J=8.61, 0.45 Hz, 1H), 4.49-3.65 (m, 5H), 3.61 (s, 3H), 3.38-3.02 (m, 2H), 2.29 (s, 3H). 156 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.21 (s, 1H), 8.54 (s, 1H), 8.41 (d, J=2.27 Hz, 1H), 8, 26 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.79 (dd, J=8.6, 2.31 Hz, 1H), 7.5 (d , J=8.35 Hz, 1H), 4.47-3.67 (m, 3H), 3.62 ppm (s, 3H), 3.4-2.72 ppm (m, 4H), 2, 28 (s, 3H), 0.93-0.79 (m, 1H), 0.53-0.14 (m, 4H). 157 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm : 10.2 (s, 1H), 8.53 (s, 1H), 8.38 (d, J=1.52 Hz, 1H), 8, 29 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.76 (dd, J=8.34, 1.76 Hz, 1H), 7.51 (d , J=8.35 Hz, 1H), 4.15-3.64 (m, 3H), 3.6 (s, 3H), 3.55-2.95 (m, 4H), 2.34- 2.24 (m, 4H), 1.08-0.63 (m, 6H). 158 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.24 (s, 1H), 8.58-8.49 (m, 2H), 8.31-8.24 (m, 2H), 8 .13 (d, J=4.5 Hz, 1H), 7.94-7.84 (m, 1H), 7.54-7.47 (m, J=4.3 Hz, 1H), 4, 83-4.54 (m, 2H), 3.99-3.65 (m, 2H), 3.61 ppm (s, 3H), 3.59-3.25 ppm (m, 2H), 2, 28 (s, 3H), 1.94-1.75 (m, 2H), 159 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.22 (s, 1H), 8.54 (s, 1H), 8.38 (d, J=2.05 Hz, 1H), 8, 29 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.76 (dd, J=8.59, 2.33 Hz, 1H), 7.52-7 .5 (m, J=2.51 Hz, 1H), 3.9-3.57 (m, 7H), 3.56-3.27 (m, 3H), 2.28 (s, 3H), 1.57-1.48 (m, 1H), 0.55-0.43 (m, 2H), 0.32-0.25 (m, 1H), 0.15-0.06 (m, 1H ), 160 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.28 (s, 1H), 8.55 (s, 1H), 8.45-8.45 (m, J=1.83, 0, 44 Hz, 1H), 8.45 (dd, J=2.28, 0.44 Hz, 1H), 8.27 (s, 2H), 8.12 (s, 1H), 7.81 (dd, J=8.61, 2.33 Hz, 1H), 7.53 (dd, J=8.6, 0.45 Hz, 1H), 5.09-4.99 (m, 1H), 4.09 -3.57 (m, 8H), 3.43-3.32 (m, 1H), 2.27 (s, 3H). 161 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 10.19 (s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 8.2 (s, 1H), 8.11 (s, 1H), 7.86 (dd, J=8.6, 2.28 Hz, 1H), 7.49 (d, J=8.59 Hz , 1H), 3.77-3.4 (m, 6H), 3.04-2.96 (m, 1H), 2.83-2.69 (m, 3H), 2.31-2.09 (m, 7H), 2.06-1.85 (m, 1H), 1.59-1.45 (m, 1H). 163 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm : 9.84 (s, 1H), 8.53 (s, 1H), 8.19 (d, J=1.59 Hz, 2H), 8, 1 (s, 1H), 7.63 (d, J=9.66 Hz, 1H), 7.41 (d, J=9.67 Hz, 1H), 4.83-4.81 (m, 1H ), 4.16 (d, J=12.59 Hz, 1H), 3.97 (d, J=10.88 Hz, 2H), 3.64-3.58 (m, 0.61 Hz, 4H ), 3.56-3.49 (m, 2H), 3.48-3.43 (m, 1H), 2.9 (td, J=12.23, 3.06 Hz, 1H), 2, 64 (dd, J=12.59, 10.39 Hz, 1H), 2.31 (s, 3H) 164 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.83 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.1 (s, 1H), 7.62 (d, J=9.78 Hz, 1H), 7.4 (d, J=9.77 Hz, 1H), 3.6 (s, 3H), 2.29 (s, 3H) 165 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.82 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.62 (d, J=9.66 Hz, 1H), 7.4 (d, J=9.78 Hz, 1H), 4.81 (s, 1H), 4.14 (d, J=12.47 Hz, 1H), 3.96 (d, J=10.88 Hz, 2H), 3.63-3.57 (m, 4H), 3.52 (ddd , J=20.17, 5.26, 2.81 Hz, 2H), 3.43 (td, J=11.0, 5.5 Hz, 1H), 2.89 (td, J=12.35 , 3.06 Hz, 1H), 2.66-2.6 (m, 1H), 2.29 (s, 3H) 166 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.79 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.59 (d, J=9.66 Hz, 1H), 7.39 (d, J=9.66 Hz, 1H), 4.07-4.03 (m , 2H), 3.62-3.58 (m, 5H), 3.21 (dd, J=12.72, 6.23 Hz, 2H), 2.29 (s, 3H), 1.17 ( d, J=6.48Hz, 6H) 167 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.72 (s, 1H), 8.5 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.57 (d, J=9.78 Hz, 1H), 7.27 (d, J=9.78 Hz, 1H), 3.81-3.78 (m , 2H), 3.76-3.72 (m, 4H), 3.61-3.58 (m, 5H), 2.3 (s, 3H), 1.9-1.87 (m, 2H ) 168 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.79 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.6 (d, J=9.78 Hz, 1H), 7.39 (d, J=9.78 Hz, 1H), 4.07-4.03 (m , 2H), 3.62-3.57 (m, 5H), 3.21 (dd, J=12.72, 6.24 Hz, 2H), 2.29 (s, 3H), 1.17 ( d, J=6.36Hz, 6H) 169 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.83 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.18 (s, 1H), 8.1 (s, 1H), 7.62 (d, J=9.77 Hz, 1H), 7.4 (d, J=9.78 Hz, 1H), 4.8 (t, J=5 .38 Hz, 1H), 4.15 (d, J=12.47 Hz, 1H), 3.98-3.95 (m, 2H), 3.64-3.57 (m, 4H), 3 .55-3.48 (m, 2H), 3.47-3.42 (m, 1H), 2.93-2.86 (m, 1H), 2.63 (dd, J=12.48, 10.27Hz, 1H), 2.3(s, 3H) 170 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.78 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 8.1 (s, 1H), 7.59 (d, J=9.77 Hz, 1H), 7.3 (d, J=9.78 Hz, 1H), 4.45 (s, 2H), 3.79 (d, J=11.98 Hz, 2H), 3.6 (s, 3H), 3.0 (dd, J=12.23, 2.21 Hz, 2H), 2.3 (s , 3H), 1.86-1.78 (m, 4H) 171 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.9 (s, 1H), 8.52 (s, 1H), 8.19 (s, 1H), 8.18 (s, 1H), 8.1 (s, 1H), 7.67 (d, J=9.77 Hz, 1H), 7.5 (d, J=9.58 Hz, 1H), 5.17 (t, J=3 .55 Hz, 1H), 4.09 (dd, J=13.46, 3.42 Hz, 1H), 3.94-3.9 (m, 2H), 3.87-3.84 (m, 1H), 3.6 (s, 3H), 3.49 (dd, J=13.47, 3.43 Hz, 1H), 3.28-3.21 (m, 1H), 2.3 (s , 3H) 172 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.82 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.1 (s, 1H), 7.62 (d, J=9.78 Hz, 1H), 7.41 (d, J=9.78 Hz, 1H), 4.11-4.07 (m , 1H), 4.01-3.96 (m, 1H), 3.95-3.91 (m, 1H), 3.67-3.55 (m, 5H), 2.9-2.82 (m, 1H), 2.57-2.52 (m, 1H), 2.3 (s, 3H), 1.16 (d, J=6.12 Hz, 3H) 173 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.82 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.18 (s, 1H), 8.1 (s, 1H), 7.63 (d, J=9.78 Hz, 1H), 7.45 (d, J=9.78 Hz, 1H), 4.16-4.1 (m , 1H), 4.0-3.94 (m, 2H), 3.6 (s, 3H), 3.58-3.55 (m, 1H), 3.24-3.17 (m, 1H ), 2.9-2.82 (m, 1H), 2.66-2.58 (m, 1H), 2.3 (s, 3H), 1.79-1.69 (m, 1H), 0.98-0.95 (m, 6H) 174 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.74 (s, 1H), 8.51 (s, 1H), 8.17 (s, 2H), 8.17 (s, 3H), 8.17 (s, 1H), 8.14 (s, 1H), 8.1 (s, 1H), 7.59 (d, J=9.65 Hz, 1H), 7.13 (d, J =9.54 Hz, 1H), 4.85 (s, 1H), 4.67 (s, 1H), 3.79-3.78 (m, 1H), 3.68 (d, J=7, 46 Hz, 1H), 3.6 (s, 3H), 3.53-3.5 (m, 1H), 3.32-3.32 (m, 1H), 2.31 (s, 3H), 1.96-1.93 (m, 1H), 1.89-1.87 (m, 1H) 175 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.8 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.16 (s, 1H), 8.1 (s, 1H), 7.6 (d, J=9.78 Hz, 1H), 7.4 (d, J=9.67 Hz, 1H), 3.76-3.74 (m , 2H), 3.6 (s, 3H), 3.46-3.44 (m, 2H), 3.35 (s, 2H), 2.3 (s, 3H), 1.21 (s, 6H) 176 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.79 (s, 1H), 8.52 (s, 1H), 8.17 (s, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.6 (d, J=9.67 Hz, 1H), 7.39 (d, J=9.78 Hz, 1H), 4.05 (td, J=6 .24, 3.3 Hz, 2H), 3.62-3.58 (m, 5H), 3.21 (dd, J=12.72, 6.24 Hz, 2H), 2.3 (s, 3H), 1.17 (d, J=6.36 Hz, 6H) 177 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.82 (s, 1H), 8.51 (s, 1H), 8.18 (s, 2H), 8.09 (s, 1H), 7.62 (d, J=9.78 Hz, 1H), 7.44 (d, J=9.78 Hz, 1H), 4.13 (d, J=12.59 Hz, 1H), 3. 97 (td, J=3.18, 2.69 Hz, 2H), 3.6 (s, 3H), 3.58-3.54 (m, 1H), 3.2 (ddd, J=10, 27, 6.6, 2.2 Hz, 1H), 2.91-2.81 (m, 1H), 2.65-2.57 (m, 1H), 2.3 (s, 3H), 1 .79-1.68 (m, 1H), 0.97-0.94 (m, 6H) 179 1H NMR (300 MHz, DMSO-d6) δ ppm 9.03 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.50 (s, 1H), 6, 99 (d, J=9.00 Hz, 1H), 6.47 (s, 2H), 6.19 (s, 1H), 4.64-4.53 (m, 1H), 3.62 (s , 3H), 1.19-1.09 (m, 1H), 0.63-0.55 (m, 1H), 0.50-0.37 (m, 3H). 180 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.67 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 8 .11 (s, 2H), 8.01 (br.s., 1H), 7.45 (br.s., 1H), 7.33-7.41 (m, 1H), 3.59 (s , 3H), 3.11 (br.s., 3H), 2.96 (br.s., 4H), 2.29 (s, 4H). 181 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.62 (br.s., 1H), 8.49 (br.s., 1H), 8.08 (br.s., 3H), 7 .99 (brd, 1H), 7.24-7.55 (m, 2H), 3.50-3.68 (brd, 6H), 2.24-2.29 (br. s., 2H), 2.11-2.22 (m, 6H), 1.81 (br.s., 2H), 1.50 (br.s., 2H), 1.23 (b.s. ., 2H), 0.84 (br.s., 1H) 182 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.46 (br s, 1H), 8.48 (s, 1H), 8.09 (d, J=4.01 Hz, 2H), 7.95 (s, 1H), 7.68 (br.s., 1H), 7.30 (d, J=8.71 Hz, 1H), 7.04 (d, J=6.62 Hz, 1H), 3.57 (br.s., 3H), 2.95-3.10 (m, J=7.50 Hz, 2H), 2.79 (br.s., 2H), 2.27 (br.s., 3H), 2.19 (br.s., 6H), 1.70-1.90 (m, J=9.80 Hz, 1H), 1.23 (br.s., 1H), 0.84 (br.s., 1H). 183 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.49 (s, 1H), 8.48 (s, 1H), 8.09 (d, J=5.40 Hz, 2H), 7.99 (s, 1H), 7.82 (d, J=2.61 Hz, 1H), 7.13-7.35 (m, 2H), 3.57 (s, 3H), 3.47 (s, 3H), 3.24 (s, 3H), 2.90 (s, 3H), 2.27 (s, 4H). 184 1H NMR (300 MHz, DMSO-d ₆ ) : δ ppm 9.61 (s, 1H), 8.49 (s, 1H), 8.12 (s, 1H), 8.08 (d, J=3 .83 Hz, 2H), 7.99 (br.s., 1H), 7.37-7.51 (m, 1H), 7.23-7.36 (m, 1H), 4.35-4 .56 (m, 1H), 3.64 (br.s., 2H), 3.57 (s, 3H), 2.55-2.79 (m, 2H), 2.27 (s, 3H) , 1.74 (d, J=12.37 Hz, 2H), 1.48 (br.s., 1H), 1.26 (br.s., 2H), 0.72-0.93 (m , 2H). 185 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.52 (s, 1H), 8.48 (s, 1H), 8.09 (d, J=6.62 Hz, 2H), 8.01 (s, 1H), 7.85 (d, J=2.61 Hz, 1H), 7.19-7.39 (m, 2H), 3.57 (s, 3H), 2.86 (s, 6H), 2.27 (s, 3H). 186 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.88 (br.s., 1H), 8.44 (s, 1H), 8.05 (br.s., 2H), 7.92 ( brd, 1H), 7.47 (s, 1H), 6.23 (s, 1H), 4.20 (brd, 2H), 3.54 (brd, 7H), 2.68 (brd, 2H), 2.40 (brd, 4H), 2.24 (brd, 3H). 187 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 9.18 (br.s., 1H), 8.57 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.13 (s, 1H), 6.34 (br s, 2H), 5.97 (d, 1H), 4.66 (d, 1H) , 3.97-3.90 (m, 2H), 3.54-3.46 (m, 1H), 3.48 (s, 3H), 1.99 (s, 3H), 0.96 (d , 3H).

Biological examples

Example 1 In Vitro Assays

1.1. JAK1 inhibition assay

Recombinant human JAK1 (catalytic domain, amino acids 866-1154; catalog number PV4774) was purchased from Invitrogen. 1 ng JAK1 (or 2 ng JAK1 depending on the amount of the enzyme lot) is incubated with 20 nM Ulight-JAK1(tyr1023) peptide (Perkin Elmer catalog number TRF0121) in kinase reaction buffer (15 mM MOPS pH 6.8, 0.01 % Brij-35, 5 mM MgCl ₂ , 2 mM DTT, 20 μM ATP) with or without 4 μl containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 20 μl, in a white 384 Optiplate ( Perkin Elmer, part number 6007290). After 60 min at room temperature, reactions are stopped by adding 20 µl/well detection mixture (1x detection buffer (Perkin Elmer, cat. no. CR97-100), 0.5 nM europium anti-phosphotyrosine (PT66) (Perkin Elmer, cat. no. catalog AD0068/AD0069), 10 mM EDTA). Readings are made after 60 min incubation at room temperature using Envision with excitation at 320 nm and emission measurements at 615 nm and 665 nm (Perkin Elmer). The ratio of relative fluorescence units (RFU) at 665 nm and 615 nm (RFU 665/RFU 615 multiplied by a factor of 1000) is used for further calculations. Kinase activity is calculated by subtracting the ratio obtained in the presence of a positive control inhibitor (1 μM staurosporine) from the ratio obtained in the presence of vehicle. The ability of a test compound to inhibit this activity (or percent inhibition) is defined as:

(1-(Test compound fluorescence ratio-control fluorescence ratio)/(Carrier fluorescence ratio-control fluorescence ratio))*100

Where

Test Compound Fluorescence Ratio = RFU 665/RFU 615 * 1000 Ratio Determined from Test Compound Sample

Control Fluorescence Ratio = RFU 665/RFU 615 * 1000 Ratio Determined for Positive Control Inhibitor Sample

Carrier Fluorescence Ratio = RFU 665/RFU 615 * 1000 Ratio determined from carrier sample

Dose dilution series were prepared for the compounds, which allowed the study of dose-response effects in the JAK1 assay and the calculation of the IC ₅₀ for the compound. Each compound is typically tested at a concentration of 20 μM followed by a serial dilution of 1/5, 10 points at a final concentration of 1% DMSO. As the activity of a number of compounds increases, more dilutions are obtained and/or the upper concentration is reduced (eg 5 μM, 1 μM). The data obtained are expressed as the average value of the IC ₅₀ according to the results of the analyses.

Table V. JAK1 Activity of Exemplary Compounds of the Invention

Compound IC ₅₀ (nM) one 153.4 2 70.3 3 110.3 four 92.3 5 23.4 6 49.7 7 8.5 eight 23.1 9 47.2 ten 83.9 eleven 27.2 12 26.9 13 24.4 fourteen 91.4 fifteen 12.2 16 71.0 17 64.6 eighteen 293.9 19 80.9 twenty 8.6 21 208.2 22 23.0 23 234.2 24 61.8 25 243.1 26 338.4 27 347.6 28 348.7 29 505.0 thirty 398.8 31 186.5 32 117.0 33 67.6 34 100.7 35 52.4 36 40.5 37 84.3 38 40.9 39 101.6 40 269.4 41 268.2 42 145.9 43 53.8 44 54.1 45 80.6 46 66.8 47 77.5 48 35.5 49 34.9 fifty 85.6 51 29.2 52 37.9 53 68.0 54 11.2 55 100.1 56 99.2 57 780.9 58 97.8 59 460.7 60 85.5 61 60.3 62 86.7 63 102.4 64 343.3 65 69.4 66 146.4 67 51.4 68 112.6 69 61.3 70 115.7 71 103.2 72 8.9 73 60.2 74 23.6 75 32.7 76 199.5 77 43.8 78 60.2 79 18.5 80 19.9 81 150.0 82 103.2 83 277.7 84 57.1 85 30.4 86 197.5 87 73.1 88 5.3 89 71.5 90 199.7 91 156.8 92 9.6 93 57.1 94 217.2 95 249.8 96 21.8 97 21.8 98 28.2 99 110.7 100 63.5 101 48.9 102 52.0 103 46.2 104 54.0 105 54.1 106 38.9 107 132.9 108 91.7 109 215.8 110 314.9 111 310.4 112 55.9 113 44.0 114 78.8 115 107.3 116 151.2 117 204.8 118 29.1 119 26.8 120 30.2 121 25.2 122 48.3 123 124.4 124 36.4 125 47.8 126 121.9 127 43.6 128 176.8 129 105.6 130 123.8 131 52.7 132 139.7 133 178.2 134 55.4 135 28.2 136 43.0 137 54.6 138 37.8 139 33.8 140 51.5 141 52.6 142 85.1 143 92.1 144 44.4 145 43.9 146 22.3 147 40.6 148 52.2 149 79.3 150 136.9 151 97.0 152 205.4 153 54.4 154 62.0 155 41.4 156 34.8 157 19.8 158 23.6 159 34.6 160 37.3 161 137.1 162 34.3 163 51.5 164 53.6 165 39.1 166 76.2 167 52.4 168 50.0 169 62.8 170 59.0 171 27.2 172 45.2 173 53.4 174 37.2 175 73.6 176 37.8 177 74.5 178 85.3 179 14.5 180 81.7 181 151.0 182 164.7 183 95.4 184 59.0 185 93.6 186 77.2 187 126.9 188 41.8 189 43.3 190 41.6

1.2. JAK2 inhibition assay

Recombinant human JAK2 (catalytic domain, amino acids 808-1132; catalog number PV4210) was purchased from Invitrogen. 0.83 ng JAK2 was incubated with 25 nM Ulight-JAK1(tyr1023) peptide (Perkin Elmer catalog number TRF0121) in kinase reaction buffer 25 mM MOPS pH7.0, 0.01% Triton X-100, 7.5 mM MgCl ₂ , 2 mM DTT, 0.7 µM ATP) with or without 4 µl containing test compound or vehicle (DMSO, 1% final concentration), for a total volume of 20 µl, in a white 384 Optiplate (Perkin Elmer, catalog number 6007290 ). After 60 min at room temperature, reactions are stopped by adding 20 µl/well detection mixture (1 x detection buffer (Perkin Elmer, cat. no. CR97-100) with 0.5 nM europium anti-phosphotyrosine (PT66) (Perkin Elmer, part number AD0068/AD0069) and 10 mM EDTA). Readings are made after 60 min incubation at room temperature using Envision with excitation at 320 nm and emission measurements at 615 nm and 665 nm (Perkin Elmer). The ratio of relative fluorescence units (RFU) at 665 nm and 615 nm (RFU 665/RFU 615 multiplied by a factor of 1000) is used for further calculations. Kinase activity is calculated by subtracting the ratio obtained in the presence of a positive control inhibitor (1 μM staurosporine) from the ratio obtained in the presence of vehicle. The ability of a test compound to inhibit this activity (or percent inhibition) is defined as:

(1-(Test compound fluorescence ratio-control fluorescence ratio)/(Carrier fluorescence ratio-control fluorescence ratio))*100

where

Test Compound Fluorescence Ratio = RFU 665/RFU 615 * 1000 Ratio Determined for Test Compound Sample

Control Fluorescence Ratio = RFU 665/RFU 615 * 1000 Ratio Determined for Positive Control Inhibitor Sample

Carrier Fluorescence Ratio = RFU 665/RFU 615 * 1000 Ratio determined from carrier sample

Dose dilution series were generated for the compounds, allowing dose-response effects to be investigated in the JAK2 assay and the IC ₅₀ for the compound to be calculated. Each compound is typically tested at a concentration of 20 μM followed by a serial dilution of 1/5, 10 points at a final concentration of 1% DMSO. As the activity of a number of compounds increases, more dilutions are obtained and/or the upper concentration is reduced (eg 5 μM, 1 μM). The data obtained are expressed as the average value of the IC ₅₀ according to the results of the analyses.

Table VI. JAK2 activity of exemplary compounds of the invention

Comm. IC ₅₀ (nM) one 67.3 2 19.36 3 77.99 four 16.45 5 6.96 6 8.46 7 3.17 eight 2.39 9 16.52 ten 8.35 eleven 4.75 12 3.04 13 3.16 fourteen 17.02 fifteen 2.4 16 24.97 17 14.6 eighteen 31.48 19 11.19 twenty 1.3 21 18.29 22 3.35 23 66.66 24 43.9 25 78.31 26 872.85 27 280.15 28 207.65 29 906.75 thirty 777.1 31 43.8 32 26.18 33 23.09 34 23.38 35 20.44 36 9.17 37 20.13 38 7.72 39 10.65 40 27.09 41 21.96 42 14.37 43 7.42 44 10.98 45 11.11 46 7.29 47 18.25 48 9.7 49 14.59 fifty 25.91 51 7.16 52 21.41 53 72.66 54 2.03 55 45.5 56 179.5 57 229.07 58 35.5 59 133.2 60 98.89 61 58.44 62 139.05 63 69.95 64 213.6 65 12.42 66 198.73 67 28.23 68 175.1 69 69.97 70 81.29 71 86.15 72 1.91 73 13.13 74 13.84 75 8.56 76 19.85 77 16.65 78 31.62 79 5.58 80 5.2 81 10.44 82 17.69 83 27.06 84 45.46 85 10.48 86 22.86 87 38.82 88 1.42 89 110.41 90 15.04 91 42.03 92 1.17 93 16.4 94 39.68 95 37.97 96 15.74 97 6.29 98 6.31 99 51.07 100 39.44 101 37.76 102 13.28 103 19.42 104 17.11 105 10.15 106 14.48 107 27.12 108 9.66 109 197.43 110 237.47 111 29.72 112 21.58 113 15.07 114 19.96 115 29.13 116 28.32 117 32.26 118 17.27 119 13.18 120 13.28 121 18.85 122 23.67 123 40.24 124 7.71 125 13.27 126 16.76 127 18.26 128 16.85 129 32 130 21.82 131 14.8 132 36.48 133 25.8 134 14.46 135 12.64 136 19.62 137 12.88 138 8.22 139 23.7 140 14.55 141 10.45 142 21.26 143 22.89 144 15.85 145 14.64 146 6.95 147 11.78 148 15.81 149 21.23 150 10.84 151 9.32 152 26.59 153 16.7 154 22.18 155 17.83 156 12.3 157 5.95 158 11.74 159 7.25 160 11.23 161 17.48 162 11.33 163 5.77 164 5.99 165 4.43 166 11.47 167 6.22 168 5.94 169 6.61 170 5.27 171 5.97 172 6.99 173 5.22 174 3.01 175 8.77 176 4.86 177 6.91 178 11.58 179 2.23 180 18.23 181 36.91 182 76.4 183 41.22 184 22.11 185 41.39 186 22.22 187 42.33 188 7.53 189 9.7 190 7.98

1.3. JAK3 inhibition assay

Recombinant human JAK1 catalytic domain (amino acids 781-1124; catalog number PV3855) was purchased from Invitrogen. 0.5 ng of JAK3 protein is incubated with 2.5 μg of polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (25 mM Tris pH 7.5, 0.5 mM EGTA, 10 mM MgCL ₂ , 2.5 mM DTT , 0.5 mM Na3VO4, 5 mM b-glycerophosphate, 0.01% Triton X-100, 1 µM non-radioactive ATP, 0.25 µCi 33P-gamma-ATP (Perkin Elmer, catalog number NEG602K001MC) final concentrations) with or without 5 µl containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 µl, in a polypropylene 96-well plate (Greiner, catalog number 651201). After 45 min at 30°C, the reactions are stopped by adding 25 μl/well of 150 mM phosphoric acid. All completed kinase reactions are transferred to pre-washed (75 mM phosphoric acid) 96-well filter plates (Perkin Elmer cat. no. 6005177) using a cell harvester (Perkin Elmer). The plates are washed 6 times with 300 μl per well of 75 mM phosphoric acid solution and the bottom of the plates is sealed. 40 µl/well of Microscint-20 (Perkin Elmer, catalog number 6013621) is added, the top of the plates is sealed and reading is performed using a Topcount (Perkin Elmer). Kinase activity is calculated by subtracting the counts per minute (cpm) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from the cpm obtained in the presence of vehicle. The ability of a test compound to inhibit this activity (or percent inhibition) is defined as:

(1-(test compound cpm - control cpm)/(carrier cpm - control cpm))*100

test compound cpm=cpm defined for sample with test compound under test

control cpm=cpm determined for sample with positive control inhibitor

media cpm=cpm defined for sample with media

Dose dilution series were prepared for the compounds, which allowed the study of dose-response effects in the JAK3 assay and the calculation of the IC ₅₀ for the compound. Each compound is typically tested at a concentration of 20 μM followed by a serial dilution of 1/5, 10 points at a final concentration of 1% DMSO. As the activity of a number of compounds increases, more dilutions are obtained and/or the upper concentration is lowered (eg 5 μM, 1 μM).

The following compounds were tested for their activity against JAK3 and the average IC ₅₀ values determined using the assays described herein are shown in the table below.

Table VII. IC ₅₀ JAK3 values of exemplary compounds of the invention

cpd IC ₅₀ (nM) one 1493.67 2 130.7 3 2159.67 four 783.97 5 329.15 6 210.47 7 65.73 eight 47.51 9 499.78 ten 459.3 eleven 142.9 12 36.68 13 9.66 fourteen 278.75 fifteen 73.98 16 220.8 17 237.1 eighteen 187.25 19 231.4 twenty 13.05 21 437.43 22 97.93 23 2925.5 24 919.2 25 2295.5 26 4000 27 1855 28 3152 29 4000 thirty 4000 31 1046.45 32 601.35 33 503.4 34 1109 35 452.47 36 417.27 37 439.15 38 395.91 39 363.16 40 759.45 41 389.13 42 912.57 43 254.1 44 475.95 45 486.05 46 205 47 200.05 48 266.05 49 495.4 fifty 476.47 51 188.55 52 516.88 53 495.05 54 36.32 55 481.33 56 2868.33 57 3041 58 1102.67 59 3782 60 2061 61 1111.93 62 2374 63 583.9 64 3221.5 65 69.69 66 972.07 67 258.2 68 2762.5 69 1314.5 70 1262 71 1083 72 24.34 73 1065 74 466.45 75 283.94 76 579.03 77 591.63 78 736.7 79 573.07 80 391.53 81 386.3 82 207.8 83 368.03 84 907.8 85 478.55 86 445.7 87 979.35 88 188.5 89 1989.5 90 1128.75 91 207.85 92 13.01 93 77.4 94 87.08 95 177.25 96 457.97 97 36.36 98 48.23 99 915.97 100 911.73 101 909.57 102 334.13 103 560.2 104 449.67 105 258.76 106 270.4 107 364.98 108 666.17 109 2810.67 110 1968 111 1050.37 112 541.83 113 495.03 114 392.6 115 2113.5 116 1201 117 2030 118 432.35 119 481.15 120 536.2 121 781.45 122 586.6 123 657 124 203.5 125 225 126 316.7 127 587.15 128 258.6 129 730.7 130 416.5 131 256.55 132 463.35 133 314.55 134 370.5 135 402.65 136 526.85 137 491.35 138 272.85 139 672.95 140 500 141 334.15 142 639.95 143 579.87 144 391.23 145 372.33 146 215.5 147 385.33 148 301.2 149 567.33 151 136.62 152 539.9 153 229.25 154 300.8 155 238.55 156 194.4 157 90.07 158 186.45 159 255.85 160 514.15 161 455.15 162 452.97 178 291.77 179 25.36 180 408.6 181 396.5 182 721.4 183 561.03 184 487.33 185 871.13 186 256.87 187 659.7

1.4. TYK2 inhibition assay

1.4.1. TYK2 radioactive polyGT substrate assay

Recombinant human TYK2 catalytic domain (amino acids 871-1187; catalog number 08-147) was purchased from Carna Biosciences. 6 ng TYK2 was incubated with 0.05 mg/ml polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (25 mM MOPS pH 7.2, 50 mM NaCl, 0.5 mM EDTA, 1 mM DTT, 5 mM MnCl ₂ , 10 mM MgCl ₂ , 0.01% Brij-35, 0.1 µM non-radioactive ATP, 0.125 µCi ³³ P-gamma-ATP (Perkin Elmer, catalog number NEG602K001MC) final concentrations) with or without 5 µl containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 µl, in a polypropylene 96-well plate (Greiner, catalog number 651201). After 120 min at 30° C., the reactions were stopped by adding 25 μl/well of 150 mM phosphoric acid. All completed kinase reactions were transferred to pre-washed (75 mM phosphoric acid) 96-well filter plates (Perkin Elmer cat. no. 6005177) using a cell harvester (Perkin Elmer). The plates are washed 6 times with 300 μl per well of 75 mM phosphoric acid solution and the bottom of the plates is sealed. 40 µl/well of Microscint-20 (Perkin Elmer, catalog number 6013621) is added, the top of the plates is sealed and reading is performed using a Topcount (Perkin Elmer). Kinase activity is calculated by subtracting the counts per minute (cpm) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from the cpm obtained in the presence of vehicle. The ability of a test compound to inhibit this activity (or percent inhibition) is defined as:

(1-(test compound cpm - control cpm)/(carrier cpm - control cpm))*100

where

test compound cpm=cpm defined for sample with test compound under test

control cpm=cpm determined for sample with positive control inhibitor

media cpm=cpm defined for sample with media

Dose dilution series were generated for the compounds, allowing dose-response effects to be explored in the TYK2 assay and IC ₅₀ calculated for each compound. Each compound is typically tested at a concentration of 20 μM followed by a serial dilution of 1/5, 10 points at a final concentration of 1% DMSO. As the activity of a number of compounds increases, more dilutions are obtained and/or the upper concentration is lowered (eg 5 μM, 1 μM).

The following compounds have been tested for their activity against TYK2; and mean IC ₅₀ values determined using the assays described herein are shown in the table below.

Table VIII. IC ₅₀ TYK2 values of exemplary compounds of the invention

Compound IC ₅₀ (nM) one 10.05 2 4.65 3 12.66 four 4.37 5 0.95 6 1.46 7 0.59 eight 0.68 9 1.02 ten 6.18 eleven 1.81 12 1.42 13 1.92 fourteen 3.83 fifteen 0.42 16 13.39 17 10.18 eighteen 30.48 19 10.69 twenty 0.96 21 7.62 22 3.07 23 18.32 24 9.01 25 19.2 26 74.02 27 38.9 28 27.14 29 97.37 thirty 55.71 31 8.01 32 6.08 33 2.93 34 5.49 35 2.3 36 1.41 37 3.62 38 2.51 39 2.43 40 9.69 41 3.37 42 2.74 43 1.58 44 1.97 45 2.17 46 1.47 47 2.02 48 0.84 49 3.6 fifty 5.54 51 1.19 52 2.87 53 9.22 54 1.18 55 5.27 56 14.43 57 45.35 58 7.42 59 69.16 60 9.72 61 10.27 62 12.68 63 7.58 64 51.59 65 7.84 66 11.72 67 3.38 68 15.65 69 6.07 70 12.05 71 13.56 72 1.41 73 3.44 74 3.66 75 1.96 76 6.71 77 2.98 78 9.69 79 3.57 80 2.22 81 6.83 82 8.15 83 16.26 84 10.98 85 4.81 86 9.06 87 8.81 88 0.52 89 10.97 90 12.38 91 24.09 92 one 93 4.99 94 30.74 95 26.3 96 2.51 97 3.08 98 3.04 99 17.81 100 8.06 101 9.36 102 1.98 103 2.73 104 2.88 105 1.87 106 1.43 107 5.44 108 2.63 109 24.38 110 26.68 111 5.53 112 4.29 113 2.05 114 3 115 8.88 116 5.41 117 8.47 118 2.81 119 2.56 120 1.57 121 1.9 122 3.03 123 9.38 124 2.51 125 2.26 126 5.54 127 3.36 128 5.87 129 5.84 130 4.67 131 2.87 132 8.93 133 6.67 134 2.1 135 2.08 136 2.76 137 2.32 138 1.66 139 5.64 140 2.87 141 3.34 142 4.53 143 4.55 144 2.15 145 2 146 1.15 147 1.66 148 2.08 149 3.66 152 12.47 153 1.83 154 3.36 155 2.05 156 1.75 157 0.97 158 1.21 159 1.02 160 1.39 161 2.14 162 2.06 178 3.39 179 1.1 180 6.61 181 7.08 182 17.16 183 12.9 184 6.42 185 16.96 186 6.27 187 6.54

1.4.2. TYK2 ADPglo kinase analysis^TM

Recombinant human TYK2 catalytic domain (amino acids 871-1187; catalog number 08-147) was purchased from Carna biosciences. 10 ng TYK2 was incubated in kinase reaction buffer (25 mM MOPS pH7.2, 50 mM NaCl, 0.01% Brij-35, 0.5 mM EDTA, 10 mM MgCl ₂ , 1 mM DTT, 12 μM ultra pure ATP (Promega , catalog number V915B) final concentrations) with or without 1 µl containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 5 µl, in a white 384 Optiplate (Perkin Elmer, catalog number 6007290). After 120 minutes at room temperature, the reactions were stopped and the remaining ATP was depleted by the addition of 5 μl/well of ADP Glo reagent (Promega, catalog number V912B). After 40 minutes at room temperature, 10 µl of Kinase Detection Reagent (Kinase Detection Substrate (Promega, Cat. No. V914B) dissolved in Kinase Detection Buffer (Promega, Cat. No. V913B)) is added to convert ADP to ATP and measure this newly synthesized ATP in the luciferase/luciferin reaction. Data is read after 30 min incubation at room temperature using Envision. Kinase activity is calculated by subtracting the relative light units (RLU) obtained in the presence of a positive control inhibitor (10 μM staurosporine) from the RLU obtained in the presence of vehicle. The ability of a test compound to inhibit this activity (or percent inhibition) is defined as:

(1-((RLU of test compound-RLU of control)/(RLU of carrier-RLU of control))*100

where

Test Compound RLU=RLU defined for the sample with the Test Compound being tested

Control RLU=RLU determined for a positive control inhibitor sample

Carrier RLU=RLU defined for carrier sample

Dose dilution series were prepared for the compounds, which allowed the study of dose-response effects in the TYK2 assay and the calculation of the IC ₅₀ for the compound. Each compound is typically tested at a concentration of 20 μM followed by a serial dilution of 1/5, 10 points at a final concentration of 1% DMSO. As the activity of a number of compounds increases, more dilutions are obtained and/or the upper concentration is reduced (eg 5 μM, 1 μM). The data obtained are expressed as the average value of the IC ₅₀ according to the results of the analyses.

Table IX. IC ₅₀ TYK2 values of exemplary compounds of the invention

Compound IC ₅₀ (nM) eight 0.32 38 1.1 48 0.48 88 0.11 92 0.58 105 0.68 150 1.1 163 1.06 164 1.84 165 1.09 166 2.28 167 2.55 168 2.39 169 1.47 170 1.46 171 0.88 172 0.92 173 1.3 174 1.03 175 2.64 176 0.93 177 1.2 188 0.79 189 0.67 190 0.75

1.5. Conclusions

The in vitro assay described above demonstrates the selectivity of exemplary compounds of the invention for TYK2 over the rest of the JAK family.

Example 2 Selectivity Assays

To determine the selectivity of exemplary compounds of the invention, specific pathway inhibition is measured.

In particular, while IFNα and IL-12 signaling are TYK2 dependent, IFN can also be inhibited by a JAK1 selective inhibitor. However, activation of STAT1 by IL-6 is strongly dependent on JAK1.

2.1. Cellular analyzes

2.1.1. IFNα activation of STAT1 in PBMC

2.1.1.1. Protocol

Peripheral blood mononuclear cells (PBMCs) are isolated from the buffy coat under sterile conditions by density gradient centrifugation using LymphoPrep™ medium (Axis-Shield catalog number 1114545), followed by 2 consecutive washing steps in PBS (Sigma catalog number P4417-100TAB). After these two washing steps, the cell pellet is dissolved in ammonium chloride buffer (1.5 M NH ₄ Cl, 100 mM NaHCO ₃ and 10 mM Na ₂ .EDTA) to lyse the erythrocytes. The cells are then centrifuged and the PBMCs are resuspended in plain RPMI 1640 medium (Lonza catalog number BE12-115F/U1) containing 10% (v/v) heat inactivated FBS (Sigma Aldrich catalog number F7524).

Immediately after isolation, PBMCs are plated in 96-well plates at 1.0E06 cells/well in a volume of 180 μl of RPMI 1640 containing 10% (v/v) FBS.

PBMC treated with test compound for 30 min at 37°C 5% CO ₂ . 0.6 µl of a 333x concentrated compound dilution is added to the wells using Mosquito. After 30 min pre-treatment with test compound/vehicle, PBMCs are stimulated for 30 min at 37°C with 5% CO ₂ recombinant human IFNα (PeproTech, catalog number 300-02A) at a final concentration of 5 ng/mL by adding ) cytokine trigger to obtain a final volume of 200 µl per well.

All compounds are tested in a single dose starting at 30 µM followed by a 1/3 serial dilution for a total of 10 doses (30 µM, 10 µM, 3.3 µM, 1.11 µM, 0.370 µM, 0.123 µM, 0.0412 µM, 0 .0137 µM, 0.0046 µM and 0.0015 µM) at a final concentration of 0.3% DMSO.

After 30 min of cytokine stimulation, 200 µl of the cell suspension is transferred into a 96-well V-bottom plate, centrifuged for 5 min at 1000 rpm until the cells pellet, followed by removal of the supernatant. The cell pellet is reconstituted in 100 μl of 1x lysis buffer supplemented with EDTA-free protease inhibitor mixture (Roche Applied Sciences, Product Number 11836170001), followed by freezing and storing the sample at -80°C. 1x Lysis Buffer is supplied with the Phospho-STAT1 Elisa kit and contains phosphatase inhibitors. Endogenous levels of phosphorylated STAT1 are quantified using the PathScan® Phospho-STAT1 (Tyr701) 96-well sandwich ELISA kit (Cell Signaling, Product Number #7234) according to the manufacturer's instructions.

HRP activity (HRP conjugated with a secondary antibody) is measured by adding 100 µl of freshly prepared luminol substrate (BM Chemiluminescence ELISA Substrate (POD), Roche, Product Number 11582950001), incubation for 5 min at room temperature in the dark and measured in Envision (Perkin Elmer ) (integration time 100 ms).

2.1.1.2. results

A positive control (CAS#[1187594-09-7], 10 μM in vehicle)] and a negative control (vehicle, 0% inhibition) are used for "percent inhibition (PIN)" values.

Percent inhibition is calculated as:

(1-((RCLU(test compound)-RCLU(positive control))/((RCLU(carrier control)-RCLU(positive control)))*100

where

RCLU (carrier control): relative chemiluminescent signal determined in the presence of carrier and trigger

RCLU (test compound): relative chemiluminescent signal determined in the presence of test compounds and a trigger

RCLU (positive control): relative chemiluminescent signal determined in the presence of positive control and trigger

PIN values are plotted for compounds tested as a function of dose and mean IC ₅₀ values are determined using GraphPad Prism software using non-linear regression (sigmoid) curve fitting.

Table X. IFNα signaling inhibitory activity of exemplary compounds of the invention

Compound IC ₅₀ (nM) one 85.5 2 87 3 119 four 91 6 84.33 7 49 9 thirty 12 25 22 fifty 23 160 24 151 25 198 31 94 33 72 36 79 38 81.25 39 77.3 40 114.6 41 80.62 43 70 44 79 46 76 47 52 48 63 49 109 fifty 95 51 107.5 52 42.75 53 119 54 35 55 76 57 405 58 88 59 407 60 73 61 112 62 116 63 128 65 96 66 138.5 67 51 68 128 69 90 71 111 72 124.5 73 81 74 62 75 65 80 93 81 56 82 126 83 137 84 178 85 114.97 86 121.16 87 158.47 88 fourteen 89 266 90 288 92 67 93 65 96 73 98 38 102 75 103 68 104 65 105 73.89 106 102.5 107 110 108 52 111 123 112 130 115 144 116 113 117 148 118 110 119 81 133 121 137 62 138 91 144 119 145 134 146 122 147 121 148 142 149 218 150 278 153 234 154 351 158 87 161 96 166 84 167 129 168 82 169 147 170 83 171 45 172 66 173 114 174 72 175 94 176 66.5 177 71 178 189 179 51 180 84 186 229

2.1.2. IL-12 STAT4 activation in NK-92 cells using AphaLISA SureFire technology

2.1.2.1. Protocol

NK-92 cells (human malignant non-Hodgkin's lymphoma, interleukin-2 (IL-2) dependent natural killer cell line, ATCC #CRL-2407).

NK-92 cells are maintained in minimal maintenance medium (MEM) alpha medium without ribonucleosides and deoxyribonucleosides, 2 mM L-glutamine, 2.2 g/L sodium bicarbonate (Invitrogen, Product Number 22561-021) containing 0.2 mM myo -inositol, 0.1 mM 2-mercapto-EtOH, 0.02 mM folic acid, 12.5% heat-inactivated horse serum (Invitrogen, Catalog Number 26050-088), 12.5% heat-inactivated FBS (Sigma, catalogue) number F7524), 1% Pen-Strep (100 U/mL penicillin and 100 µg/mL streptomycin) and 10 ng/mL recombinant human IL-2 (R&D Systems, Catalog Number 202-IL). IL-2 is added to the medium only after each medium upgrade step. Cells are cultured in a humidified incubator at 37°C 5% CO ₂ .

The subcultured fraction of NK-92 cells was washed once in culture medium without rhIL-2 the day before the experiment and incubated overnight in a culture flask. On the day of the experiment, cells were collected by centrifugation, resuspended in Hank's balanced salt solution (-Ca, -Mg) (Invitrogen, Catalog Number 14170088) and plated in 384-well plates at 60,000 cells/well in a volume of 30 μl.

NK-92 cells are treated with test compounds for 30 min prior to stimulation with rhIL-12 by adding 180 nl 333x dilution of concentrated compound and incubation at 37°C 5% CO ₂ . After 30 minutes of compound/vehicle pretreatment, cells are stimulated with recombinant human IL-12 (R&D Systems, Product Number 219-IL) at a final concentration of 25 ng/ml by adding 30 µl (2x concentrated) tricine trigger to produce a final volume of 60 µl per well . NK-92 cells are stimulated with rhIL-12 for 30 min at 37°C 5% CO ₂ .

After 30 min of cytokine stimulation, cells are lysed by adding 15 μl of 5x lysis buffer (supplemented with AlphaLISA kit). After 10 minutes, plates are frozen at -80°C overnight and phospho-STAT4 levels are quantified the next day using AlphaLISA SureFire ULTRA p-STAT4 (Tyr693) (Perkin Elmer, Catalog number ALSU-PST4-A10K) according to manufacturer's instructions. The AlphaLISA signal (relative light units) was measured using Envision (Perkin Elmer).

All compounds are tested in duplicate, starting at 30 µM followed by a 1/3 serial dilution, for a total of 10 doses (30 µM, 10 µM, 3.3 µM, 1.11 µM, 0.370 µM, 0.123 µM, 0.0412 µM, 0.0137 µM, 0.0046 µM and 0.0015 µM) at a final concentration of 0.3% DMSO.

2.1.2.2. results

A positive control (CAS#[1187594-09-7], 10 μM in vehicle)] and a negative control (vehicle, 0% inhibition) are used for "percent inhibition (PIN)" values.

Percent inhibition is calculated as:

(1-((RLU(test connection)-RLU(pol. control))/(RLU(trigger/carrier)-RLU(pol. control)))*100

where

RLU (trigger/carrier): relative luminescent signal determined in the presence of carrier and trigger

RLU(test compound): relative luminescent signal determined in the presence of test compounds and a trigger

RLU(pol. control): relative luminescent signal determined in the presence of 10 µM CAS#[1187594-09-7] and trigger

PIN values are plotted for compounds tested as a function of dose and mean IC ₅₀ values are determined using GraphPad Prism software using non-linear regression (sigmoid) curve fitting. Data are expressed as the mean IC ₅₀ value from different experiments.

Table XI. IL12 signaling inhibitory activity of exemplary compounds of the invention

Compound IL12 pSTAT4 IC ₅₀ (nM) one 110.84 2 73.54 3 273.5 four 197.5 6 207.33 7 133 9 41 19 72 22 22 31 110 33 129 36 fifty 38 82 39 256 40 3528 41 314 43 49 44 fifty 46 210 47 84 48 56 49 150 fifty 248 51 274.5 52 fifty 54 16 55 77.75 61 221 62 100 65 80 66 205.35 67 54.14 68 122 69 42.77 71 127.5 72 57.23 73 158.05 74 62.94 75 159 80 83 81 224 82 195 83 987 84 87 85 153.5 86 505.5 87 265.5 88 22 89 476 90 1519 93 25.36 96 358 98 18.9 102 302 103 63.5 104 108 105 147.33 106 150.5 107 622 108 94 111 393 112 1103 113 190 115 968 116 79 117 181 118 299 119 261 133 981 137 89 138 332 144 211 145 238 146 215 147 213 148 160 149 347 150 1021 153 7577 154 8720 158 204 161 864 166 97 167 88 168 87 169 665 170 73 171 127 172 58 173 33 174 61 175 137 176 40.5 177 24 178 2573 179 13 180 769 186 241

2.1.3. IL-12 STAT4 activation in NK-92 cells using MSD as an indication

NK-92 cells (human malignant non-Hodgkin's lymphoma, interleukin-2 (IL-2) dependent natural killer cell line, ATCC #CRL-2407).

NK-92 cells are maintained in minimal maintenance medium (MEM) alpha medium without ribonucleosides and deoxyribonucleosides, 2 mM L-glutamine, 2.2 g/L sodium bicarbonate (Invitrogen, Product Number 22561-021) containing 0.2 mM myo -inositol, 0.1 mM 2-mercapto-EtOH, 0.02 mM folic acid, 12.5% heat-inactivated horse serum (Invitrogen, Catalog Number 26050-088), 12.5% heat-inactivated FBS (Hyclone, catalogue) number SV30160.03), 1% Pen-Strep (100 U/mL penicillin and 100 µg/mL streptomycin) and 10 ng/mL recombinant human IL-2 (R&D Systems, Catalog Number 202-IL). IL-2 is only added to the medium after each medium upgrade step. Cells are cultured in a humidified incubator at 37°C 5% CO ₂ .

The subcultured fraction of NK-92 cells is collected by centrifugation, the cell pellet is resuspended in culture medium without rhIL-2 and 200,000 cells in 160 µl are plated in a 96-well plate (Greiner, catalog number 651201) already containing 20 µl diluted test compound or vehicle.

NK-92 cells are pre-incubated with test compounds or vehicle for 30 minutes at 37° C. 5% CO ₂ . The cells are then stimulated with recombinant human IL-12 (R&D Systems, Product Number 219-IL) at a final concentration of 25 ng/ml by adding 20 μl (10x concentrated) tricine trigger to obtain a final volume of 200 μl per well. NK-92 cells are stimulated with rhIL-12 for 45 min at 37°C 5% CO ₂ .

After 45 minutes of cytokine stimulation, cells are lysed by adding 50 μl of ice-cold lysis buffer (supplemented with MSD kit). The plates are frozen at -80°C for at least 1 hour to completely lyse the cells. After thawing, phospho-STAT4 levels are quantified using the Phospho-STAT4 (Tyr693) kit (MSD, Catalog number K150PAD-2) according to the manufacturer's instructions. The electroluminescent signal is measured on an MSD reader.

All compounds are tested in duplicate, starting at 30 µM followed by a 1/3 serial dilution, for a total of 10 doses (30 µM, 10 µM, 3.3 µM, 1.11 µM, 0.370 µM, 0.123 µM, 0.0412 µM, 0.0137 µM, 0.0046 µM and 0.0015 µM) at a final concentration of 0.3% DMSO.

2.1.4. results

A positive control (CAS#[1187594-09-7], 10 μM in vehicle)] and a negative control (vehicle, 0% inhibition) are used for "percent inhibition (PIN)" values.

Percent inhibition is calculated as:

(1-((RLU(test connection)-RLU(pol. control))/(RLU(trigger/carrier)-RLU(pol. control)))*100

where

RLU (trigger/carrier): relative luminescent signal determined in the presence of carrier and trigger

RLU(Test Compound): Relative luminescent signal determined in the presence of test compounds)

RLU(pol. control): relative luminescent signal determined in the presence of 10 µM CAS#[1187594-09-7] and trigger

PIN values are plotted for compounds tested as a function of dose and mean IC ₅₀ values are determined using GraphPad Prism software using non-linear regression (sigmoid) curve fitting. Data are expressed as the mean IC ₅₀ value from different experiments.

Table XII. IL12 signaling inhibitory activity of exemplary compounds of the invention

Compound IL12 pSTAT4 IC ₅₀ (nM) one 538.8 2 259.3 eight 416.2 9 252.0 ten 529.8 eleven 377.3 12 540.0 fourteen 1501.0 fifteen 185.7 17 905.3 eighteen 4683.0 19 805.9 twenty 377.8 21 1050.0 23 247.7 24 3371.0 25 1117.0 26 1527.0 52 400.9 53 409.3 54 290.9 55 264.6 57 7459.0 58 595.3 59 4724.0 60 1150.0 62 809.2 63 1144.0 66 1654.0 67 232.8 68 1444.0 69 203.5 72 27.7 73 199.0 74 88.6 88 90.1 91 3150.0 92 281.5 93 200.6

2.2. Human Whole Blood Analysis (hWBA)

2.2.1. IL-6 and IFNα stimulation protocol

Flow cytometry analysis is performed to determine the potency of compounds against JAK1 and TYK2 ex vivo using human whole blood. Therefore, blood is taken from human volunteers who have given informed consent, then equilibrated for 30 minutes at 37° C. with gentle shaking, and aliquoted in Eppendorf tubes. The compound is added at various concentrations and incubated at 37°C for 30 min with gentle shaking and then stimulated for 20 min at 37°C with gentle shaking with interleukin 6 (IL-6) to stimulate the JAK1-dependent pathway or IFNα to stimulate TYK2 -dependent path. Phospho-STAT1 is then evaluated using FACS analysis.

2.2.1.1. Obtaining Reagents

Buffer 5X Lyse/Fix (BD PhosFlow, Cat. no 558049) is diluted 5 times with distilled water and preheated to 37°C. The remaining diluted Lyse/Fix buffer is discarded.

10 μg of rhIL-6 (R&D Systems, Cat no 206-IL) is dissolved in 1 ml of PBS 0.1% BSA to make a 10 μg/ml stock solution. The generic type I IFN stock solution (R&D Systems, Cat no 11200-2) is aliquoted and stored at -80°C.

A 3-fold dilution series of the compound was prepared in DMSO (10 mM stock). Control treated samples received DMSO instead of compound. All samples are incubated with a final concentration of 1% DMSO.

2.2.1.2. Incubation of blood with compound and stimulation with IL-6 or IFNα

Human blood is collected in tubes treated with heparin. The blood is divided into aliquots of 148.5 µl. Then, 1.5 µl of the test compound dilution is added to each blood aliquot and the blood samples are incubated for 30 minutes at 37° C. with gentle shaking. One and a half microliters of a 10-fold diluted stock solution of IL-6 or generic IFN type 1 is added to the blood samples (final concentration 10 ng/ml and 1000 U/ml, respectively) and the samples are incubated at 37°C for 20 min with gentle shaking.

2.2.1.3. White blood cell preparation

At the end of the stimulation period, 3 ml of 1X prewarmed Lyse/Fix buffer is immediately added to the blood samples, shaken briefly and incubated for 15 min at 37° C. in a water bath to lyse the erythrocytes and fix the leukocytes.

The tubes are centrifuged for 5 min at 400xg at 4°C. The cell pellet is washed with 3 ml cold 1X PBS and after centrifugation, the cell pellet is resuspended in 100 µl ice-cold 1X PBS and 900 µl ice-cold 100% MeOH is added. The cells are then incubated at 4° C. for 30 min to permeabilize.

The permeable cell is then washed with 1X PBS containing 3% BSA and finally resuspended in 80 ml of 1X PBX containing 3% BSA.

2.2.1.4. Cell labeling with anti-phospho-STAT1 and anti-CD4 antibodies

Add 20 µl of mouse anti-STAT1 PE (pY701) or PE of mouse IgG2aκ isotype control antibody (BD Biosciences, Cat. nos 612564 and 559319, respectively) and FITC-conjugated anti-CD4 antibody or control FITC-conjugated isotype antibody and mix, then incubated for 30 min at 4°C in the dark.

Cells are then washed once with 1X PBS and analyzed on a FACSCanto II flow cytometer (BD Biosciences).

2.2.1.5. Fluorescence analysis on FACSCanto II

50,000 total events read and measure phospho-STAT1-positive cells after cell sorting on CD4+ cells in the lymphocytic window. Data are analyzed using FACSDiva software and percentage inhibition of IL-6 or IFNα stimulation is calculated based on the percentage of positive cells for phospho-STAT1 relative to CD4+ cells.

2.2.1.6. results

Using the above protocol, the following results are obtained.

Compound# IFNα IC ₅₀ (nM) IL6 IC ₅₀ (nM) 38 622.41 8010.63 52 355.9 3589.22 75 476.43 3467.37 102 175.12 ND 105 137.54 2519.61 106 532.8 ND 112 446.68 ND 150 269.15 6812.92 166 1445.44 ND 168 1071.52 ND 176 756.83 ND

ND: not determined

2.3. Conclusions

Whereas JAK1 is a key factor in IFNα, IL6, IL10, and IL22 signaling, TYK2 is involved in type I interferons (including IFNα, INFβ), IL23, and IL12 signaling (Gillooly et al., 2016; Sohn et al. , 2013). Although similar inhibitory activity on IFNα and IL12 signaling is observed in the cellular assay, activity is measured at least 7-fold higher on IFNα signaling than on IL-6 signaling for exemplary compounds of the invention, confirming TYK2- selectivity compared to JAK1.

Example 3 In Vivo Assay

3.1. Mouse model of psoriasis-like epidermal hyperplasia induced by intradermal injections of IL22 or IL23

3.1.1. materials

Carrier free recombinant murine IL22 (582-ML-CF) provided by R&D systems. Recombinant mouse IL23, uncarrier (14-8231, CF) courtesy of e-Bioscience.

3.1.2. Animals

Balb/c mice (female, body weight 18-20 g) were obtained from CERJ (France). Mice were maintained on a 12-hour light/dark cycle (07:00-19:00). The temperature was maintained at 22°C, food and water were provided as desired.

3.1.3. Study plan

Study design adapted from Rizzo et al, 2011.

On the first day (D1), mice are shaved around two ears.

For 4 consecutive days (D1 to D4), mice received a daily intradermal dose of mouse recombinant IL22 or IL23 (1 μg/20 μl in PBS/0.1% BSA) in the right pinna and 20 μl PBS/0.1% BSA in the ear of the left auricle under anesthesia, by isoflurane inhalation.

From D1 to D5, mice are treated with test compound (3, 10, 30, or 100 mg/kg, po once a day in MC 0.5%) 1 hour prior to injection of IL23/IL22 or vehicle.

3.1.4. Disease assessment

The thickness of both ears was measured daily using an automatic caliper. Body weight was assessed at initiation and at sacrifice. On the fifth day, 2 hours after the last dosing, the mice were sacrificed. The auricles are excised, excluding the cartilage. The auricles were weighed and then placed in a vial containing 1 ml of RNAlater solution or in formaldehyde.

At D4, blood samples were also collected from the retro-orbital sinus for the PK profile just before dosing (T0) and 1 h, 3 h, 6 h post-dose.

There were 10 mice in each group. Results are expressed as mean ± sem and statistical analyzes are performed using one-way ANOVA followed by Dunnett's post hoc test compared to IL22 or IL23 carrier groups.

3.1.5. Histology

After sacrificing, the ears are harvested and fixed in 3.7% formaldehyde before being embedded in paraffin. Sections are made 2 µm thick and stained with hematoxylin and eosin. The thickness of the ear epidermis is measured by image analysis (Sis'Ncom software) with 6 images per ear acquired at x20 magnification. Data are expressed as mean ± sem and statistical analysis is performed using one-way ANOVA followed by Dunnett's post hoc test compared to IL22 or IL23 carrier groups.

3.1.6. RNA extraction, RT-PCR and real-time PCR

The levels of IL-17a, IL-22, IL-1β, LCN2 and S100A9 transcripts in ear tissue are determined by quantitative real-time PCR.

3.1.7. results

Using the above protocol using IL-23 injection, ear thickness measurements below were obtained showing, for example, that at 3, 10, and 30 mg/kg per day, exemplary compound 38 significantly prevented IL-23-induced ear thickening.

Table XIII. IL23-induced thickening of the ear (mm)

Day 1 Day 2 Day 3 Day 4 Day 5 PBS+vehicle 0.213 0.216 0.220 0.220 0.216 sem 0.002 0.002 0.002 0.002 0.002 IL23+carrier 0.210 0.223 0.248 0.267 0.312 sem 0.002 0.002 0.003 0.003 0.004 p-value vs vehicle on the same day ns ns *** *** *** IL23+Conn. 38 3 mg/kg once a day 0.210 0.220 0.236 0.258 0.260 sem 0.001 0.002 0.003 0.002 0.002 p-value vs vehicle on the same day ns ns ** ns *** IL23+Conn. 38 10 mg/kg once a day. 0.213 0.218 0.241 0.251 0.258 sem 0.002 0.002 0.002 0.003 0.005 p-value vs vehicle on the same day ns ns ns ** *** IL23+Conn. 38 30 mg/kg once a day 0.212 0.219 0.236 0.243 0.255 sem 0.001 0.002 0.003 0.003 0.004 p-value vs vehicle on the same day ns ns ** *** ***

Sem: standard error of the mean

10 mice/group

*p<0.05, **p<0.01, ***p<0.001 daily significance vs IL23-vehicle group using analysis of variance and Dunnett's test

Final remarks

Those skilled in the art will appreciate that the above descriptions are exemplary and explanatory in nature and are intended to illustrate the invention and its preferred embodiments. Through routine experimentation, the skilled person will recognize obvious modifications and changes that can be made without deviating from the gist of the invention. All such modifications falling within the scope of the appended claims are intended to be included therein. In this connection, the present invention is intended to be defined not only by the foregoing description, but also by the following claims and equivalents of embodiments of the invention.

All publications, including, but not limited to, patents and patent applications cited herein are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated herein by reference in its entirety.

It should be understood that factors such as the differential cell penetration ability of various compounds may contribute to discrepancies between the activity of compounds in in vitro biochemical and cellular assays.

At least some of the chemical names for the compounds of the invention that are given and defined in this application can be obtained automatically using commercially available chemical naming software and cannot be independently verified. Typical programs that perform this function include the Lexichem value program supplied by Open Eye Software, Inc. and the Autonom Software program supplied by MDL, Inc. In the case where the indicated chemical name and the depicted structure differ, the depicted structure takes precedence.

Links

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Fabian, M.A., Biggs, W.H., Treiber, D.K., Atteridge, C.E., Azimioara, M.D., Benedetti, M.G., Carter, T.A., Ciceri, P., Edeen, P.T., Floyd, M., Ford, J.M., Galvin, M. , Gerlach, J.L., Grotzfeld, R.M., Herrgard, S., Insko, D.E., Insko, M.A., Lai, A.G., Lélias, J.-M., Mehta, S.A., Milanov, Z.V., Velasco, A.M., Wodicka, L.M., Patel, H.K., Zarrinkar, P.P., Lockhart, D.J., 2005. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23, 329-336. https://doi.org/10.1038/nbt1068

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Neubauer, H., Cumano, A., Müller, M., Wu, H., Huffstadt, U., Pfeffer, K., 1998. Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis. Cell 93, 397-409. https://doi.org/10.1016/S0092-8674(00)81168-X

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Parganas, E., Wang, D., Stravopodis, D., Topham, D.J., Marine, J.-C., Teglund, S., Vanin, E.F., Bodner, S., Colamonici, O.R., van Deursen, J.M., Grosveld, G., Ihle, J.N., 1998. Jak2 Is Essential for Signaling through a Variety of Cytokine Receptors. Cell 93, 385-395. https://doi.org/10.1016/S0092-8674(00)81167-8

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Claims (70)

1. Compound of formula I:

, where Cy is phenyl or 5-6 membered heteroaryl containing one or two N atoms; L ₁ is a single bond, -O-, -C(=O)-, -S(O) ₂ -, -NR ^6a -, -C(=O)NR ^6b - or -S(O) ₂ NR ^6c -; R ¹ is: -H, - C _1-6 alkyl optionally substituted with one to four independently selected Oh, halogen C _1-4 alkoxy, -NR ^7a R ^7b , -C(=O)NR ^7c R ^7d , or -C(=O)OC _1-4 alkyl, or 5-6 membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O; - C _3-7 cycloalkyl, optionally substituted with one OH or C _1-4 alkoxy, - octadeuteriomorpholin-4-yl, or - 4-9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one, two or three heteroatoms independently selected from N, S and O; where heterocycloalkyl is optionally substituted with one to three independently selected R ¹¹ groups; each R ¹¹ is independently: -OH, - CN, - halogen, - -NR ^8a R ^8b , - C _3-7 cycloalkyl, - C _1-4 alkyl optionally substituted with one to three independently selected halo, OH, C _1-4 alkoxy, -NR ^9a R ^9b , - C _1-4 alkoxy, optionally substituted with one C _1-4 alkoxy, - 4-6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, - -C(=O)OC _1-4 alkyl or - -NR ^8c C(=O)OC _1-4 alkyl; R ² is - halogen, or - C _1-4 alkyl; subscript n is 0 or 1; L ₂ is O or -NR ⁴ -, R ³ is - C _1-6 alkyl optionally substituted with one to four independently selected halogen, or C _3-7 cycloalkyl, - phenyl substituted with one R ^5a group and one or two independently selected R ^5b groups, - 6-membered heteroaryl containing one or two N atoms, substituted by one R ^5a group and one or two independently selected R ^5b groups, - 4-9 membered monocyclic or spirobicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b , or - 4-10-membered monocyclic or bridged cycloalkyl, optionally substituted with one, two or three groups independently selected from R ^5a and R ^5b ; R ⁴ is -H, - C _1-4 alkyl optionally substituted with one or two independently selected OH or C _1-4 alkoxy, or - C _3-7 cycloalkyl; R ^5a is -CN, -SO ₂ -C _1-4 alkyl or -CF ₃ ; each R ^5b is independently selected from halogen, C _1-4 alkyl and C _3-7 cycloalkyl; each R ^7a and R ^7b is independently selected from - H, and - C _1-4 alkyl, optionally substituted with one -NR ^10a R ^10b ; and each R ^6a , R ^6b , R ^6c , R ^7c , R ^7d , R ^8a , R ^8b , R ^8c , R ^9a , R ^9b , R ^10a and R ^10b is independently selected from H and C _1-4 alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, where L ₂ is O. 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, where R ³ is selected from:

and

. 4. The compound or pharmaceutically acceptable salt thereof according to claim 1, where R ³ is

or

. 5. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-4, where R ^5a represents -CN, -SO ₂ -C _1-4 alkyl or -CF ₃ . 6. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R ^5b is independently selected from halo, C _1-4 alkyl, and C _3-7 cycloalkyl. 7. A compound or a pharmaceutically acceptable salt thereof according to claim 1, where the compound corresponds to formula IIIa, IIIb, IIIc or IIId:

8. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 7, wherein L ₁ is a single bond or -C(=O)-. 9. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-8, where R ¹ is a 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O; where heterocycloalkyl is optionally substituted with one, two or three independently selected R ¹¹ groups. 10. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-8 wherein R ¹ is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, tetrahydropyranyl, piperazinyl, dioxanyl, each substituted with one, two or three independently selected R ¹¹ groups. 11. A compound or pharmaceutically acceptable salt thereof according to claim 9 or 10, wherein R ¹¹ is C _1-4 alkyl optionally substituted with one to three independently selected halo, OH, C _1-4 alkoxy, -NR ^9a R ^9b , where each R ^9a and R ^9b is independently H or C _1-4 alkyl. 12. Pharmaceutical composition with inhibitory activity against JAK1, JAK2, JAK3 and/or TYK2, containing a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of paragraphs. 1-11. 13. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-11 or a pharmaceutical composition according to any one of paragraphs. 11, 12 for use in medicine, where said use includes inhibition of the kinases JAK1, JAK2, JAK3 and/or TYK2. 14. Connection according to any one of paragraphs. 1-11 or a pharmaceutical composition according to any one of paragraphs. 12, 13 for use in the treatment or prevention of diseases associated with inhibition of JAK1, JAK2, JAK3 and/or TYK2 selected from inflammatory diseases, autoinflammatory diseases, autoimmune diseases and/or diseases associated with hypersecretion of IFNα, IL12 and/or IL23.

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