NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS

Abstract

The present document describes compounds according to formula (1), where R 1 , L 1 , R 2 , L 2 , R 3 The terms "Cy" and "n" are as defined herein. This document refers to compounds, methods for their production, pharmaceutical compositions comprising them, and treatment methods using them, for the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired cartilage turnover, congenital malformations of cartilage, and / or diseases associated with hypersecretion of IFN-γ, IL-12, and / or IL-23 by administration of the compound described herein.

Description

NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS FIELD OF INVENTION The present invention relates to compounds that may be useful in the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired turnover of cartilage, congenital cartilage malformations and / or diseases associated with the hypersecretion of IFNot, IL12 and / or IL23. In particular, the compound of the invention inhibits JAK, a family of tyrosine kinases, and more particularly TYK2. The present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations and / or diseases associated with hypersecretion of IFNot, IL12 and / or IL23 through administration of the compound of the invention. BACKGROUND OF THE INVENTION Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four members of the JAK family are described, JAK1, JAK2, JAK3 and TYK2. After the cytokine binds to its receptor, the members of C. 233.104 AGM 1 IF-2019-17407397-APN-ANP#INPI1 Page 1 of 545 IF-2019-17407397-APN-ANP#INPI Page 2 of 545 the JAK family self- and / or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription. JAK-STAT intracellular signal transduction serves interferons, most interieukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, L1F, CNTF, GM-CSF and PRL. (Vainchenker et al., 2008). The combination of genetic modeling and small molecule JAK inhibitor research revealed the therapeutic potential of JAK inhibitors (JAKinibs) (Babón et al., 2014). The last decade has seen the development of JAKinibs with varying degrees of selectivity profiles compared to members of the JAK family. In particular, while targeting multiple JAKs may not be detrimental (Broekman et al., 2011), the development of selective JAKinibs would be highly desirable to develop a treatment course tailored to patient needs despite the challenge it represents ( Fabian et al., 2005). For example, while JAK2 inhibition has been shown to be useful in the treatment of polycythemia and myelofibrosis, undesirable effects associated with JAK2 inhibition have been observed (O*Shea and Plenge, 2012), making compounds with JAK2-inhibiting components may not be suitable for the treatment of non-JAK2-mediated diseases. Using TYK2 knockout mice, it has been shown that IL-6, IL-10, IL11, IL 12, IL-13, IL-19, IL-20, IL-22, IL—23, IL- 27, IL- 28, IL-29, IL-31, lL-35 and / or type 1 interferon signaling depend on TYK2 (Schwartz et al., 2016). However, it has recently been shown that while JAK1 is a key driver in IFNa, 1L6, IL10 and IL22 signaling, TYK2 is involved in the IF-2019-17407397- APN-ANP#INPI Page 3 of 545 IF-2019-17407397-APN-ANP#INPI Page 4 of 545 type I interferons (including IFNa, INFp), IL23 and IL12 signaling (Gillooly et al., 2016; Sohn et al., 2013). Since the activity of IL12 and IL23 is particularly higher in patients with autoimmune diseases (O'Shea and Plenge, 2012) such as psoriasis and / or inflammatory bowel disorders, selective inhibition of TYK2 may be particularly advantageous in the treatment of these diseases, while preventing JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer et al., 1998; Parganas et al., 1998). Furthermore, TYK2 has been reported as a target for multiple autoimmune disorders, providing protection against inflammatory diseases as well as type 2 diabetes with limited impact on the immune system. (Dendrou et al., 2016). Consequently, there remains a need for new compounds that effectively and selectively inhibit JAK enzymes, in particular TYK2, thus allowing the design of specific treatments and doses adapted to the pathology. SUMMARY OF THE INVENTION The present invention relates to compounds useful in the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired cartilage turnover, congenital malformations of cartilage, and / or diseases associated with hypersecretion of IFNa, IL12 and / or IL23. In particular, the compound of the invention inhibits JAK, a family of tyrosine kinases, and more particularly TYK2. The present invention also IF-2019-17407397-APN-ANP#INPI3 Page 5 of 545 IF-2019-17407397-APN-ANP#INPI Page 6 of 545 provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, diseases proliferative, transplant rejection, diseases that involve impaired cartilage turnover, congenital cartilage malformations and / or diseases associated with the hypersecretion of IFNot, IL12 and / or IL23 through the administration of the compound of the invention. Accordingly, in a first aspect of the invention, the compounds of the invention are provided with a Formula (I): CK3where Cy is phenyl, or 5-6 membered heteroaryl comprising one, two or three N atoms; Li is a single bond, -O-, -C(=O)-, -C(=O)O-, -S(O)?-t-NR63-, C(=O)NR6b-, -S( O)2NR6c-, or C(=O)NR6dS(O)z-; R1es: H, IF-2019-17407397-APN-ANP#INPI4 Page 7 of 545 IF-2019-17407397-APN-ANP#INPI Page 8 of 545 Ci-e alkyl optionally substituted with one or more independently selected o OH, or halo, or Cj-4 alkoxy, or -NR7aR7b, or -C(=O)OH-, or -C(=O)NR7cR7d , or -C(=O)OCi^alkyl, or or 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O; 63.7 cycloalkyl optionally substituted with one or more OH, C1-4 alkoxy, or 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O; said heterocycloalkyl is optionally substituted with one or more independently selected R11 groups; each R11 is independently: OH, CN, halo, oxo, -NR8aRBb, 63-7 cycloalkyl, IF-2019-17407397-APN-ANP#INPI5 Page 9 of 545 IF-2019-17407397-APN-ANP#INPI Page 10 of 545 C-m alkyl optionally substituted with one or more independently selected from halo, OH, C-i-* alkoxy, -NR9aR9b, Ci-4 alkoxy optionally substituted with a Ci^ alkoxy, 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S, and O, -C(=O)OCi^alkyl, or -NR8cC(=O)C^Oalkyl; R2is halo, CN, or Ci^ alkyl; the subscript n is 0, or 1; L2 is O, o-NR4-, R3 is Ci-e alkyl optionally substituted with one or more independently selected from o halo, o o C3-7 cycloalkyl. - Phenyl substituted with one R5a group and one or two independently selected R5b groups, - 6-membered heteroaryl comprising one or two N atoms, substituted with one R5a group and one or two independently selected R5b groups, - 4-10 membered monocyclic or fused, bridged or spiro bicyclic heterocycloalkyl comprising one or two selected heteroatoms IF-2019-17407397-APN-ANP#INPI6 Page 11 of 545 IF-2019-17407397-APN-ANP#INPI Page 12 of 545 independently of N, S and O, optionally substituted with one, two or three groups independently selected from R5a and R5b, or - 4-10 membered monocyclic or fused, bridged or spiro bicyclic cycloalkyl, optionally substituted with one, two or three groups independently selected from R5a and R5b; R4es -H - Cu alkyl optionally substituted with one or more independently selected from OH or Ci-* alkoxy, or - C3-7 cycloalkyl; R5a is -ON, -SOa-C1-4 alkyl, or -CF3; each R5b is independently selected from halo, C1-4 alkyl and 63-7 cycloalkyl; each R7a and R7b are selected independently of -H,y - C1-4 alkyl optionally substituted with one -NR10aR10b; and each R6a, R8b, R8c, R6d, R7c, R7d, R0a, R8b, R8c, R9a, R9b, R10a, and R10b is independently selected from H, and C1-4 alkyl. In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proferative diseases, transplant rejection, diseases involving deterioration of cartilage turnover, congenital cartilage malformations and / or diseases associated with hypersecretion of IFNa, 1L12 and / or 1L23. IF-2019-17407397- APN-ANP#INPI7 Page 13 of 545 IF-2019-17407397-APN-ANP#INPI Page 14 of 545 Furthermore, the compounds of the invention have also unexpectedly been shown to exhibit improved selectivity towards TYK2 over other members of the JAK family, which may be advantageous in the treatment of diseases associated with IFNa, IL12 and / or IL23, particularly diseases autoimmune diseases such as psoriasis and / or inflammatory bowel disorders. Furthermore, the compounds of the invention and their TYK2 selectivity may be advantageous for the design of patient-specific treatments and doses tailored to the patient. In a further aspect, the present invention provides pharmaceutical compositions comprising 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 particular aspect, the additional therapeutically active ingredient is an agent for the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving deterioration of cartilage turnover, congenital cartilage malformations and / or diseases associated with hypersecretion of IFNa, IL12 and / or IL23. Furthermore, the compounds of the invention, useful in the pharmaceutical compositions and methods of treatment described herein, are pharmaceutically acceptable as prepared and used. In a further aspect of the invention, this invention provides a method of treating a mammal, in particular humans, with a IF-2019-17407397-APN-ANP#INPI8 Page 15 of 545 IF-2019-17407397-APN-ANP#INPI Page 16 of 545 condition selected from those listed herein, and particularly allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired cartilage turnover, congenital malformations of cartilage and / or diseases associated with hypersecretion of IFNa, IL12 and / or IL23, a method comprising administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein. The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent suitable for medium use. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired turnover. of cartilage, congenital cartilage malformations and / or diseases associated with hypersecretion of IFNct, IL12 and / or IL23. In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and routes described later herein. Other objectives and advantages will be apparent to those skilled in the art from a consideration of the detailed description that follows. It will be appreciated that the compounds of the invention can be metabolized to produce biologically active metabolites. IF-2019-17407397-APN-ANP#INPI9 Page 17 of 545 IF-2019-17407397-APN-ANP#INPI Page 18 of 545 BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 shows the effect of a test compound of the Invention on day 1-5 in the murine psoriatic-type epidermal hyperplasia model, versus the vehicle (filled diamonds) and the control group (filled squares), when dosed q.d. at 3 mg / kg (crosses), 10 mg / kg (asterisks) and 30 mg / kg (filled circles). DETAILED DESCRIPTION OF THE INVENTION Definitions The following terms are intended to have the meanings presented 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 said compounds and methods of using said compounds and compositions, the following terms, if present, have the following meanings, unless otherwise indicated. It should also be understood that when described herein any of the moieties defined below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set forth below. Unless otherwise noted, the term “substituted” shall be defined as set forth below. It should be further understood that the terms groups and radicals may be considered interchangeable when used herein. The articles 'un' and 'one / a* may be used in this document to refer to one or more than one (i.e. at least one) of the grammatical objects IF-2019-17407397- APN-ANP#INPI10 Page 19 of 545 IF-2019-17407397-APN-ANP#INPI Page 20 of 545 of the article. By way of example, an analogue means one analogue or more than one analogue. Alkyl means linear or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular 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 linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CHz-Chh), n-propyl (-CHz-CHj-CHa), isopropyl (-CH(CH3)2), n-butyl (CHz-CH2-CH2 -CH3), tere-butyl (-CH^CÍCHsh), sec-butyl (-CH?-CH(CH3)2), n-pentyl (-CHz-CHs-CHj-CHz-CHs), n-hexyl (- CH2-CH2-CH^CH2-CH2-CH3)1y 1,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms. Alkenyl refers to monovalent oleophilically (unsaturated) hydrocarbon groups with the specified number of carbon atoms. The particular alkenyl has 2 to 8 carbon atoms, and more particularly, 2 to 6 carbon atoms, which may be straight chain or branched and have at least 1 and particularly 1 to 2 olefinic unsaturation sites. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenium (CHjCH=CH2), isopropenyl (-C(CH3)=CH2) and the like. Alkylene refers to divalent alkene radical groups having the specified number of carbon atoms, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which may be straight chain or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (CH2-CH2-), or -CH (CH3>- and the like. IF-2019-17407397- APN-ANP#INPI11 Page 21 of 545 IF-2019-17407397-APN-ANP#INPI Page 22 of 545 Alkynylene refers to divalent alkyne radical groups having the specified number of carbon atoms and number of triple bonds, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which may be straight chain or branched. This term is exemplified by groups such as -C=C-, -CHz-C=C-, and -C(CH3)HC=CH-. Alkoxy refers to the O-alkyl group, where the alkyl group has the specified number of carbon atoms. In particular, the term refers to the -O-alkyl Ci-e group. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, that is, with between 1 and 6 carbon atoms. Additional particular alkoxy groups have between 1 and 4 carbon atoms. “Amino refers to the radical -Nhfe. Aillo refers to a monovalent aromatic hydrocarbon group derived from the removal of a hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular, aryl refers to a fused monocyclic or polycyclic aromatic ring structure, with the number of ring atoms specified. Specifically, the term includes groups that include 6 to 10 ring members. Particular aryl groups include phenyl and naphthyl. Cycloalkyl refers to a non-aromatic, monocyclic, fused polycyclic, bridged polycyclic or spirocyclic hydrocarbyl ring structure, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, IF-2019-17407397- APN-ANP#INPI12 Page 23 of 545 IF-2019-17407397-APN-ANP#INPI Page 24 of 545 single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyano refers to the radical -CN. ''Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The particular halo groups are fluorine or chlorine. Hetero when used to describe a compound or a group present in a compound means that one or more carbon atoms in the compound or group have been replaced by a heteroatom of nitrogen, oxygen or sulfur. Hetero can be applied to any of the hydrocarbyl groups described above, such as alkyl, for example heteroalkyl, cycloalkyl, for example heterocycloalkyl, aryte, for example heteroaryl, and the like having 1 to 4, and particularly 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom. Heteroaryl means a fused polycyclic, monocyclic or aromatic ring structure, which includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have 5 to 9 ring members. The heteroaryl group may be, for example, a five- 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, by way of further example, two rings. of five merged members. Each ring can contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more generally up to 2, for example a single heteroatom. In one embodiment, the ring IF-2019-17407397- APN-ANP#INPI13 Page 25 of 545 IF-2019-17407397-APN-ANP#INPI Page 26 of 545 heteroaryl contains at least one ring nitrogen atom. The nitrogen atoms in heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including substituents on the ring amino group, will 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, thiazolite, 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. Particular 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. Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl groups. , isoindolyl, indolizinyl, purinyl (for example adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl. Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, IF-2019-17407397- APN-ANP#INPI14 Page 27 of 545 IF-2019-17407397-APN-ANP#INPI Page 28 of 545 phthalazinyl, naphthyridinyl and pteridinyl. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, plridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl. Examples of representative heteroaryls include the following: where each Y is selected from >C=O, NH, O and S. Heterocycloalkyl means a non-aromatic, monocyclic, fused polycyclic, spirocyclic or bridged polycyclic fully saturated ring structure, including one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring can contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more generally up to 2, for example a single heteroatom. Examples of heterocyclic rings include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 220 tetrahydrofuranyl, and 3-tetrahydrofuranyl). , tetrahydrothiophenyl (for example 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (for example 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), IF-2019-17407397- APN-ANP#INPI15 Page 29 of 545 IF-2019-17407397-APN-ANP#INPI Page 30 of 545 tetrahydropyranyl (for example 4-tetrahydropyranyl), tetrahydrothiopyranyl (for example 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. As used herein, the term heterocycloalkenyl means a heterocycloalkyl, comprising at least one double bond. The 5 particular examples of heterocycloalkenyl groups are shown in the following illustrative examples: Particular examples of monocyclic rings are shown in the following illustrative examples: where each W and Y is selected independently of -CH?-, -NH-, -O-and-S-, Particular examples of fused bicyclic rings are shown in the following illustrative examples: where each W and Y is selected independently of -CHz-, -NH-, -O-and-S-. Particular examples of bridged bicyclic rings are shown in the following illustrative examples: IF-2019-17407397- APN-ANP#INPI16 Page 31 of 545 IF-2019-17407397-APN-ANP#INPI Page 32 of 545 where each W and Y is selected independently from -CH2-, -NH-, -O- and -S- and each Z is selected from N and CH. Particular examples of spirocyclic rings are shown in the following illustrative examples: where each Y is selected from -CH2-, -NH-, -O- and -S-. “Hydroxyl refers to the -OH radical. Oxo refers to the radical =0. Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituents. Sulfo or "sulfonic acid" refers to a radical such as -SO3H. “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 it refers to one to three substituents. In additional embodiments it refers to one or two substituents. In yet a further embodiment, it refers to a substituent. Thioalkoxy refers to the -S-alkyl group where the alkyl group has the specified number of carbon atoms. In particular, the term refers to the group -S-alkyl Ci-«. Particular thioalkoxy groups are thiomethoxy, thioethoxy, nthiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n-thiopentoxy, nthiohexoxy and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, that is, with between 1 and 6 carbon atoms. Additional particular alkoxy groups have between 1 and 4 carbon atoms. IF-2019-17407397- APN-ANP#INPI17 Page 33 of 545 IF-2019-17407397-APN-ANP#INPI Page 34 of 545 One skilled in the art of organic synthesis will recognize that the maximum number of heteroatoms in a chemically feasible stable heterocyclic ring, whether aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valency of the heteroatoms. In general, a heterocyclic ring can have from one to four heteroatoms as long as the heteroaromatic ring is chemically viable and stable. Pharmaceutically acceptable means approved or approvable by a federal or state government regulatory agency or the appropriate agency in countries other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals. , and more particularly, in human beings. Pharmaceutically acceptable salt refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such non-toxic salts may be addition salts of organic and inorganic acids and addition salts of bases. Specifically, 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, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, melic acid, maleic acid, maleteo acid, fumaric acid, tartaric acid, citric acid, citric acid, benzoic acid, 3-( 4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-cyorobenzenesulfonic acid, 2-naphthalenesulfonic acid, acid IF-2019-17407397- APN-ANP#INPI18 Page 35 of 545 IF-2019-17407397-APN-ANP#INPI Page 36 of 545 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2J-oct-2-ene1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethiecetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid , salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and when 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 a cationic acceptable counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations and the like. Pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. Prodrugs refer to compounds, including derivatives of the compounds of the invention, that have cleavage groups and are converted by solvolysis or under physiological conditions to the compounds of the invention that 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. IF-2019-17407397- APN-ANP#INPI19 Page 37 of 545 IF-2019-17407397-APN-ANP#INPI Page 38 of 545 Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonds. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention can be prepared, for example in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include stoichiometric solvates and non-stoichiometric solvates. In certain cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. ’•Solvate’’ encompasses solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates. ’’Subject includes human beings. The terms human, patient, and subject are used interchangeably in this document. “Effective amount means the amount of a compound of the invention that, when administered to a subject to treat a disease, is sufficient to effect said treatment for the disease. The effective amount may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. Prevent or “prevention” refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject who may be exposed to a causative agent. of disease, or predisposed to disease before the onset of disease. The term prophylaxis is related to prevention and refers to a measure or procedure whose purpose is to prevent, rather than treat or cure, a disease. IF-2019-17407397-APN-ANP#INPI20 Page 39 of 545 IF-2019-17407397-APN-ANP#INPI Page 40 of 545 disease. Non-limiting examples of prophylactic measures may include the administration of vaccines: the administration of low molecular weight heparin to hospitalized patients at risk of thrombosis due to, for example, immobilization; and administration of an antimalarial agent, such as chloroquine, before a visit to a geographic region where malaria is endemic or the risk of contracting it is high. “Treat” or treatment of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., stopping the disease or reducing the manifestation, extent or severity of at least one of its clinical symptoms). ). In another embodiment, treat or treatment refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, treating or treatment refers to the modulation of the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, treating or treatment refers to slowing the progression of the disease. As used herein, the term allergic disease(s) refers to the group of conditions characterized by a hypersensitivity disorder of! immune system including allergic respiratory disease (e.g., asthma, rhinitis), sinusitis, eczema, and hives, as well as food allergies or allergies to insect venom. As used herein, the term asthma as used herein refers to any disorder of the lungs characterized by variations in pulmonary gas flow associated with IF-2019-17407397-APN-ANP#INPI21 Page 41 of 545 IF-2019-17407397-APN-ANP#INPI Page 42 of 545 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 the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis) chronic obstructive pulmonary disease (COPD), inflammatory diseases of the liver (e.g. primary biliary cholangitis (PBC) and / or primary sclerosing cholangitis (PSC)), inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g., complications after bypass surgery or chronic endotoxin states contributing to e.g., chronic heart failure), and related diseases involving cartilage, such as those of the joints. In particular, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases. More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases. More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases. As used herein, the term "metabolic disease(s)" refers to the group of conditions that involve the ability of the IF-2019-17407397-APN-ANP#INPI22 Page 43 of 545 IF-2019-17407397-APN-ANP#INPI Page 44 of 545 body to process certain nutrients and vitamins. Metabolic disorders include phenylketonuria (PKU), type II diabetes, hyperlipidemia, gout, and rickets. A particular example of metabolic disorders is type II diabetes and / or obesity. As used herein, the term autoinflammatory disease(s) refers to the group of diseases that include Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), and factor receptor-associated periodic syndrome. tumor necrosis (TRAPS), Behgets, systemic onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. As used herein, the term autoimmune disease(s) refers to the group of diseases that include obstructive airway disease, including conditions such as COPD, asthma (e.g., intrinsic asthma, extrinsic asthma, dust, childhood asthma) particularly chronic or long-standing asthma (e.g. late-onset asthma and airway hyperresponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome , multiple sclerosis, psoriasis, dry eye disease, diabetes mellitus type I and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis), contact dermatitis and additional eczematous dermatitis, inflammatory bowel disease (for example, Crohn's disease and ulcerative colitis), interferonopathy, atherosclerosis, and amyotrophic lateral sclerosis. In particular, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease. IF-2019-17407397-APN-ANP#INPI23 Page 45 of 545 IF-2019-17407397-APN-ANP#INPI Page 46 of 545 As used herein, the term proliferative disease(s) refers to conditions such as cancer (e.g., uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g., polycythemia vera, essential thrombocytosis, and myelofibrosis). , leukemia (for example, 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 in organs of the body, for example, but not limited to, breast, prostate, lung, kidney, pancreas, stomach or intestine. . A cancer tends to infiltrate adjacent tissue and spread (metastasize) to distant organs, for example, 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 types of tissue carcinoma (such as, but without limitation, 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 myeloidleukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone (osteosarcoma and malignant fibrous histiocytoma), brainstem glioma, IF-2019-17407397-APN-ANP#INPI24 Page 47 of 545 IF-2019-17407397-APN-ANP#INPI Page 48 of 545 brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt's lymphoma, cancer of the uterus, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma T cells, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, stromal tumor gastrointestinal stromal cell tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, liver cell tumors islets (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer , non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma medulloepithelioma, melanoma, mesothelioma, oral cancer , chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, asopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, epithelial cancer ovary, ovarian germ cell tumor, low malignant potential ovarian tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, parenchymal tumors IF-2019-17407397- APN-ANP#INPI25 Page 49 of 545 IF-2019-17407397-APN-ANP#INPI Page 50 of 545 intermediate differentiation pineals, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasia / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer (kidney), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma , squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, cancer. uterine, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia and Wilms tumor. As used herein, the term 'leukemia' refers to neoplastic diseases of the blood and blood-forming organs. These diseases can cause bone marrow and immune system dysfunction, making the host highly susceptible to infection and bleeding. In particular, the term leukemia refers to acute myeloid leukemia (AML), and 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 of, for example, pancreatic islets, stem cells, bone marrow, skin, muscle, tissue. corneal, neuronal tissue, heart, lung, IF-2019-17407397-APN-ANP#INPI26 Page 51 of 545 IF-2019-17407397-APN-ANP#INPI Page 52 of 545 combined heart-lung, kidney, liver, intestine, pancreas, trachea or esophagus, or graft-versus-host diseases. As used herein, the term diseases involving impairment of cartilage turnover includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as endemic osteoarthritis deformans, Mselení disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosis, scleroderma, and ankylosing spondylitis. In a particular embodiment, the term refers to ankylosing spondylitis. As used herein, the term congenital cartilage malformation(s) includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but not limited to, microtia, anotia, metaphyseal chondrodysplasia and related disorders. As used herein, the term *disease(s) associated with hypersecretion of IFNa, IL12 and / or 1L23 includes conditions such as systemic and cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome , psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21 and / or Crohn's disease. “Compound(s) of the invention, and equivalent terms, are intended to encompass compounds of the Formula(s) as described herein, which term includes pharmaceutically acceptable salts and solvates, e.g., hydrates, and solvates of pharmaceutical salts IF-2019-17407397-APN-ANP#INPI27 Page 53 of 545 IF-2019-17407397-APN-ANP#INPI Page 54 of 545 acceptable where the context allows. Similarly, reference to intermediate products, whether claimed or not themselves, is intended to encompass their salts and solvates, where the context permits. When reference is made to ranges herein, for example, but not limited to, Ci^ alkyl, the citation of a range should be considered a representation of each member of that range. Other derivatives of the compounds of this invention have activity in both their acidic and acid-derived forms, but the acid-sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard , H, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of 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 pendant acidic groups in the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly such prodrugs are the C^alkyl, the C2-e alkenyl, the optionally substituted Ce-io aryl, and the esters (C&-ioC1-4 arylHalkyl) of the compounds of the invention. The present disclosure includes all isotopic forms of the compounds of the invention provided herein, either in a form (i) in which all atoms of a given atomic number have a IF-2019-17407397- APN-ANP#INPI28 Page 55 of 545 IF-2019-17407397-APN-ANP#INPI Page 56 of 545 mass number (or a mixture of mass numbers) that predominates in nature (referred to herein as the natural isotopic form) or (ü) where one or more atoms are replaced by atoms having the same atomic number, but a different mass number from the mass number of atoms that predominates in nature (referred to herein as a “non-natural variant isotopic form”). It is understood that an atom can exist naturally as a mixture of mass numbers. The term non-natural variant isotopic form also includes embodiments in which the proportion of an atom of a given atomic number that has a mass number less frequently found in nature (referred to herein as a rare isotope) has increased in relation to that which occurs naturally, for example at the level of > 20%, > 50%, > 75%, > 90%, > 95% or > 99% in number of atoms of that atomic number (the latter embodiment is called isotopically enriched variant form). The term non-natural variant isotope form also includes embodiments in which the proportion of a rare isotope has been reduced relative to that which occurs naturally. Isotopic forms may include radioactive forms (i.e., they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms. A non-natural variant isotopic form of a compound may contain one or more artificial or rare isotopes, such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulfur-35 (35S), chlorine -36 (38CI), chlorine-37 (37CI), fluorine-18 (18F) IF-2019-17407397-APN-ANP#INPI 29 Page 57 of 545 IF-2019-17407397-APN-ANP#INPI Page 58 of 545 iodine-123 (123l), iodine-125 (1251) in one or more atoms or may contain a higher proportion of said isotopes compared to the proportion that predominates in nature in one or more atoms. Non-natural variant isotopic forms comprising radioisotopes can, for example, be used for tissue distribution studies of substrate and / or drug. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and available means of detection. Unnatural variant isotopic forms incorporating deuterium, i.e., 2H or D may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore both may be preferable in some circumstances. Additionally, isotopic forms with unnatural variants incorporating positron-emitting isotopes, such as 11C, 10F, 150, and 13N, can be prepared and would be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. It should also be understood that compounds having the same molecular formula but differing in the nature or bonding sequence 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 that are non-superimposable mirror images of each other are called enantiomers. When a compound has an asymmetric center, for example, it is attached to four different groups, it is IF-2019-17407397-APN-ANP#INPI30 Page 59 of 545 IF-2019-17407397-APN-ANP#INPI Page 60 of 545 a pair of enantiomers possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and S sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levo rotatory, (i.e., as (+) or (-) isomers respectively). A chiral compound can exist as an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a racemic mixture. Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Therefore, two structures can be in / equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by acid or base treatment. Another example of tautomerism© are the aci- and nitro-forms of phenylnitromethane, which are also formed by treatment with acid or base. Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest. The compounds of the invention may have one or more asymmetric centers; Therefore, such compounds can be produced as individual (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, racemic or otherwise, of IF-2019-17407397-APN-ANP#INPI31 Page 61 of 545 IF-2019-17407397-APN-ANP#INPI Page 62 of 545 the same. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art. It will be appreciated that the compounds of the invention can be metabolized to produce biologically active metabolites. THE INVENTION The present invention relates to compounds that may be useful in the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases that involve impairment of cell turnover. cartilage; congenital cartilage malformations and / or diseases associated with hypersecretion of IFNa, IL12 and / or IL23. In particular, the compound of the invention inhibits JAK, a family of tyrosine kinases, and more particularly ΊΓΥΚ2. The present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, diseases proliferative, transplant rejection, diseases that involve impaired cartilage turnover, congenital cartilage malformations and / or diseases associated with the hypersecretion of IFNa, IL12 and / or IL23 through the administration of the compound of the invention. Accordingly, in a first aspect of the invention, the compounds of the invention are provided with a Formula (I): IF-2019-17407397-APN-ANP#INPI32 Page 63 of 545 IF-2019-17407397-APN-ANP#INPI Page 64 of 545 CH3 where Cy is phenyl, or 5-6 membered heteroaryl comprising one, two or three N atoms; Li is a single bond, -O-, -C(=O)-, -C(=O)O-, -S(O)?-, -NR6a-, C(=O)NR6b-, -S( O)2NR6c-, or C(=O)NR6dS(O)z-; R1es: H, Ci-b alkyl optionally substituted with one or more independently selected or OH, or halo, or C-i-4 alkoxy, or -NR7aR7b, or -C(=O)OH-, or -C(=O)NR7eR7d, or -C(=O)OC1-4alkyl. or o 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O; IF-2019-17407397- APN-ANP#INPI Page 65 of 545 IF-2019-17407397-APN-ANP#INPI Page 66 of 545 Cs-7 cycloalkyl optionally substituted with one or more OH, C1-4 alkoxy, or 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloaikyl comprising one, two or three heteroatoms independently selected from N, S I; said heterocycloaikyl is optionally substituted with one or more independently selected R11 groups: each R11 is independently: OH, CN, halo, oxo, -NR8aR8b, 03-7 cycloalkyl, C1-4 alkyl optionally substituted with one or more independently selected from halo, OH, C1-4 alkoxy, -NR9aR9b, Cf-4 alkoxy optionally substituted with a C1-4 alkoxy, 4-monocyclic heterocycloaikyl -7 members comprising one, two or three heteroatoms independently selected from N, S, and O, -C(=O)OC^alkyl, or -NRecC(=O)Oalqui!o Ch; R2es halo, CN, or C1-4 alkyl; the subscript n is 0, or 1; IF-2019-17407397- APN-ANP#INPI34 Page 67 of 545 IF-2019-17407397-APN-ANP#INPI Page 68 of 545 The is O, o-NR4-, R3 is Ci-e alkyl optionally substituted with one or more independently selected from o halo, o o cycloalkyl €3-7, - Phenyl substituted with one R5a group and one or two independently selected R5b groups, - 6-membered heteroaryl comprising one or two N atoms, substituted with one R53 group and one or two independently selected R5b groups, - 4-10 membered monocyclic or fused, bridged or spiro bicyclic heterocycloalkyl comprising one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R53 and R5b, or - 4-10 membered monocyclic or fused, bridged or spiro bicyclic cycloalkyl, optionally substituted with one, two or three groups independently selected from R5a and R5b; R4es -H - C1-4 alkyl optionally substituted with one or more independently selected from OH or C1-4 alkoxy, or - C3-7 cycloalkyl; R53is -CN, -SOa-C1-4alkyl, or -CF3; IF-2019-17407397-APN-ANP#INPI35 Page 69 of 545 IF-2019-17407397-APN-ANP#INPI Page 70 of 545 each R5b is independently selected from halo, C1-4 alkyl and Cj-7 cycloalkyl; each R7a and R7b are selected independently of ____ -H,y - C1-4 alkyl optionally substituted with one -NR10aR10b; and each R63, R6b, R60, R“, R7c, R7d, R8a, R8b, R8c, R9a, R9b, R10a, and R10b is independently selected from H, and C1-4 alkyl In another embodiment, the compound of the invention is according to Formula I, where L2 is NR4, where R4 is as previously described. In a particular embodiment, R4 is H. In another particular embodiment, R4 is “CH3, -CH2-CH2-CH2-OH, -CH2-CHOH-CH3. CHz-CHz-CHz-OCHs, or cyclopropyl. In one embodiment, the compound of the invention is according to Formula I, wherein L2 is O. In one embodiment, the compound of the invention is according to Formula I, wherein R3 is Ci-β alkyl. In a particular embodiment, R3 is -CH3, -CH2CH3, -CH(CK3)CH(CH3)2, or -CH(CH3)C(CH3)3. In one embodiment, the compound of the invention is according to Formula I, wherein R3 is C1-6 alkyl substituted with one or more independently selected from halo, or C3-7 cycloalkyl. In a particular embodiment, R3 is -Chfe, -CH2CH3, -CH(CH3)CH(CH3)2, CH(CH3)C(CH3)3, each of which is optionally substituted with one or more independently selected from halo, or C3-7 cycloalkyl. In another particular embodiment, R3 is C1-6 alkyl optionally substituted with one or IF-2019-17407397-APN-ANP#INPI36 Page 71 of 545 IF-2019-17407397-APN-ANP#INPI Page 72 of 545 more independently F, ciciopropyl or cyclobutyl. In a more particular embodiment, R3 is selected from: In another embodiment, the compound of the invention is according to Formula I, wherein R3 is phenyl substituted with one R5a group and one or two independently selected R5b groups. In a particular embodiment, R3 is phenyl substituted with one R53 group and two independently selected R5b groups. In another embodiment, the compound of the invention is according to Formula I, wherein R3 is 6-membered heteroaryl substituted with one R53 group and one or two independently selected R5b groups. In one embodiment, R3 is pyridinyl or pyridazinyl, each of which is substituted with an R53 group and an R5b group. In one embodiment, the compound of the invention is according to Formula I, wherein R3 is either where R53 and R5b are as described above. In one embodiment, the compound of the invention is according to Formula I, wherein R3 is as described above, and R53 is -CN, -SOz-C1-4 alkyl, or -CF3. In a particular embodiment, R53 is -CN, IF-2019-17407397-APN-ANP#INPI37 Page 73 of 545 IF-2019-17407397-APN-ANP#INPI Page 74 of 545 -SO2CH3, or -CF3. In a more particular embodiment, R53 is -CN. In one embodiment, the compound of the invention is according to Formula I, wherein R3 is as described above, and each R5b is independently selected from halo, C1-4 alkyl and C3-7 cycloalkyl. In a particular embodiment, each R5b is independently selected from F, -CH3, -CH2CH3 and cyclopropyl. In one embodiment, the compound of the invention is according to Formula I, wherein R3 is 4-10 membered monocyclic or fused, bridged or spiro bicyclic heterocycloalkyl comprising one or two heteroatoms independently selected from N, S and O In a particular embodiment, R3 is tetrahydropyranyl or oxa-spiro[3.5]nonane. In one embodiment, the compound of the invention is according to Formula I, wherein R3 is 4-10 membered monocyclic or fused, bridged or spiro bicyclic heterocycloalkyl comprising one or two heteroatoms independently selected from N, S and O , optionally substituted with one, two or three groups independently selected from R5a and R5b. In a particular embodiment, R3 is tetrahydropyranyl or oxaspiro[3.5]nonane, each of which is optionally substituted with one, two or three groups independently selected from R53 and R5b. In another particular embodiment, R3 is 4-10 membered monocyclic or fused, bridged or spiro bicyclic heterocycloalkyl comprising one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R53y R5bt where R53 is -CN, -SO2CH3, or -CF3, and R5b is selected from F, -CH3, CH2CH3 and cyclopropyl. IF-2019-17407397- APN-ANP#INPI 38 Page 75 of 545 IF-2019-17407397-APN-ANP#INPI Page 76 of 545 In one embodiment, the compound of the invention is according to Formula I, wherein R3 is 4-10 membered monocyclic or fused, bridged or spiro bicyclic cycloalkyl. In a particular embodiment, R3 is cyclohexyl or bicyclo[1.1.1]pentane. In one embodiment, the compound of the invention is according to Formula I, wherein R3 is 4-10 membered monocyclic or fused, bridged or spiro bicyclic cycloalkyl, optionally substituted with one, two or three groups independently selected from R5a and R5a. R5b. In a particular embodiment, R3 is cyclohexyl, or bicyclo[1.1.1]pentane, each of which is optionally substituted with one, two or three groups independently selected from R5a and R5b. In another particular embodiment, R3 is a 4-10 membered monocyclic or fused, bridged or spiro bicyclic heterocycloalkyl comprising one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R5a and R3a. R5b, where R5a is -CN, SO2CH3, or -CF3, and R5b is selected from F, -CH3, -CH2CH3 and cyclopropyl. In one embodiment, the compound of the invention is according to any of Formula II: IF-2019-17407397-APN-ANP#INPI39 Page 77 of 545 IF-2019-17407397-APN-ANP#INPI Page 78 of 545 where R1, Li, R2, Cy and the subscript n is as described above. In one embodiment, the compound of the invention is according to Formula I, or II, wherein Cy is phenyl. In one embodiment, the compound of the invention is according to Formula I, or II, wherein Cy is 5-6 membered heteroaryl comprising one, two or three nitrogen atoms. In a particular embodiment, Cy is pyrazolyl, pyridinyl, pyrimidinyl or pyridazinyl. In a more particular embodiment, Cy is pyridinyl, pyrimidinyl or pyridazinyl. In a more particular embodiment, Cy is pyridazinyl. In one embodiment, the compound of the invention is according to Formula I, or II, wherein the subscript n is 1, and R2 is as previously described. In a particular embodiment, R2 is F, CN or -CH3. In one embodiment, the compound of the invention is according to Formula I, or II, wherein the subscript n is 0. In one embodiment, the compound of the invention is according to the formula Illa, lllb, lile or 11Id: NC^N O N CH3en where L1 and R1 are as described previously. In one embodiment, the compound of the invention is according to any one of Formula l-llld, wherein L-ι is a single bond. IF-2019-17407397- APN-ANP#INPI40 Page 79 of 545 IF-2019-17407397-APN-ANP#INPI Page 80 of 545 In one embodiment, the compound of the invention is according to any one of Formula l-llld, where L-i is -OIn one embodiment, the compound of the invention is according to any one of Formula l- llld, where L-ι is -C(=O)-. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein Li is -S(O)?-. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein L-ι is -NR63, and R63se selected from H, and alkyl Cm- In a particular embodiment, R63se select from H, and -ch3. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein L1 is -C(=O)NR6b-, and R6b is selected from H, and Cm alkyl. In a particular embodiment, R6b is selected from H, y-CHa. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein Li is -SfO^NR60-, and R6c is selected from H, and C-m alkyl. In a particular embodiment, R60 is selected from H, y-CHa. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein L1 is -C(=O)NRWS(O)2-» and R6dis selected from H, and alkyl Cm En In a particular embodiment, R6d is selected from H, y-CHa. In one embodiment, the compound of the invention is according to any one of Formula l-llld, wherein R1 is H. IF-2019-17407397-APN-ANP#INPI41 Page 81 of 545 IF-2019-17407397-APN-ANP#INPI Page 82 of 545 In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is Ci-e alkyl. In a particular embodiment, R1 is -CH3, or -CH2CH3. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is C1-6 alkyl substituted with one or more independently selected OH, halo, C1-4 alkoxy, -NR7aR7b, C (=O)OH-, —C(=O)NR7cR7dt -C(=O)OC1-4alkyl, or 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O, and where each R7a, R7b, R7c and R7d are as previously described. In a particular embodiment, R1 is -CH3, -CH2CH3, -CH2CH2CH3. -CH2CH(CH3)2 “CH2CH2CH2CH3. or -CH2CH2CH(CH3)2. each of which is substituted with one or more independently selected from OH, halo, Cim alkoxy, -NR7aR7b, -C(=O)OH-, -C(=O)NR7cR7d, -C(=O)OC1alkyl- 4, 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O, and wherein each R7a, R7b, R7c and R7d are as described above. In a particular embodiment, each R7a and R7bes are independently H, or C1-4 alkyl optionally substituted with one NR10aR10b, wherein each R10a and R10b are independently selected from H, CH3, or -CH2CH3. In a more particular embodiment, each R7a and R7bes independently H, or -CH3, or -CH2CH3, each of which is optionally substituted with one -NR10aR10ben where each R10a and R10b is independently selected from H, -CH3 or -CH2CH3. In another particular embodiment, each R7c and R7is independently H, -CH3 or -CH2CH3. IF-2019-17407397- APN-ANP#INPI42 Page 83 of 545 IF-2019-17407397-APN-ANP#INPI Page 84 of 545 In another particular embodiment, R1 is Ci-6 alkyl substituted with one or more OH, F, -OCH3, -OCH2CH3. -NH2, -NHCH3, -NHCH2CH2-N(CH3)21 NHCH2CH31 -C(=O)OH-, -C(=O)NH2, -C(=O)NHCH3i -C(=O)NHCH2CH3, C(= O)N(CH3)2, -C(=O)OaC1-4Ikyl, dioxanyl, morpholinyl. In a more particular embodiment, R1 is -CH3l -CH2CH3, -CH2CH2CH31-CH2CH(CH3)21CH2CH2CH2CH3, or -CH2CH2CH(CH3)2, -each of which is substituted with one or more OH, F, -OCH3, -OCH2CH3, -NH2, -NHCH3, -NHCH2CHzN(CH3)2. -NHCH2CH3, -C(=O)OH-, -C(=O)NH2, -C(=O)NHCH3, C(=O)NHCH2CH3, -C(=O)N(CH3)21-C(= O)C1-4alkyl, dioxanyl, morpholinyl. In a more particular embodiment, R1 is -CH3, -CH2CH3, CH2NH2, -CH2CH(OH)CH3, -CH2-CH2OCH3, -CH2CH2CH2OH, CH2CH2CH2OCH3, -CH2CH2CH(CH3)OCH3, -CH2CH2C(CH3)OH. -CHzC(=O)NHCH2CH3, -CH2- morpholinyl, -CH2-dioxanyl, or CH2N(CH3)CH2CH2N(CH3)2. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is C3-7 cycloalkyl. In a particular embodiment, R1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is C3-7 cycloalkyl substituted with one or more independently selected from OH, or C1-4 alkoxy. In a particular embodiment, R1 is C3-7 cycloalkyl substituted with one, two or three independently selected from OH, C1-4 alkoxy. In a more particular embodiment, R1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two or three selected 4α IF-2019-17407397- APN-ANP#INPI Page 85 of 545 IF-2019-17407397-APN-ANP#INPI Page 86 of 545 independently of OH, C1-4 alkoxy. In another more particular embodiment, R1 is C3-7 cycloalkyl substituted with one, two or three independently selected from OH, -OCH3u -OCH2CH3. In one embodiment, the compound of the invention is according to any one of Formula l-llld, wherein R1 is a 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one. two or three heteroatoms independently selected from N, S and O. In a particular embodiment, R1 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-azaspiro[3.3]eptanyl, Octahydro-pyrrolo[3,4-bjpyrrolyl, 2-Oxa-6-azaspiro[3.4]octanyl, 2- Oxa -7-aza-spiro[4.4]nonanyl, 2,6-Diazaspiro[3.3]heptanyl, or 2,5-Diaza-bicyclo[2.2.1]heptanyl. In a more particular embodiment, R1 is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, tetrahydropyranyl, piperazinyl or dioxanyl. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three independently selected heteroatoms of N, S and W; whose heterocycloalkyl is substituted with one or more independently selected R11 groups. In a particular embodiment, R1 is 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O; whose heterocycloalkyl is substituted with one, two or three independently selected R11 groups. In a way of IF-2019-17407397- APN-ANP#INPI44 Page 87 of 545 IF-2019-17407397-APN-ANP#INPI Page 88 of 545 more particular embodiment, R1 is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, piperidinyl, tetrahydropyranyl, piperazinyl, dioxanyl, [1,4]oxazepanyl, 2-oxa-5-aza-bicic!o[ 2.2.1]heptanyl, 1-oxa-6-aza spiro[3.3]heptanyl, octahydro—pyrrolo[3t4—b]pyrrolyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-7-aza-spiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, or 2,5-diaza-bicyclo[2.2.1 Jheptanyl, each of which is substituted with one, two or three independently selected R11 groups. In a more particular embodiment, R1 is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholín-4-yl, tetrahydropyranyl, piperazinyl or dioxanyl, each of which is substituted with one, two or three independently selected R11 groups. In one embodiment, the compound of the invention is according to any of Formula l-llid, wherein R1 is 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three independently selected heteroatoms of N, S and W; whose heterocycloalkyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is OH. In one embodiment, the compound of the invention is according to any of Formula l-Illd, wherein R1 is 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three independently selected heteroatoms of N, S and W; whose heterocycloalkyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is CN. IF-2019-17407397- APN-ANP#INPI45 Page 89 of 545 IF-2019-17407397-APN-ANP#INPI Page 90 of 545 In one embodiment, the compound of the invention is according to any of Formula I-IIId, wherein R1 is monocyclic or spirobicyclic or bridged or fused bicyclic 4- to 9-membered heterocycloaikyl comprising one, two or three independently selected heteroatoms of N, S and W; whose heterocycloaikyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is halo. In a particular embodiment, R11 is F, or Cl. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is monocyclic or spirobicyclic or bridged or fused bicyclic 4- to 9-membered heterocycloaikyl comprising one, two or three independently selected heteroatoms of N, S and W; whose heterocycloaikyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is oxo. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is monocyclic or spirobicyclic or bridged or fused bicyclic 4- to 9-membered heterocycloaikyl comprising one, two or three independently selected heteroatoms of N, S and W; whose heterocycloaikyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is NR8aR8b, and each R8a and R8bes as previously defined. In a particular embodiment, each R8a and R8bes independently H, or C1-4 alkyl. In a more particular embodiment, each R8a and R8bes independently H, CH30-CH2CH3. IF-2019-17407397-APN-ANP#INPI46 Page 91 of 545 IF-2019-17407397-APN-ANP#INPI Page 92 of 545 In one embodiment, the compound of the invention is according to any one of Formula 1-llld, wherein R1 is 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three selected heteroatoms regardless of N, S and O; whose heterocycloalkyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is C3-7 cycloalkyl. In a particular embodiment, R11 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, the compound of the invention is according to any one of Formula I-llId, wherein R1 is 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three selected heteroatoms regardless of N, S and O; which heterocycloalkyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is C-m alkyl optionally substituted with one or more independently selected from halo, OH, C-m alkoxy, -NR9aR9b, wherein each R9a and R9bes as defined previously. In a particular embodiment, R11 is CH3, "CH2CH3, or -CH2CH2CH3, each of which is optionally substituted with one or more independently selected from halo, OH, C1-4 alkoxy, -NR9aR9b, where each R9a and R9bes as was previously defined. In another particular embodiment, R11 is C-m alkyl, optionally substituted with one or more independently selected from F, -OCH3, -OCH2CH3, -NH2, NHCHs, or -NfCHsV. -CH(CH3)2or -CH2CH2CH3, each of which is optionally IF-2019-17407397-APN-ANP#INPI47 Page 93 of 545 IF-2019-17407397-APN-ANP#INPI Page 94 of 545 replaced with one or more independently selected from F, -OCH3. OCH2CH3, -NH2, -NHCH3)or -N(CH3)2. In one embodiment, the compound of the invention is according to any one of Formula 1-1 lid, wherein R1 is a 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one. two or three heteroatoms independently selected from N, S and O; which heterocycloalkyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is C1-4 alkoxy optionally substituted with a C1-4 alkoxy. In a particular embodiment, R11 is -OCH3, -OCH2CH3, or -OCH2CH2CH3l each of which is optionally substituted with one or more independently selected Ci_< alkoxy. In another particular embodiment, R11 is C1-4 alkoxy, optionally substituted with one or more independently selected from OCH3, -OCH2CH3, or -OCH2CH2CH3. In a more particular embodiment, R11 is —OCH3, -OCH2CH3, or -OCH2CH2CH3, each of which is optionally substituted with one or more independently selected from OCH3, -OCH2CH3, or -OCH2CH2CH3. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three independently selected heteroatoms of N, S and W; which heterocycloalkyl is substituted with one or more R11 groups independently selected, wherein one or more of the R11 groups is 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N. S and O. In a form of IF-2019-17407397-APN-ANP#INPI48 Page 95 of 545 IF-2019-17407397-APN-ANP#INPI Page 96 of 545 particular embodiment, R11 is azetidinyl, oxetanyl, pyrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl or morpholinyl. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three independently selected heteroatoms of N, S and W; whose heterocycloalkyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is C(=O)OC1-4alkyl. In a particular embodiment, R11 is -C(=O)OCH3. In one embodiment, the compound of the invention is according to any of Formula l-llld, wherein R1 is 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three independently selected heteroatoms of N, S and W; whose heterocycloalkyl is substituted with one or more independently selected R11 groups, wherein one or more of the R11 groups is NR8cC(=O)OC1-4alkyl, wherein R8ces as previously defined. In a particular embodiment, R11 is -NHC(=O)OCH3, -NCH3C(=O)OCH3, or NHC(=O)OCH2CH3. In one embodiment, the compound of the invention is selected from: 4-{[7-(6-Amino-pyrimidin-4-ylamino)-3-methiI-3H-imidazo[4,5-b]pyridin-5 -yl]methyl-amino)-3-ethyl-5-fluoro-benzonitrile, 5-{[7-(6-Amino-pyrimidin-4-ylamino)-3-methyl-3H-imidazo[4, 5-b]pyridin-5-yl]methyl-amino}-4-methyl-pyridin-2-carbonitrile IF-2019-17407397-APN-ANP#INPI49 Page 97 of 545 IF-2019-17407397-APN-ANP#INPI Page 98 of 545 4—{[7—(6—Amino—pyrimidin—4—ylamino)—3—methyl—3H—imidazo[4t5—bjpyridln—5—yl}— methyl-aminoj-cyclohexanecarbonitrile, N7-(6-Amino-pyrimidin- 4-yl}-N5-(3l3-dimethyl-tetrahydro-pyran-4-yl)-3lN5dimethyl-SH-imidazo^.S-bjpyridin-SJ-diamine, N7-(6-aminopyrimidin-4-yl}-N5,3-dimethyl-N5-[(1 S)-1,2,2trimethylpropyl]imidazo[4,5-b]pyridin-5,7-diamine, (± H1R.3R)-3H[7-(6“Amino“Pyrimici'n“4“iIamIno)3-methi,“3H-lmidazo[4)5b]pyridin-5-yl]-methyl-amino}-cyclohexanecarbonitrile, 4 -{[7-(6-Amino-pyrimidin-4-ylamino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl]methikamino)-3-cyclopropyl-5-fluoro-benzonitrile, 5-{[7-(6-Amino-pyrimidin-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-[(1 R)—1 —cyclop ropylethyl]—N 5,3-d i methyl—imidazo[4,5-b]pyridin-5,7-diamine, N7-(6-Amino-pyrimidin-4-yl}-3,N5-dimethyl-N5-((3R,4S}-3-methyl-tetrahydropyran-4-i1)-3H-imidazo[4,5-b] pyridin-5,7-d amine, N7-(6-Amino-pyrimidin-4-yl}-N5-bicyclo[1.1,1]pent-1-yl-3,N5-dimethyl-3Himidazo[4,5- b]pyridin-5,7-diamine, N7-(6-Amino-pyrimidin-4-yl}-3,N5-dimethi!-N5-(3-methyl-tetrahydro-pyran-4-yl)3H-imidazo[4,5-b]pyridin-5, 7-diamine, N7-(6-Amino-pyrimidin-4-i!)-N5-(1-cyclopropyl-2,2,2-trifluoro-eti1}-3,N5-dimethyl3H-imidazo[4,5-b]pyridin-5 ,7-diamine, N7-(6-Amino-pyrimidin-4-yl)-3.N5-dimethi!-N5-(5-oxa-spiro[3.5]non-8-yl}-3Himidazo[4,5-b]pyridin-5 ,7-diamine, IF-2019-17407397-APN-ANP#INPI50 Page 99 of 545 IF-2019-17407397-APN-ANP#INPI Page 100 of 545 5—(1—clcloproprl—2,2,2—trifluoro—ethoxy)—3—methyl—N—(5—methylsulfonyl—2— pyridylJimidazo^.S-bJpyridin-T-amine, 6-[5-(6- Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-7¡lamino}-pyridaz¡n-3-carboxylic acid ethylamide, 6-(5-(6-Cyano-4-methyl-pyridin-3-yloxy}-3-methyl-3H-imidazo[4,5-b]pyridin-7ylaminohN-P-hydroxy-propylJ-nicotinamide, (2- 6-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3methyl-SH-lmidazo^.S-bJpyridiiW-ylaminoJ-pyridazine-S-carboxylic acid hldroxy-propyl}-amide, Ethylamide 5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3Himidazo[4,5-b]pyridin-7-iIamino]-pyridine-2-carboxnic acid, 2-{4-[5-(6-Cyano-4-methyl-pyridin-3-yloxy}-3-methyl-3H-imidazo[4.5-b]pyridin-7ylamino]-pheniI}-N-ethyl-acetamide, 4-Methyl -5-{3-methyl-7-[6-(morpholin-4-carbonyl}-pyridin-3-ylamino]-3Hlmidazo[4,5-b]pyridin-5-yloxy}-pyridin-2-carbonitrile, Methylamide of 5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3-methyl-3Himidazo[4,5-b]pyridin-7-ylamino}-pyridine-2-carboxylic acid, (2 5-[5-(6-Cyano-4-methyl-pyridin-3-yloxy)-3metü-SH-imidazofd.S-bJpyridin^-ylaminoJ-pyridine^-carboxylic acid -hydroxy-propyl)-amide, 5- {746-(2-Methoxy-ethylamino}-pyrimidin-4-ylamino]-3-niethyl-3H-imidazo[4l5b]pyridin-5-yloxy)-4-methyl-pyridin-2-carbonitrile, 5-{7- [6-(3-Methoxy-propyIamino}-pyrimidin-4-ylaminol-3-niethyl-3H-imidazo[4,5b]pyridin-5-yloxy)-4-methyl-pyridin-2-carbonitrile, 5-{7 -(6-(3-Hydroxy-3-niethyl-butylamino)-pyrimidin-4-ylamino]-3-methyl-3Himidazo[415-b]pyridin-5-yloxy}-4-methyl-pyridin-2-carbonitrile, IF-2019-17407397-APN-ANP#INPI 51 Page 101 of 545 IF-2019-17407397-APN-ANP#INPI Page 102 of 545 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-{&-[(

[114] Dioxan-2-ylmethyl)-amino]-pyrimidin-4-ylamino}-3-niethyl-3Himidazo[4,5-b]pyridin- 5-ylox¡)-4-methyl-p¡r¡din-2-carbonitrile, 5-{7-[6-(3-Methoxy-cyc!obutylamino}-pyrimidin-4-ylamino]-3-methyl-3Himidazo [4,5-b]pyridin-5-yloxy}-4-methyl-pyridin-2-carbonitrile, 5-{7-[6-(3-Methoxy-butylamino}-pyrimidin-4-ilamino}- 3-nietyl-3H-imidazo[4,5bjpyridin—5—yloxy)—4—methyl—pyridin—2—carbonitrile, 4-Methyl-5-[3-methyl-7-(6-morpholin-4 -yl-pyridazin-3-ylamino)-3H-imidazo[4,5bjpyridin-5- yloxyj-pyridin—2-carbonitrile, 4-Methyl-5-[3-methyl-7-[6-(4-methyl-piperazin -1-yl}-pyridazin-3-ylamino]-3Himidazo^.S-blpyridin-S-yloxyy-pyridin^-carbonitrile, 5-{7-[6-(3-Dimethylanriinometi!-azetidin-1-yl}- pyridazin-3-ylamino]-3-methyl-3Himidazo[4,5-b]pyridin-5-yloxy)-4-methyl-pyridin-2-carbonitrilot(±}-4-Methyl-5-{3-methyl- 7-[6-({3R15S)-3,415-trimethyl-piperazin-1-yl}-pyridazin-3ylamino]-3H-imidazo[415-b]pyridin-5-yloxy}-pyridin-2-carbonitrile , 4-Methyl-5-(3-methyl-7-{6-[4-(2l2l2-trifluoro-ethyl)-piperazin-1-yl}-pyridazin-3ylamino}-3H-imidazo[4,5- b]pyridín-5-yloxy)-pyridin-2-carbonitrile, (±)-5-{7-[6-((2R,6S}-2l6-Dimethyl-morpholin-4-yl}-pyridazin-3 -iIamino]-3-methylSH-imidazo^.S-bjpyridin-fj-yloxyy-^-methyl-pyridine^-carbonitrile, 4-Methyl-5-{3-methi!-7-[6-((S)- 2-methyl-niorfolin-4-yl)-pyridazin-3-ylamino]-3Himidazo[4,5-b]pyridin-5-yloxy}-pyridin-2-carbonitrile, 5-{7-[6-{4- Cyano-piperidin-1-yl)-pyridazin-3-ylamino]-3-methyl-3H-imidazo[4,5b]pyridin-5-yloxy)—4-methyl-pyridin-2-carbonitri!o, IF-2019-17407397-APN-ANP#INPI52 Page 103 of 545 IF-2019-17407397-APN-ANP#INPI Page 104 of 545 4—methi!—5—[3—methyl—7—[[5—(4—propan—2—ylpiperazin—1—carbonyl)pyridin—2—yl]amino]imidazo[4,5-b]pyrid ¡n-5-yl]oxypyridin-2-carbonitrile, 5—[7—[[5—(4—cyclobutylpiperazin—1—carbonyl)pyridin—2—yljamino]—3—methylimidazo[4t5— bjpyridin—5—yl]oxy—4—methylpyridin—2—carbonitrile, 5-[ 7-[[5-(4-cyc!opropylpiperazin-1-carbonyl)pyridin-2-i!]amino]-3methylímidazo[415-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbon trilo, 4-methyl-5-[3-methyl-7-[(5-morpholin-4-llpyridin-2-yl)amino]imidazo[4,5-b]pyridin-5ll]oxypyridin-2-carbonitrile, 4-methyl -5-[3-methyl-7-[[5-(4-methylplperazin-1-yl)pyridin-2-ll]amino]imldazo[4,5bjpyridin-5-yljoxypyridin—2-carbonitrile, 4-methyl-5 -[7-[[5-(4-methylpiperazin-1-carbonyl)pyridin-2-yl]amino}-3(trideuteriomethyl)imidazo[415-b]pyridin-5-yl]oxypyridin-2-carbonitrile, 5-[7-[(6-aminopyrimidin-4-II)arTiino]-3-methyl-imldazo[415-b]pyridin-5-yl]oxMmethyl-pyridin-2-carbonitrile, 4-[[5-[(6-cyano-4-methi!-3-pyridyl)oxy]-3-methyl-imidazo[4,5-b]pyridin-7-n]amino]N-ethyl-benzenesulfonamlde, N4-[5-(1-cyclopropyl-2l2,2-trifluoro-ethoxy)-3-methyl-imidazo[4l5-b]pyridin-7yl]pyrimidin-4,6-diamine, 5-[[7-[(6-aminopyrimidin-4-i!)amino}-3-methiHmidazo[4,5-b]pyridin-5-yl]amino}4-methyl-pyridin-2-carbonitri!o, Sa! 5-[7-[4-(aminomethyl)anilino]-3-methyl!-lmidazo[4,5-b]pyridin-5yl]oxl-4-methyl-pyridin-2-carbonitrile formate, 4-methyl-5 -[3-methyl-7-[(5-methylsulfonyl-2-plridyl)amino]imidazo[4,5-b]plridin-5yl]oxl-pyridin-2-carbonitrile, IF-2019-17407397-APN-ANP#INPI53 Page 105 of 545 IF-2019-17407397-APN-ANP#INPI Page 106 of 545 4-methyl-5-[3-methyl-7-[[5-(trifluoromethyl)—2-pyridyl]amino]imidazo[4,5-bjpyridin-5yljoxy—pyridin—2-carbonitrile, 4-rnetyl-5-[3-metik7-(4-rnetylsulfonylanilino)irnidazo[4,5-b]pyridin-5-yl]oxy-pyridin2-carbonitrile, 4-methyl-5-[3-methyl-7-[(1-methylpyrazol-4-yl)amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-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]oxypyridin-2-carbonitrile, 6-[[5-[(6-cyano-4-methyl-3-pyridyl)oxy]-3-methyl-lmidazo[415-b]pyridin-7-yl]amino]N-ethyl-4-methyl-pyridin -3-ca rboxamide, 3—methyl—N7—(5—methylsulfonll—2—pyridyl)—N5—[2—methyl—1— (trifluoromethylJpropiqimidazo^.S-blpyridin-SJ-diamine, 4-[[5-[(6-cyano-4 -methyl-3-pyridyl)amino]-3-methyl-irnidazo[4,5-b]pyridin-7yl]amino]-N,N-dimethyl-benzamide, 6-[[5-[(6-cyano-4 -methyl-3-pyridyl)amino]-3-methyl-imidazo[4t5-b]pyridin-7yl]aminoJ-NtN-dimethyl-pyridine-3-carboxamide, 5-[7-[4-(difluoromethylsulfonyl)anilino]-3-methyl-imidazo[4,5-b]pyridin-5-yl]oxMmeti!-pyridin-2-carbonitrile, 5-[7-(4-cyclopropylsulfonylanylino)-3-methyl-imidazo[415-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile, 5-[7-[(1> 1-dimethi!-3-oxo-isoindolin-5-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5yl]oxy-4-methyl-pyridin -2-carbonitrile, IF-2019-17407397-APN-ANP#INPI54 Page 107 of 545 IF-2019-17407397-APN-ANP#INPI Page 108 of 545 5—[7—[4—{3—methoxypropylsulfonyl)anilino]—3—methyl—imidazo[4,5—b]pyridin—5—yljoxy—4—methyl-pyridin-2-carbonitrile, N4—[5—(1—cyclopropylethoxy)—3—methyl—imidazo[4,5—b]pyridin—7—H]pyrimidin—4,β— diamine, 6—[[5—[(6—cyano—4—methyl—3—pyridyl)oxy]—3—methyl—imidazo[4.5—b]pyridin—7—yl]amtnoj— N,N-dimethyl-pyridazin-3 -carboxamide, 6-[[5-[(6-cyano-4-methyl-3-pyridyl)oxyl-3-methyl-imidazo[4,5-b]pyridin-7-ll]amino]N,N-dimethyl -pyridine-3-carboxamide, 4-methyl-5-[3-methyl-7-[[5-(morpholine-4-carbonyl}-2-pyridyl]amino]imidazo[4,5bjpyridin—5-yljoxy—pyridin— 2-carbonitrile, 6-[[5-[(6-cyano-4-methyl-3-pyridyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7iI]amino]-N,N- dimethyl-pyridazine-3-carboxamide, 6-[[5-[(&-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-[(&-cyano-4-methyl-3-pyridÍI)oxy]-3-metÍHmidazo[4,5-b]pyridin-7-yl]amino]N-ethyl-2-methiI-pyridin -3-carboxamide, 5-Pr-[[5-[(dimethylamino)methyl]pyridin-2-yl]aminoJ-3-methylimidazo[415-b]pyridin-5yljoxy-4-methylpyridin-2-carbonitrile formate salt, 4-Methyl-5-[3-methyl-7-[[5-(morphoIin-4-ylmethyl)pyridin-2yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2 formate salt -carbonitrile, 5-[7-[[5-[[2-(dimethylamino)ethyl-methylamino]methyl]pyridin-2yl]aminoJ-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4 formate salt -methylpyridin-2-carbonitrile, 5-[7-[(5-methoxypyridin-2-yl)amino]-3-methylimidazo[4,5-b]pyridin-5-i1]oxy-4methylpyridin-2-carbonitrile, IF-2019-17407397-APN-ANP#INPI 55 Page 109 of 545 IF-2019-17407397-APN-ANP#INPI Page 110 of 545 4-methi!-5-[3-methyl-7-[[5-[(3S}-3-niethiImorfolin-4-yl]pyridin-2¡l]amino]imidazo[4,5-b]p¡rÍdin -5-yl]oxypyridin-2-carbonitrile, 4—methyl—5—[3—methyli—7—[[5—(1—methylpiperidin—4—yl)oxypyridin—2—yl]amino]imidazo[4 ,5— bjplridin—5- iljoxypyrid in-2-carbonitrile, 4-methi!-5-[3-methyl-7-[[5-(oxan-4-yl)pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5yljoxypyridin—2—carbonitrile, 5 -[[7-[(6-aminopyrimidin-4-yl)amino}-3-niethyl-imidazo[4,5-b]pyridin-5-yl]cyclopropy!-amino]-4-niethyl-pyridin-2- carbonitrile, 5-[7-[4-(3-hydroxyoxetan-3-yl)anilino}-3-methylimidazo[4,5-b]pyridin-5-iI]oxy-410 methylpyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[6-(1-methylazetidin-3-yl)oxypyridazin-3yllaminolimidazo^.S-blpyridin-S-ylJoxypyridin^-carbonitrile,5-[[5-[( 1-c*cl°PropH-2.2,2-trifluoro-ethyl)amino]-3-methyl-imidazo[4,5-b]pyridin-7ylJaminoJ-N-ethyl-pyridine-2-carboxamide, N5-(1“cycloProP>l-2.2l2-trifluoro-ethyl)-3-methyl-N7-(5-methylsulfonyl-2pyridyl)imidazo[4,5-b]pyridin-5,7-diamine, N7-(6 -aminopyrimidin-4-yl)-3-niethyl-N5-[2-methyl-1(trifluoromethyl)propyl]imidazo[415-b]pyridin-5,7-diamine1 N7-(6-aminopyrimidin-4-yl)-N5-(1-cyclobutylethyl)-3-methyl-imidazo[4l5-b]pyridin20 5,7-diamine, N7-(6-aminopyrimidin-4-yl)-N5-(dicyclopropylmethyl)-3-methyl-imidazo[415b]pyridin-5,7-diamine( S-r-nS-iS-hydroxyazetidin-l-carbonyl-Z-pyridylJaminoJ-S-metiklmldazo^.SbJpyridin-S-illoxM-methyl-pyridin^-carbonitrile, IF-2019-17407397-APN-ANP#INPI Page 111 of 545 IF-2019-17407397-APN-ANP#INPI Page 112 of 545 N.N-dimettl—6-{[3—methyl—5- [[(1 R}-2-methyl-1(trifluoromethyl)propyl]amino]Imidazo[415-b]pyridin-7-ÍI]amino]pyridín -3-carboxamide, N7-(6-aminopyrimidin-4-yl)-3-methyl-N5-[(1 R}-2-methyl-1 (trifluormethi!)propyl]imidazo[4,5-b]pyridin- 5,7-diamine, 6-[[5-[(&-cyano-4-methyl-3-pyridyl)oxy]-3-methyl-Ímidazo[4,5-b]pyridÍn-7-yl]amino]N-(2- dimethylaminoethyl)pyridin-3-carboxamide, 6-[[5-[(&-cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[415-b]pyridin-7-yl]amino]N -(3-methoxypropyl )pyridin-3-ca rboxa mida, 6-[[5-[(6-cyano-4-methyl-3-pyridyl)oxy]-3-methyl-imidazo[415-b]pyridin-7-yl]amino}N-(3-hydroxypropyl)pyridin- 3-carboxamide, 5-[7-[[5-[3-(1-hydroxy-1-methyl-ethyl)azetidin-1-carbonyl]-2-pyridyl]amino}-3-methylimidazo[4,5-b ]pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrile, 5-[7-[[5-(3-methoxyazetidin-1-carbonyl}-2-pyridyl]amino]-3-methyl-imidazo [4,5b]pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrile, 5-[7-[[5-[3-(methoxymethyl)azetidin-1-carbonyl]-2-pyridyl]amino ]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[5-(4-methylpiperazin-1-carbonyl)-2pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridin-2 -carbonitrile, 5-[7-[[5-[3-(dimethylamino)azetidin-1-carbonyl]-2-pyridyl]amino]-3-methylimidazo[4,5--b]pyridin-5-yl]oxy -4-methyl-pyridin-2-carbonitrile, 5-[7-[[5-[(3R}-3-(dimethylamino)pyrrolidin-1-carbonyl]pyridin-2-yl]amino]-3methylimidazo[4,5-b]pyridin-5-yl] oxy-4-methylpyridin-2-carbonitrile, 4-methyl-5-[3-methyl-74[6-(morpholin-4-carbonyl)pyridazin-3-yl]arTiino]imidazo[415b]pyridin- 5-yljoxypyridin— 2-carbonitrile, IF-2019-17407397-APN-ANP#INPI57 Page 113 of 545 IF-2019-17407397-APN-ANP#INPI Page 114 of 545 4-methyl—5-[3-methyl-7-(4-morpholinoanilino)imidazo[415- b]pyridin-5-yl]ox¡-pyridin-2carbonitrile, 4-methyl!-5-[3-methyl-7 -(4-(4-methylpiperaz¡n-1-yl)anÍIÍno]Ímidazo[415-b]pyridin-5yl]oxy-pyridin-2-carbonitrile, 5-[7-[[&-[3-(1 -hyd roxy-1 —methyl—ethyl)azetid in-1 -ca rbonii]pyridazin-3-yl]amino]-3methyl-imidazo[4l5-b]pyridin -5-yl]oxy-4-methyl-pyridin-2-carbonitrile, 5-[7-[[5-[(3S)-3-h id roxypyrrolid in-1-carbo nilJ-2-py ridyl]amino ]-3-m ethylimidazo[4,5-b]pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrile, 5-[7-[[5-(3-cyclopropyl-3-hydroxy-azetidine -1-carbonyl)-2-pyridyl]amino]-3-rmethylimidazo[4,5-b]pyridin-5-H]oxy-4-niethyl-pyridin-2-carbonitrile, 4-methyl-5-[3- methyl-7-[[5-(8-oxa-3-azaspiro[4.4]nonane-3-carbonyl)-2pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridin-2- carbonitrile, 5-[7-[[6-(3-hydroxyazetidin-1-carbonyl)pyridazin-3-yl]amino}-3-methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methyl -pyridin-2-carbonitrilot5-[7-[[6-(3-methoxyazetidin-1-carbonyl)pyridazin-3-yl]amino]-3-niethylimidazo[4,5-b]pyridin-5-yl]oxy- 4-methyl-pyridin-2-carbonitrile, 5-[7-[[6-[3-(methoxymethyl)azetidin-1-carbonyl]pyridazin-3-yl]amino]-3-methylimidazo[4,5-b] pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrile, 5-[7-[[5-[3-(hydroxymethyl)azetidin-1-carbonyl}-2-pyridyl]amino]-3-rnetthylimidazo [4t5-b]pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrilot 5-[7-[[5-(3-hydroxy-3-methyl-azetidin-1-carbonyl)-2-pyridyl]amino]-3-methylimidazo[4,5-b]pyridin-5-yl]oxy- 4-methyl-pyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[5-(3-oxa-6-azaspiro[3.3]heptan-6-carbonyl)-2pyridyl]amino]imidazo[4,5-bjpyridin-5-yl ]oxy-pyridin-2-carbonitriium, IF-2019-17407397-APN-ANP#INPI58 Page 115 of 545 IF-2019-17407397-APN-ANP#INPI Page 116 of 545 5—p'—[[5—(3—methoxy—3—methyl—azetidin—1—carbonyl)—2—pyridyrjamino]—3—methyl—imidazo[4,5-b]pyridin-5-yl]oxy- 4-methyl-pyridin-2-carbonitrile, tert-butyl 1-[6-[[5-[(&-cyano-4-methyl-3-pyridyl)oxyJ-3-methyl-imidazo[4l5-b]pyridin7- l]amÍno]pyridin-3-carbonÍI]azetidin-3-carboxylate, 4-methyl-5-[3-methyl-7-[[5-(6-methyl-2(6-diazaspiro[3.3]heptan-2-carbonyl)-2pyridyl]amino]imidazo[4,5-b]plridin -5-yl]oxy-pyridin-2-carbonitrile, 547-[[5-(4-hydroxypiperidin-1-carbonyl)pyridin-2-yl]amino]-3-methylimidazo[4,5bjpyridin—5—HJoxy—4 —methylpyridin—2—carbonitrile, 5-[7-[[5-(4-methoxypiperidin-1-carbonyl)pyridin-2-iI]amino}-3-niethylimidazo[4.510 b] pyrid ΐ n—5—HJoxy—4 —I put I pi ri d i n—2—carbon n ytrile, 5-[7-[[5-[4-(dimethylamino)piperidin-1-carbonyl]pyridin-2-yl]amino]-3methylimidazo[4,5-b]pyridin-5-yl]oxl-4-niethylpyridin- 2-carbonitrile, 5—[7—[[5—«3 R)—3—hydroxypyrrolidin—1 -carbon yl]pyridin—2—yl]a mino]-3methylimidazo[4,5-b]pyridin-5-yl ]oxy-4-methylpyridine-2-carbonitrile, 4—{6—[5—(6—Cyano—4—methyl—plridin—3—yloxy)—3—methyl—3H-imidazo[4,5-b]pyridin-7- acid tert-butyl ester Ílamino]-pyridin-3-carbonÍI}-piperazin-1-carboxylic, 5-[7-[[5-[(3R}-3-(2-niethoxyethoxy)pyrrolidtn-1-carbonyl]pyridin-2-yl]amino ]-3methylimidazo[4)5-b]pyridín-5-ÍI]oxy-4-methylpyridin-2-carbonitrile, (1—{6—[5—(6—Cyano—4—methyl—pyridine—3—yloxy)—3—methyl—acid tert-butyl ester 3H-imidazo[4,5-b]pyridin-7-ylamino]-pyridin-3-carbonyl}-pyrrolidin-3-yl)-methylcarbamic, 4-methyl-5-[3-methyl-7-fl5-(2 -oxa-7-azaspiro[3.4]octan-7-carbon¡l)pyridin-2¡l]amino]imidazo[4|5-b]pyridin-5-yl]oxypyridÍn-2-carbonítrile, 5-[7- [[5-[3-[(dimethylamino)methyl]azetidin-1-carbonyl]pyridin-2-yl]amino]-325 methylamidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin -2-carbonitrile, IF-2019-17407397-APN-ANP#INPI59 Page 117 of 545 IF-2019-17407397-APN-ANP#INPI Page 118 of 545 5—[7—[[5—[(3S)—3—(dimethylaminoJpyrTOIidin—1—carbonyljpyridin—2—yl]amino}—3— methylimidazo[4,5-b]pyridin-5-ÍI]oxM- nnet¡lpyridÍn-2-carbonítrile, 4-methyl-5-[3-methiP74[5-(2-oxa-6-azaspiro[3.3]heptan-6-carbonyl)pyridin-2ii]amino]imidazo[4, 5-b]pyridin-5-II]oxypyridín-2-carbonitrile, 5-[7-[[5-[3,3-bis(hydroxymethyl)azetidin-1-carbonyl]pyridin-2-ii]amino}-3methylinnidazo [4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrilol 6-[[5-(6-cyano-4-methylpyridÍn-3-yl)oxyÍ-3-methylimidazo[4,5-b]pÍr¡din-7-Íl]amino]N-(2-hydroxyethyl}-N -methylpyridine-3-carboxamide, 4-methi!-5-[3-methyl-7-[[5-(3-propan-2-yloxyazetidin-1-carbonyl)pyridin-2yl]amino]ímidazo[4,5 —b]pyridin—5—yl]oxypyridin—2—carbonitrile, 5—[7—[[5—(4—hydroxy—4—methylpiperidin—1—carbonyl)pyridin—2—ílaminoj—3— methylimidazo[ 4,5-b]pyridin-5-ii]ox¡-4-methylpyridin-2-carbonitriloI 6-[[5-(6-cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7-yl]amino]N-[rac-(1R.3R}- 3-hydroxyclopentyl]pyridine-3-carboxamide, 4-methyl-5-[3-methyl-7-¿[5-[rac-(3R,4R)-3-fluoro-4-hydroxypimoI¡din-1carbonyljpyridin— 2—yl]amino]imidazo[4,5—b]pyridin—5—yljoxypyridin—2—carbonitrile, 4-methyl-5-[3-methyl-7--[[5-[rac-(3R,4R) -3,4-dihydroxy¡piperidin-1-carbonyl]pyridin2-yl]amino]imidazo[4,5-b]pyridin-5-II]oxypyridín-2-carbonitriIo, 4-methyl-5-[3- methyl-7-[[5-[rac-(3 R,4 R)-3-fluor-4-methoxypyrrolidin-1 carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5- yl]oxypyridin-2-carbonitrileI5-[7-[[6-[3-(dimethylamino)azetidin-1-yl]pyridazin-3-yl]amino]-3-methylimidazo[4,5b]pyridin-5-yl] oxy-4-methylpyridin-2-carbonitrile( 4-methi!-5-[3-metii-7-[[5-[(2S)-2-rThietylmorphol¡n-4-carboniI]pyridin-2yl]amino]imidazo[415-b]pyridin-5-yl ]oxypyridine-2-carbonitrile, IF-2019-17407397-APN-ANP#INPI60 Page 119 of 545 IF-2019-17407397-APN-ANP#INPI Page 120 of 545 4—methyl—5—[3—methyl—7—[[5—[(2R)—2—methylmorpholine—4—carbonyl]pyricin—2—!]amino]¡midazo[4,5-b]pyridin- 5-¡l]oxypyridín-2-carbonitrile, 4—methyl—5—[3—methyl—7—[[5—[(3R)—3—methylmorpholine—4—carbonyl]pyridin—2—yl]amino]imÍdazo[4,5-b]pyridin-5- iI]oxypyridin-2-carbonitrile, ---- ---4-methyl-5-[3-methyl-7-[[5-[(3S)-3-methylmorpholin-4-carbonyl]pyridin-2ylJaminoJimidazofd .S-blpyridin-S-ylJoxypyridin^-carbonitrile, 4-methyl-5-[3-methyl-7-[[5-[rac-(2R(6S)-2,6-dimethylmorpholine-4-carbonyl]pyridin- 2yl]amino]imidazo[4,5-b]pyridin-5-yljoxypyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[5-[rac-(2R)6R}-2,&-dimethylmorpholin-4-carbonyl]pyridin-2i1]amino]imidazo[4,5-b] pyridin-5-II]oxypyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[6-(4-methylpiperazin-1-carbonyl)pyridazin-3yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2- carbonitrile, 3,5-difluor-4-[3-methyl-7-[[5-(4-methylpiperazin-1-carbonyl)pyridin-2yl]amino]imidazo[4,5-b]pyridin-5-yl]oxybenzonitriIo, 4-methyl-5-[3-methyl-7-[[6-[(1R,4R}-5-nnetyl-2l5-diazabicyclo[2.2.1]heptan-2¡l]pyridazin-3-yl]amino] imidazo[4,5-b]pyridin-5-yl]oxypyridín-2-carbonitrile, 5-{745-((3R,4R)-3-Dimethylamino-4-hldroxy-pyrrolidin-1-carbonll>-pyridin-2ylamino}-3-methyl-3H-imidazo[4,5-b]pyridin- 5-yloxy}-4-methyl-pyridin-2-carbonitrile15-{7-[5-((3S,4S)-3-H¡d roxy-4-morpholin-4-yl-pyrrolidin-1 -carbonyl}-pyridín-2ylamino}-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy}-4-methyl-pyridin-2-carbonitrile, 4-methyl-5-[3 -methyl-7-[[5-[2-(trifluonnet¡l)morphol¡n-4-carbonyl]pyridin-2ÍI]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2-carbonitrile , 5-(7-[[5-{2-cyclopropylmorpholin-4-carbonyl)pyridin-2-yl]amino]-3methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile , IF-2019-17407397-APN-ANP#INPI61 Page 121 of 545 IF-2019-17407397-APN-ANP#INPI Page 122 of 545 4—methyl—5—[3—methyl—7—[[S—[(3R>—3—propan—2—ylmorpholin—4—carbonyl]pyridrn—2—yl]amino]imidazo[4(5-b] pyridin-5-yl]oxypyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[5-(2-oxa-5-azabicyclo[2.2.1]heptan-5-carbonyl )pyridin— 2—yl]amino]imidazo[4l5-b]pyridin-5-yl]oxypyridin-2-carbonitrilol 5-[7-[[5-(3-cyc!opropylmorpholirH4-carbonyl)pyridin-2-yl]aminoJ-3methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile, 4-[6-[[5-(6-ctane-4-methi!pyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7yl]amino]pyridin-3-carbonyl]morpholin- 2-carbonitrile, 4-Methyl-5-{3-niethyl-7-[5-((3aSl6aS}-1“nrietil-hexahydro-pyrrolo[3l4-b]pyrro!-510 carbonyl)-pyridin-2-ylamino] -3H-imidazo[4,5-b]pyridin-5-yloxy)-pyridin-2carbonitrile, 4-[6-[[5-(6-cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[ 4)5-b]pyridin-7yl]amino]pyridin-3-carbonyl]morpholine-3-carbonitrile, 5-[7-[[6-[(2R)-2-(hydroxymethyl)morpholin-4-i!] pyridazin-3-yl]amino}-3. 15 methylimidazo[4,5-b]pyridin-5-yl]oxy-4-methylpyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[6-(2,2,3l3,5 ,5,6,6-octadeuteriomorpholin-4-yl)pyridazin-3yl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridin-2-carbonitrile, 5—[7—[[6— [(2S)—2—(hydroxymethyl)morpholin—4—yl]pyridazin—3—yl]amino]—3—methylímídazo[4,5-b]pyridÍn-5-ÍI]oxy-4-methylp ridin-2-carbonitrilot 5-[7-[[6-[(2S,6S)-2,6-dimethylmorpholin-4-yl]pyridazin-3-yl]amino]-3methylimidazo[4l5-b]pyridin-5-yl]oxy-4 -methylpyridin-2-carbonitrile, 4-methyl-5-[3-methiI-7-[[6-(1,4-oxazepan-4-yl)pyridazin-3-yl]amino]imidazo[4l5b]pyridin-5 -yl]oxypyridin-2-carbonitrile, 5-[7-[[6-[(2R,6R)-2)6-dimethylmorpholirH4-yl]pyridazin-3-yl]amino]-325 methinmidazo^.S-bJpyridin- S-illoxM-rnetylpyridin-^-carbonitrile, IF-2019-17407397- APN-ANP#INPI62 Page 123 of 545 IF-2019-17407397-APN-ANP#INPI Page 124 of 545 5—[7—[[6—[2—(hydroxymethyl)morpholin—4—IJpyridazin—S-ylJamino]—3—methylimidazo[4,5— b]pyridin-5-yl]oxy-4-methylpyridin-2 -carbonitrile, 4-methyl-5-[3-methyl-7-[[6-(&-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3yl]amino]imidazo[4l5-b]pindin- 5-yl]oxypyridin-2-carbonitrile, 4-[6-[[5-(6-cyano-4-methylpyridin-3-yl)oxy-3-methylimidazo[4,5-b]pyridin-7yl]amino]pyridazin-3-yl]morpholin-2- carbonitrile, 4-methyl-5-[3-methyl-74[6-[(2R)-2-methylmorpholin-4-yl]pyridazin-3yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin- 2-carbonitrile, 4-methyl-5-[3-methi!-7-[[&-[(2R)-2-propan-2-ylmorpho!in-4-yl]pyridazjn-3ylJaminoJimidazofd.S-bJpyridin-S-ylJoxypyridin^- carbonitrile, 4-methyl·-5-[3- methyl-7-([6- [(1 S,4S)-2-oxa-5-azabicyl!o[2.2.1 ]heptan-5yl]pyridazin-3-iI] amino]imidazo[4,5-b]pyridin-5-yl]oxypyridin-2-carbonitrile, 5-[7-[[6-(2,2-dimethylmorpholin-4-yl)pyridazin-3-ll]amino] -3-methylimidazo[4,5bjpyridin—5—yl]ox>—4—methylpyridin—2—carbonitrile, 4-methyl-5-[3-methyl-7-[[6-[rac-(2R,6R}-2l6-dimethylmorpholin-4-yl]pyridazin-3yl]amino]imidazo[4,5-b]pyridin- 5-yl]oxypyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[6-[(2S)-2-propan-2-ylmorpholin-4-yl]pyridazin-3ylJaminojimidazo^.S-bJpyridin-S-yljoxypyridin^-carbonitrile, 4-methyl-5-[3-methyl-7-[[5-(piperazin-1-carbontl)pyridin-2-yl]amino]imidazo[4l5bjpyridrn—5—yljoxypyridin—2—carbonitrile, N7-(6-aminopyrimidin-4-yl)-N5-(1-cyclopropyl-2(2,2-trifluoro-ethyl)-3-methylimidazo[4,5-b]pyridin-5,7-diamine, 4-methyl-5-[3-methyl-7-[(5-piperazin-1-yl-2-pyridyl)amino]imidazo[4t5-b]pyridin-5yl]oxy-pyridin-2-carbonitrile, IF-2019-17407397-APN-ANP#INPI63 Page 125 of 545 IF-2019-17407397-APN-ANP#INPI Page 126 of 545 5-[7-[[5-[4-(dimethylamino)-1-piperidyl-2-pyridyl]amino]-3-methyl-imidazo[4,5b]pyridin—5—yl]oxl—4—methyl—pyridin —2—carbonitrile, S-^-nS-tS-ídimethylaminoJpyrrolidin-l-yl^-pyridylJaminoJ-S-methyl-imidazo^.Sb]pyridin-5-yl]oxy-4-methyl-pyridin-2-carbonitrile, 5 -[7-[[5-[2-methoxyethyl(methyl)amino]-2-pyridyl]amino]-3-methyl-imidazo[4,5bjpyridin—5—yljoxy—4—methyl—pyridin—2—carbonitrile, 5 -[7-[[5-[4-(hydroxymethyl)-1-piperidyl]-2-pyridÍI]amino]-3-methiHmidazo[4.5b]pyridin-5-ÍI]oxy-4-methyl-pyridin- 2-carbonitrile, S-^-nS-fdimethylamino^-pyridillarninoJ-e-methyl-imidazo^.S-bJpyridin-S-ylJoxMmethyl-pyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7-[[1-( 2-morphol¡noethyl)pyrazoM-yl]amino]imidazo[4I5b]pyridin-5-yl]oxy-pyridin-2-carbonitrile, 5-[[7-[(6-aminopyrimidin-4-yl)amino]-3 -methyl-imidazo[4)5-b]pyridin-5-ylH2hydroxypropyl)amino]-4-methyl-pyridin-2-carbonitrile, 4-methyl-5-[3-methyl-7 -[[5-(2,2,3,3,5,5,6,6-octadeuterium-4-methyl-piperazín-1rarbonyl)-2-pyridyl]amino]imidazo[4,5-b ]pyridin-5-yl]oxy-pyr¡din-2-carbonitrile)4-methi!-5-[3-methyl-7-[[5-(212l6,6-tetradeuterium-4-methyl!-p¡peraz¡ n-1-carbon¡l)2-pyridyl]amino]imidazo[4,5-b]pyridin-5-yl]oxy-pyridin-2-carbonitrile, and 4-methyl-5-[3-methyl-7- [[5-[2,2,3,3,5,5,6,6-octadeuterium-4(trideuteriomethyl)piperazin-1-carbonyl]-2-pyridyl]amino]imidazo[4,5-b]pyridin- 5yl]oxy-pyridín-2-carbonitrile. In one embodiment, the compound of the invention is 4—Eti1—5—{3—methyl-7-[5-(morpho!yn-4-carbonyl)-pyridin-2-ílamino]-3H-imidazo[ 415-b]pyridin-5yloxy}-pyridin-2-carbonitri!o. IF-2019-17407397-APN-ANP#INPI64 Page 127 of 545 IF-2019-17407397-APN-ANP#INPI Page 128 of 545 In another embodiment, the compound of the invention is not 4—EtiI—5—{3-methyl-7-[5-(morpholín-4-carbonyl}-pyridin-2-ylamino]-3H-Imidazo[ 415-b]pyridin5~yloxy)—pyrid in-2-carbonitril. In one embodiment, the compound of the invention is 4—Methyl—5—[3-methyl-7-(6-morpholín-4-yl-pyridazín-3-Ylamino}-3H-imidazo[4 ,5-b]pyridin-5yloxy]-pyridín-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]pyridin-5yloxy]—prridin—2-carbonitrile. In one embodiment, the present invention provides a compound for the preparation of the compounds of the invention according to Formula A: To where R5a is -CN, -SO2C-m alkyl, or -CF3; R5b is selected from halo, Ci_4 alkyl and C3-.7 cycloalkyl. In a further embodiment, the present invention provides a compound for the preparation of the compounds of the invention according to Formula A, wherein R53 is -CN, -SO2CH3, or -CF3. In a particular embodiment, R53 is -CN. In a further embodiment, the present invention provides a compound for the preparation of the compounds of the invention according to IF-2019-17407397- APN-ANP#INPI65 Page 129 of 545 IF-2019-17407397-APN-ANP#INPI Page 130 of 545 Formula A, wherein R5b is selected from halo, C1-4 alkyl and C3-7 cycloalkyl. In a particular embodiment, R5bes F, -CH3, -CFfeCHs or cyclopropyl. In a more particular embodiment, R5bes -CH3. In one embodiment, the present invention provides a compound for the preparation of the compounds of the invention according to Formula A wherein R53 is -CN and R5bes -CH3. In one embodiment, the compounds of the invention are provided in a natural isotopic form. In one embodiment, the compounds of the invention are provided in a non-natural variant isotopic form. In a specific embodiment, the non-natural variant isotopic form is a form in which deuterium (i.e., 2H or D) is incorporated where hydrogen is specified in the chemical structure on one or more atoms of a 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. Suitably radioactive isotopes are stable isotopes. Suitably, the non-natural variant isotopic form is a pharmaceutically acceptable form. In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in a non-natural variant isotopic form. IF-2019-17407397-APN-ANP#INPI66 Page 131 of 545 IF-2019-17407397-APN-ANP#INPI Page 132 of 545 Non-natural isotopic variant forms may generally be prepared by conventional techniques known to those skilled in the art or by the processes described herein, for example processes analogous to those described in the accompanying examples for the preparation of natural isotopic forms. In this way, unnatural isotopic variant forms could be prepared using appropriate isotopic (or labeled) variant reagents instead of the normal reagents used in the Examples. In one embodiment, a compound of the invention is not an isotopic variant. In one aspect, a compound of the invention according to any one of the embodiments described herein is present as the free base. In one aspect, a compound of the invention according to any one of the embodiments described herein is a pharmaceutically acceptable salt. In one aspect, a compound of the invention according to any one of the embodiments described herein is a solvate of the compound. In one aspect, a compound of the invention according to any one of the embodiments described herein is a solvate of a pharmaceutically acceptable salt of a compound. Although the groups specified for each embodiment have generally been listed separately above, a compound of the invention includes one in which several or each embodiment in the IF-2019-17407397-APN-ANP#INPI67 Page 133 of 545 IF-2019-17407397-APN-ANP#INPI Page 134 of 545 Formula above, as well as other formulas presented herein, are selected from one or more particular members or groups designated, respectively, for each variable. Therefore, this invention is intended to include all combinations of said embodiments within its scope. Although the groups specified for each embodiment have generally been listed separately above, a compound of the invention may be one for which one or more variables (e.g., R groups) are selected from one or more embodiments according to with any of the Formula(s) listed above. Therefore, the present invention is intended to include all combinations of variables of any of the described embodiments within its scope. Alternatively, the exclusion of one or more of the specified 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 compounds according to the above formulas. 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 this invention have activity in both their acidic and acidic forms, but the acid-sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). The IF-2019-17407397- APN-ANP#INPI 68 Page 135 of 545 IF-2019-17407397-APN-ANP#INPI Page 136 of 545 prodrugs They include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reaction of the main acid with a suitable alcohol, or amides prepared by reaction of the main acid compound with a substituted amine or unsubstituted, or acid anhydrides, or mixed anhydrides. Preferred prodrugs are simple aliphatic or aromatic esters, amides and anhydrides derived from pendant acidic groups in the compounds of this invention. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonü)oxy)alkyl esters. Particularly useful are the Ci to C8 alkyl, Ca-Ce alkenyl aryl, substituted C7-C12 aryl and aryl-Cz-C^ alkyl esters of the compounds of the invention. CLAUSES 1). A compound according to Formula (I): where Cy is phenyl, or 5-6 membered heteroaryl comprising one, two or three N atoms; L1 is a single bond, -O-, -C(=O)-, -C(=O)O-, -S(O)z-, -NR6a-, C(=O)NR6b-, -SfOJjNR80- , or C(=O)NRedS(O)2-: IF-2019-17407397- APN-ANP#INPI Page 137 of 545 IF-2019-17407397-APN-ANP#INPI Page 138 of 545 R1es: Η, Ci-« alkyl optionally substituted with one or more independently selected o OH, o halo, o Ci-4 alkoxy, o -NR7aR7b, o -C(=O)OH-,o-C(=O)NR7cR7d, or -C (=O)O C-m alkyl, or or 4-8 membered monocyclic heterocycloaikyl comprising one, two or three heteroatoms independently selected from N, S and O; C3-7 cicioalkyl optionally substituted with one or more OH, C1-4 alkoxy, or 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloaikyl comprising one, two or three heteroatoms independently selected from N, S and O; said heterocycloaikyl is optionally substituted with one or more independently selected R11 groups; each R11 is independently: OH, CN, halo, oxo, IF-2019-17407397-APN-ANP#INPI70 Page 139 of 545 IF-2019-17407397-APN-ANP#INPI Page 140 of 545 -NR8aR8b, Cj-γ cycloalkyl, Cm alkyl optionally substituted with one or more independently selected from halo, OH, Cm alkoxy. -NR9aR9b, Cm alkoxy optionally substituted with a Cm alkoxy. 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S, and O, -C(=O)Oalkyl Cm. o -NR8cC(=O)Oalkyl Cm! R2is halo, CN.or alkyl CmÍ the subscript n is 0, or 1; L2 is Ο,ο-NR4-, R3 is Cm alkyl optionally substituted with one or more independently selected from o halo, o o C3-7 cycloalkyl, - Phenyl substituted with one R5a group and one or two independently selected R5b groups, - 6-membered heteroaryl comprising one or two N atoms, substituted with one R5a group and one or two independently selected R5b groups, IF-2019-17407397- APN-ANP#INPI71 Page 141 of 545 IF-2019-17407397-APN-ANP#INPI Page 142 of 545 - 4-10 membered monocyclic or fused, bridged or spiro bicyclic heterocycloalkyl comprising one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R53 and R5b, or - 4-10 membered monocyclic or fused, bridged or spiro bicyclic cycloalkyl, optionally substituted with one, two or three groups independently selected from R53 and R5b; R4es -H - Cm alkyl optionally substituted with one or more independently selected from OH or Cm alkoxy or - C3-7 cycloalkyl; R53es -CN, -SOj-alkyl Cm> or -CF3: each R5b is independently selected from halo, Cm alkyl and C3-7 cycloalkyl; each R73 and R7b are selected independently of -H,y - Cm alkyl optionally substituted with one -NR10aR10b; and each R63, R6b, R60, RM, R7c, R7d, R8a, R8b, R8c, R93, R9btR10a, and R10b is independently selected from H, and Cm¡ alkyl or a pharmaceutically acceptable salt thereof, or a solvate or the solvate of a pharmaceutically acceptable salt thereof. 2) . The compound or pharmaceutically acceptable salt thereof according to clause 1ten where L2 is NR4. IF-2019-17407397- APN-ANP#INPI72 Page 143 of 545 IF-2019-17407397-APN-ANP#INPI Page 144 of 545 3) . The compound or pharmaceutically acceptable salt thereof according to clause 2, where R4 is H. 4) . The compound or pharmaceutically acceptable salt thereof according to clause 2, wherein R4 is -CH3t-CH2-CH2-CH2-OH, -CH2-CHOH-CH3, -CH2-CH2-CH2-OCH3, or cyclopropyl. 5) . The compound or pharmaceutically acceptable salt thereof according to clause 1. where L2 is O. 6). The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is Ci-6 alkyl optionally substituted with one or more independently selected from halo, or C3-7 cycloalkyl. 7). The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is -CH3, -CH2CH3, -CH(CH3)CH(CH3)2, CH(CH3)C(CH3)3. each of which is optionally substituted with one or more independently selected halo, or C3-7 cycloalkyl. 8). The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is Ο-μβ alkyl optionally substituted with one or more independently F, cyclopropyl or cyclobutyl. 9). The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is selected from: X X X... η X„ X, » » , , ,y 10). The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is phenyl substituted with one R58 group and one or two independently selected R5b groups. IF-2019-17407397-APN-ANP#INPI73 Page 145 of 545 IF-2019-17407397-APN-ANP#INPI Page 146 of 545 eleven) . The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is phenyl substituted with one R53 group and two independently selected R5b groups. 12). The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is 6-membered heteroaryl substituted with one R53 group and one or two independently selected R5b groups. 13) . The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is pyridinyl or pyridazinyl, each of which is substituted with an R53 group and an R5b group. 14). The compound or pharmaceutically acceptable salt thereof according to clause 1, where R3 is fifteen) . The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-14, wherein R5a is -CN, -SOr-Ci_ 4 alkyl, or —CF3. 16). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-14, wherein R5a is -CN, -SO2CH3, or CF3. 17). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-14, wherein R53 is -CN. 18). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-17, wherein R5b is independently selected from halo, C1-4 alkyl and C3-7 cycloalkyl. IF-2019-17407397- APN-ANP#INPI74 Page 147 of 545 IF-2019-17407397-APN-ANP#INPI Page 148 of 545 19). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-17, wherein R5b is independently selected from F, -CH3, -CH2CH3 and cyclopropyl. twenty) . The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is 4-10 membered monocyclic or fused, bridged or spiro bicyclic heterocycloatkyl comprising one or two heteroatoms independently selected from N, S and O, optionally substituted with one, two or three groups independently selected from R5a and R5b. twenty-one) . The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein R3 is tetrahydropyranyl or oxa-spiro[3.5]nonane, each of which is optionally substituted with one, two or three groups independently selected from R53 and R5b. 22). The compound or pharmaceutically acceptable salt thereof according to clause 1-9,20 or 21, wherein R5a is -CN, -SO2CH3lo -CF3. 23) . The compound or pharmaceutically acceptable salt thereof according to clauses 1-9, 20, 21 or 22, wherein R5b is selected from F, -CH3, CH2CH3 and cyclopropyl. 24). The compound or pharmaceutically acceptable salt thereof according to clause 20, wherein R3 is a 4-10 membered monocyclic or fused, bridged or spiro bicyclic cycloalkyl, optionally substituted with one, two or three groups independently selected from R53 and R5b. 25). The compound or pharmaceutically acceptable salt thereof according to clause 24, wherein R3 is cyclohexyl or bicyclo[1.1.1]pentane, each IF-2019-17407397-APN-ANP#INPI75 Page 149 of 545 IF-2019-17407397-APN-ANP#INPI Page 150 of 545 of which is optionally replaced with one, two or three groups independently selected from R5a and R5b. 26). The compound or pharmaceutically acceptable salt thereof according to clause 1-9,24 or 25, wherein R5a is -CN, -SO2CH3, or -CF3. 27). The compound or pharmaceutically acceptable salt thereof according to clause 1-9, or 24-26, wherein R5b is selected from F, -CH3, -CH2CH3 and cyclopropyl. 28). The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein the compound is according to formula II: 29). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-28, wherein Cy is phenyl. 30). The compound or pharmaceutically acceptable compound thereof according to any one of clauses 1-28, wherein Cy is 5-6 membered heteroaryl comprising one, two or three N atoms. 31). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-28, wherein Cy is pyrazolyl, pyridinyl, pyrimidinyl or pyridazinyl. IF-2019-17407397-APN-ANP#INPI76 Page 151 of 545 IF-2019-17407397-APN-ANP#INPI Page 152 of 545 32). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-28, wherein Cy is pyridinyl, pyrimidinyl or pyridazinyl. 33). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-28, wherein Cy is pyridazinyl. 3. 4) . The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-33, wherein the subscript n is 1. 35). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-34, wherein R2 is F, CN or -CH3. 36). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-33, wherein the subscript n is 0. 37). The compound or pharmaceutically acceptable salt thereof according to clause 1, wherein the compound is according to the formula Illa, lllb, lilcollld: Illa lllb lile or llld 38). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein Li is a single bond. 39). The compound or pharmaceutically acceptable salt thereof according to the clause of any of clauses 1-37, where L1 is -O- 40). The compound or pharmaceutically acceptable salt thereof according to any of clauses 1-37, where L1 is -C(=O)-. IF-2019-17407397-APN-ANP#INPI77 Page 153 of 545 IF-2019-17407397-APN-ANP#INPI Page 154 of 545 41). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein Li is -S(O)2~. 42). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, where Li is -NR63-. 43) . The compound or pharmaceutically acceptable salt thereof according to clause 42 has where R63 is H, or C1-4 alkyl. 44). The compound or pharmaceutically acceptable salt thereof according to clause 42, wherein R63 is H, or -CH3. Four. Five) . The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein L| is -C(=O)NR6b-. 46). The compound or pharmaceutically acceptable salt thereof according to clause 45, wherein R6bes H, or C^ alkyl. 47). The compound or pharmaceutically acceptable salt thereof according to clause 45, wherein R6bes H, or -CH3. 48). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, where L1 is -SfO^NR60-. 49). The compound or pharmaceutically acceptable salt thereof according to clause 48, wherein R60 is H, or C1-4 alkyl. fifty) . The compound or pharmaceutically acceptable salt thereof according to clause 48, wherein R6 is H, or -CH3. 51). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein L1 is -C(=O)NR6dS(O)2-. 52). The compound or pharmaceutically acceptable salt thereof according to clause 51, wherein R6des H, or C1-4 alkyl. IF-2019-17407397-APN-ANP#INPI78 Page 155 of 545 IF-2019-17407397-APN-ANP#INPI Page 156 of 545 53) . The compound or pharmaceutically acceptable salt thereof according to clause 51, wherein R6des H, or -CH3. 54). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-53, where R1 is H. 55). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is Cm alkyl. 56). The compound or pharmaceutically acceptable salt thereof according to clause 55, wherein R1 is -CH3, or -CH2CH3. 57). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is Cm alkyl substituted with one or more OH, halo, Cm alkoxy -NR7aR7b, -C(=O)OH-, -C (=O)NR7cR7d, C(=O)OC1-4alkyl independently selected or 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O. 58). The compound or pharmaceutically acceptable salt thereof according to clause 57, wherein R1 is -CH3, -CH2CH31-CH2CH2CH3, CH2CH(CH3)2, -CH2CH2CH2CH3, or -CH2CH2CH(CH3)2, each of which is substituted with one or more OH, halo, alkoxy Cm. -NR7aR7b, -C(=O)OH-, C(=O)NR7cR7d, -C(=O)Oalkyl Cm independently selected, 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O. 59). The compound or pharmaceutically acceptable salt thereof according to clause 57, or 58, wherein R7a is H, or Cm alkyl optionally substituted with a -NR10aR10b. IF-2019-17407397-APN-ANP#INPI79 Page 157 of 545 IF-2019-17407397-APN-ANP#INPI Page 158 of 545 60). The compound or pharmaceutically acceptable salt thereof according to clause 57 or 58, wherein R7a is H. 61). The compound or pharmaceutically acceptable salt thereof according to clause 59, wherein R7a is -CH3to -CH2CH3, each of which is optionally substituted with one -NR10aR10b. 62). The compound or pharmaceutically acceptable salt thereof according to clause 61, wherein each R10a and R10b is independently selected from H,-CH3,or-CH2CH3. 63). The compound or pharmaceutically acceptable salt thereof according to clause 57, or 58, wherein R7bes H, or C1-4 alkyl optionally substituted with a -NR10aR10b. 64). The compound or pharmaceutically acceptable salt thereof according to clause 57 or 58, wherein R7bes H. 65). The compound or pharmaceutically acceptable salt thereof according to clause 63, wherein R7bes -CH3, or -CH2CH3, each of which is optionally substituted with one -NR10aR10b. 66). The compound or pharmaceutically acceptable salt thereof according to clause 65, wherein each R10a and R10b is independently selected from H, -CH30-CH2CH3. 67). The compound or pharmaceutically acceptable salt thereof according to clause 57, or 58, wherein R7ces H. 68). The compound or pharmaceutically acceptable salt thereof according to clause 57, or 58, wherein R7 is -CH3, or -CH2CH3. 69). The compound or pharmaceutically acceptable salt thereof according to clause 57, or 58, wherein R7des H. IF-2019-17407397-APN-ANP#INPI80 Page 159 of 545 IF-2019-17407397-APN-ANP#INPI Page 160 of 545 70). The compound or pharmaceutically acceptable salt thereof according to clause 57, or 58, wherein R7des -CH3, or -CH2CH3. 71). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is Cv$ alkyl substituted with one or more OH, F-OCH3. -OCH2CH31-NH2, -NHCH3, -NHCH2CH2-N(CH3)2, -NHCH2CH3, -C(=O)OH-, -C(=O)NH2, -C(=O)NHCH3, -C(=O )NHCH2CH3, C(=O)N(CH3)2, -C(=O)OC1-4alkyl, dioxanyl or morpholinyl. 72). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is -CH3, -CH2CH3. CH2CH2CH3, -CH2CH(CH3)2-CH2CH2CH2CH3, or -CH2CH2CH(CH3)2, each of which is substituted with one or more OH, F, -OCH3(-OCH2CH3, -NH21NHCH3, -NHCH2CH2-N(CH3) 2, -NHCH2CH3i-C(=O)OH-, -C(=O)NH21C(=O)NHCH3, -C(=O)NHCH2CH3-C(=O)N(CH3)2, -C(=O )C^alkyl, dioxanyl or morpholinyl. 73). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is ¢3-7 cycloalkyl. 74). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 75). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is C3-.7 cycloalkyl substituted with one or more independently selected OH, or C-m alkoxy. 76). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is C3-7 cycloalkyl IF-2019-17407397-APN-ANP#INPI81 Page 161 of 545 IF-2019-17407397-APN-ANP#INPI Page 162 of 545 substituted with one, two or three OH, or C1-4 alkoxy selected independently. 77). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one, two or three OH, or C1-alkoxy 4 independently selected. 78). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is 63-7 cycloalkyl substituted with one, two or three independently selected OH, -OCH3 or -OCH2CH3. 79). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is a 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, SyO. 80). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 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, octahydro-pyrrolo[3,4-b]pyrrolyl, 2-oxa-6aza- spiro[3,4]octanyl, 2-oxa-7-aza-spiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, or 2,5-dÍaza-bicyclo[2.2.1]heptanyl. 81). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl IF-2019-17407397-APN-ANP#INPI82 Page 163 of 545 IF-2019-17407397-APN-ANP#INPI Page 164 of 545 comprising one, two or three heteroatoms independently selected from N, S and O; whose heterocycloalkyl is substituted with one or more independently selected R11 groups. 82). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is 4- to 9-membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O; whose heterocycloalkyl is substituted with one, two or three independently selected R11 groups. 83). The compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-37, wherein R1 is azetidinyl, oxetanyl, pyrrolidinyl, morpholinyl, octadeuteriomorpholin-4-yl, piperidinyl, tetrahydropyranyl, piperazinyl, dioxanyl, [1,4] oxazepanyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, 1oxa-6-aza-spiro[3.3]heptanyl, octahydro—pyrrolo[3,4—b]pyrrolyl, 2-oxa-6-azaspiro[ 3,4]octanyl, 2-oxa-7-aza-spiro[4.4]nonaniIo, 2,6-diazaspiro[3.3]heptanyl, or 2,5-diaza-bicyclo[2.2.1]heptanyl, each of which is replaced with one, two or three independently selected R11 groups. 84). The compound, according to clause 81,82 or 83, where R11 is OH. 85). The compound, according to clause 81,82 or 83, where R11 is CN. 86). The compound, according to clause 81, 82 or 83, where R11 is halo. 87). The compound, according to clause 81,82 or 83, where R11 is F, or Cl. 88). The compound, according to clause 81, 82, or 83, wherein R11 is oxo. IF-2019-17407397-APN-ANP#INPI83 Page 165 of 545 IF-2019-17407397-APN-ANP#INPI Page 166 of 545 89). The compound, according to clause 81, 82 or 83, wherein R11 is NRBaR8b, and each R8a and R8bes independently H, or C1-4 alkyl. 90). The compound, according to clause 81, 82 or 83, where R11 is NR8aR8b, and each R8a and R8bH, CH3o -CH2CH3. 91). The compound, according to clause 81, 82 or 83, wherein R11 is ¢3-7 cycloalkyl. 92). The compound, according to clause 81, 82 or 83, wherein R11 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 93). The compound, according to clause 81, 82, or 83, wherein R11 is C1-4 alkyl optionally substituted with one or more independently selected halo, OH, C1-4 alkoxy or NR9aR9bs, wherein each R9a and R9bes independently H, or alkyl C1-4. 94). The compound, according to clause 81, 82 or 83, wherein R11-CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2CH3, each of which is optionally substituted with one or more halo, OH, C1-4 alkoxy, -NR9aR9bselected independently, where each R9a and R9bes independently H, or C1-4 alkyl. 95). The compound, according to clause 81, 82 or 83, wherein R11 is C1-4 alkyl, optionally substituted with one or more independently selected F, -OCH3, OCH2CH3, -NH2, -NHCH3, or -N(CH3)2 . 96). The compound, according to clause 81, 82 or 83, wherein R11 is CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2CH3, each of which is optionally substituted with one or more independently of F, -OCH3 , OCH2CH31-NH2. -NHCH3to -N(CH3)2. IF-2019-17407397-APN-ANP#INPI84 Page 167 of 545 IF-2019-17407397-APN-ANP#INPI Page 168 of 545 97). The compound, according to clause 81, 82 or 83, wherein R11 is Ch alkoxy optionally substituted with a C1-4 alkoxy. 98). The compound, according to clause 81, 82 or 83, wherein R11 is OCH3, -OCH2CH3, or -OCH2CH2CH3, optionally substituted with a C-m alkoxy. 99). The compound, according to clause 81, 82, or 83, wherein R11 is Ci^4 alkoxy optionally substituted with one -OCH3, OCH2CH3, or OCH2CH2CH3. 100). The compound, according to clause 81, 82 or 83, wherein R11 is OCH3, OCH2CH3, or -OCH2CH2CH3, optionally substituted with one -OCH3, OCH2CH3 or -OCH2CH2CH3. 101). The compound, according to clause 81, 82 or 83, where R11 is OCH3, or OCH2CH2OCH3. 102). The compound, according to clause 81, 82 or 83, wherein R11 is a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O. 103). The compound, according to clause 81, 82 or 83, wherein R11 is azetidinyl, oxetanyl, pyrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl or morpholinyl. 104). The compound, according to clause 81, 82 or 83, wherein R11 is C(=O)OC1-4alkyl. 105). The compound, according to clause 81, 82 or 83, where R11 is C(=O)OCH3. 106). The compound, according to clause 81, 82 or 83, wherein R11 is NR8cC(=O)OC^alkyl. IF-2019-17407397-APN-ANP#INPI85 Page 169 of 545 IF-2019-17407397-APN-ANP#INPI Page 170 of 545 107). The compound, according to clause 81, 82 or 83, where R11 is NHC(=O)OCH3, -NCH3C(=O)OCH3, or -NHC(=O)OCH2CH3. 108). A pharmaceutical composition comprising a. pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of clauses 1-107. 109). The pharmaceutical composition according to clause 108 comprising an additional therapeutic agent. 110). The compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-107, or the pharmaceutical composition according to any one of clauses 108-109, for use in medicine. 111). A compound according to any one of clauses 1-107, or the pharmaceutical composition according to any one of clauses 108109, for use in the treatment, or prophylaxis of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, diseases autoimmune diseases, proliferative diseases, transplant rejection, diseases that involve impaired cartilage turnover, congenital cartilage malformations and / or diseases associated with hypersecretion of IFNa, 1L12 and / or IL23. 112). The compound or the pharmaceutically acceptable salt thereof according to any one of clauses 1-107, or the pharmaceutical composition according to any one of clauses 108-109, is administered in combination with an additional therapeutic agent. 113). The pharmaceutical composition according to clause 109, or the method according to clause 112, wherein the additional therapeutic agent is an agent for the treatment, or prophylaxis of allergic diseases, diseases IF-2019-17407397-APN-ANP#INPI86 Page 171 of 545 IF-2019-17407397-APN-ANP#INPI Page 172 of 545 inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired cartilage turnover, congenital cartilage malformations and / or diseases associated with hypersecretion of IFNa, IL12 and / or IL23. 114). The compound for the preparation of the compound or pharmaceutically acceptable salt thereof according to clause 1, wherein the compound for the preparation is according to Formula A: fjlH2 R53 To where R5aes -CN, -SO2C1-4alkyl, or -CF3: R5b is selected from halo, C1-4 alkyl and 63-7 cycloalkyl. 115). The compound for the preparation according to clause 114, wherein R5a is -CN, -SO2CH31or -CF3. 116). The compound for the preparation according to clause 114, wherein R5a is -CN. 117). The compound for preparation according to any one of clauses 114-116, wherein R5bes F, -CH3, -CH2CH3, or cyclopropyl. 118). The compound for preparation according to any one of clauses 114-116, wherein R5bes -CH3. PHARMACEUTICAL COMPOSITIONS Formulation I - Tablets IF-2019-17407397-APN-ANP#INPI87 Page 173 of 545 IF-2019-17407397-APN-ANP#INPI Page 174 of 545 A compound of the invention according to Formula I can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into tablets of 240-270 mg (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press. Formulation 2 - Capsules A compound of the invention according to Formula I can be mixed as a dry powder with a starch diluent in a weight ratio of approximately 1:1. The mixture can be filled into 250 mg capsules (125 mg of the active compound of the invention according to Formula I per capsule). Formulation 3 - Liquid A compound of the invention according to 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 an EE sieve . US No. 10 mesh, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor and color can be diluted with water and added with stirring. Sufficient water can then be added with stirring. Then, enough more water can be added to produce a total volume of 5 ml. Formulation 4 - Tablets A compound of the invention according to Formula I can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed in IF-2019-17407397-APN-ANP#INPI88 Page 175 of 545 IF-2019-17407397-APN-ANP#INPI Page 176 of 545 tablets of 450-900 mg (150-300 mg of active compound of the invention according to Formula I) in a tablet press. Formulation 5 - Injection A compound of the invention according to Formula I can be dissolved or suspended in an injectable aqueous medium of sterile buffered saline to a concentration of about 5 mg / ml. 6-Topical Formulation Stearyl alcohol (250 g) and a white petroleum jelly (250 g) can be melted at about 75°C and then a mixture of compound A of the invention according to Formula I (50 g) methylparaben (0.25 g) , propylparaben (0.15 g), sodium lauryl sulfate (10 g) and propylene glycol (120 g) dissolved in water (about 370 g) can be added and the resulting mixture can be stirred until frozen. TREATMENT METHODS In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, diseases autoimmune diseases, proliferative diseases, transplant rejection, diseases that involve impaired cartilage turnover, congenital cartilage malformations and / or diseases associated with the hypersecretion of IFNa, IL12 and / or 1L23. IF-2019-17407397- APN-ANP#INPI 89 Page 177 of 545 IF-2019-17407397-APN-ANP#INPI Page 178 of 545 In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of allergic diseases, inflammatory diseases, diseases metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases that involve impaired cartilage turnover, congenital cartilage malformations and / or diseases associated with the hypersecretion of IFNa, IL12 and / or 1L23. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected by allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving the impaired cartilage turnover, congenital cartilage malformations and / or diseases associated with hypersecretion of IFNct, IL12 and / or IL23, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an agent for treating allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, IF-2019-17407397-APN-ANP#INPI90 Page 179 of 545 IF-2019-17407397-APN-ANP#INPI Page 180 of 545 transplant rejection, diseases that involve impaired cartilage turnover, congenital cartilage malformations and diseases associated with hypersecretion of IFNa, IL12 and / or IL23. In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of allergic diseases. In a particular embodiment, the allergic disease is asthma. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of allergic diseases. In a particular embodiment, the allergic disease is asthma. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected with allergic diseases, methods comprising the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition. In a particular embodiment, the allergic disease is asthma. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other agent IF-2019-17407397-APN-ANP#INPI 91 Page 181 of 545 IF-2019-17407397-APN-ANP#INPI Page 182 of 545 therapeutic is an agent for treating allergic diseases. In a particular embodiment, the allergic disease is asthma. In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of inflammatory diseases. In a particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases. In a more particular embodiment, the Inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of inflammatory diseases. In a particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases. In a more particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases. IF-2019-17407397-APN-ANP#INPI92 Page 183 of 545 IF-2019-17407397-APN-ANP#INPI Page 184 of 545 In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected by inflammatory diseases, methods comprising the administration of an effective amount of a compound of the invention or one or more of the 5 compositions pharmaceuticals described herein for the treatment or prophylaxis of said condition. In a particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases. In a more particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an inflammatory disease treatment agent. In a particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and inflammatory bowel diseases. 20 In a more particular embodiment, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases. In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In one embodiment IF-2019-17407397-APN-ANP#INPI93 Page 185 of 545 IF-2019-17407397-APN-ANP#INPI Page 186 of 545 In particular, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of metabolic diseases. In a particular embodiment, the metabolic disease is type II diabetes and / or obesity. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of metabolic diseases. In a particular embodiment, the metabolic disease is type II diabetes and / or obesity. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected with metabolic diseases, methods comprising the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition. In a particular embodiment, the metabolic disease is type II diabetes and / or obesity. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a metabolic disease treatment agent. In a particular embodiment, the metabolic disease is type II diabetes and / or obesity. IF-2019-17407397- APN-ANP#INPI94 Page 187 of 545 IF-2019-17407397-APN-ANP#INPI Page 188 of 545 In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of autoimmune diseases. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic erythematosis lupus, diabetes mellitus type I, interferonopathy and inflammatory bowel disease. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of autoimmune diseases. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosis, diabetes mellitus type I, interferonopathy and inflammatory bowel disease. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal suffering from autoimmune diseases, methods comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions. described herein for the treatment or prophylaxis of said condition. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosis, diabetes mellitus type I, interferonopathy and inflammatory bowel disease. IF-2019-17407397-APN-ANP#INPI95 Page 189 of 545 IF-2019-17407397-APN-ANP#INPI Page 190 of 545 In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an autoimmune disease treatment agent. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosis, diabetes mellitus type I, interferonopathy and inflammatory bowel disease. In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of autoinflammatory diseases. In a particular embodiment, the autoimmune disease is cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behgets, Juvenile onset juvenile idiopathic arthritis systemic (SJIA) or Still's disease. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of autoinflammatory diseases. In a particular embodiment, the autoimmune disease is cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF) and IF-2019-17407397-APN-ANP#INPI96 Page 191 of 545 IF-2019-17407397-APN-ANP#INPI Page 192 of 545 periodic syndrome associated with! tumor necrosis factor receptor (TRAPS), Behcets, systemic onset juvenile idiopathic arthritis (SJIA) or Still's disease. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected by autoinflammatory diseases, methods comprising the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition. In a particular embodiment, the autoimmune disease is cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behgets, Systemic-onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an autoinflammatory disease treatment agent. In a particular embodiment, the autoimmune disease is cryopyrin-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Beh$ets, Juvenile idiopathic arthritis of systemic onset (SJIA) or Still's disease. In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, IF-2019-17407397-APN-ANP#INPI97 Page 193 of 545 IF-2019-17407397-APN-ANP#INPI Page 194 of 545 for use in the prophylaxis and / or treatment of proliferative diseases. In a particular embodiment, the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of proliferative diseases. In a particular embodiment, the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal suffering from proliferative diseases, methods comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions. described herein for the treatment or prophylaxis of said condition. In a particular embodiment, the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a proliferative disease treatment agent. In a particular embodiment, the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In one embodiment IF-2019-17407397- APN-ANP#INPI98 Page 195 of 545 IF-2019-17407397-APN-ANP#INPI Page 196 of 545 In particular, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of transplant rejection. In a particular embodiment, transplant rejection is a graft versus host disease. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of transplant rejection. In a particular embodiment, transplant rejection is a graft versus host disease. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected with transplant rejection, methods comprising the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition. In a particular embodiment, transplant rejection is a graft versus host disease. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a transplant rejection treatment agent. In a particular embodiment, transplant rejection is a graft versus host disease. IF-2019-17407397-APN-ANP#INPI99 Page 197 of 545 IF-2019-17407397-APN-ANP#INPI Page 198 of 545 In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases involving impairment of cartilage turnover. In a particular embodiment, the disease involving impaired cartilage turnover is ankylosing spondylitis. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of diseases involving impaired cell turnover. cartilage. In a particular embodiment, the disease involving impairment of cartilage turnover is ankylosing spondylitis. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected with a disease involving impairment of cartilage turnover, methods comprising administering an effective amount of a compound of the invention. or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition. In a particular embodiment, the disease involving impairment of cartilage turnover is ankylosing spondylitis. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and IF-2019-17407397-APN-ANP#INPI100 Page 199 of 545 IF-2019-17407397-APN-ANP#INPI Page 200 of 545 another therapeutic agent. In a particular embodiment, the other therapeutic agent is a disease treatment agent involving impairment of cartilage turnover. In a particular embodiment, the disease involving impairment of cartilage turnover is ankylosing spondylitis. In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of congenital cartilage malformations. In a particular embodiment, congenital cartilage malformations are selected from microtia, anotia and / or metaphyseal chondrodysplasia. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of congenital cartilage malformations. In a particular embodiment, congenital cartilage malformations are selected from microtia, anotia and / or metaphyseal chondrodysplasia. In further method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected with congenital cartilage malformations, methods comprising the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition. In one embodiment IF-2019-17407397-APN-ANP#INPÍ01 Page 201 of 545 IF-2019-17407397-APN-ANP#INPI Page 202 of 545 In particular, congenital cartilage malformations are selected from microtia, anotia and / or metaphyseal chondrodysplasia. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a congenital cartilage malformation treatment agent. In a particular embodiment, congenital cartilage malformations are selected from microtia, anotia and / or metaphyseal chondrodysplasia. In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases associated with the hypersecretion of IFNa, IL12 and / or IL23 . In a particular embodiment, the disease associated with the hypersecretion of IFNa, IL12 and / or IL23 is systemic and cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and / or Crohn's disease. In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of diseases associated with hypersecretion of IFNot, IL12 and / or IL23. In a particular embodiment, the disease associated with hypersecretion of IFNa, IL12 and / or IL23 is erythematosis. IF-2019-17407397-APN-ANP#INPÍ02 Page 203 of 545 IF-2019-17407397-APN-ANP#INPI Page 204 of 545 systemic and cutaneous lupus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and / or Crohn's disease. In the additional method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal affected by diseases associated with the hypersecretion of IFNct, IL12 and / or IL23, methods comprising the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein for the treatment or prophylaxis of said condition. In a particular embodiment, the disease associated with hypersecretion of IFNot, IL12 and / or IL23 is systemic and cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and / or Crohn's disease. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a disease treatment agent associated with hypersecretion of IFNa, IL12 and / or IL23. In a particular embodiment, the disease associated with the hypersecretion of IFNa, IL12 and / or 1L23 is systemic and cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and / or Crohn's disease. Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all from about 1 to about 120 h, and especially from 24 to 96 h. I also know IF-2019-17407397-APN-ANP#INPÍ03 Page 205 of 545 IF-2019-17407397-APN-ANP#INPI Page 206 of 545 may deliver a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more to achieve adequate steady-state levels. The maximum total dose is not expected to exceed approximately 1 g / day for a 40 to 80 kg human patient. For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, the treatment regimen usually extends over many months or years, so oral administration is preferred for convenience and patient tolerance. With oral dosing, one to four (1-4) regular daily doses, especially one to three (1-3) regular daily doses, usually one to two (1-2) regular daily doses, and most typically of one (1) regular daily dose are representative regimens. Alternatively, for long-lasting drugs, with oral doses, once every two weeks, once a week, and once a day are representative regimens. In particular, the dosage regimen may be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and more particularly 1-3 days. By utilizing these dosage patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially from about 30 to about 250 mg. Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injection doses. IF-2019-17407397-APN-ANP#INPÍ θ4 Page 207 of 545 IF-2019-17407397-APN-ANP#INPI Page 208 of 545 When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk of developing the condition, typically with the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk of developing a particular condition generally include those who have a family history of the condition, or those who have been identified through genetic testing or screening to be particularly susceptible to developing the condition. A compound of the invention may be administered as the sole active agent or may be administered in combination with other therapeutic agents, including another compound of the invention that demonstrates the same or similar therapeutic activity and is considered safe and effective for such administration. combined. In a specific embodiment, coadministration of two (or more) agents allows the use of significantly lower doses of each, thereby reducing the side effects observed. In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific 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 prophylaxis of a disease involving inflammation, particular agents include, but are not limited to, immunoregulatory agents, for example azathioprine , corticosteroids IF-2019-17407397-APN-ANP#INPÍ05 Page 209 of 545 IF-2019-17407397-APN-ANP#INPI Page 210 of 545 (for example, prednisolone or dexamethasone), cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate, mofetil, muromonab-CD3 (OKT3, for example, 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 prophylaxis of arthritis (e.g., rheumatoid arthritis), particular agents including, but not limited to, analgesics. , non-steroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDS (for example, but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, 10 chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib and cyclosporine) and biologic DMARDS (for example, 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 prophylaxis of proliferative disorders, particular agents include, but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluoruracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. HerceptinTM), capecitabine, raloxifene hydrochloride, inhibitors of EGFR (e.g., Iressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g., Avastin™), proteasome inhibitors (e.g., Velcade™), Glivec® and hsp90 inhibitors (e.g., 17- AAG). Furthermore, the compound of the invention according to Formula I can be administered in combination with other therapies including, but not limited to, IF-2019-17407397-APN-ANP#INPI106 Page 211 of 545 IF-2019-17407397-APN-ANP#INPI Page 212 of 545 radiotherapy 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 prophylaxis of autoimmune diseases, particular agents include, but are not limited to: glucocorticoids, cytostatic agents (for example, purine analogs ), alkylating agents (for example, nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds of the inventions and others), antimetabolites (for example, methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (for example, dactinomycin, anthracyclines, mitomycin Ctbleomycin and mithramycin), antibodies (for example, anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (for example, IFN-β ), TNF-binding proteins (for example, 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 prophylaxis of transplant rejection, particular agents include, but are not limited to: calcineurin inhibitors (for example, cyclosporine or tacrolimus (FK506)), mTOR inhibitors (e.g., sirolimus, everolimus), antiproliferatives (e.g., azathioprine, mycophenolic acid), corticosteroids (e.g., prednisolone, hydrocortisone), antibodies (e.g., anti-receptor monoclonal antibodies). IL-2Ra, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g., anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)). IF-2019-17407397-APN-ANP#INPfl 07 Page 213 of 545 IF-2019-17407397-APN-ANP#INPI Page 214 of 545 In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of asthma and / or rhinitis and / or COPD, particular agents including, but not limited to: agonists beta2-adrenoceptor (for example, salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (for example, ipratropium bromide), glucocorticoids (oral or inhaled). Long-acting β2-agonists (e.g., salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), combinations of inhaled spheroids and long-acting bronchodilators (e.g., fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists, and inhibitors synthesis (e.g., montelukast, zafiriukast, and zileuton), inhibitors of mediator release (e.g.,cromoglycate and ketotifen), biological regulators of IgE response (e.g., omalizumab), antihistamines (e.g., ceterizine, cinnarizine , fexofenadine) and vasoconstrictors (for example, oxymetazoline, xylometazoline, naphazoline and tramazoline). Additionally, a compound of the invention may be administered in combination with emergency therapies for asthma and / or COPD, such therapies include the administration of oxygen or heliox, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g., ipratropium). , systemic spheroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g. epinephrine, isoetarine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, for example glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamipilin), inhalation anesthetics that have an IF-2019-17407397-APN-ANP#INPI108 Page 215 of 545 IF-2019-17407397-APN-ANP#INPI Page 216 of 545 bronchodilator (e.g., isoflurane, halothane, enflurane), ketamine, and magnesium sulfate intravenously. In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of inflammatory bowel disease (IBD), particular agents include, but are not limited to: glucocorticoids (e.g. , prednisone, budesonide) synthetic disease modifiers, immunomodulatory agents (for example, methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6mercaptopurine and cyclosporine) and biological disorder modifiers, 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 prophylaxis of SLE, particular agents including, but not limited to: human monoclonal antibodies (belimumab (Benlysta)), antirheumatic drugs disease-modifying drugs (DMARDs), such as antimalarials (e.g., plaquenil, hydroxychloroquine), immunosuppressants (e.g., methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, analgesics and immunosuppressive drugs, such as non-steroidal anti-inflammatory drugs, opioids (e.g. for example, dextropropoxyphene and codecamol), opioids (for example hydrocodone, oxycodone, MS Contin, or methadone), and the fentanyl duragesic transdermal patch. In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of psoriasis, particular agents include, but are not limited to: topical treatments such as bath solutions, moisturizers and creams. medications and ointments containing coal tar, dithranol (anthralin), corticosteroids such as IF-2019-17407397-APN-ANP#INPÍ09 Page 217 of 545 IF-2019-17407397-APN-ANP#INPI Page 218 of 545 desoxymetasone (Topicort™), fluocinonide, vitamin D3 analogs (e.g., calcipotriol), argan oil and retinoids (etretinate, acitretin, Tazarotene), systemic treatments 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-23 blocker). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to, phototherapy or photochemotherapy (e.g., psoralen and ultraviolet A phototherapy (PUVA)). In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prophylaxis of the allergic reaction, particular agents include, but are not limited to: antihistamines (e.g., cetirizine, diphenhydramine, fexofenadine , levocetirizine), glucocorticoids (for example, prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or anti-leukotrienes (for example, montelukast or zafirlukast), anticholinergics and decongestants. Coadministration includes any means of administering two or more therapeutic agents to the patient as part of the same treatment regimen, as will be apparent to the skilled person. Although the two or more agents may be administered simultaneously in a single formulation, that is, as a single pharmaceutical composition, this is not essential. The agents can be administered in different formulations and at different times. CHEMICAL SYNTHETIC PROCEDURES General IF-2019-17407397-APN-ANP#INPÍ> 10 Page 219 of 545 IF-2019-17407397-APN-ANP#INPI Page 220 of 545 The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions are provided (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.), other process conditions may also be used unless otherwise indicated. . Optimal reaction conditions may vary with the particular reagents or solvent used, but such conditions can be determined by one skilled in the art through routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. The choice of a suitable protecting group for a particular functional group as well as the appropriate conditions for protection and deprotection are well known in the art (Greene, TW; Wuts, P G M;, 1991). The following methods are presented with details regarding the preparation of a compound of the invention as defined herein above and comparative examples. A compound of the invention can be prepared from reagents and starting materials known or commercially available to one skilled in the art of organic synthesis. All reagents were of commercial quality and were used as received without further purification unless otherwise indicated. Commercially available anhydrous solvents were used for the reactions carried out in an inert atmosphere. Reagent grade solvents were used in all IF-2019-17407397- APN-ANP#INPÍ 11 Page 221 of 545 IF-2019-17407397-APN-ANP#INPI Page 222 of 545 all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm). Thin layer chromatography is carried out using pre-coated F-254 silica gel plates (0.25 mm thickness). 1H NMR spectra were recorded on a Bruker Advance 300 NMR spectrometer (300 MHz). Chemical shifts (δ) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (6 0.00) or the appropriate residual solvent peak, i.e., CHCh (δ 7.27), as an internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintuplet (quin), multiplet (m) and width (br). Electrospray MS spectra were obtained on a Waters platform LC / MS spectrometer or with a Waters Acquity class H UPLC coupled to a Waters mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 50 mm L, Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 30 mm L, or Waters Xterra MS 5pm C18, 100 x 4.6mm. The methods use gradients of MeCN / H2O (H2O contains 0.1% TFA or 0.1% NH3) or MeOH / H2O (H2O contains 0.05% TFA). Microwave heating is done with a Biotage starter. Racemic mixtures were separated on an Agilent HP1100 system with UV detection. Column used: Chiralpak 1A (10x250 mm, 5 pm). Solvents used: / PrOH and tBME. Enantiomeric purity is determined on an Agilent HP1100 system with UV detection. Column used: Chiralpak IA (4.6 x 250 mm, 5 pm). Solvents used: / PrOH and tBME. Table I. List of abbreviations used in the experimental section: IF-2019-17407397- APN-ANP#INPÍ12 Page 223 of 545 IF-2019-17407397-APN-ANP#INPI Page 224 of 545 Abbreviation Definition DCM Dido remeta no MeCN Acetonitrile DMF Ν,Ν-di metí Ifonma mida Cat. Catalytic amount TFA Trifluoroacetic acid THF Tetrahydrofuran NMR Nuclear Magnetic Resonance DMSO Dimethylsulfoxide LC-MS Liquid Chromatography Mass Spectrometry EtOAc ethyl acetate APCI chemical ionization at atmospheric pressure Rt retention time s singlet brs singlet width d doublet dd doublet m multiplet min minute mL milliliter μι microliter g gram mg milligram TEA Triethylamine mmol millimoles Abbreviation Definition HPLC High Pressure Liquid Chromatography NMP N-Methylpyrrolidone AcCI Acetyl Chloride ppm parts per million Pd2(dba)3 Tris(dibenclideneacetone)dip aladium(O) Pd(OAch Palladium(II) acetate XPhos 2-Didclohexylphosphino2',4 ',6-triisopropylbiphenyl Comp Compound Mtd Method Int Intermediate PM Molecular weight Month Measured molecular weight NA Not active Pd(dppf)CLi DCM 1,1Bis(diphenylphosphino)didoromethaneferrocenc>palladium(ll) dichloride pm micro meter tBME methyl ether tert- butyl íPrOH iso-Pro panol DMA dimethyl cetamide TFA Trifluoroacetic acid DBU l,8-Diazabicycloundec-7ene DiPPF l,l-Bís(dHsopropyl phosphinojferrocene IF-2019-17407397-APN-ANP#INPÍ13 Page 225 of 545 IF-2019-17407397-APN-ANP#INPI Page 226 of 545 Abbreviation Definition HATU 1—[Bis(dimethylamylno)methylene]lH-1,2,3-triazolo[4,5b]pyridinium 3-oxide hexafluorophosphate NIS N-Iodosucinimide XantPhos 4,5-BIs(dtphenylphosphino)-9#9dimethylxanthene XantPhos pd G3 2-morpholymphenylphosphine MorDALPhos Pd G3 (2—{Di— 1-adamantylfos fine)morpholinbenzene)(2-(2amino-l,r-biphenyl)l palladium(ll) methanesulfonate BrettPhos 2-{Dicidohexlyphos fine)3,6-dimethoxy-2 *,4*,6trüsopropyl—1,1*—biphenyl BrettPhos Pd G3 Methanesulfonate (2'-amino-l,l'-biphenyl) ] palladium(ll) methane sulfonate SPhos 2-Diddohexylphosphino-2',6dimethoxybiphenyl SPhos Pd G2 Chloro(2-dicidohexy1 phosphin o-2',6'-d i m ethoxy- 1,1biphenyl)[2-(2-amino-l,rbiphenyl)]palladium(ll) RuPhos 2-Dicyclohexylphosphino-2',6diisopropoxybiphenyl Abbreviation Definition RuPhos Pd G3 (2Diddohexylphosphino-2',6diisopropoxy-l,r-biphenyl)[2(2-amino-l,rbiphenyl)]palladium(ll) methanesulfonate tBuBrettPhos PdG3 [(2—Di—tert-butylphosphino) methanesulfonate -3,6dimethoxy-2',4',6'triisoproptl—1,1-biphenyl)-2(2-amlno-l,lbiphenyl)]palladium(ll) TMHD 2,2,6,5Tetramethyl heptandione T3P Propylphosphonic anhydride IF-2019-17407397- APN-ANP#INPÍ14 Page 227 of 545 IF-2019-17407397-APN-ANP#INPI Page 228 of 545 SYNTHETIC PREPARATION OF THE COMPOUND OF THE INVENTION General synthetic methods The compounds of the invention and comparative examples can be produced according to the following schemes. Scheme 1 l ;i Scheme 2 Scheme 3 IF-2019-17407397-APN-ANP#INPI115 Page 229 of 545 IF-2019-17407397-APN-ANP#INPI Page 230 of 545 Scheme 4 Ri General methods used for the synthesis of compounds and intermediates Method A1-a +R3'N'R2 H A-N.C A solution of the acid (1 eq), HATU (1.3 eq) and EtaN (2.5 eq) in NMP is stirred for 1 minute, after which the amine (1 eq) is added. Once complete, the mixture is filtered and the filtrate is purified by preparative chromatography to provide the desired product. Method A1-b To a suspension of the acid (1 eq), EtaN (5 eq) and the amine (1 to 3 eq) in DMF, a 50% solution of T3P 15 in AcOEt (2 eq) is slowly added at room temperature. The reaction mixture is stirred at room temperature until complete. The reaction mixture is poured into ice / water and extracted with IF-2019-17407397-APN-ANP#INPÍ16 Page 231 of 545 IF-2019-17407397-APN-ANP#INPI Page 232 of 545 SUN. The organic layer is concentrated to dryness to provide the desired product. Step 1: To a solution of the acid (1 eq) and EDCI.HCI (1.5 eq) in dry DCM at room temperature, the amine (1.1 eq) is added followed by DIPEA (2.0 eq). The mixture is stirred at room temperature for 18 h. It is then quenched with aqueous NaHCOa followed by extraction with DCM. The organic layer is concentrated to dryness and the crude material is used as is, or purified by column chromatography using EtOAc / DCM or MeOH / DCM as eluent to provide 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 h. It is then concentrated to dryness to remove excess TFA. The compound is purified via SCX column using MeOH and then 2N NH3 in MeOH as eluent to provide the desired product as free base. Method A3: Step 1: To a solution of the acid (1 eq) and HATU (1.1 eq) in dry DMF at room temperature, the amine (1.5 eq) is added followed by DIPEA (1.5 eq). The mixture is stirred at room temperature for 18 h. It is then diluted with water and then EtAOc is extracted. The organic layer is concentrated to dryness and the crude material is used as is, or purified by column chromatography. IF-2019-17407397-APN-ANP#INPÍ17 Page 233 of 545 IF-2019-17407397-APN-ANP#INPI Page 234 of 545 using EtOAc / DCM or MeOH / DCM as eluent to provide the desired amide. Method B1 Ri N t¡IH2R2 Aryl halide (1.0 eq), amine or aniline (1.0 eq), Pd2CL2(allylophe (0.02 eq), MorDALPhos (0.04 eq), and Cs2CO3 (1.2 eq) are mixed under N2a room temperature, after which, 4-dioxane is added. The resulting mixture is stirred at 110°C. The mixture is then allowed to cool to room temperature, further diluted in DMSO and filtered. Preparative HPLC to provide the desired product. Method B2-a nh2 JTjTN> ♦ Ar-X Ri N Aniline (1.0 eq), aryl halide (1.2 eq), XantPhos Pd G3 (0.04 eq) and Cs2CO3 (1.2 eq) are mixed under N2 at room temperature, after which they are add 1,4-dioxane. The resulting mixture is stirred at 80°C. The mixture is then allowed to cool to room temperature, further diluted in DMSO and filtered. The filtrate is purified by preparative HPLC to provide the desired product. Alternatively, the mixture is poured into water and subsequently filtered. The resulting solid is washed with water and dried to provide the desired product. Method B2-b IF-2019-17407397-APN-ANP#INPI118 Page 235 of 545 IF-2019-17407397-APN-ANP#INPI Page 236 of 545 A suspension of aniline (1.0 eq), aryl halide (1.1 eq), and K3PO4 (3.0 eq) in degassed dioxane was heated to reflux. To this solution, a solution of Pd(OAc)2 (0.14 eq) and Xantphos (0.28 eq) in degassed dioxane was added dropwise (over 7 hours). Once complete, the reaction mixture was hot filtered on a pad of Dicalite (Cario Erba, ref. P8880014), and the filter agent was rinsed with THF and CHCl3. The solvent was evaporated and the solid was ground in acetonitrile. The solid was filtered and washed with acetonitrile. The crude product was purified by column chromatography using CHCfe / MeOH: 98 / 2 as eluent to provide the desired product. Method B3 r2 Intermediate 1 (1.0 eq), aniline or amine (2.0 eq), XantPhos Pd G3 (0.03 eq), environment, after which 1,4-dioxane is added. The resulting mixture is stirred at 110°C. Once completed, the mixture is cooled to room temperature and coated with silica. The crude material is purified by column chromatography using EtOAc / petroleum ether or MeOH / DCM as eluent. Method C1 IF-2019-17407397- APN-ANP#INPf19 Page 237 of 545 IF-2019-17407397-APN-ANP#INPI Page 238 of 545 Step 1: To a solution of dry THF containing the aniline (1 eq) NaH (60% dispersion in mineral oil, 2.2 eq) is added under Ns. The mixture is stirred for 5 minutes at room temperature before adding iodomethane (2 eq). The reaction mixture is then stirred at room temperature overnight. The conversion of the reaction is monitored by LCMS. The reaction is quenched with MeOH and then concentrated to dryness. The crude residue is purified by column chromatography using MeOH / DCM, NH37N in MeOH / DCM or EtOAc / petroleum ether as eluent. Step 2: To a solution of the dibenyl-protected amine (1 eq) in dry DCM (0.25M) at 0eC, Τί2Ο (8 eq) is added drop by drop. The mixture is then stirred at room temperature for 18 h. The reaction conversion is monitored by LCMS. The reaction is quenched with NaHCO3 and the mixture is extracted with DCM. The organic layer is concentrated to dryness to provide the desired crude material which is used as is or purified by chromatography. Step 3: Aniline (1 eq), 2-chloro-4-amino-plrimÍdine (2.0 eq), BrettPhos Pd G3 (0.1 eq), BrettPhos (0.1 eq), Cs2CO3 (2.0 eq) They are mixed under an inert atmosphere. Solvent, usually 1,4-dioxane, is added and the mixture is stirred at 110°C for 18 h. The reaction is then cooled to room temperature, quenched with H2O, and the compound is extracted with DCM. The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is purified by chromatography to provide the desired compound. Method C2 IF-2019-17407397-APN-ANP#INPI120 Page 239 of 545 IF-2019-17407397-APN-ANP#INPI Page 240 of 545 Step 1: NaH (60% dispersion in mineral oil, 1.5 eq) is added to a solution of aniline (1.0 eq) in dry THF under N2a 0eC. After 10 minutes, iodomethane (2.0 eq) is added and the mixture is stirred at 40eC. Once the reaction is complete (monitored by LCMS), the mixture is allowed to cool to room temperature and quenched with a saturated aqueous NaHCO3 solution. The mixture is then extracted with DCM, dried over MgSO4, filtered and concentrated to dryness. The crude material is purified by column chromatography using EtOAc / petroleum ether or MeOH / DCM as eluent to provide the desired product. Step 2: Aryl chloride (1.0 eq), aniline (2.0 eq), MorDALPhos Pd G3 (0.03 eq), MorDALPhos (0.03 eq) and CS2CO3 (1.3 eq) are mixed under N2a room temperature after which 1,4-dioxane is added and the mixture is stirred at 110°C. At the end, the mixture is cooled to room temperature and diluted in DM SO. After filtration, the filtrate is purified by preparative HPLC to provide the desired product. Method D1 R _ _______b. p NHBxK'NH2 The Boc-protected amine (1.0 equiv.) is dissolved in anhydrous 1,4-dioxane in N2. HCl (4.0 M in dioxane, 10 eq) is added dropwise and the reaction mixture is stirred at room temperature. After 2 h, all volatiles are evaporated in vacuo. The crude oil is collected in DCM, washed with a saturated aqueous solution. NaHCO3 solution, dry and evaporate in vacuo. The crude product is used as is or purified by chromatography to provide the desired product. IF-2019-17407397-APN-ANP#INPI121 Page 241 of 545 IF-2019-17407397-APN-ANP#INPI Page 242 of 545 Method P1 To a solution of 4-amino-6-chloropyrimidine (CAS [5305-59-9], 1.0 eq) and amine (1.2 eq) in dry NMP under N2, TEA (1.3 eq) is added. The mixture is stirred at 160°C overnight. It is then cooled to room temperature and diluted in H2O. The reaction is basified using a saturated aqueous NaHCO3 solution. This mixture is extracted with EtOAc. The organic layer is washed with brine (3x), dried over MgSO4 (filtered and concentrated to dryness to provide the crude product. The crude product is used as such, whether purified by chromatography. Method P2 jfY ♦ HN^ --|^VN'r2 HjN'V-”r< h.nAn’n 6-Iodopyridazin-3-amine (CAS [187973-60-0], 1.0 eq), Amine (2.0 eq), Cul (0.1 eq), L-hydroxyproline (CAS [51-35-4 ], 0.2 eq) and K3PO4(3.0 eq) are mixed together under N2. DMSO is added and the mixture is stirred at 60°C. After two nights, the mixture is cooled to room temperature and the DMSO is removed under reduced pressure. The residue is diluted in MeOH and filtered. The filtrate is purified by column chromatography using NH37N in MeOH / DCM as eluent to provide the desired product. Method P3 HN Ri IF-2019-17407397-APN-ANP#INPI122 Page 243 of 545 IF-2019-17407397-APN-ANP#INPI Page 244 of 545 To a solution of the amine (1 eq) in anhydrous dioxane (10 ml), DIPEA (4 eq) and 3,6-dichloropyridazine (CAS [141-30-0], 1.0 eq) are added and the mixture is stir 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 provide a crude product which is used as is or purified by chromatography. Synthesis of intermediaries Intermediate 1: 7-chloro-5-iodo-3-methi!-3H-ImÍdazo[4,5-b]pyridine Step 1: 2,4-dichloro-6-iodo-pyridin-3-ylamine: to a solution of 2,4dichloro-3-aminopyridine (250 g, 1.54 mmol, 1 eq) in dry MeCN (1.2 L ) in a N2 atmosphere at room temperature, NIS (382 g, 1.70 mmol, 1.1 eq) and TFA (35.45 mi, 0.46 mmol, 0.3 eq) were added. 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 Na2S2O3 (500 ml) and NaHCO3 (700 ml). The organic layer was washed with saturated NaHCOs and the aqueous layers were washed twice with EtOAc (2 x 700 ml). The combined organic layers were dried over MgSO4, filtered and concentrated to dryness to obtain a crude product. Purified by column chromatography using cyclohexane and EtOAc (10%) to give the desired product LCMS: m / z = 289 [M + HJ. Step 2:4-chloro-6-iodo-N2-methyl-pyridine-2,3-diamine 2,4-Dichloro-6-iodo-pyridIn-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 N2 at room temperature. The mixture was stirred at IF-2019-17407397-APN-ANP#INPfl 23 Page 245 of 545 IF-2019-17407397-APN-ANP#INPI Page 246 of 545 180°C for 18 hours and then cooled to room temperature. This step was repeated twice and at the end, all reaction mixtures were combined and concentrated to provide 60 g of the title compound which was used in the next step as such. LCMS: m / z = 284 [M + H]. Step 3: 7-cIoro-5-iodo-3-methyl-3H-imidazo[4,5-bjprídine to a solution of 4-cIoro-6-iodo-N-2-methyl-pyridÍne-2,3-diamine ( 60 g, 021 mmol, 1 eq) in formic acid (30 ml) trimethyl orthoformate (69.5 ml, 0.64 mmol, 3 eq.) was added. The mixture was stirred at 60°C for 1 h. The reaction was concentrated to dryness, after which the residue was diluted with DCM and quenched with a saturated aqueous NaHCOs solution. After extraction with DCM, the organic layer was dried over Na2SO4, filtered and concentrated to dryness to provide a crude material. It was purified by column chromatography using eluent cyclohexane / EtOAc from 10 to 60% EtOAc to provide the desired product. LCMS: m / z = 294 [M + H].1H NMR (300 MHz, DMSO-d6) 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-methylpyridine-2-carbonitrile Intermediate 1 (68.51 g, 233.83 mmol, 1.0 eq), Intermediate 21 (47.00 g, 350.75 mmol, 1.5 eq), Cul (8.89 g, 46.77 mmol, 0.2 eq), TMHD (97.45 mL, 467.66 mmol, 2 eq) and CS2CO3 (152 g, 467.66 mmol, 2 eq) were mixed in air, DMF (234 mL) was added and the mixture It was stirred at 85eC for 2 nights. If complete conversion was not achieved, additional Cul (0.1 eq) and TMHD (1 eq) were added, after which the mixture was further stirred at 85°C for another night. IF-2019-17407397-APN-ANP#INPÍ24 Page 247 of 545 IF-2019-17407397-APN-ANP#INPI Page 248 of 545 The mixture was then cooled to 0°C. The resulting thick paste was filtered and the cake was washed with ice-cold DMF (2 x 20 ml). It was then washed with ice-cold MTBE (3x150 ml). After the cake was dried, it was suspended in 500 ml of a 10% aqueous solution of TMEDA. Stirred for 2 h, filtered and the cake was washed with HsO to give the desired product. LCMS: m / z = 300 [M + H]+. Intermediate 3: S-ÍT-amino-S-methyl-SH-lmldazo^.S-blpIrldin-S-iloxl)-^methyl-pÍrÍdine-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) in a N2 atmosphere, 1,4-dioxane (100 ml) was added and the mixture was stirred at 110°C for 24 h. After allowing to cool to room temperature, the mixture was diluted with EtOAc and filtered over celite. The cake was washed with EtOAc (100 ml) and the filtrate was poured into a 2N HCl aqueous solution (200 ml), stirring for 10 minutes. After extraction with EtOAc, the aqueous phase was neutralized to pH = 7 using NaHCO3. This was followed by extraction with EtOAc (5 x 100 ml), after which the combined organic layers were dried over MgSO4, filtered and concentrated to dryness to provide the crude material which was triturated with DCM to provide the product wanted. LCMS: m / z = 281 [M + H]+. Alternative synthesis of! Intermediate 3: 5-(7-Amino-3-methyl-3Hlmidazo[4,5-b]pyridin-5-i!oxy)-4-methyl-pyrid¡n-2-carbonitrile IF-2019-17407397-APN-ANP#INPfl 25 Page 249 of 545 IF-2019-17407397-APN-ANP#INPI Page 250 of 545 Step 1: 2,6-dichloro-4-amino-5-nitropyridine (520 g, 2.5 mol, 1.0 eq) was added to acetonitrile (5.2 I) at room temperature. To the mixture were added, with stirring at room temperature, Boc20 (710 g, 3.25 mol, 1.3 eq) and K3PO4 (1000 5 g, 4.71 mol, 1.9 eq). The reaction mixture was heated at reflux for 1-2 hours. A solution of Boc2O (110 g, 0.5 mol, 0.2 eq) in acetonitrile (100 ml) was then added and the reaction mixture was heated at reflux for an additional hour. The reaction mixture was cooled to room temperature and filtered through a pad of Na2SO4. The Na2SO4 was washed with acetonitrile (2 I). The filtrate was evaporated under reduced pressure and redissolved in DCM (5 I). The DCM layer was washed with water. The organic layer was extracted with DCM (5 I) and the combined organic layers were dried over Na2SO4, filtered and evaporated to give the desired product. CLEM: m / z = 306 / 308 [M + HJ. Step 2: 2,6-Dichloro-4 Boc-amino-5-nitropyridine (770 g, 2.5 mol, 1.0 eq) was added to isopropanol (11 I) at room temperature. To the mixture, with stirring at room temperature, 33% methylamine in EtOH (800 ml, 3.0 eq) was added for 1 h 30. The reaction mixture was stirred at room temperature for 1 h 30. The suspension was filtered, washed with isopropanol (1 I) and IF-2019-17407397-APN-ANP#INPÍ 26 Page 251 of 545 IF-2019-17407397-APN-ANP#INPI Page 252 of 545 then with water (4 I). After drying, the desired product was obtained. LCMS: m / z = 302.9 / 304.8 [M + HJ. Step 3: Tere-butyl N-[6-chloro-2-(methylamino)-3-nitro-4-pyridyl]carbamate (788 g, 2.6 mol, 1.0 eq) was added to acetonitrile (5. 5L) at room temperature. To the mixture were added, with stirring at room temperature, 5hydroxy-4-methyl!-pyridin-2-carbonitriIo (384 g, 2.86 mol 1.1 eq) and Na2CO3 (414 g, 3.9 mol, 1. 5 eq). The reaction mixture was heated at reflux for 48 hours. The reaction mixture was cooled to room temperature and the insoluble substance was filtered and washed with acetonitrile (2 I). The combined organic layers were evaporated. The crude oil was washed with water (5 I), collected and dried to provide the desired product. CLEM: m / z = 401.1 [M + H]; m / z = 399.2 [MH].1H NMR (400 MHz, DMSO-d6) 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). Step 4: Tere-butyl N-[6-[(6-cyano-4-methyl-3-pyridyl)oxy]-2-(methylamino)-3-nitro-415 pyridylcarbamate (150 g , 375 mmol, 1.0 eq) were added to a mixture of acetic acid (750 ml, 35 eq) and trimethyl orthoformate (750 m!, 18 eq) at room temperature. Zn powder <10 pm (total of 120 g, 4.9 eq, added in portions of 15 g) was added to the mixture in portions, under vigorous stirring at 20-21qC. Each addition was made after the reaction mixture was cooled to 20-2ΓΟ. The reaction mixture was stirred for one hour after the last addition. The suspension was filtered through Dicalite 4158 (Cario Erba, ref. P8880014), washed with THF (1 I) 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 liters). The resulting solid was filtered, washed with water (2 I) and dried to provide the desired product. LCMS: m / z = IF-2019-17407397-APN-ANP#INPÍ 27 Page 253 of 545 IF-2019-17407397-APN-ANP#INPI Page 254 of 545 381.0 [Μ + Η]: m / z = 379.2 [Μ—Η].1Η NMR (400 MHz, DMSO-d6) δ 9.32 (bs, 1Η), 8.55 (s, 1 Η ), 8.22 (s, 1Η), 8.10 (s, 1Η), 7.54 (s. 1Η). 3.60 (s, 3H), 2.27 (s, 3H), 1.49 (s, 9H). Step 5: tert-Butyl N-[6-[(6-cyano-4-methyl-3-pyridyl)oxy]-2-{methylamino)-3-nitro-pyridylcarbamate (197 g, 0.518 mol, 1, 0 eq) were suspended in a mixture of hydrochloric acid, 4N solution in water (1 I) and THF (1 I). The reaction mixture was heated at 60°C for 5 hours. The reaction mixture was cooled to room temperature and the solid was filtered, washed with THF (1 I) and dried to provide the desired product as a hydrochloric salt. LCMS: m / z = 281.4 [M + H).1H NMR (400MHz, DMSO-de) δ ppm: 9.28 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 7. 57 (bs, 2-3H), 6.33 (s, 1H), 3.67 (s, 3H), 2.25 (s, 3H). Intermediate 4: 5-(7-chloro-3-methyl-3H-lmldazo[4,5-b]pyridin-5-ylamino)-4methyl-pyridin-2-carbonitrile 7-Chloro-5-iodo-3-methyl-3H-imÍdazo[4,5-b]pyridine (Int 1, 50 mg, 0.171 mmol, 1.0 eq), 5-amino-4-methylpyridine-2-carbonitrile (Int 17, 24 mg, 0.205 mmol, 1.2 eq), XantPhos Pd G3 (5 mg, 0.005 mmol, 0.03 eq), , 0.342 mmol, 2.0 eq) were mixed under N2 at room temperature. Diglyme (1 ml) was added and the mixture was stirred at 80°C. After overnight, it was cooled to room temperature, quenched with water and the mixture was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (EtOAc / petroleum ether, 7:3 to 1:0) to provide the desired product. LCMS: m / z = 299 [M + H]*. IF-2019-17407397-APN-ANP#INPl 28 Page 255 of 545 IF-2019-17407397-APN-ANP#INPI Page 256 of 545 Intermediate 5: 5-I(7-chloro-3-methyl-3H-imidazo[415-b]pyridin-5-yl)-methylamino]-4-methyl-pyridin-2-carbonitrile 7-chloro-5-iodo-3-methyl-3H-imidazo[4,5-b]pyridine (Int 1, 50 mg, 0.171 mmol, 1.0 eq), 5-amino-4-methylpyridine-2-carbonitriium (Int 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 K3PO4 (72 mg , 0.342, 2.0 eq) were mixed under N2 at room temperature. Diglyme (1 ml) was added and the mixture was stirred at 80°C. After overnight, it was cooled to room temperature, quenched with water and the compound was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (EtOAc / petroleum ether, 1:1 to 1:0) to provide the desired product. LCMS: m / z = 313 [M + H]+. Intermediate 8: (7-c!oro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-methi!-((S)1,2,2-trimethi!-propyl)- amine To a solution of Int 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 an N2 atmosphere. After 5 minutes, methyl iodide (46 pL, 0.73 mmol, 1.5 eq) was added. The reaction was heated at 40°C for 18 hours. The reaction was then diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The resulting raw product IF-2019-17407397-APN-ANP#INPÍ29 Page 257 of 545 IF-2019-17407397-APN-ANP#INPI Page 258 of 545 was purified by column chromatography (PE / EtOAc gradient elution from 20% to 80% EtOAc) to provide the desired product. LCMS: m / z = 281 [M + H]+. Intermediate 12: (7-chloro-3-methyl-3H-imidazo[4,5-b]plrldin-5-yl)-((R)-1cyclopropyl-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 atmosphere from NJ. After 5 minutes, methyl iodide (82 pL, 1.32 mmol, 1.5 eq) was added. The reaction was heated at 40°C for 18 h. The reaction was then diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The resulting crude product was purified by column chromatography (PE / EtOAc gradient elution from 20% to 80% EtOAc) to provide the desired product. LCMS: 15 m / z = 265 [M + H]+. Intermediate 14: Dibenzyl-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl}amlna IF-2019-17407397-APN-ANP#INPI130 Page 259 of 545 IF-2019-17407397-APN-ANP#INPI Page 260 of 545 Step 1:2,6-Didoro-3-nithm-pyridin~4~ylamine To 25 ml of concentrated H2SO4 in a round-bottom flask at -5°C was added 2,6-dichloro-plridin-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 equivalents) of nitric acid in 5 ml of H2SO4 were slowly added, keeping the internal T below 10eC. 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 NH3 to pH*4. The product was filtered and washed with ice water to obtain the desired product. LCMS: m / z = 209 [M + H]+. Step 2: Dibendf-(2,6~didoro-3-nitro-pindin~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 K2CO3 (16.6 g, 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. NaHCOs, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica chromatography (petroleum ether / EtOAc: 100 / 0 to 80 / 20) to provide the desired product. LCMS: m / z = 388 [M + H]+. Step 3: N4,N4-Dibencif-6-chloro-N2-met¡t-3-nitro-pyridine-2,4-diamine To a mixture of dibenzyl-(2,6-dichloro-3-nitro-pyridin-4-II)-amine (6.9 g, 17.8 mmol) and Cs2CO3 (5.8 g, 17.8 mmol , 1.0 eq) in THF (100 ml) MeNH2 (2N in THF, 8.9 ml, 17.8 mmol, 1 eq) was added at 0°C and the mixture was stirred at IF-2019-17407397-APN-ANP#INPÍ31 Page 261 of 545 IF-2019-17407397-APN-ANP#INPI Page 262 of 545 room temperature for 24 hours. Complete conversion was observed by LCMS. The volatiles were removed a! empty. The residue was dissolved in DCM and washed twice with water and brine. The organic layer was dried over NajSO^, filtered and concentrated under reduced pressure to provide the desired product which was used as such in the next step. LCMS: m / z = 383 [M + Hf Step 4: N4,N4~Dibenzyl~6~chloro-N2-methyl-pyridin~2t3,4~triamine To a solution of N4,N4-dibenzyl-6-chloro-N2-methyl-3-nitro-pyridine-2,4diamine (crude mixture, 15.5 mmol) in MeOH / THF (1:1) (100 mi) zinc (5.0 g, 77.5 mmol 5 eq) and NH4Cl (170 mg, 3.0 mmol, 0.2 eq) were added. The resulting mixture was stirred at rt. After overnight, the reaction was heated to 50°C until the reaction was complete by LCMS. The reaction was then cooled to room temperature and then filtered over celite. The filtrate evaporated. The residue was dissolved in DCM and washed with saturated NaHCCh. The organic layer was dried over Na2SO4. It was filtered and concentrated to obtain the desired product which was used as such in the next step. LCMS: m / z = 353 [M + H]+. Step 5: Dibenzii-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-amine (Intermediate 14) To a suspension of N4,N4-dibenzyl-6-chloro-N2-methyl-pyridine-2,3,4triamine (crude material, 15.5 mmol) in acetonitrile (100 ml) was added 20 triethyl orthoformate (5 .1 ml, 31 mmol, 2 eq) and the mixture was stirred at 80°C. After 18 h, LCMS showed complete conversion toward the desired product. The acetonitrile was removed in vacuo. The residue was dissolved in DCM and washed with sat. NaHCOa, dried over NajSO^, filtered and concentrated. The crude material was purified by silica chromatography (petroleum ether / EtOAc: 100 / 0 25 to 70 / 30) to obtain the desired product. LCMS: m / z = 363 [M + H]+. IF-2019-17407397-APN-ANP#INPÍ>32 Page 263 of 545 IF-2019-17407397-APN-ANP#INPI Page 264 of 545 Intermediate 15:4-amino-3-ethyl-5-fluorobenzonitrile From commercially available 4-amino3-fluorobenzonitrile [6306950-1], 4-amino-3-ethyl-5-fluorobenzonitrile was prepared in 2 steps according to WO2017012647 (intermediary 13, page 61). LCMS: m / z = 165 [M + Hf. Intermediate 16: 4-(7-dibenzylamino-3-methyl~3H~imidazo[4l5-b]pyridín~5~ Hamino)-3-ethyl-5-fluoro-benzonitrile Step 3: 4-(7-dibenzylamino-3-methyl-3H-Imidazo[4t5-b]pyridin-5-ylamino)-3-ethyl5-fluoro-benzonitrile Dibenzyl-(5-chloro-3-methyl-3H-imidazo[4,5-b]pyridín-7-yl}-amine (Int 14, 200 mg, 0.552 mmol, 1.0 eq), 4- amino 3-ethyl-5-fluorobenzonitrile (Int 15, 181 mg, 1.104 mmol, 2.0 eq), XantPhos Pd G3 (52 mg, 0.055 mmol, 0.1 eq), 1 eq), CS2CO3 (360 mg, 1.104 mmol, 2.0 eq), were mixed together under N2. Dry 1,4-dioxane (3 ml) was added and the mixture was stirred at 110°C for 18 h. reaction mixture was cooled to room temperature and quenched with H2O. Extraction was carried out with DCM. The organic layer was dried over Na2SO4, 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-metüpÍridin~2~carbonitrile IF-2019-17407397-APN-ANP#INPI133 Page 265 of 545 IF-2019-17407397-APN-ANP#INPI Page 266 of 545 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(PPhs) 4 (580 mgt0.5 mmol, 0.1 eq) were mixed in dry DMF (10 ml) under N2 and heated in a closed microwave tube at 150°C for 5 minutes under microwave irradiation. The reaction mixture was cooled to room temperature and poured into an aqueous NaHCOs solution. Extraction was carried out with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The crude residue obtained was triturated with Et2O to provide the desired product. LCMS: m / z = 134 [M + H]+. Intermediate 18:3-MetH-4-methylamine~benzonitrile A solution of 5-amino-4-methylpyridine-2-carbonitrile (Int 17, 1.0 g, 7.52 mmol, 1.0 eq) in dry THF (25 ml) under N2 was cooled to -78°C. LiHMDS (1M in THF, 7.52 ml, 7.52 mmol, 1.0 eq) was then slowly added. The resulting mixture was stirred at room temperature for 3 h, after which iodomethane (940 μΙ, 15.04 mmol, 2.0 eq) was added dropwise. The mixture was stirred at room temperature for 18 h. It was then quenched with 1 ml of water and concentrated to dryness. The crude material obtained was purified by column chromatography (acetone / petroleum ether, 1:3) to provide the desired product. LCMS: m / z = 148 [M + H]+. Intermediate 19:4-Amino-3-cyclopropyl-5-fluoro-benzonitrile IF-2019-17407397-APN-ANP#INPI134 Page 267 of 545 IF-2019-17407397-APN-ANP#INPI Page 268 of 545 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) TFA (680 pL, 8.84 mmol, 0.3 eq) was added. The reaction mixture was stirred at room temperature for 24 h. It was then quenched with a saturated NaHCOa solution, followed by extraction with DCM. The resulting organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to provide the desired product. This was used as such in the next step. LCMS: m / z = 263 [M + H]+. Step 2:4-Amino-3-cycloprop¡l-5-fIuor-benzonitri!o 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 N2 at room temperature and cyclopropylzinc bromide (0.5 M 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, taken up in DCM, overlaid on silica, and purified by column chromatography (EtOAc / petroleum ether, gradient elution from 15 % EtOAc up to 30% EtOAC) to provide the desired product LCMS: m / z =177 [M + H]+. Intermediate 20:5-Amino-4-ethyl-pyridín-2-carbonátrile IF-2019-17407397-APN-ANP#INPI135 Page 269 of 545 1; IF-2019-17407397-APN-ANP#INPI Page 270 of 545 5-Amino-4-methylpyridine-2-carbonitrile was prepared from 6-Bromo-4ethyl-pyridin-3-ylamine (CAS [929617-29-8]) as described in the patent WO2017012647 (page 55). LCMS: m / z = 148 [M + H]+. Intermediate 21:5-hydroxy-4-methi!pyrid¡n-2-carbon¡tri!o A mixture of 5-bromo-2-cyano-4-methylpyridine (CAS [886364-86-9], 26.8 g mg, 136 mmol, 1 eq), 4,4,4',4',5,5 ,5,,5'-octamethyl-2,2-bi(1,3,2dioxaborolane) (CAS [73183-34-3], 48.4 g, 190 mmol, 1.4 eq), Pd (dppf)CL2 .CH2CL2 (5.55 g, 6.80 mmol, 0.05 eq), potassium acetate (40 g, 408 10 mmol, 3 eq) were stirred under N2 in 1,4-dioxane (500 ml) for 2 hours at 110°C. The reaction mixture was then cooled to 0°C before dropwise addition of 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 3 times with DCM. The combined organic extracts were dried and evaporated in vacuo. The resulting crude product was purified by column chromatography (ΡΕ / EtOAc gradient elution from 30% to 50% EtOAc). The material obtained was triturated with pentane and diethyl ether to provide the desired product. Intermediate 22: 5-amino-pyridine-220 carboxylic acid (2-hydroxy-propyl)~amide Step 1: 5-nitro-pyridine-2-carboxylic acid (2-hydroxy-propH)-amide IF-2019-17407397-APN-ANP#INPI136 Page 271 of 545 IF-2019-17407397-APN-ANP#INPI Page 272 of 545 A methyl ester solution of! 5-nitro-pyridine-2-carboxylic acid (CAS [29682-14-2], 1.0 g, 5.49 mmol, 1.0 eq) and 1-amino-propan-2-ol (CAS [ 76-96-6], 472 pl, 6.04 mmol, 1.1 eq) in dry EtOH (15 m!) under N2 was stirred at 110°C in a sealed tube. After overnight, it was cooled to room temperature and concentrated to dryness and the crude residue was purified by column chromatography (EtOAc / petroleum ether, gradient from 50% to 80% EtOAc) to give the desired product. LCMS: m / z = 226 [M + H]+. Step 2: 5-amino~pyridine~2~carboxylic acid (2-hydroxyhyropil)-amide A suspension of 5-nitro-pyridine-2carboxylic acid (2-hydroxy-propyl}-amide and Pd / C in MeOH under N2 was placed under H2 atmosphere. Then it was stirred at room temperature. After 3 h, the reaction was stopped and filtered over coarse Pall-Seitz filter paper. The resulting cake was washed with MeOH and the filtrate was concentrated to dryness to give 1.08 g of colorless oil. It was suspended in H2O and lyophilized to give the product. desired LCMS: m / z = 196 [M + H]+. Intermediate 23:2-fluor-6-methyl--4-methylsulfonyl-phenol Step 1:2-bromo-6-fluoro-4-methylsulfonyl-phenol A mixture of 2-fluoro-4-methylsulfonyl-phenol (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 BR2 (0.812 ml, 15.7 mmol, 1 eq) was added dropwise. The mixture was stirred for 30 minutes at 0°C, then IF-2019-17407397-APN-ANP#INPI137 Page 273 of 545 IF-2019-17407397-APN-ANP#INPI Page 274 of 545 was concentrated and the precipitate was filtered to give the desired product. LCMS: m / z = 269.18 [M + H]. Step 2: 1-fluoro-2-(methoxymethoxy)-3-bromo-5-methylsulfonyl-benzene. Chloromethyl methyl ether (107-30-2, 0.87 ml, 11.45 mmol, 1.1 eq) was added dropwise to the 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 was stirred at room temperature overnight. Then, the reaction mixture was washed with water and the isolated organic layer was dried and evaporated to obtain a 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.1H NMR (300 MHz, DMSO-de) δ ppm 8.02-7.98 (m, 1H), 7.91 (dd, J, = 10.7Hz, J2= 2 ,1 Hz, 1H), 5.31 (s, 2H), 3.52 (s, 3H), 3.30 (s. 3H). Step 3:1-fJuor-2-(methoxymethoxy)-3-methyl-5-methyl!sulfonyl-benzene The reaction was performed on a 2 x 1.4 g scale in parallel microwave vials. 1-Fluor-2-(methoxymethoxy)-3-bromo-5-methylsulfonyl-benzene (2.8 g, 8.9 mmol, 1 eq) and CS2CO3 (8.74 g, 26.8 mmol, 3 eq) were suspended in dioxane (34 ml) and the reaction mixture was purged with argon for 10 minutes in a microwave vial. The catalyst Pd(dppf)CLz.DCM (1.638 g, 1.8 mmol, 0.2 eq) and methylboronylco acid (CAS [13061-96-6], 803 mg, 13.4 mmol, 1.5 eq) were added to the reaction mixture and the reaction was sealed. The reaction is 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 obtain 5.8 g of crude product. The crude product was purified by column chromatography using a IF-2019-17407397- APN-ANP#INPI138 Page 275 of 545 IF-2019-17407397-APN-ANP#INPI Page 276 of 545 gradient of MeOH in DCM (0% to 5% MeOOH) providing the desired product. LC-MS: m / z = 249 [M + H]. Step 4:2-fluor-6~methyl-4-methylsulfonyl-phenol 1-Fluor-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 (2 mi) were added. The reaction was stirred at room temperature for 2 h. The reaction mixture was then evaporated to dryness to obtain a crude product. The crude product was dissolved in EtOAc and precipitated with cyclohexane. The precipitate was filtered and dried to obtain the desired product. LCMS: m / z = 205.33 [M + HJ.1H NMR (300MHz, CDCI3) δ ppm 7.55-7.50 (m, 2H), 5.74 (d, J = 5.4Hz, 1H) , 3.01 (s, 3H), 2.33 (s, 3H). intermediate 28: (7~cioro~3-methii~3H~imidazo[4,5-b]pyridin-5-yl)-(1-cyclopropyl2,2,2-trifluoro-ethyl)-amine Int 1 (450 mg, 1.53 mmol, 1.0 eq.), Cul (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 dimethoformamide (2 mL), then 1-cyclopropyl-2,2, 2-trifluoretan-1-ol (CAS [1993-77-7], 858 mg, 6.13 mmol, 4.0 eq) was added and the mixture was heated to 80°C. The reaction was diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The resulting crude product was purified by column chromatography (ΡΕ / EtOAc gradient elution from 20% to 80% EtOAc) to provide the desired product. LCMS: m / z = 306 [M + H]+. IF-2019-17407397-APN-ANP#INPI139 Page 277 of 545 IF-2019-17407397-APN-ANP#INPI Page 278 of 545 Intermediate 32: amino-pyridine-2-carboxylic acid ethylamide A 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 N2. The mixture was placed under an H2 atmosphere. It was then stirred at room temperature. After 3 h, the mixture was filtered. The resulting cake was washed with MeOH and the filtrate was concentrated to dryness to provide the desired product. LCMS: m / z = 166 [M + H]+. Intermediate 48: 7-chloro-5-(1-cyclopropyl-ethoxy¡)-3-methi!-3H-ímidazo[4t5bjpyridine An ice-cold solution of Intermediate 57 (225 mg, 1.23 mmol, 1.0 eq.), tri-n-butylphosphine (460 pL, 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 for 10 minutes. Then, azodicarboxylic dimorpholide (CAS [10465-82-4], 472 mg, 1.84 mmol, 1.5 eq) was added at 0°C. The reaction was allowed to warm to room temperature and stirred for 18 h. Mixture diluted with EtOAC and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The resulting crude product was purified by column chromatography (PE / EtOAc gradient elution from 20% to 80% EtOAc) to provide the desired product. LCMS: m / z = 252 [M + Hf. Intermediate 50: N-ethyl-4-methyl-pyridine-3-carboxamide IF-2019-17407397-APN-ANP#INPÍ>40 Page 279 of 545 IF-2019-17407397-APN-ANP#INPI Page 280 of 545 2-Amino-4-methyl-5-pyridinecarboxylic acid (CAS 179555-114, 250 mg, 1.64 mmol, 1.0 eq.) was mixed with HATU (686 mg, 1.80 mmol, 1.1 eq.) , DIPEA (857 pL, 4.92 mmol, 3.0 eq) and DMF (1.0 M). The mixture was stirred for 5 minutes at room temperature, EtNH3Cl (201 mg, 2.5 mmol, 1.5 eq) was added and stirring was continued overnight. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 ml), saturated aqueous NaHCO3 solution (10 ml) and brine again (10 ml). The organic layer was then dried and evaporated in vacuo to provide 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-methylimidazo[4,5-b]pindin-7-yl]aminoJ-2-methi acid !-pyrid¡n-3-carboxylic Int 51 (550 mg, 1.1 mmol, 1.0 eq) and Lil (573 mg, 4.3 mmol, 4.0 eq) were suspended in anhydrous pyridine (5 ml) under a N2 atmosphere and heated until 115°C for 48 h. Then, the reaction mixture was evaporated in vacuo and the residue was suspended in a saturated aqueous solution of NaaCOs 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 provide the desired product. LCMS: m / z = 416 [M + H]+. IF-2019-17407397- APN-ANP#INPÍ41 Page 281 of 545 IF-2019-17407397-APN-ANP#INPI Page 282 of 545 Intermediate 53:5-((S)-3-methyl-4-morpholinyl)-2-pyridinamine HzN Br ft, R' A reaction vial was charged with 2-amino-5-bromopyridine (CAS [107297-5], 250 mg, 1.45 mmol, 1.0 eq), (S}-3-methylmorpholíne (CAS [350595-57- 2], 246 μΙ, 2.17 mmol, 1.5 eq) and RuPhos Pd G3 (61 mg, 0.073 mmol, 0.05 eq). 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 then quenched with a few drops of MeOH. crude was purified by chromatography (DCM / MeOH 95 / 5 Socratic elution) to give the desired product LCMS: m / z = 194 [M + Hl*. Intermediate 54:5-((S)-3-methyl~4~morpho!ynyl)-2-pyridinamine NiCL2.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. Next, 2-(Boc-amino)-5-bromopyridine (CAS [159451-66-8], 204 mg, 0.75 mmol, 1.0 eq), (tetrahydro-2H-pyran-4-yl ) potassium trifluoroborate (CAS [1279123 -50-0], 152 mg, 0.79 mmol, 1.05 eq), 2,6-lutidine (140 pL, 1.2 mmol, 1.6 eq) and [Ir {dFCFappyhíbpyJJPFe (24 mg, 0.023 mmol, 0.03 eq) were added in succession. The mixture was stirred until all solids were dissolved, after which anhydrous 1,4-dioxane (12 ml) was added and stirred overnight at room temperature under irradiation with blue light (Kessíl KSH150B LED Grow Light 150, Blue, 34W). Notes: the vial is IF-2019-17407397-APN-ANP#INPI142 Page 283 of 545 IF-2019-17407397-APN-ANP#INPI Page 284 of 545 placed in a crystallization dish containing water. Air flow was applied to keep the reaction below 20°C. The distance between the vial and the lamp was approx. 5cm. The distance between the funnel (air flow) and the vial was approx. 5cm. 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 resulting crude product was purified by column chromatography (petroleum ether / EtOAc 8 / 2 to 1 / 1) to provide the desired product. LCMS: m / z = 279 [M + H]+. Intermediate 56:3-chloro~&~(1~met¡lazetÍd¡n-3~yl)oxypyridazine To a solution of 1-methylazetidin-3-ol (CAS [111043-48-2], 250 mg, 1.68 mmol, 1.0 eq) in anhydrous THF (4 ml) was added NaH (101 mg , 2.52 mmol, 4.5 eq, 60% in mineral oil). The mixture was stirred at room temperature for 10 min and subsequently heated to 50°C for another 10 min. It 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 hours at room temperature. . Then, the mixture was added dropwise to a stirred NaHCO3 solution (10 ml of saturated solution + 10 ml of water) and extracted with DCM (3x10 ml). The combined organic extracts were dried and evaporated in vacuo to provide the desired product. LCMS: m / z = 200 [M + H]+. Intermediate 57: 7-chloro-3-methyl-3H-imidazo[4,5-b]pindin-5-ol IF-2019-17407397-APN-ANP#INPÍ43 Page 285 of 545 IF-2019-17407397-APN-ANP#INPI Page 286 of 545 Intermediate compound 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 eq ) were mixed in 1,4-dioxane (40 ml) after which H2O (3.68 ml, 204.80 mmol, 10 eq) was added. The mixture was stirred at room temperature. After overnight, the reaction mixture was quenched with H2O 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 MgSO4, filtered and concentrated to dryness to provide the desired product. LCMS: m / z =184 [M + HJ*. Intermediate 61: 6-[5-(6-cyano-4-methi!-pyridín-3-yloxy)-3-met¡f-3Himidazo[4,5-b]pyridin-7-ylamino] acid -nicotinic Intermediate 60 (1.24 g, 3.0 mmol, 1.0 eq) and Lil (1.20 g, 9.0 mmol, 3.0 eq) were suspended in anhydrous pyridine (10 mL, 0.3 M ) in a N2y atmosphere were heated to 115°C for 2 days. The reaction mixture was then evaporated in vacuo and the residue was suspended in a saturated aqueous solution of Na2CO3 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 provide the desired product. LCMS: m / z = 402 [M + H]+. Intermediate 63: 6-[5-(6-cyano-4-methyl-pyridin-3-yloxy)-3-methi!-3Himidazo[4,5-b]pyridín-7-ylamÍno]-pyridaz¡n acid -3-carboxylic IF-2019-17407397-APN-ANP#INPÍ44 Page 287 of 545 IF-2019-17407397-APN-ANP#INPI Page 288 of 545 Intermediate 62 (1.24 g, 3.0 mmol, 1.0 eq) and Lil (1.20 g, 9.0 mmol, 3.0 eq) were suspended in anhydrous pyridine (10 mL) under N2y atmosphere. They were heated to 115°C for 48 h. The reaction mixture was then evaporated in vacuo and the residue was suspended in a saturated aqueous solution of Na2CO3 and EtOAc. The EtOAc phase was discarded and the pH of the aqueous phase was adjusted to a pH between 5 and 6. The resulting precipitate was filtered and dried overnight under vacuum at 50°C to provide 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) 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 18h. The reaction was then diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo to provide the desired product. LCMS: m / z = 179 [M + Hf. Intermediate 84:6-amino-pyridin-3-yl)-(4-methyl-p¡peraz¡n-1-yl)-methanone IF-2019-17407397-APN-ANP#INPI145 Page 289 of 545 IF-2019-17407397-APN-ANP#INPI Page 290 of 545 6-amino-nicotinic acid (CAS [3167-49-5], 19.6 g, 142 mmol, 1.0 eq), N-methyl-piperazine (CAS [109-01-3], 19 m!, 170 mmol, 1.2 eq) and DIPEA (54 ml, 313 mmol, 2.2 eq) were stirred in dry EtOH (250 ml) before the addition of HATU (81 g, 213 mmol, 1.5 eq). The mixture was stirred at room temperature for 18 h, then concentrated. A solid appeared which was filtered and discarded. The filtrate was purified by column chromatography using DCM / EtOH / 25% aqueous NH3 (in a ratio of 7 / 1 / 0.1) as eluent to provide 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 similar to Intermediary 1. Step 3:4-cyoro-6-iodo-N2-(trideuteriometH)pyridín-2,3-diamine 2,4-Dichloro-6-iodo-pyridin-3-amine (10 g, 0.03 mmol, 1 eq) was dissolved in n-butanol (150 ml) in an autoclave (300 ml). Methyl-d3amine 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 N2 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 in the next step as such. LCMS; m / z = 287 [M + H]. Step 4:7~chloro~5~iodine~3~(trideuteriomethyl)imidazo[4,5~b]pyridine Trimethyl orthophonniate (10 mL, 0.09 mmol, 3 eq). The mixture was stirred at 60°C for 1 h. The IF-2019-17407397-APN-ANP#INPI146 Page 291 of 545 IF-2019-17407397-APN-ANP#INPI Page 292 of 545 reaction was concentrated to dryness, the residue was diluted with DCM and quenched with a saturated aqueous NaHCCb solution. After extraction with DCM, the organic layer was dried over NajSC^, filtered and concentrated to dryness to provide a crude material. Purified by column chromatography using cyclohexane / EtOAc eluent, gradient from 0 to 70% EtOAc to provide the desired product. LCMS: m / z = 297 [M + H]. Intermediate 86: 5-[(7-chloro-3-methyl-imidazo[4,5-b]pyridin-5-yl)-cyclopropylamino}~4~methyl~pyridina~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 CS2CO3 (106.44 mg, 1 0 mmol, 2 eq) was suspended in DMF (5 ml) in a round bottom flask equipped with drying tube and 4A 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 80eC for 10 minutes. After 10 minutes, the hot solution was added to the suspension of compounds in DMF. The reaction mixture was stirred overnight at room temperature. After stirring overnight at room temperature, the reaction temperature was raised to 55°C, the reaction was stirred overnight at 55°C. The reaction was cooled, water was added and the suspension obtained was extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and evaporated to obtain a crude product. The crude product was purified by chromatographic separation using 0-25% IF-2019-17407397-APN-ANP#INPÍ47 Page 293 of 545 IF-2019-17407397-APN-ANP#INPI Page 294 of 545 (10% MeOH / DCM) in a DCM system to obtain the desired product. LCMS: m / z = 340 [M + H]. Intermediate 87:4~ethif-5-~hydroxy-pyridin-2-carbonitrile Step 1:4-ethyl-5-iodine-pin’din-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 a aqueous solution (3 ml) of sodium nitrite (0.518 g, 7.5 mmol, 1.1 eq). The reaction mixture was allowed to stir at 0°C for 15 minutes, after which an aqueous solution (5 ml) of potassium iodide (1.24 g, 7.5 mmol, 1.1 eq) was added. The reaction mixture was continued to stir at room temperature for 1 h. The reaction mixture was then 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 crude product obtained was purified by column chromatography (cyclohexane as solvent A and cyclohexane: ethyl acetate = 5:1 as solvent B gradient from 0-100% solvent B). . The fractions containing the product were combined and evaporated to provide the desired product. LCMS: m / z = 259 [M + H]. Step 2:4-ethyl!-5-hydroxy-pyrid¡n-2-carbonitrile The reaction was carried out in 2 microwave containers. Bis(pinacolato)diboron ( 1.9 g, 7.49 mmol, 1.4 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed with dichloromethane (0.441 g, IF-2019-17407397-APN-ANP#INPÍ*48 Page 295 of 545 IF-2019-17407397-APN-ANP#INPI Page 296 of 545 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 minutes at 150°C. The reaction mixtures were cooled to 0°C, after which a hydrogen peroxide solution (30% w / w 3.28 ml, 32.1 mmol, 6 eq) was slowly added. The reaction mixture was continued to stir at room temperature for 18 h. 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 provide the crude oil. Purification is performed by column chromatography using cyclohexane as solvent A and cyclohexane:ethyl acetate = 1:1 as solvent B (gradient 0-100% solvent B) to provide the desired product. LCMS: m / z = 149.05 [M + H]. Intermediate 89: 5-[7-chloro-3-(trideuteriomethyl)imÍdazo[4,5-b]pyridin-5-yl]oxy-4methyl-pyridin-2-carbonitrile Intermediate 85 (2.1 g, 7.1 mmol, 1.0 eq), Intermediate 21 (1.43 g, 10.6 mmol, 1.5 eq), Cul (270 mg, 1.42 mmol, 0, 2 eq), TMHD (3.0 mL, 14.2 mmol, 2 eq) and CS2CO3 (4.61 g, 14.2 mmol, 2 eq) were mixed in air, DMF (12 mL) was added and the mixture It was stirred at 85°C for 72 h. The mixture was then cooled to 0°C. The resulting thick paste was filtered and the cake was washed with ice-cold DMF. It was then washed with ice-cold MTBE. After the cake was dried, it was suspended in 25 ml of 10% TMEDA aqueous solution. Stirred for 2 h, filtered and the cake was washed with water to give the desired product. LCMS: m / z = 303 [M + H]+. IF-2019-17407397- APN-ANP#INPÍ49 Page 297 of 545 IF-2019-17407397-APN-ANP#INPI Page 298 of 545 Intermediate 92: 4-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-3,5difluoro-benzonitrile N A mixture of Int 57 (300 mg, 1.63 mmol, 1 eq), 3,4,5-trifluorobenzonitril ([134227-45-5], 300 mg, 1.63 mmol, 1 eq), K2CO3 (452 ​​mg , 3.26 mmol, 2 eq) in NMP (3 ml) were heated for 18 hours at 100°C. The reaction was then diluted with EtOAc and washed with brine. The combined organic extracts were dried and evaporated in vacuo. The resulting crude product was purified by column chromatography (PE / EtOAc 50 / 50 to 0 / 100) to provide the desired product. LCMS: m / z = 321 [M + H]+. Intermediate 93: (6-bromo-3-pyridyl)-[2,2,3,3,5,5,6,6-octadeuterium-4(tride uteriomethyl)pipe razin-1-yl] metanone Step 1: tert-butif-4-(6-bromopyridin-3-carbonyl)-2,2,3,3,5,5,6,6-octadeuteriopiperazin-1-carboxylate A mixture of 6-bromonicotinic acid ([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 EtsN (0.93 ml, 6.7 mmol, 2 eq) in DCM (15 ml) were stirred for overnight at room temperature. The mixture was then diluted with DCM and extracted twice with saturated aqueous NH4Cl solution. The resulting organic layer was evaporated to provide an oil. He IF-2019-17407397-APN-ANP#INPÍ50 Page 299 of 545 IF-2019-17407397-APN-ANP#INPI Page 300 of 545 resulting oil was purified by column chromatography (DCM / MeOH 100 / 0 to 98 / 2) to provide the desired product. Step 2: (6-bromo-3-pyridyl}-(2r2,3,3,5,5,6,6-octadeuteriopiperazin-1-yl)methanone Tert-but¡l^-(6-bromopyridin-3-carbon¡l}-2,2,3l3,515(6,6-octadeuteriopiperazin-1-carboxylate (1.1 g, 2.9 mmol, 1 eq) was mixed with 4 M HCl in dioxane solution (7 ml, 29 mmol, 10 eq) in dioxane (20 ml). A small amount of water was added to improve the overall solubility. Once the reaction was complete, the mixture was concentrated. to dryness to provide the HCl salt of the desired product. Step 3: (6-bromo-3-pyridyl)-[2,2,3,3,5,5,6,6-octadeuterium-4(trideuteriomethyl)piperazin-1-yl]methanone The HCl salt of (6-bromo-3-pyridyl)-(2,213,315,5,6,6-octadeuteriopiperazin1-1)methanone (300 mg, 0.96 mmol, 1 eq.) was mixed with NaH (115 mg, 2.88 mmol, 3 eq) in THF (6 ml). The resulting mixture was stirred at room temperature for 30 min. Then,idomethane-da (60 pl, 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 provide the desired crude product which was used as such. Table II. Intermediaries towards compounds Illustrative of the invention. Int Structure Name SM Method PM Month 1 Cl 7-Cloro-5~iodo-3methyl-3H-ImÍdazo[4,5bjplridine CAS (2587-022] Exemplified 293 294 IF-2019-17407397- APN-ANP#INPI151 Page 301 of 545 IF-2019-17407397-APN-ANP#INPI Page 302 of 545 Int Structure Name SM Method PM Month 2 ΐ' Λχ Λα 5—(7—Cio ro—3—m ethyl— 3H-ímidazo[4,5b]pyridín-5-yloxyÍ)-4metif—pyridín—2— carbonitrile intl Exemplify do 300 300 3 λΧΧΧ> 5-(7-Amino-3-methyl3 H-i m idazo [4,5-b] pyridin—5-yloxy)—4methyl-pyridyrk-2carbonitrile lnt2 Exemplified do 280 281 4 \X¿Q 5— (7—Chloro—3—methyl— 3H-imidazo[4,5-b]pyridin-5-ylamino)—4methyl-pyridin-2carbo nitrile Int 1, Int 17 Exemplified 299 299 5 CI 1 XXJUO 1 ​​' 5-[ (7-Chloro-3-methyl3H-imidazo[4,5-b]pyridin- 5-11)—methylaminoJ-4-methylpyridin-2-carbonitrile Int 1, Int 18 Exemplified 313 313 6 ζ ο ό * ιζ =0 “2 -Ο (±)—4—[(7—chloro—3— methiWmidazo^Sb]pyridin-5-yl)amino] cyclohexancarbonitrile Int 1, [87353733-8] B3 290 290 7 CI ΟίΛ' 7-chloro- N-{3,3~ dimethyltetrahydropyran4-i l)-3-m ethyl l-imide zo [4,5-bJpyridin-S-amine Int 1, [140058054-2] B3 295 295 8 Ζ^ Ζ'''* _ Η ο—(' ζ \=< Ζ— (7-Chloro-3-methyl-3Himidazo[4,5-b]pyridinS-ylHnetiHíSHWtrimethyl-propyl)-amine Int 67 Exemplified 280 281 IF-2019-17407397-APN-ANP#INPÍ 52 Page 303 of 545 IF-2019-17407397-APN-ANP#INPI Page 304 of 545 Int Structure Name 5M Method PM Month 9 Cl NC H \ (±HlR3R)-3-[(7-chloro -3-methyl-4midazo[4,5b] pyridin—5-yljamino] cyclohexancarbonitrile Int 1, [92096630-9 ] B3 290 290 10 Cl z*^v-*N XXw P ' 4-[(7-cforo-3-methylimldazo[4,5-b]pyridin5-yl)amino}-3cyclopropi 1-5-fluoro rbenzonitrile Inti , Int 19 B3 342 342 11 a Y1 JD> YSrVS JH ' 5—{(7-chloro—3—methyl— imidazo[4,5-b]pyridin5-yl)amIno]-4-ethylpyridin-2-carbonitrile Int 1 , Int 20 B3 313 313 12 C! A_N 1Ώ? V 1 \ (7-Chloro-3-methyl-3 Himidazo[4,5-b]pyridin5-iIH(RHcyclopropyl-ethiiy-methylamine Int 65, [6240-966] Exemplified 264 265 13 IZ vra ^2^,2 (±)-7-c!oro-3-methyl-N[(3R,4S)-3-methyltetra hydropyran—4-yl]imidazo [4,5-b ]pyridin-5-amlna Int 1, [168265557-7] B3 281 281 14 Bn Bn N jTT'> ci^n-^-n Dibenzyl-(5-chloro-3metik3H-4midazo [4,5b]pyridin-74l} -amine [2587-0221 Exemplified 362 363 15 NC>rX^F TJC. 4-a m ino-3-ethyl-5fluorobenzonitrile [6306950-1] Exemplified 164 165 IF-2019-17407397-APN-ANP#INPI153 Page 305 of 545 IF-2019-17407397-APN-ANP#INPI Page 306 of 545 Int Structure Name SM Method PM Month 16 Bn^kl,Bn N 4-(7-Dibenzylamino-3methyl-3 H-imidazo[4,5b]pyridin—5-¡lamino}-3ethyl—5-fluorobenzonitrile Int 15, Int. 16 Exemplified 490 491 17 nc n 5-amino-4methylpyridine-2carbonitrile (15611816-0] Exemplified 133 134 18 NC N 3-Methyl-4-methyllaminobenzonitrile Int 17 Exemplified 147 148 19 NC>*r^^ F Υ^νη2 4-Amino-3-cyclopropyl5-fluoro-benzonitrile (6306950-1] Exemplified 176 177 20 NC N 5-Amino-4-ethylpyridin—2-carbonitrile [92961729-8] Exemplified 147 148 21 NCxV^ N^ Y^OH 5-h id roxy-4-methi 1 pi ridin-2-carbo nitrile (88636486-9] Exemplified 134 135 22 O αΛυ H Jj °” HjN (2- Hydroxy-propyl)amide of 5Amino acid -pyridyrv-2carboxylic [2968214-2], [78-96-6] Exemplified 195 226 23 9 ..o χω 205 IF-2019-17407397- APN- A API API154 Page 307 of 545 IF-2019-17407397-APN-ANP#INPI Page 308 of 545 Int Structure Name SM Method PM Month 24 Cl H\N-(3- biddo[l.l.l] pentanyl}-7-dort>-3methyl-i midazo[4,5-b]pyridin-5-amine Inti, [2287-350 ] B3 249 249 25 Cl °Cl S-'St'SX^n 7-doro-3-methyl-N-(3m eti Itetra hydro py ra n-4yl)imidazo[4,5b]pyridin-5-amine Inti , [178790612-0] B3 281 281 26 Cl TjTX'> V H \ 7-chloro-N-¿lddopropyl-2,2,2trifl uor-ethyl)-3-methi ΙΙ mida zo [4,5-b] pi rid i n5-amine Inti, [7570299-7] B3 305 305 27 z^z-'* zx □ 7-clo ro-3-m eti 1-N-(5oxaspiro[3.5]nonan-8yl)imidazo[4,5b ]pyridin-5—amine Int 1, [130943430-7] B3 307 307 28 Cl F F ' 7-Chloro-5-{lddopropyl-2,2,2trifl uor-ethoxy)-3-m ethyl— 3H-4midazo[4 ,5bjpyridine Int 1, [1993-777] Exemplified 305 306 29 ^X o=Z ζ^Λ * / 2 \ z A2 166 167 30 0 JÍJJ H OH 6-Amino-N-(2hydroxy-propyl)— nicotinamide [23195814-8]y [78-96-6] A2 195 196 IF-2019-17407397-APN-ANP#INPÍ 55 Page 309 of 545 IF-2019-17407397-APN-ANP#INPI Page 310 of 545 Int Structure Name SM Method PM Month 31 O N'V^N'V' ULJ h OH h2n^^ (2-H idroxy-pro pi 1)6amino-pyridazine-3carboxylic acid amide [30154808-3] and 178-9& -6] A2 167 168 32 0 JI J H η2ν^^ 5Amino-pyridine-2carboxylic acid ethylamide [143779442-7] Exemplified 165 166 33 H N^N N-p-Methoxh-ethyl}pyri midin-4,6-diamine [5305 -59- 9] and [10985-3] Pl 168 169 34 H H^x / ^v'Nk / \z°s. Ύ Ί N^N N-(3-Methoxy-propyl}pyrimidin-4,6-diamine [5305-599]y [5332-730] Pl 182 183 35 H ii ίΓ Γοη N^N 1 Wn 4-(6- Amino-pyrimidin4-ílamino}-2-methylbutan-2-ol [5305-599]y [2673408-7] Pl 196 197 36 mino Hpropa n-1o! -599] Y [8827783-2] Pl 210 211 38 \ O 0 z I N-(3-MetoxH cyclobutyl}—pyrimidin— 4,6-diamine [5305-559] y [123461598-5] Pl 194 195 IF-2019-17407397-APN-ΑΝΡ#ΙΝΡΪΐ 56 Page 311 of 545 IF-2019-17407397-APN-ANP#INPI Page 312 of 545 Int Structure Name SM Method PM Month 39 H - O h η ί T N^N । 4-(6-Amino-pyrimidin4-1 lam i no)-but uta n-2-ol 15305-599]y [3988448-51 Pl 182 183 40 1 n | n'n^nh2 6-(3Dimethylaminomethylazetidin-1-ÍI)pyridazin-3-ylamine [18797360-0] and [32189022-6] P2 207 208 41 <1 Ί n 'N^NH2 (±H-((3R3SHA5- Trimethyl-piperazirv-liy-p>ridazin-3-ylamine [187973600] and [14753961-5] P2 221 222 42 T* o d 0 z X K» 6-(4-(2,2,2-TrifIuoretil) —pfperazin—1—yl]— pyridazin-3-ylamine [18797360-0] and [13349901] P2 261 262 43 °^Ί ii Ί N <L 'ν^Ίμη2 (1)-6-( (2 R,6S}-2,6Dimethyl-morpholine-4-41)pyridazin-3-YlamÍn [18797360-0] and [6485-558] P2 208 209 44 «Μ X X 0 / -Z O—< 6-((S)-2- Methylmo rfol in-4-41 )pyridazirb-3-ylamine [18797360-0] and [7457213-7] P2 194 195 45 0 0 z -0] and [4395-986] P2 203 204 IF-2019-17407397-APN-ANP#INPl57 Page 313 of 545 IF-2019-17407397-APN-ANP#INPI Page 314 of 545 Int Structure Name 5M Method PM Month 46 Cl Ϊ IX'> 1 H ' (7—Clo ro—3—m eti 1—3 H— imidazo[4,5-b]pyridin5—i 1)—(2—methyl— 1— trifluoromethyl—propyl)— amine Int 1, (1582-189] B3 307 307 47 NHBoc “ Ί IT 5-(7-[4—(N—Bo c— aminomethyl)anilino]-3methyl-imidazo[4,5bjpyridin —S—HJoxl·—4— methyl-pyridin-2carbo nitrile Int 1, [9483855-8] Bl 485 486 48 Cl Y ^o-^n^n 7-Chloro-5-(lcyclopropyl-ethoxy)-3methiF- 3 H-imidazo[4,5~ bjpyridine Int 57 Exemplified 251 252 49 Oh jíj CFs 4-Methyl-5—(3-methyl-7[[542,2,2-trifluoro-lhydroxl—ethyl}—2—pyridyl ]amino]imidazo[4, S—b]pyridin—5—yljoxy— pyridyrh-2-carbonitrile Int 3, [118847781-7] B3 455 456 50 iSAc- H2i\r>r Λ / —ethyl—4—methyl— pyridine— 3-carboxamide [17955511-4] Exemplified 179 180 51 0 'ÓX ^N^NH 6—[[5—[(6-Cyano—4— nnetil—3—pyridyljoxy]—3— m ethyl-imidazo Methyl [4,5bjpyridin—7—yl]amino]—2-methyl-pyridin-3carboxylate lnt2, [87235552-7] Bl 429 430 IF-2019-17407397-APN-ANP#INPfl 58 Page 315 of 545 IF-2019-17407397-APN-ANP#INPI Page 316 of 545 Int Structure Name SM Method PM Month 52 x^n^nh Acid 6—[[5—[(6—cyano— 4-methyl-3-pyridyljoxy}3-methiHmidazo[4,5bjpyridin-7-yljamino}2-methyl- pyridine-3— carbox Hico Int 51 Exemplified 415 416 53 BocHN^hr AMJoc-5-(tetrahydro2H-pyra n-4-yl) pi ridi n2-amine [15945166-8], [127912350-0] Exemplified 278 279 55 0-1 \ H z <N X 5-{tetrahydro -2Hpyran-4-yljpyridin- 2amine Int 54 DI 178 179 56 JC N Vn^ CI^N* 3-chloro-6-(lmethylazetidin-3yl)oxrpyridazine [11104348-2], [141-300] Exemplified 200 200 57 Cl jQCx> hct^n^n 7-Chloro-3-meti 1-3 HImidazo [4,5-b] pi rid i n5-ol Inti Exemplified 184 184 58 Z^Z^ - H °-Q (7— Go ro—3—methyl·-3 H— i midazo [4,5—b] py rid in5-i IH 1-cyclobutyl-ethyl)amine Int 1, [6063796-9] B3 264 265 IF-2019-17407397-APN-ANP#INPI159 Page 317 of 545 IF-2019-17407397-APN-ANP#INPI Page 318 of 545 Int Structure Name SM Method PM Month 59 Cl (7-€lo ro-3-m eti 1-3 Himldazo[4,5-b]plridin5—yl}—dicyclopropylmethyl— amine Int 1, [1337529-6] B3 276 277 60 °=< 2CXO >—r ' Γ 6[5—(6—Cia no-4-methylplridin-3-yloxl}-3methyl-3 H-innidazo[4,5b]pyridln-7-ylamino] acid methyl ester nicotlnico Int 2, [3605224-1] Bl 415 416 61 H0 ifjL Acid 6-[5-{6-Cyano4-methi 1—pyrid i n-3yloxy)-3-methi 1-3 Himldazo[4,5-b ]pyridin7-ylamino]-nicotinylco Int 60 Exemplified 401 402 62 ki Ju5 6[5-{&-Cyano-4-methylpyrldin—3-yloxy)-3methyl-3 H-imidazo acid methyl ester [4,5 — b]pyridin-7-ylamino}pyridazio-3-carboxnico Int 2, [9814096-6] Bl 416 417 63 KoAjAi M '^^NH ΎιΛ^ 6-[5—(6-Cyano4-πΊεΙΙ1-ρΐΓίύΙη-3yloxy) acid )-3-metll-3Himidazo[4,5-b]pyridin7-ylamno]-pyridazine-3carboxHico Int 62 Exemplified 402 403 IF-2019-17407397-APN-ANP#INPI160 Page 319 of 545 IF-2019-17407397-APN-ANP#INPI Page 320 of 545 Int Structure Name SM Method PM Month 64 Cl j ÍI x> 1 H \ (7-Chloro-3-methyl-3Himidazo[4,5-b]pyridin5—yl H (R)~2-m ethyl—1— trifl uormethyl -propyl}arrtlna Int 1, [103218163-7] B3 306 307 65 Cl 1 jQTx> --- V H \ (7—Chloro—3—methyl—3 Η— lmldazo[4,5-b]plridin5-ylH(RHcyclopropyl -ethylj-amine Int 1, [6240-966] B3 251 251 66 or H.N-V (6-amÍnop¡rÍdazin-3ylH4-methylpiperazín-lyljmethanone [30154808-3]y [109-013] A3 221 222 67 Cl j. . JI N Cl^N* [ (R}-4-(6-Clo ropyridazin-3-yl)— morpholín-2-Íl]-tnetanol [141-300], [143643617-7] P3 229 230 69 ° xA° AA “0 o 4-{6-chloro pyridazin-3yl)-2,2,3,3,5,5,6,6octadeuterium-morpholine [141-300], [34261102-3] P3 207 208 70 Χ^Ο^ΟΗ ci^n*n [(SHH6-Chloropyridazin—3—yl)—morpholin-2-yl]-fnetanol [141-300], [131358492-7] P3 229 230 IF-2019-17407397-APN-ANP#INPÍ61 Page 321 of 545 IF-2019-17407397-APN-ANP#INPI Page 322 of 545 Int Structure Name SM Method PM Month 71 or ti (2S,6S)-4-(6-C!oropyridazin—3—yl)—2,6— dimethyl-niorpholine [141-3001, [27625276-4] P3 227 228 72 o ti 4-(6-Chloro-pyridazin3-ÍI)-[l,4]oxazepane [141-30- 0], [563860-8] P3 213 214 73 í^° cAn*n (2R,6RHH&-Chloropyridazin —3—yl)—2,6— dimethiPmorpholine [141-300], [17175374-5] P3 227 228 74 [141-300], [10300301-6] P3 229 230 75 (r° / ti o 3-(&-Clo ro—pyridazín3—yl)—8—oxa—3—aza— bicyclo[3.2.1]octane (141-300], [5474574-31 P3 225 226 76 / / Cl—N 0 N=N \--f 4-46-Chloro-pyridazin3-ylHnorfolin-2carbo nitrile [141-300], [120575107-0] P3 224 225 77 í^° A Á·, fV CtA*N (R)-4-(6-Chloropyridazin—3—II)—2—methyl— morpholine [141-300], [16803814-0] P3 213 214 IF-2019-17407397-APN-ANP#INPÍ62 Page 323 of 545 IF-2019-17407397-APN-ANP#INPI Page 324 of 545 Int Structure Name SM Method PM Month 78 ___J Í N CI^N* (R)-4-(6-Chloropyridazin-3-ÍIJ-2isopropyl-morpholine [141-300], [79288864-7] P3 241 242 79 JC n CI^N* (lS,4S)-5-{6-Chloropyridazin-3-yl)-2-oxa5—aza— bidclo[2.2.1]heptane [141-30OL [54771611-0] P3 211 212 80 eV o 4-(6-Chloro-pyride zin3—yl)—2,2-dimethyl—morpholine [141-300], [14768858-2] P3 227 228 81 Cl—N? VO N=N (re / H2S,6SHH&Chloro—pyridazin—3—II)— 2,6-d ί metí l-m orpho lina [141-30- 0], [648545-6] P3 227 228 82 C\-^~ \-u 0 N=N — / (5)-4—(6—Chlorine— pyridazin-34l)-2Isopropyl-morpholine [141-30OL [128676831-7] P3 241 242 83 h2nXJ hn^ 2-{4-Am I n o-fenll )-Netyl-acetamide [1197-553L17504-7] Exemplified 178 179 84 0 lil i^1 h2nAn^ 6-am ino-pyrid i n-3-i 1)(4-m ethyl—pipe ra zin-1yl)-methanone [3167-495], [10901-3] Exemplified 220 221 IF-2019-17407397-APN-ANP#INPI163 Page 325 of 545 IF-2019-17407397-APN-ANP#INPI Page 326 of 545 Int Structure Name SM Method PM Month 85 D zx z^\_ 0—4 z 7-chloro-5-iodo-3(trideuteriomethyl)imidaz o[4,5-b]plrldine [2587-022) Exemplified 297 297 86 5-[(7-chloro-3-methyllidazo[4,5-b]pyridin5-yl)-cidopropylaminoJ-4-methylpyridin-2-ca rbo nitrile Int 4, [41123557-9] Exemplified 339 340 87 X O / 4-ethyl-5-hydroxypyridin-2-carbonitrile Int 20 Exemplified 148 149 88 0 « 1nah XX XX'> 4—£64(5-[(6-Qano-4—methyl-3-pyridii)oxy]-3methyl tert-butyl -imidazo[4,5b]pyridin—7—yl]amlnol— 3—pl rid i 1] pipe razin-1carboxylate Int 2, [57118859-5] Bl 542 543 89 D o° 5-[7-chloro- 3(trideuteriomethyl)imidaz o[4,5- bjpyridln—5ΐΙ]οχΐ—4—methyl—pyridin— 2-ca rbo nitrile Int 85, Int 21 Exemplified 303 303 90 1 ZVN^ α^Ν*Ν 146-doropyridazin- 3yl}-N,N-dimethylazetidin-3-amine [141-300], [93567007-8] P3 213 213 IF-2019-17407397-APN-ANP#INP?64 Page 327 of 545 IF-2019-17407397-APN-ANP#INPI Page 328 of 545 Int Structure Name SM Method PM Month 91 1 Φ o (lR,4R)-2-{6-Chloropyridazin-3-yl)-5-methylÍl·2,5-dlazabicyclo[2.2.1]heptane [141-300], [12522464-8] P3 224 225 92 VQw F ' 4-(7-Chloro-3-met¡l3H-lmidazo[4,5b]pirldin-5-yloxy)-3,5d ifluo r-be nzo nitri lo Int 57 , [13422745-5] Exemplified 321 321 93 0 D el Λ D D (6-bromo-3-pirídl 1)[2,2,3,3,5,5,6,6octadeuterium-4(trldeuteriomethyl)pipera zin-l-yl]methanone [112662186-0], [6311-359] and [86550-9] Exemplified 295 295 297 Illustrative Examples Compound 1: N-[3-Methyl-5-(4-methyl-6-trifluorometH~pyridin~3~yloxy)~3H imidazo[4,5-b]pyridin~7-yl}-pyrimidin- 4,6-diamine Step 1: 7-Chlora-3-metÍI-5-(4-met¡k&-trifuormethyl-pyridin-3~yloxy¡}-3H imidazo[4t5-b]pyridine Intermediate 1 (110 mg, 0.377 mmol, 1.0 eq), 4-methyl-6-trifluoromethyl pyridin—3—o! (CAS [1253790-72-5], 100 mg, 0.565 mmol, 1.5 eq), Cul (7 mg, IF-2019-17407397-APN-ANP#INPI165 Page 329 of 545 IF-2019-17407397-APN-ANP#INPI Page 330 of 545 0.038 mmol, 0.1 eq), TMHD [1118-71^1] (78 pL, 0.377, 1.0 eq) and Cs2CO3 (246 mg, 0.754 mmol, 2.0 eq) were mixed 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 coarse Pall-Seitz filter paper. The resulting cake was washed with EtOAc. The filtrate obtained was washed with H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (EtOAc / DCM, gradient from 20% to 60% EtOAc) to provide the desired product. LCMS: m / z = 343 [M + H]+. Step 2: N-[3-Methyl-5-(4-methyl-6-trifluoromethyl-pyridin-3-yloxy)-3H-im¡dazo[4,5b]pyridín-7-yl]pyrimid¡ n-4,&-d¡am¡na 7-chloro-3-methyl-5-{4-methyl-6-trifluoromethyl-pyridín-3-yloxy)-3Himidazo[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), Cs2CO3 (46 mg, 0.140 mmol, 1.2 eq) were mixed under N2, after which 1,4-dioxane (1 ml) was added. The resulting mixture was stirred at 110°C. After overnight, it was cooled to room temperature. The mixture was diluted with 2 ml of DMSO and purified preparative HPLC to provide the desired product. LCMS: m / z = 417[M + H] *. Compound 2: N-[5-(2-Fluoro-4-methansu!phonyl-6-methyl-phenoxy)-3-methyl-3H¡midazo[4,5-b]pindin-7-H]-pyrimidin~4t6 -diamine IF-2019-17407397-APN-ANP#INPI166 Page 331 of 545 IF-2019-17407397-APN-ANP#INPI Page 332 of 545 Step 1: 7-Chloro-5-(2-fluoro~4~methanesulfonyl-6-metÍ / ~phenoxy)~3~metÍI-3Himldazo[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 μΙ, 3.27, 1.0 eq) and CS2CO3 (2.13 g, 6.54 mmol, 2.0 eq) were mixed into air, dry DMF was added (10 ml) and the mixture was stirred at 85°C. After a week, it was cooled to room temperature and filtered through coarse pall·seitz filter paper. The resulting cake was washed with EtOAc. The filtrate obtained was washed with H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (EtOAc / / DCM, 10% to 100% EtOAc) to provide the desired product. Step 2: N-[5-(2-F!uor-4-methanesulfonyl-6-methyl-phenoxy)-3-inethyl-3Himidazo[4, &~b]pyridin-7~yl}~pinmidin-4,6 -diamine 7-chloro-5-(2-fluoro-4-methanesulfonyl-6-methyl-phenoxy)-3-methyl-3Hymidazo[4,5-b]pyridine (50 mg, 0.136 mmol, 1.0 eq), PYRIMIDINE- 4,8-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 .02 eq) and Cs2CO3 (53 mg. 0.163 mmol, 1.2 eq) were mixed together under N2, 1,4-dioxane (1 mL) was added. IF-2019-17407397-APN-ANP#INPÍ67 Page 333 of 545 IF-2019-17407397-APN-ANP#INPI Page 334 of 545 The resulting mixture was stirred at 110°C. After overnight, it was cooled to room temperature. The mixture was diluted with 2 ml of DMSO and purified preparative HPLC to provide the desired product. LCMS: m / z = 444 [M + H]+. Compound 3: 6-[7-(6-Amino-pyrimid¡n-4-¡lamino}-3-methyl-3H-imidazo[4,5b]p¡rídin-5-i!oxy}-5-met¡ f-pyridazín-3-carbonphtrile Step 1: 7-chlorΌ-3-methyl-3H~imΐdazo[4t5-b]p¡ríd¡r^~&-ol Intermediate compound 1 (6.0 g, 20.48 mmol, 1.0 eq), tBuBrettPhos Pd 10 G3 (348 mg, 0.410 mmol, 0.02 eq) and CsOH monohydrate (10.08 g, 61.44 mmol , 3.0 eq) were mixed in 1,4-dioxane (40 ml) and HjO (3.68 ml, 204.80 mmol, 10 eq) was added. The mixture was stirred mechanically at room temperature. After overnight, the reaction mixture was quenched with H2O and impurities were extracted with EtOAc. The aqueous layer was acidified to pH = 5 and 15 extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to dryness to provide the desired product. LCMS: m / z = 184 [M + H]+. Step 2: 6-(7-Chloro-3-methyl-3H-im¡dazo[4,5-b]pyridin-5-¡!oxy)-5-met¡l-pyridazin3-carbonitrile IF-2019-17407397-APN-ANP#INPÍ68 Page 335 of 545 IF-2019-17407397-APN-ANP#INPI Page 336 of 545 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 K2CO3 (566 mg, 4.10 mmol, 1.5 eq) were mixed together under N2. Dry DMF (8 ml) was then added and the mixture was stirred at 100°C. After 3 h, it was cooled to room temperature and inactivated with H2O to give a suspension. Filtration gave a solid which was washed with H2O and then dried in the vacuum oven to provide the desired product. LCMS: m / z = 301 [M + H]+. Step 3: 6-[7-(6-Am¡no-pyrim¡dirb-4-i!amino)-3-methyl-3H-im¡dazo[4,5-b]pyridin—5-yloxy]-5 -met¡l-p¡ridazÍn-3-carbon¡tri!o 6-(7-Chloro-3-methyl-3H-imidazo[4)5-b]pyridin-5-iIoxy)-5-methyl-pyridazine3-carbonitrile (50 mg, 0.167 mmol, 1.0 eq), Pyrimidine- 4,6-diamine [79364-63-9] (37 mg, 0.333 mmol, 2.0 eq), Pd2(dba)3(3 mg, 0.003 mmol, 0.02 eq), MorDALPhos (3 mg, 0.006 mmol , 0.04 eq) and Cs2CO3 (65 mg, 0.200 mmol, 1.2 eq) were mixed under N2, dioxane (1 ml) was added and the mixture was stirred at 110°C. After overnight, it was cooled to room temperature. The mixture was diluted with 2 ml of DMSO and purified preparative HPLC to provide the desired product. LCMS: m / z = 375 [M + H]+. Compound 4: 5-[[7-(&-Amino-pinmidirb-4-ylamino)-3-methyl-3H-imidazo[4,5b]pyridin~&-yl}-(3-methoxy-propíl)- amino}~4~-met¡l-pyrid¡n-2~carbonitrile Step 1: 5-[(7-Chloro-3-metith-3H-imidazo[4,5-b]pyridin-5-yl)-(3-methoxy-propyl)amino]-4-methyl-pyridin-2- carbontrile IF-2019-17407397-APN-ANP#INPÍ69 Page 337 of 545 IF-2019-17407397-APN-ANP#INPI Page 338 of 545 To a solution of intermediate 4 (150 mg, 0.48 mmol, 1.0 eq) and CS2CO3 (186 mg, 0.57 mmol, 1.2 eq) in dry DMF (3 ml) under N2 was added 1-bromo -3methoxypropane (CAS [36865-41-5], 147 mg, 0.96 mmol, 2.0 eq). The mixture was stirred at 50°C for 3 h. It was then cooled to room temperature and inactivated with H2O. The compound was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude oil was purified by column chromatography (MeOH / DCM, 2% MeOH) to provide the desired product. LCMS: m / z = 371 [M + H]+. Step 2: 5~[[7~(6-Am¡no~pyrím / d¡n-4-Í / am / no)~3-methyl-3H-imidazo[4t5-b]pyridin~ &~yl]- (3-methoxy¡-propyl)-amino}~4-methyl-pyridín-2-carbonítrile 5-[(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-(3-methoxy-propyl)amino]-4-methyl-pyridin-2 -carbonitrile (113 mg, 0.30 mmol, 1.0 eq), pyrimidine4,6-diamine (CAS [79364-63-9], 66 mg, 060 mmol, 2.0 eq), Pd2(dba)3 ( 5 mg, 0.006) mmol, 0.02 eq), MorDALPhos (5 mg, 0.012 mmol, 0.04 eq) and Cs2CO3 (117 mg, 0.36 mmol, 1.2 eq) were mixed together under N2, after to which 1,4-dioxane (2 ml) was added and the mixture was stirred at 110”C. After overnight, it was cooled to room temperature and DMSO (1 ml) was added. The mixture was filtered and purified by preparative HPLC to provide the desired product. LCMS: m / z = 445 [M + H]+. Compound 5: 5-[[7-(6-Amino-pyrimidyrh-4-i!amino)-3-methyl-3H-imidazo[4,5b]pyridin~5-¡l]-(3-hydroxy¡-prop ¡l)~amino]-4-met¡l-pyridín~2-carbonphtrile IF-2019-17407397-APN-ANP#INPÍ>70 Page 339 of 545 IF-2019-17407397-APN-ANP#INPI Page 340 of 545 Passed 1: 5-[[3-(tert-buty!-d¡met¡l-silanyloxy)-propyl}-(7-chlor&-3-methiF3H imidazo[4,5-b]pyridin~5~yl)~amino}~4~met¡l~pyrid¡n~2~carbon¡trile To a solution I intermediate 4 (100 mg, 0.33 mmol, 1.0 eq) in dry DMF (1 ml) in N2, LHMDS (1M in THF, 390 μΙ, 0.39 mmol, 1.2 eq) was added. The mixture was stirred at room temperature for 5 minutes and then 3-bromopropoxy-tert-butyl-dimethyl-silane (CAS [89031-84-5], 98 mg, 0.39 mmol, 1.2 eq) was added and the mixture was stirred at 50°C for 3h. It was then cooled to room temperature and inactivated with H2O. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4. It was filtered and concentrated to dryness. The crude oil was purified by column chromatography (EtOAc / petroleum ether, 6:4) to provide the desired product. LCMS: m / z = 471 [M + H]*. Step 2: 5-[[7-(6-Amino-pyrimidir}-4-ylamino)-3-met¡l-3H-imidazo[4l5-b]pyrid¡n5-yl]-(3-hydroxy-propy! )-am¡no]-4-met¡l-pyrid¡n-2-carbon¡tri!o 5—[[3—(tert—butyl—dimethyl—silanyloxy)—propyl]—(7—chloro—3—methyl—3H—imidazo[4,5-b]pyridin-5-iI)-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 under N2, after which 1,4-dioxane (2 mL) was added. The mixture was then stirred at 110eC overnight. After allowing the mixture to cool 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 min at room temperature. The reaction mixture was filtered and then purified by preparative HPLC to provide the desired product. LCMS: m / z = 431 [M + H]*. IF-2019-17407397-APN-ANP#INPÍ>71 Page 341 of 545 IF-2019-17407397-APN-ANP#INPI Page 342 of 545 Compound 6: 4-methif-5-[3~methyl-7-[[5-[4-(trideuteriomethyl)piperazin-1- carbonyl]pyridin-2-yl]amino]imidazo[4,5-b]pyridin-5-yl]oxypindin-2-carbonitonlo Step 1: (6-Amino-pyridin-3-yl)-(4-trideuteriomethyph-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 pL, 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 h. It was then concentrated to dryness and redissolved in DCM. A precipitate formed and was filtered. The filtrate was purified by column chromatography using DCM / EtOH / 25% aqueous NH3 (7 / 1 / 0.1) as eluent to obtain the desired product. Step 2: 4-metii-5-[3-met¡!-7-[[5-[4-(trideuteriometH)piperazir}-1carbonyl]pyridin-2-yl]amino]¡mÍdazo[4,5-b] pyridine 5-yl]oxypyridine-2-carbonite Intermediate 2 (201 mg, 0.673 mmol, 1.0 eq), (6-amino-pyridin-3-yl}-(4trideuteriomethyl-piperazin-1-yl)-methanone (150 mg, 0.673 mmol, 1.0 eq )), Pd2CI2(allyl)2(5 mg, 0.013 mmol, 0.02 eq), MorDALPhos (12 mg, 0.026 mmol, 0.04 eq) and Cs2CO3(263 mg, 0.808 mmol, 1.2 eq) were mixed together under N after which 4-dioxane (3 ml) was added. The mixture was stirred at 110°C. After overnight, it was cooled to room temperature followed by IF-2019-17407397-APN-ANP#INPÍ72 Page 343 of 545 IF-2019-17407397-APN-ANP#INPI Page 344 of 545 addition of 0.5 ml of DMSO. The mixture was filtered and the filtrate was purified by preparative HPLC to give the desired product. LCMS: m / z = 487 [M + Hf. Compound 7: 4-ethyl~5-{3-methyl-7~[5-(morpholine~4~carbonyl)~pyridir>~2~ylamino]3H-imidazo[4,5-b pyridin-5-yloxy}~ pyridine-2-carbonitrile Step 1: 5~(7~chloro-3-methyl~3H-ímidazo[4t5-b]pyridin-5-yloxy)-4-ethyl-pyridín-2carbonitrile Intermediate 1 (215 mg, 0.733 mmol, 1.0 eq), 4-ethyl-5-hydroxy-pyridine-2-carbonitrile (Int 87, 141 mg, 0.953 mmol, 1.3 eq), Cul (28 mg, 0.147 mmol), 0.2 eq), TMHD (CAS [1118-71-4], 305 pL, 1.466 mmol, 2.0 eq) and Cs2CO3 (478 g, 1.466 mmol, 2.0 eq) were mixed in air, Solvent was added and the mixture was mixed and stirred at 85°C. After 48 h, it was cooled to room temperature and quenched with 10% aq. The TMEDA solution and the compound were extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (EtOAc / DCM, 7:3) to provide the desired product. LCMS: m / z = 314 [M + Hf. Step 2: 4-ethyl-5-{3-methyl-7-[5-(morpholine-4-carbonyl)-pyridin-2-i!amino]-3f-l·imidazo[4,&~b]pyridin~ 5~yloxy}-pyridin-2-carbonitril 5-(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-4-ethyl-pyridin-2carbonitrile (82 mg, 0.263 mmol, 1.0 eq), 5- [(morphoIin-4-yl)carbonyl]pyridin-2IF-2019-17407397-APN-ANP#INPÍ*73 Page 345 of 545 IF-2019-17407397-APN-ANP#INPI Page 346 of 545 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[123758812-3] (2 mg, 0.005 mmol, 0.02 eq) and CS2CO3 (103 mg, 0.316 mmol, 1.2 eq) were mixed together under N2 after which 1,4- dioxane (1 ml) and the mixture was stirred at 110°C. After overnight, the mixture was allowed to cool to room temperature and then diluted with 2 ml of DMSO. The resulting mixture was filtered and the filtrate was purified by HPLC. preparation to provide the desired product LCMS: m / z = 485 [M + H]*. Compounds 79 and 80: 5-[7-[[5-[1-(όίΜΘΐίΐ3ηΊίηο)-2,2,2-(πΑυοΓ6ϊιΊ]ρΐΓίζ1ΐη-210 H]amino]-3-metH¡m¡dazo[4.5~ b]pyridin5~yl]ox¡~4-methyl¡lp¡ridin~2~carbonitrile and 5[7-[[5-[1-(ethylamino)-2t2,2-trifluorethit]pyridin-2-yl]am¡ no]-3-methyímidazo[4l5b]pyridín-5-yl]oxy-4-methHyrídin-2-carbonítrilo Step 1: a solution of Int 49 (75 mg, 0.16 mmol, 1.0 eq) and EtaN (46 μΙ, 0.33 mmol, 2.0 eq) in anhydrous DCM (1 mL, 0.2 M ) was cooled to 0eC under N2. MsCl (CAS [124-63-0], 25 μΙ, 0.33 mmol, 2.0 eq) was added dropwise into 0.1 ml of anhydrous DCM and the mixture was allowed to warm to room temperature. After 1 h, the reaction was diluted with DCM (5 mL) and quenched with saturated aqueous NaHCOa (5 mL). The organic layer was washed with brine (5 ml), dried and IF-2019-17407397-APN-ANP#INPÍ74 Page 347 of 545 IF-2019-17407397-APN-ANP#INPI Page 348 of 545 evaporated under vacuum to provide the desired product that was used as such. MS m / z 474 / 476 (75 / 25%). Step 2: 5-[7-[[5-(1-chloro-2,2,2-trifluoro-ethyl)-2-pyridyl]amino]-3-methylimidazo[4,5-b]pyridín-5 -yl]oxy-4-methyl-pyridine-2-carbonitrile (31 mg, 0.066 mmol, 1.0 eq), Me2NH2CI (53 mg, 0.66 mmol, 10 eq) and K2CO3 (182 mg, 1, 32 mmol, 20 eq) were mixed together in anhydrous DMF (0.3 ml). The mixture was stirred for 1 hour at 80°C under N2 atmosphere. The reaction mixture was then diluted with water (5 ml) and extracted with EtOAc (2x5 ml). The combined organic extracts were dried and evaporated in vacuo. The residue was dissolved in MeOH, purified by filtration by preparative HPLC to give the desired products. LCMS 79: m / z = 483 [M + H]+; LCMS 80: m / z = 483 [M + H]*. Compound 187: S-^-KG-aminopyrimidin-^-ylJaminoJ-S-methyl-imidazo^, 5b]pyridin-5-yl]-(2-hydroxypropyl)amino]-4-methyl-pyrid ¡n-2-carbonitrile Step 1:5-[2-[tert-butyl(dimethyl)silH]oxypropylaminoJ-4-methyl-pyridin-2-carbonitri!o In a 5 ml vial, 2-[tere-butyl(dimethyl)sil¡I]oxypropylamine (CAS [178968015-4], 380 mg, 2 mmol, 2.0 eq), 2-cyano-4-methyl -5-bromopyridine (CAS [88636486-9], 200 mg, 1 mmol, 1.0 eq), XantPhos (CAS [161265-03-8], 17.5 mg, 0.03 mmol, 0.03 eq) and Cs2CO3 (975 mg, 3.0 mmol, 3.0 eq) were added. 1,4-dioxane was added IF-2019-17407397- APN-ANP#INPI175 Page 349 of 545 IF-2019-17407397-APN-ANP#INPI Page 350 of 545 dry (3 ml) and the mixture was brought to N2 and degassed. The mixture was stirred overnight at 70°C. Water and ethyl acetate were added, after stirring, the water layer separated. The organic layer was washed once more with water. The precipitate in the organic layer was separated by filtration. The organic layer was dried over MgSO4, filtered and evaporated. Purification column chromatography of 5 to 25% EtOAc in PE gave the desired product (200 mg, 33% yield). LCMS: m / z = 306 [M + H]+. Step 2: 5-[2-[tert-but¡l(dimethyl)siW]ox¡propif-(7-chloro-3-met¡l-!midazo[4t5b]p¡ríd¡n-5-yl)amino ]-4-methyl-pyridín-2-carboniton In a 5 ml vial, 5-[2-[tere-but¡I(dimethyl)silyl]oxypropylamino]-4-methylpyridine-2-carbonitrile (50 mg, 0.16 mmol, 1.0 eq), Int 1 (48 mg, 0.16 mmol, 1.0 eq), Pd2dba3(15 mg, 0.016 mmol, 0.1 eq), P(tBu)3.HBF4 (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 brought to N2. It was degassed and stirred for 5 h at 110°C. Water and ethyl acetate were added, the mixture was filtered over celite. The layers were separated and the organic layer was dried over MgSO4, filtered and evaporated. The crude oil was purified with column chromatography using eluents of 5% EtOAc to 70% EtOAc in PE to provide the desired product. LCMS: m / z = 471 [M + H]+. Step 3: 5-[[7-[(&-aminopin'midin-4-yl)amino]-3-methyl-imidazo[4t5-b]pyridin-5-yl][2-[tert-buty!(dimethyl )silyl]oxypropyl]amino]-4~methyl-pyridine-2-carbonitrile In a 5 ml vial, 5-[2-[tert-butyl(dimethyl)silyl]oxypropyH7-cIoro-3-methylimidazo[4,5-b]pyridin-5-yl)amino]-4-methyl- pyridín-2-carbonátrile (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 Cs2CO3 IF-2019-17407397-APN-ANP#INP1176 Page 351 of 545 IF-2019-17407397-APN-ANP#INPI Page 352 of 545 (143 mg, 0.44 mmol, 2 eq) were added. Anhydrous 1,4-dioxane was added, the mixture was brought to N2 and degassed. It was subsequently stirred at 110°C for 2 h. 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 provide the desired product which was used as such. LCMS (M+1): 545.3 Step 4:5-[[7-[(6-aminopyrimidin-4-yl)amino]-3-methyl-imidazo[4,5-b]pyridin-5-yl}(2-hydroxypropyl)amino ]-4-methyl-pin'din-2-carbonitri!o A 1 M solution of TBAF in THF (0.2 ml, 0.2 mmol, 2 eq) was added to a solution of 5-[[7-[(&-aminopyrimidin-4-i!)amino]-3- niethyl-lmidazo[4,5bjpyridin-5-yl]—[2-[tere-butyl(dimethyl)silyl]oxypropyl]amino]-4-methyl-pyridin-2carbonitrile (50 mg, 0.1 mmol, 1 equiv.) into 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 provide the desired product. LCMS: m / z = 431 [M + H]+. Compound 38: 4-Methyl-5-[3-methyl-7-(6-morpholin-4-yl-pyridazin-3-ylamino)-3Himidazo[4,5~b]pyridin-5-yloxy] pyridin~2-carbonitrile Path 1 IF-2019-17407397-APN-ANP#INPÍ77 Page 353 of 545 IF-2019-17407397-APN-ANP#INPI Page 354 of 545 Intermediate 3 (1.0 eq, 409g, 1.459 mol) and 4-(6-bromopyridazin-3¡1)morpholine (CAS [66346-91-6], 1.1 eq, 392g) were added to the mixture. xylene isomers (8L) 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 in 2h30. 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 was heated at reflux for 1h30. Then, a suspension of Pd(OAc)2 (2 mol%, 6.6 g) and Xantphos (4 mol%, 33.8 g) in xylenes (50 ml) was added and the reaction was heated to reflux for 1h30 additional. A suspension of Pd(OAc)2 (2 mol%, 6.6 g) and Xantphos (4 mol%, 33.8 g) in xylenes (50 ml) was then added for the last time. The reaction was refluxed for an additional 1h30. The reaction mixture was cooled to room temperature and stirred overnight. The suspension was filtered, washed with acetonitrile (5 I). The solid was washed with water (15 I) to neutral pH, dried with suction, then suspended in acetonitrile (6.5 I) and stirred at room temperature for 1 h. The suspension was filtered, washed with acetonitrile (2 I) and dried. Chromatography on SIO2 (1 g of SiO2 for 1 g of crude oil) using eluent CHCls / acetone (70 / 30) and then CHCh / MeOH (96 / 4) produced the desired product. Way 2 Intermediate 3 (280 mg, 1 mmol, 1.0 eq), 4-(6-bromopyridazin-3yl)morpholine (268 mg, 1.1 mmol, 1.1 eq) and CsCO3 (977 mg, 3 mmol, 3 eq) ) are mixed in an argon atmosphere at room temperature and degassed tert-amyl alcohol or DMF (5 ml) is added. [Pd(cinnamyl)CI]2(5.18 mg, 0.010 mmol, 0.01 eq) and JosiPhos (CAS [1702311-34-9]) (13 mg, 0.024 mmol, 0.024 eq) were IF-2019-17407397-APN-ANP#INPfl78 Page 355 of 545 IF-2019-17407397-APN-ANP#INPI Page 356 of 545 added under argon as a solid or as a pre-mixed solution in 1 m! of degassed tert-amyl alcohol or DMF. The mixture is heated to 100eC for at least 2 h. The reaction mixture is then cooled to room temperature and acetonitrile is added. The suspension is filtered, the solid is ground first with water and then with acetonitrile, and dried to obtain the desired product. Table III. Illustrative compounds of the invention. Comp # Structure Name SM Mtd PM Month 8 2 O —z -n z 7— z 4-{[7-(6-AmÍnopyrimidi n-4-yl mi no)-3methyl-3H-imidazo[4,5blpyridin—5- yl]-methylamino)-3-ethyl-5-fl uo rbenzonitrile Int 16 C1 417 418 9 nh2 A —NH N Y1 5-{[7-(6-Aminopyrimidin-4-ylamlno)-3methi!-3H-im ¡dazo[4,5bjpi ridi n-5-yl]-methi 1a m i no)-4-methyl-pyri¡di n-2carbonitrile Int 4 C2 386 387 10 nh2 nlS ^N^NH NCn 1 ' 4-{[7 -{6-AminoplrimÍdin-4-ÍlamÍno)-3methyl-3H-imÍdazo(4^b] pi ridi n—5—i 1]—m ethyl·aminoH cyclohexanecarbonitrile Int 6 C2 378 378 IF-2019-17407397-APN-ANPtfINPfl79 Page 357 of 545 IF-2019-17407397-APN-ANP#INPI Page 358 of 545 Comp # Structure Name SM Mtd PM Month 11 nh2 Ljl ^N^'NH η N7-(6-Amino-pyrimidin4—¡1}—N5—(3,3—dimethyl—tetrahydro-pyran-441)3,N5- dimethyl-3Himidazo(4,5-b]pyridin-5,7diamine Int 7 C2 383 383 12 N^N Ϊ Jl· HjN^^NH ID N7-(6-aminopyrimidin-4¡1)—N5,3—dimethyl— N5-((15)1,2,2tri m ethyl pro pil] i m ida zo[4,5b]pyridin-5,7-diamine Int 33, [79364 -63-9] Bl 355 355 13 nh2 yJL ^N^ NH C JL | rbo nitrile Int 9 C2 378 378 14 YK =r y2 4-{[7-(6-Aminopyrimidin-4-ylamino}-3methyl-3H-imidazo(4,5bjpyridin-5-yl]—methylamino)-3-cyclopropyl- 5fluoro-benzo nitrile Int 10 C2 430 430 IF-2019-17407397-APN-ANP#INPI180 Page 359 of 545 IF-2019-17407397-APN-ANP#INPI Page 360 ​​of 545 Comp # Structure Name SM Mtd PM Month 15 J > ¿a —Z Z 7—z —ZSS*Z 5-{[7-{&-Aminopyrimidin-4-ylamino)-3methyl-3H-imidazo[4,5bjpyridin—5 -ylj—methylamino)-4-ethyl-pyridyrv-2carbonitrile Int 11 C2 400 401 16 N^N JlXx> N7-(6-a m inopyri m idi n-4yl}-N5-[(lR)-l— cyclopropylethylj—N5 ,3— dimethyl-imidazo[4,5b]pyridin-5,7-diamine Int 34, 179364 —63—9] Bl 338 339 17 nh2nlj1 ^N^NH Ο Λα T i N \ N7-(6-Amino-pyrim id i n4-41)-3,N5-dimethyl-N5— ((3R,4S)—3—methyl—tetra hydro-pyra n-4-41)3 H-4m idazo [4,5-b] pi rldi rv5,7-diamine Int 13 C2 368 369 18 nh2 nA ^N^NH zd £±'> 1 ' N7H6-Amino-pyrimidin4-4IJ-N5— bicyclo[l.l.l]pent-l-yl3, N 5—d imethyl— 3 H— Imidazo[4,5-b]pyridin-5,7diamine Int 24 C2 336 337 IF-2019-17407397-APN-ANP#INPI181 Page 361 of 545 IF-2019-17407397-APN-ANP#INPI Page 362 of 545 Comp # Structure Name SM Mtd PM Month 19 z^z^ ,ζ-Λ z—G z z— O—' N7-(&-Amino-pÍrÍmidin4-41)-3,N5-dimethyl-N5-{3methyl-tetrahydro -plrar>-4il)-3H-lmldazo[4,5b] pi ridi n-5,7-dtamlna Int 25 C2 368 369 20 / —θ z- 2 / T| / / A —z ω z A— z N7-(6-Amino-plrimidin4-H}-N5-{l-cyclopro pil— 2,2,2-trifl uo r-ethyl )-3, N5dimethyl-3H- imidazo[4,5b]plridin-5,7-diamlna Int 26 C2 392 393 21 nh2 lUL ^N^NH N7-{6-Am¡no-pyrim¡d¡n4-ií)-3,N5-dimethi!- N5-<5oxa-spiro [3.5] not n-8-i 1)3H-imldazo[4,5-b]pyridin5,7-diamine Int 27 C2 395 395 22 Π -π O π-V %^0° ^ Ζ^,Ζ 5-(l-cÍciopropyl-2,2,2trifl uo r-ethoxy¡)-3-met¡ l-N(5-m ethylsu Ifo n i 1-2pyridyl)imidazo[4,5b]pyridin-7-amine Int 28, [35196 -11-3] B1 441 442 IF-2019-17407397-APN-ΑΝΡ#ΙΝΡΪ>82 Page 363 of 545 IF-2019-17407397-APN-ANP#INPI Page 364 of 545 Comp # Structure Name SM Mtd PM Month 23 z^z- \ F ° / 2 o=< 2U ZI )—' 6—[5— (6-Ga no-4-m ethyl-pyridine n3-yloxy) ethylamfda )-3-methyl-3Himidazo[4,5-b]pyridin-7i la mino]-py ride zin-3carboxylic Int 2, Int 29 Bl 429 430 24 Z^z< M e z o °=\^ <5V ZX V— J / Int 2, Int 30 Bl 459 459 25 Z^Z °Az zp“ oV / pi rid in-3-yloxy}3-methyl-3H-imidazo[4,5b]pyridirt-7-ylamino]pyridazine-3-carboxylic Int 2, Int 31 Bl 460 460 26 I* 1 Ncy\ xSc^ Acid ethylamide 5—[5— (6-Cia no-4-m ethyl-pyridin3-yloxy)-3-methyl-3Himidazo[4,5-b]pyridin-7ylaminol-pyridine-2carboxylic Int 2, Int 32 Bl 429 429 IF-2019-17407397-APN-ANP#INPI183 Page 365 of 545 IF-2019-17407397-APN-ANP#INPI Page 366 of 545 Comp # Structure Name SM Mtd PM Month 27 'hn^0 2-{4-[5-(6-Cyano-4methyl-pyridin-3-íloxÍ)-3methyl-3H-imidazo[4,5bjplridin-7-llamino ]phenyl}-N-ethyl-a ceta mida Int3, Int 83 B1 442 442 28 0 if jl NH 4—Metí!—5—{3-m ethyl-7—(6— (morphoIin-4-carbonyl)pyridine— 3—i la mino]-3 Himidazo[4,5-b]pyridin-5yloxy)-pyridine—2carbonitrile Int 2, [11801 31-898] B1 471 471 29 ^NH o<Vi NH Nc ίλ χ5λ Acid methylamide 5 -[5(6-Cia no-4-m ethyl—p ir id i n3—i loxi)—3—metí 1—3 H— Imidazo[4,5-b]pyridÍn-7ylamÍno]-pyridyR-2carboxylic Int 2 , [94128 4-748] B1 414 415 IF-2019-17407397-APN-ANP#INPÍ84 Page 367 of 545 IF-2019-17407397-APN-ANP#INPI Page 368 of 545 Comp # Structure Name SM Mtd PM Month 30 κ OH Sih ___.N_ kl NH (2-Hydroxy-propÍI)-amide of! 5-[5-{&-Cyano4-<n ethyl l-pyridin—3—yloxy)— 3-metÜ-3H-Imidazo[4,5b]pyridin-7-ylaminoJpyridine-2-carboxylic acid Int 2, Int 22 B1 459 459 31 Ó. N NH 5~{7—[6—(2—Methoxl— ethylamino)-pyrimidin-4yl m Íno]-3-m ethyl-3 HÍmidazo[4,5-b]pyridin-5yloxy)—4—methyl— pyridine—2— carbo nitrile Int 2, Int 33 B1 431 432 32 '^O^^'NH kt ^N^NH ΎιΛλ 5-¿7-[6-{3-MethoxyÍpropylamino)-pyrimidin-4yl mino]-3- methi h-3 HÍmidazo[4,5-b]pyridín-5yloxy)—4—methyl—pyridin—2— carbonitrile Int 2, Int 34 B1 445 446 33 HO^S^NH nlS M ^N^NH ΎλΛ·> 5-{7-[6-{3-Hydroxy-3metith-butylamino)pyrimidin-4-ylaminol-3_ methyl-3H-imidazo[4f5b]pyridin—5—íioxy}-—4—methyl—pyridin-2 -carbonitrile Int 2, Int 35 B1 459 460 IF-2019-17407397-APN-ANP#INPÍ85 Page 369 of 545 IF-2019-17407397-APN-ANP#INPI Page 370 of 545 Co mp # Structure Name 5M Mtd MW Month 34 ho^^^nh ^νλνη AixA 5-(7-[6-(3-Hydroxypropylamino)-pyrimidin-4ylamino]-3-methyl-3Himidazo[4,5-b|pyridin -5yloxy}—4—methyl—pyridin—2— carbonitrile Int 2, Int 36 Bl 431 432 35 Ο^γ^ΝΗ nA kt ^n^nh 5-(7-{6-[([l,4]Dioxan- 2ylmethyl)-amino}-pyrimidin4-yl amino}-3-methyl-3 Hlmldazo[4,5-b]pyridin-5Ποχϊ)—4—methyl—pyridin—2— carbonitrile Int 2, Int 37 Bl 473 474 36 '^ NH nlS N^NH 5—{7-(6-(3-M ethoxy— cidobutylaminojpyrimidin-4-ylamlnoJ-3~ methyl-3H-imidazo[4,5b]pyridin-5-yloxy}-4-methylpyrid i n -2-ca rbon it ri Io Int 2, Int 38 Bl 457 458 37 lS ^N^NH XX xX5 V-O^^N 5—{7—[6—(3—Methoxy— butylamino}-pyrimidin-4yl m ino] -3-methyl-3 Himidazo[4,5-b]plridin-5i loxy]—4—methyl—pyridine n-2carbonitrile Int 2, Int 39 Bl 459 460 IF-2019-17407397-APN-ANP#INPI186 Page 371 of 545 IF-2019-17407397-APN-ANP#INPI Page 372 of 545 Comp # Structure Name SM Mtd PM Month 38 M * ^Z^Z 4—Methyl—5—[3—methyl—7—(6— morph li n—4-i 1—pyridazi n-3ylamIno)-3H- 4midazo[4,5b]pyridin—5—yloxy]—pyridin— 2-carbonitrile Int 2, [66346 -91-6] or Int 3, [66346 -91-6] Bl 0 see above 443 444 39 u j N 'N^NH Xi, '' γΌΛΝ^Ν 4-M ethyl-5-{3-methyl-7-{6(4-methyl-piperazin-l-yl)pyridazin-3-ylamino]-3Himlda zo [4, 5—b] pyridine n-5yloxy)-pyridin-2carbo nitri Io Int 2, [66346 -94-9] Bl 456 457 40 / — Q-i *-z^z 5-{7-[H3Dimethylaminomethylazetidin-l-yl)- pyridazin-3ylamino]-3-methyl-3Himidazo[4,5-b]pyridin-5yloxy}-4-ni eti k-pi rid i n-2car bo nit ril Int 2, Int 40 Bl 470 471 41 π η n A . tl 'N^NH Ύ1 / A γΌΛΝ^Ν (±}-4—Methyl—5—{3—methyl·7-[6-{(3R,5S}-3A5trimethyl-piperazin-l-yl)pyridazin-3 -i1amino]-3Himidazo[4,5-b]pyridin-5lloxy)-pyridine-2carbonitrile Int 2, Int 41 Bl 484 485 IF-2019-17407397-APN-ANP#INPÍ87 Page 373 of 545 IF-2019-17407397-APN-ANP#INPI Page 374 of 545 Comp # Structure Name SM Mtd PM Month 42 FaC^N^i H J N << M N^NH 4—M ethyl—5—(3—methyl—7—{6— [4—(2,2,2—trifluor— ethyl)—plperazln-1-ilj—pyridazin3-ylamino}-3Himidazo[4,5-b]pyridin-5ΐίοχΐ}—pyridin-2carbonitrile Int 2, int 42 B1 524 525 43 0^ h j N kt 'N^NH ΎιΔλ Y <ox<N^'N (±)-5-{7-[6-((2R,6S}-2,6Di methyl l-morpholi n—4—yl )pyridazln-34lamlno]-3met¡l-3H- imÍdazo[4,5b] pyridin- 5-iloxl)-4-methylpy rid in-2-ca rbon it rilo Int 2, Int 43 B1 471 472 44 z -Z Z-^-' 00 M 1 ^-Z^Z 4—Methyl—5—{3-methyl-7—[6— ((S)-2-methyl l-morphol¡ n-4yl)-pyrldazin-3-ylamino}3H-imidazo[4,5-b]pyridin5 —iioxy}—pyridin—2— carbonitrile Int 2, Int 44 B1 457 458 45 z ,z o -¿ ü V 0 w 5-{7-[6-(4-Qanopipe ridi n-1-ιΊ)—pyridazin3- ila m i no}-3-methyl-3 HÍmidazo[4,5-b]pÍrldin-5yloxy)—4—methyl—pyridin—2— carbonitrile Int 2, Int 45 B1 466 467 IF-2019-17407397-APN-ANP#INPÍ 88 Page 375 of 545 IF-2019-17407397-APN-ANP#INPI Page 376 of 545 Comp # Structure Name SM Mtd PM Month 46 0 ---J ^AnhNC<I JlXn* 4-methi l-5-[3-meti 1-7[[5-( 4-p clothing n-2llpiperazin-1carbonyl) pyridin-2yl]amlno]imidazo[4,5b]pyridin—5—yl]oxypyridin—2— carbo nitrile Int 61, [431842-7] Ala 512 513 47 . q O Z^\ ^Ζ^,Ζ 5-(74(5-(4dclobutylpiperazin-1carbonyl)pyridin-2tl]amlno]-3methylimidazo[4,5b]plridin-5-yl]oxMmethylpyridin-2-carbonitrile Int 61, [79955 7-656] ~A1a Ξ .524 525 48 0 n-S-ylJoxMmethylpyridin-2-carbonitrile Int 61, [20327 -23-5] Ala 510 511 49 z .X O W 4-m ethyl-5-[3-methyl-7[(5-morpholirv-4-ylpyridin2-yl) amino]imidazo[4,5b] pi ridi n—5—ΪΙ] oxy pyridin—2— carbonitrile Int 2, [57118 9-781] Bl 442 443 IF-2019-17407397-APN-ANP#INPÍ89 Page 377 of 545 IF-2019-17407397-APN-ANP#INPI Page 378 of 545 Comp # Structure Name SM Mtd PM Month 50 I IL ΝΥχ JiiX 4-methyl-5-[3-fTethyl-7[[5—(4—methylpiperazin—1— iljpyridin-2ll]amino]imidazo[4,5blpyridin—5 —yljoxypyridin—2— carbonitrile Int 2, [57118 9-496] Bl 456 457 51 0 Ι^ν^ύ^ν —J NCt\ Λλ 1dVd D d 4-meti 1-5—[7—[ [5—( 4— methylpiperazin-1carbonyl)pyridin—2— ll]aminoJ-3(trideuteriomethyl)imidazo[4 ,5-b]pyridin-5yl] oxypyridin-2-ca rbonitrile Int 84, Int 89 Bl 487 487 52 nh2 lS 5- [7-[(6-aminopolyrimidin4-yl)aminoJ-3-methyllimidazo[4,5-b]pyridin-5yljoxy—4—methyl—pyridin—2— carbo nitrile Int 2, [79364 -63-9] Bl 373 374 53 H 0 0 LI Vj, Aa Y'O'V'N 4-[[5-[(6-clano-4-methyl3-pyridyljoxy]—3-methyllimidazo[4,5-b]pyridin-7(l) amino}-N-ethylbenzenesulfonamide Int 2, [170953-11 Bl 464 464 IF-2019-17407397-APN-ANP#INPI190 Page 379 of 545 IF-2019-17407397-APN-ANP#INPI Page 380 of 545 Comp it Structure Name 5M Mtd PM Month 54 τι *n )“-<] / =\ Ο Z 2—z N4-[5-( 1-cyclo pro pil2,2,2-trifluor-ethoxy}-3methyl-imidazo [4,5bjpyridin-7-iljpyrimldin4,6-diamine Int 28, [79364 -63-91 Bl 379 380 55 nh2 A Ύι xA ΥΥ'ΐΓ-Ν 5-[[7-[(6-aminopyrimidin4-yl)amino] -3-methylimidazo[4,5-b]pyridin-5yl]amino]-4-phnetyl-pyridin2-carbonitrile Int 4, [79364 -63-9] Bl 372 373 57 HCOOH Η2Ν^^| jÓ5 Formlate salt of 5— [7—[4— (aminomethyl)anilino}-3methiWmidazo[4,5bjpyridin-5-yljoxy—4-methylpyridin-2-carbonitrile Int47 DI 385 369 (Mnh2 -) 58 —(z ζ *ω. r rS° 4- m eti l-5-[3-m eti 1-7[(5-methylsulfonyl-2plrldil)amino]imidazo[4,5b]pyridin-5-yl]oxy-p>ridin2-carbo nitrile Int 2, [35196 - 11-3] Bl 436 436 IF-2019-17407397-APN-ANP#INPÍ91 Page 381 of 545 IF-2019-17407397-APN-ANP#INPI Page 382 of 545 Comp 0 Structure Name SM Mtd PM Month 59 -€?z ” >=v -2^z 4-methi t-5-[3-methyl-7[[5-{trifl uo rmethyl}-2pyridyl]amino]imidazo [4,5bjpyridin-5-yljoxy—pyridin2-carbonitrile Int 2, [74784 -70-6] Bl 425 426 60 p °'Yjl kl NH ΎιχΑ 4-m ethyl-5-[3-methyl-7-(4methylsuffonilanilinojimidaz o (4,5—b] py ridi n-5-i IJoxy—pyridÍn-2-carbonitrile Int 2, (547049-5] Bl 435 435 61 —N* Ί SZ'O-'SZ'-N 4-methyl- 5-[3-methi 1-7[(1—methylpyrazole—4yl)amino]imidazo[4,5bjpyridin—5—yljoxy—pyridin—2-carbonitrile Int 2, [69843 -13-6] Bl 360 361 62 o m NH ΎλΑό yV'tr'i 4-[[5-[(&-da no-4-methyl3-pyridyljoxy]—3-methylimidazo[4,5-b]pyridyrh-7yl]amino]-N,N-dimethylbenzamide Int 2 , [633171-1] Bl 428 428 IF-2019-17407397-APN-ANP#INP?92 Page 383 of 545 IF-2019-17407397-APN-ANP#INPI Page 384 of 545 Comp # Structure Name SM Mtd PM Month 63 / Z—< OO y . / / co / X —r z ω-ζ o ^Z^J.Z 4-methyl-5-[3-fn ethyl—7—(4— morpholinsutphonylanilino)iml dazo[4,5-b]pyridin-5yljoxr—pyridin-2carbonitrile Int 2, [21626 -70-0] Bl 506 506 64 γ%ΛΝ0 6-[[5-[(6-cyano-4-methyl3—pyridyl)oxyJ—3—methyl·Ímidazo[4,5-b]plridÍn -7yl]amino]-N-ethyl-4-metll·py rid i n-3-ca rboxa m ida Int2( lnt50 Bl 443 443 65 %* í ilx> 1 H ' 3—put I—N7—(5— methylsulfonii—2—pyridll)— N5-[2-methyl-l(trifluoromethyl)propyl]imidaz or [4,5—b]pyri di n-5,7diamine Int 46, [35196 -11-3] Bl 443 443 66 J -\2 >=o z / Γ\ ^-Γ 4-[[5-[(6-dano-4-methyl·3-pyridyl)amino}-3-methyli m idazo [4,5-b] pi ridi n-7ll]amino]-N,N-dimethiIbenzamide Int 4, (633171-1] Bl 427 427 IF-2019-17407397-APN-ANP#INPÍ93 Page 385 of 545 IF-2019-17407397-APN-ANP#INPI Page 386 of 545 Comp It Structure Name SM Mtd PM Month 67 0 ^N^NH ΎιχΑ 6—[[5—[(6-cia no—4—met 1— 3-pyridyl)amino]-3-methyllimidazo[4,5-b ]pyridin-7yl]amino]-N,N-dimethylpyridin-3-ca rboxam ida Int 4, [82758 8-330] Bl 428 428 68 iÍH °¿“o Y 5—[7—[4— (difluoromethylsulfonyl) anilino ]-3-methyl-imldazo[4,5b]pyridin—5—yl]oxl—4—metii— py rid i n-2-ca rbo nitrile Int 2, [24906 -77-2] Bl 471 471 69 / v o. / ---(Z Z 'CO. 0 0° A5 ^Z^Z 5—[7-(4cyclopropylsulfonylanilino}3-methylMmidazo[4,5bjpyridin—5—yljoxy—4—methyl— pyridin-2-carbonitrile Int 2, [ 11475 58-13H Bl 461 461 71 O 0 TH Ύλ ju5 Vo-SAn 5-[7-[4-(3methoxypropylsulfonyljanilin o]-3-methyl-imidazo[4,5b] pi ridin-5-yl]oxy-4- methi 1pyridin—2—ca rbonitrile Int 2, [12471 64-584] Bl 493 493 IF-2019-17407397-APN-ANP#INPI194 Page 387 of 545 IF-2019-17407397-APN-ANP#INPI Page 388 of 545 Comp It Structure Name SM Mtd PM Month 72 / — / =zx O Z / )—z \___ \\ / / X / =\ r~^ M Z / )—z H 1 ^.Z^Z N4-[5- {lcyclopropylethoxy)-3-methylimidazo[4,5-b]pyridin-7yl]pyrimidin-4,6-diamine Int 48, [79364 —63—9] Bl 325 326 73 0 N*N^NH 6-[[5 -[(G-cyano-4-methyl3-pyridyl)oxy}-3-methylimidazo[4,5-b]pyridin-7ll]amino]-N,N-dimethylpyridazine-3-carboxamylde Int 2, [12502 16 -83- 1] Bl 429 429 74 0 M ^n^nh V105 &—[[5—1(6—ci a no-4-methyl3-pyridi 1) oxy}-3-methylimidazo[4,5-b] pyridin-7yl]amino]-N,N-dimethylpyrid in-3-carboxa mida Int 2, [82758 8-330] Bl 429 429 75 0 OG U N^NH Xljóa 4-m ethyl-5-[3-m eti 1-7[[5-{morpholin-4-ca rbo nyl)— 2pyridyl]amino]imidazo[4,5b]pyridin—5—i!]oxt—pyridin— 2-carbonitrile Int 2, [82758 7-906 ] Bl 471 471 IF-2019-17407397-APN-ANP#INPÍ 95 Page 389 of 545 IF-2019-17407397-APN-ANP#INPI Page 390 of 545 Co mp # Structure Name SM Mtd PM Month 76 _ / f >° / = / z=< xz z Λ & ^ζ^,ζ 6-[ [5-[(6-cia no-4-meti 13-pyridi 1 ) a mino)-3-methyllmidazo[4,5- bjpyridin—7yl]amino]-N,N-dimethylpyldazin-3-carboxamide Int 4, [12502 16-8311 Bl 429 429 77 —\ / ° o=C O-z z 6-{[5-[(6-cyano-4-methyl3-pyridyl) oxyJ-3-m eti k i mida zo [4,5-b] pi ridi n-7yl]amino]-N,N,2-trimethylpyrid i n-3-ca rboxa m ida Int 52, [50659-2] Al 443 443 78 z^z-** / ° < ¿' 6-[[5-[( 6-cia no-4-meti 13— pyridyl)oxy]—3—nriethií— imidazo[4,5-b]pyridin-7yl]amino]-N-ethyl-2-methylpyridine-3-carboxamide Int 52, [55766-4] Al 443 443 81 hcooh 1 k Jk M ^N^NH NiAa 5-[7-[[5[(dimethylamino)methyl]pyridi n-2-yl]amino]-3methylimidazo[4,5bjpyridin—5—yl]oxt—-4— methyl formate salt pi ridin-2-carbo nitrile Int 2, [13844 29-177] Bl 415 415 IF-2019-17407397-APN-ΑΝΡ#ΙΝΡΪ96 Page 391 of 545 IF-2019-17407397-APN-ANP#INPI Page 392 of 545 Comp # Structure Name SM Mtd PM Month 82 HCOOH *sAnh Vj. 4-Methyl-5[3-methyl-7-[[5-(morpholin4-Π m ethyl) plridi n-2ll]amino]innidazo[4,5b]pyridin—5—ylxoxypyridin—2— carbo nitrile formate salt Int 2, [40077 5-782] B1 457 457 83 1 HCOOH 1 k JL .. ^N^NH ΎϊΛλ Formate salt of 5- [7- [[5{[2—{dimethylaminojetyl—methylamino]methyl]pyridyre> 2-yl]amino]-3methylimidazo[4,5b]pyridin—S—lljoxf—4— m eti Ipyridi n-2-ca rbo nitrile Int 2, [11973 32-209] B1 472 472 84 %^NH ^ySr' Sr^N 5-[7-[(5-methoxypyridin-2yl)amino}-3methylimidazo[4,5b]pyridin—5—H]oxl—4—methylpyridin-2-carbonitrile Int 2, [10167 -97-2] B1 387 388 85 XX ,5bjpyridin-5-yl]oxypyridin-2ca rbo nitrile Int 2, Int 53 B1 457 457 86 w. N°XX jÓ3 4-m ethyl-5-[3-m ethyl-7[[5-(1—methylpiperidyrr) -4yljoxypyridin-2¡l]amino]im¡dazo[4,5bjpyridin—5-yl]oxypyridin-2ca rbo nitrile Int 2, [12493 22-379] B1 471 471 IF-2019-17407397-APN-ANP#INPÍ 97 Page 393 of 545 IF-2019-17407397-APN-ANP#INPI Page 394 of 545 Comp # Structure Name SM Mtd PM Month 87 4-methyl-5-[3-methyl-7[[5—(oxan—4—yljpyridin—2— ¡l]amino]imidazo[4,5bjplridin-5-yljoxypyridin -2carbo nitrile Int 2, Int 55 Bl 442 442 88 N^N ϊ if h2nx^xXnh 1 XCw A ' 54(7-(( 6-amino pi ri mid i n4-yl)amino)-3-methylimidazo[4 ,5-b]pyridin-5i 1]—pro pi cycle l-a m lno]-4methi-pyridin-2carbo nitrile Int 86, [15681-0] Bl 413 414 89 0 H0 llL 5474443-hydroxyoxetar>3—iljanilino]—3 — methylimidazo[4,5b] pi ridin—5—11] oxy-4m eti 1 pi ridi n-2-ca rbo nit ri Io Int 2, [11117 35-057] Bl 429 429 90 Zz \ / / VP H i 4-methyl l-5-(3-m etith-7[(6-(1-metllazetidin-3yljoxypyridazin-3yl]amino]imidazo(4,5b] pi ridin-5-ii]oxypyrldin-2ca rbo nitrile Int 3, Int 56 B2a 444 444 IF-2019-17407397-APN-ANP#INPÍ98 Page 395 of 545 IF-2019-17407397-APN-ANP#INPI Page 396 of 545 Comp # Structure Name SM Mtd PM Month 91 0 JL H L £ f r JÍfjÓcNs> ξ / ί! n —2carboxamide Int 26, Int 32 B1 433 434 92 Z^Z**' methyl-N7(5-methylsulfonyl-2pyridyl)imidazo[4,5b]pyridin-5,7-diamine Int 26, [35196 -11-3J B1 440 441 93 NHj Λ N NH N N7-{6-aminopyrimidin- 4Π)—3-methyl—N5-[2—methyl— 1(trifluoromethyl)propyl]imidaz o[4,5-b] pi ridin-5,7diamine Int 46, [79364 -63-9] B1 380 381 94 nh2 nAi IL JL ^N^NH i jQO> Cj H \ N7-(6-amÍnopyrimidin-4yl J-N54 I-cyclobutylethyl 1)—3— methiHmidazo[4,5b]pyridin-5,7-diamÍne Int 58, [ 79364 -63-9] B1 338 339 IF-2019-17407397-APN-ANP#INPÍ99 Page 397 of 545 IF-2019-17407397-APN-ANP#INPI Page 398 of 545 Comp # Structure Name SM Mtd PM Month 95 nh2 nAs IL JL N7-{6-aminopyrimídin-4yl>—N5-{dicyclopropylmethyl}3-methi h-irn idazo [4,5— b]pyridín -5,7-diam¡na Int 59, [79364 -63-91 B1 350 351 96 0 Λ. N Υχ χ5λ 5-[7-[[5-<3hydroxyzetidin-lca rbo n i 1)—2—pyrid i IJa m inoj3-methiMmÍdazo[4,5b]pyridin—5—yl]oxl—4—methyl—pyridÍn-2 -carbonitrile Int 2, [45347 -82-8] Ala 457 457 97 z z xH Z—<' Z Ü- u_ / =< 'K ά z Z—< o=r x>- Ji— N, N-di m ethyl Int 64, [82758 8-330] B1 436 436 98 0 H L JL N7-(6-aminopyrimidín-4yl)-3-methyl-N5-[(lR)-2methyl-1(trifluoromethyl)propyl]imidaz or [4,5-b]pyridin-5,7diamine Int 64, [79364 —63—9] B1 380 381 IF-2019-17407397- ΑΡΝ-ΑΝΡ#ΙΝΡ?θθ Page 399 of 545 IF-2019-17407397-APN-ANP#INPI Page 400 of 545 Comp # Structure Name SM Mtd PM Month 99 1 ? h L IL hH2dimethylaminoethyljpyridine3-carboxamide Int 61, [10800-9] Ala 472 472 100 H L JL ^hr^NH ncYjl 6-¿ [5—[(6—cy no-4-m eti 13—pyridyl)oxy]—3—methyl· — imidazo[4,5-b]pyridin-7yl]amino]-N-¿3methoxyÍpropÍI)pyridine-3carboxamide Int 61, [533273-0] Ala 473 473 101 HO'·''--- H Ll„ ΧΝ^ΝΗ “Δ 6-[ [15687-6] Ala 459 459 102 0 NC / x Λλ 5—[7—[[5—[3—(1—hydroxy—1—methyl-ethyl)azetidin-lcarbonyl]-2-pyridyl]amino]3- methyl-Í m idazo [4,5— b] pyri di n—5—yljoxy—4—m e t Π— pÍrÍdin-2-carbonitrile Int 61, [13579 23-331] Ala 499 499 103 o αγΧί Y ^Ν^ ΝΗ NCxNx χ5λ 5-[7-[[S-{3— methoxyazetidine-1ca rbo ni 1)—2—pi ridi í] a m ino]3-m eti Wmida zo [4,5b] pi ridi rt—5—Ϊ1 ]oxM-methi 1pyridin-2-carbonitrile Int 61, [11092 5-172] Ala 471 471 IF-2019-17407397- APN-ANP#INP?°1 Page 401 of 545 IF-2019-17407397-APN-ANP#INPI Page 402 of 545 Comp # Structure Name SM Mtd PM Month 104 ~Cz 3°° 5-[7-[[5-[3(methoxymethyl)azetidin-lcarbonyl]-2-pyridii]amino]3-methyl-imidazo[4,5b] pi ridin-5-II]ox¡-4-m ethyl- pyridin-2-carbonitrile Int61, 194230 8-067] Ala 485 485 105 2.^Z — ί-λί or 4-methyl-5-[3-methi 1-7[[5-{4-m eti Ipiperaz in-1carbonyl)-2pyridyl]amlno]imldazo[4,5bjpyridin-5-yljoxy—pyridin— 2-carbonitrile Int 61, [533273-0] Ala 484 484 106 o 7 m eti 1pyridin-2-carbonitrile Int 61, [12466 8-491] Ala 484 484 107 0 KrYk ΝΥχ Λ5 5-(7-([5-[(3R)-3(dimethylamino)pyrrolidinl-carbonylJpyridin-2yl]aminoJ- 3-methylimidazo[4,5b]pyridin—5—yl]oxy—4—methylpyridine-2-carbonitrifo Int 61, [13295 8-7261 Ala 498 498 IF-2019-17407397- APN- ANP#INP?02 Page 403 of 545 IF-2019-17407397-APN-ANP#INPI Page 404 of 545 Comp # Structure Name SM Mtd PM Month 108 0 nl °-9 %Anh NC^N xk-N XI 4-methyl-5-[3-methyl-7[[6-(morpholin-4carbonyl)pyridazin-3H]amino ]imidazo[4,5bjpyridin—5—itjoxyplridin—2— carbonitrile Int 63, [11091-8] Ala 472 472 109 z^z** 04 O 0“ 0-7 / / / z. 4-m ethyl-5-[3-m eti Ϊ—7—<4— morpholinanilino)imldazo[4, 5—b] pi ridi n-5-i IJoxl·pyridin-2-carbonitrile Int 2, [252467-6 ] Bl 442 442 110 I___ . t ^SlH *3Aju5 Y'OXN<!kN 4-methyl-5-[3-methyl-7-[4(4-methylpiperazin-lil)anilino]imidazo[4,5b]pyridin—5—i!]oxy— pyridine—2-carbonitrile Int 2, [16153 -81-4] Bl 455 455 111 hoY^'VXh n°3ÍjL. Xja I m idazo [4,5-b] pyridine n-5¡IJoxy—4—methyl—pyridin—2— carbonitrile Int 63, [13579 23-331] Ala 500 500 IF-2019-17407397-APN-ANP#INP?03 Page 405 of 545 IF-2019-17407397-APN-ANP#INPI Page 406 of 545 Comp It Structure Name SM Mtd PM Month 112 0 ^N^NH Y^O'Sl^'-N 5—[7—[(54(35)-3hydroxypyrrolidin-1carbonyl]—2—pyridyl]amino}— 3- methi H midazo [4,5bjpyridin—5-yljoxt—4-methyl—pyridine-2-carbonitrile Int61, [10024 3-398] Ala 471 471 113 0 HO VN^NH ΝΎ1 jl¿5 5-[7-[[5H3 -cyclopropyl-3hydroxl-azetidin-1ca rbo ni 1}—2—pyridin l]a mino]3-methyl l-imidazo[4,5b]pyridin—5—yl]oxy—4—methyl— plrÍdin-2-carbonitrilo Int61 , [84819 2-938] Ala 497 497 114 0 οσ*η 4,5bjpyridin—5—yl]oxy—pyridin— 2-carbonitrile Int 61, [17597-3] Ala 511 511 115 o >C / A] HO N*n-Anh nYi χ5λ 5-[7-[[H3hydroxyazetidin- 1carbonyl)pyridazin-3yl]amino]-3-methylimidazo[4,5-b]pyridin-5yljoxy—4—methyl—pyridin—2—carbonitrile Int 63, [45347 -82-8] Ala 458 458 116 0 x X / A 0 N'-'N-'SiH Ύ1 Aa 5-(74(643methoxyazetidirt-1carbonyl)pyridazin-3yl]amino]-3-methylimidazo[4,5-b]pyridin-5yl]oxF-4-methyl-pyridin- 2ca rbo nitrile Int 63, [45347 -82-8] Ala 472 472 IF-2019-17407397- APN- ANPtfINP?04 Page 407 of 545 IF-2019-17407397-APN-ANP#INPI Page 408 of 545 Co mp ft Structure Name SM Mtd PM Month 117 0 N JL *Ν^ΝΗ yvS*»i 5-[7-[[6-[3(methoxymethyl)azetidin-lcarbonyljpyridazin-3yl]aminoJ-3-methylÍmídazo[4,5 -b]pÍridin-5yljoxi—4—metí!—pirldin—2— carbonitrile Int 63, [94230 8-067] Ala 486 486 118 0 -jtYi N ΧΝ^ΝΗ V(AAN 5-[7-[[5-[ 3(hydroxymethyl)azetidin-lcarbonyl]-2-pyridyl]amlnoI3-methyl-imÍdazo[4,5b] pyrid i n—5—Π] oxy-4-methi 1plridin-2-ca rbonitrile Int 61, [92803 8—44— 21 Ala 471 471 119 0 πθΧνΧΟ. pyridyl] a m i noj3-methiMmidazo[4,5b]pyridin-5-¡l]oxM-methylptrid i n-2-ca rbonitrile Int 61, [12466 8-468] Ala 471 471 120 o ?ΆνΛΧ1 < / Sr'NH NC ^N ±n γ<ΑΑ? 4-methyl-5-[3-methyl-7[[5—(3—oxa—6— azasp!ro[3.3]heptan-6carbonyl)-2pyridyl]amino]imidazo[4, 5bjpyridln—5—yljoxy—pyridin— 2-ca rbonitrile Int 61, [93694 7-34U Ala 483 483 IF-2019-17407397- APN-ANP#INP?05 Page 409 of 545 IF-2019-17407397-APN-ANP#INPI Page 410 of 545 Comp # Structure Name SM Mtd PM Month 121 / NC___N 3-m et iH mida zo [4,5— b]pyridin-5-4l]oxM-methylpyridin-2-carbonitrile Int 61, (90584 3-938] Ala 485 485 122 VAx 0 NC^N r 1 ij> 1 —[6—I[S—[(6—cyano—4— methyl—3—pyridyljoxy]—3— methyl-imidazo[4,5- b] py rid in-7yljaminojpyridin—3— carbonyl]azetidine-3carboxylate tert -butyl Int61, (53871 -08-2] Ala 541 541 123 0 NC. N 1 N XI ÍI? 4-methyl-5-[3-m ethyl-7[[5—(6—methyl—2,6diazaspiro[ 3.3]heptan-2carboni!)-2pyridyl]amino]imidazo[4,5~ bjpyridin—5—yl]oxy—pyridin— 2-carbonitrile Int 61, (12035 67-116] Ala 496 496 124 0 jXci \jlj05 5— [7—[(5-(4hydroxypiperidin-lcarbonyl)pyridin-2yl]amino]-3methylimidazo[4,5bjpyridin—5—yljoxt—4— methylpyridin-2-carbonitrile Int61, [5382— 16-1] Ala 485 485 125 0 ?£AX 5-(7-((5-(4methoxypiperidin-1carbonii)pyridin-2yl]amino}-3methylimidazo[4,5b] pyrid i n—5—ΐϊ]οχΐ—4— methylpyridin-2-carbonitrile Int61, (404524 -3] Wing 499 499 IF-2019-17407397-APN-ΑΝΡ#ΙΝΡ?0θ Page 411 of 545 IF-2019-17407397-APN-ANP#INPI Page 412 of 545 Comp # Structure Name SM Mtd PM Month 126 0 Άο. StSih I NC> N XI i , [50533 -97-6] Ala 512 512 127 0 h°oVi Sr^NH 5-[74(5-[(3RHhydroxypyrrolidin-1carbonyljpyridin-2yljamlno]-3methyli mldazo [4,5b] pi ridi n-5-yl] oxy-4methylpyridin-2-carbonitrile Int61, [279921-5] Ala 471 471 128 0 ψ οΛγΠι ΟγΝ^ SXlH 0 NC\I< J. N -yloxy)3-methyl-3 H-im Idazo [4,5b]pyridin—7—itamino]— plridin-3-carbonyl}pipe ra zin-l-ca rboxyl ico Int 61, [57260 -71-61 Ala 570 570 129 z^z·^ .op A J o r z 547-[[5-[(3R}-342methoxyethoxy) pyrro 1 idi n-1carbonyl]pyridin—2— iI]amino]-3methylimidazo[4,5bjpyridin—5—yl] oxy—4—methylpyridine-2-carbonitrile Int61, [94261 8-260] Ala 529 529 IF-2019-17407397-APN-ANP#INP?07 Page 413 of 545 IF-2019-17407397-APN-ANP#INPI Page 414 of 545 Comp # Structure Name 5M Mtd PM Month 130 0 Λη ιΊ / X-J L 4,5bJpyridin-7-ylamino]pyridin-3-carbonyl}pyrrolidin—3—yl>—methyl— carbamic Int61, [17247 8-00- 1] Ala 584 584 131 o o;nAx 4-methyl-5-[3 -m eti 1-7[[5-{2-oxa-7azaspiro[3.4]octan-7ca rbo nil) pi ridin—2— yl]amino]imldazo[4,5bjpyridin—5—yljoxypyridin—2— carbonitrile Intel, [ 39640 -71-6] Ala 497 497 132 z^z-* x H ¿-TV 4¼ V —z 5-[7-I[5-[3[(dimethylamlno)methyl]azeti din—1—carbonyljpyridin—2— yl]amino}-3methylimidazo[4,5bjpyridin—5—lljoxy—4— methylpyridin-2-carbonitrile Int 61, [32189 0-226] Ala 498 498 133 O ><AX S-[7-[[5-[( 3S)-3(dimethylamino)pyrrolidin1-ca rbo nil] py ridin—2—yl]amino]-3methylimldazo[4,5bjpyridin—5—yl]oxy—4—methylpyridin-2-carbonitrile Int 61, [13288 3-444 ) Wing 498 498 IF-2019-17407397-APN-ANP#INP?08 Page 415 of 545 IF-2019-17407397-APN-ANP#INPI Page 416 of 545 Co mp # Structure Name SM Mtd PM Month 134 z i -Tjz 3=0 O >=\ w ^.ζ^,ζ 4-methyl-5-[3-fnetyl-7[[5-(2-oxa-6a zapyro [3.3] he pta n-6carbonyljpyridin-2yl]amino]imldazo[4,5b]pyridin-5-yljoxypyridin-2carbo nitrile Int61, [10457 09-327] Ala 483 483 135 ΗΟΑ / ΌΗ V oUn Nr'NH NC N Am t 1 f T '> 5-Γ7-[[5-[3,3bis(hydroxymethyl)azetidinl-carbonyl]pyridin-2yl]aminoJ-3methylimidazo[4,5b]pyridin—5—i(]oxy—4— methylpyridin- 2-carbonitrile Int 61, [10162 32-920] Ala 501 501 136 z i o AZ ( Λ > o z 7 )=\ p-i ^Z^Z 6-[[5-(6-cyano-4methylpyridin-3-yl)oxr- 3methylimidazo[4,5b]pyridi n-7-i l]amino}-N(2—hydroxyethylJ—N—methylpyridine—3carboxamide Int61, [10983-1] Ala 459 459 137 0 XA 4-methyl-5-[3 ~methyl-7[[5-{3-propan-2yloxyazetidin-1carbonyljpi ridin-2yl]amino]imidazo[4,5b] pyrid in—5—i 1] oxypyridi n-2carbonitrile Int61, [87165 7-497] Ala 499 499 IF-2019-17407397- APN- ANP#INP?09 Page 417 of 545 IF-2019-17407397-APN-ANP#INPI Page 418 of 545 Comp # Structure Name SM Mtd PM Month 138 κ OH NVx χ^> 5—[7—[[5—(4—hydroxy—4— methylpiperidin-1carbonyljpyridin—2— ll]amino]-3mettlimidazo[4,5b]plridin -5-yl]oxy-4methylpyridin-2-carbo nitrile Int 61, [397068-1] Ala 499 499 139 f^\ o ho-< 1 ][ H k A N ^N^NH 6-( [5—(6 -cia no-4methylpyridin—3—yl)oxy—3—methylimldazo[4,5b]pyridin-7-yl]amino}-N[rac-(lR,3R)-3hydroxycyclopentylpyridin3-carboxamide Int 61, [12455 5-335 ] Ala 485 485 140 HO F y o<SOl -lcarbonyl]pyridin-2yl]amlno]imidazo[4,5bjptridin-5-yljoxfplridin—2carbonitrile Int61, [13343 20-8291 Ala 489 489 IF-2019-17407397-APN-ANP#INP?10 Page 419 of 545 IF-2019-17407397-APN-ANP#INPI Page 420 of 545 Comp # Structure Name SM Mtd PM Month 141 z^z^ A » °-p< / o u X z 4-methyl-5-{3-methyl-7[[5-[rac-{3R,4R)-3 ,4dihldroxypiperidirt-1carbonyljpyridin—2— yl]amino]imidazo[4,5bjpyridin—5—ylxoxypyridin—2— carbonitrile Int 61, [39640 -71-6] Ala 501 501 142 Z^ 'Z / Ai :»< / 1 d z 4-methyl-5-[3-methyl-7[[5—[ra c—(3 M R)—3—fl uo r4-methoxypyrrolidin-lcarboniflpyridin-2yl]amino]imidazo[4,5- b]py ridin— 5—i 1] oxyp i ridin-2carbonitrile Int 61, [12035 66-986] Ala 503 503 143 1 n*n-^nh NCίΛ 5-[7-[[6-[3(dimethylamino)azetidin-l¡Ilpyridaztn —3—yljamino}—3— methylimidazo[4,5b]pyridin-54l]oxy-4methylpyridin-2-carbonitrile Int 2, Int 90 Bl 457 457 IF-2019-17407397-APN-ANP#INP?^1 Page 421 of 545 IF-2019-17407397-APN-ANP#INPI Page 422 of 545 Comp # Structure Name SM Mtd PM Month 144 z o ? O 2 z) ^Z^Z 4-methiF-5-[3-methyl-7[[5-[(2S}-2-methylmorpholin4-carbonyl]pyridin-2U]a amino] imidazo [4,5bjpyridin—5— njoxypyridin—2— carbonitrile Int 61, [74572 -13-7] Ala 485 485 145 Z^ Z^ Í-H dz ° °pA 0~ * o z 4-methyl-5-[3-m eti J—7[[ 5-[{2R)-2methylmorpholin-4carbonyljpyridin—2—yl]amino]imidazo[4,5b]pyridin—5-yljoxrpyridin—2carbonitrile Int 61, [16803 8-140] Ala 485 485 146 or .····% > θ^ΊΓΧ ,5bjpyridin—5—HJoxypyridin—2— carbonitrile Int61, [74572 -04-6] Ala 485 485 IF-2019-17407397-APN-ANP#INP?12 Page 423 of 545 IF-2019-17407397-APN-ANP#INPI Page 424 of 545 Comp # Structure Name SM Mtd PM Month 147 Z O · —p z v-z o o z λ ^Z^Z 4-methyl-5-[3-methyl-7[[5—[(3S)—3—methylmorpholin— 4-ca r bo n i 1] pyridin-2yl]amlno]imidazo[4,5bjpyridin-5-yljoxypyridin-2carbo nitrile Int 61, [35059 5-5721 Ala 485 485 148 o ... o4rx NrNH NV1 4-methyl-5-[3- methyl-7[[5-[ra c-{2R,65)-2,6dimethylmorpholine-4carbonyljpyridin-2ll]amino]imidazo[4,5b]pyridin—5—yl]oxtpyridin—2—carbonitrile Int 61, [648555- 8] Ala 499 499 149 z -0 J-d M 1 ^Ζ^,Ζ 4-methyl-5-[3-methyl-7[[5-[rac-{2R,6R)-2,6dimethylmorpholine-4carbonyl]pyridin- 2yl]amino]imldazo[4,5bjplrldin-5-yljoxlpyridin-2carbonitrile Int 61, [648545-6] Ala 499 499 IF-2019-17407397-APN-ANP#INP?13 Page 425 of 545 IF-2019-17407397-APN-ANP#INPI Page 426 of 545 Comp # Structure Name SM Mtd PM Month 150 K0 H * ^Ζ^,Ζ 4-methyl)pyridazin-3yl]amino] imidazo[4,5bjpyridin-5-yljoxypyridin-2carbonitrile Int 66 Int2 B1 485 485 151 0 '— ^N^NH F ' 3,5-d ifluo r-4-[3-m eti 1-7[[5-( 4-m eti 1 pipe razin-1carbonyljpyridin-2yl]amino]imidazo[4,5bjpyridin—5— yljoxybenzonitrile Int 92, Int 84 B1 505 505 152 z'^z·'' “45= 0 / -( r\ 2w r ~ Χ··ξ___4-tx 'J Z—f o / Z 4-m eti !-5-[3-m ethyl-7[[6-[(lMR)-5-methyl-2,5diazabicido[2.2.1]heptan2 -iljpyridazin-3yl]amino]imidazo[4,5b]pyridin-5-yl] oxypyrid i n-2carbo nitrile Int 3, Int 91 B2a 469. 469 153 / —N OH u N^NH ncyn1 5-{745H( 3R,4R}-3Dimethylamino-4-hydroxypyrrolidin-l-carbonyl)pyridin-2-ylamino}-3methi 1-3 H-im idazo[4,5b]pyridin-S-iioxy}—4-methylplridin-2-carbonitrile Int 61, [96028 9-616] 514 Wing 514 IF-2019-17407397-APN-ANP#INP?14 Page 427 of 545 IF-2019-17407397-APN-ANP#INPI Page 428 of 545 Comp # Structure Name SM Mtd PM Month 154 °—. N OH ΥΌΛΝΛΝ 547454(35, 45)-3Hydroxl-4-morpholin-44lpyrrolidin-l-carbonyl)pyridin-24lamino]-3m eti 1-3 H-imide zo[4,5b]py ridin-54 loxi)-4- met¡ 1pyridine-2-carbonitrile Int 61, [11873 39-8161 Ala 556 556 155 z o -tiz O Z Λ O >=\ M M * -2^2 4-methyl-5-[3-fT) ethyl—7— [ (5-(2(trifluoromethyl)morpholin-4carbonyljpyrldin-2yl]amino]imidazo[4,5bjpyridv—5-yl]oxypyridin-2ca rbo nitrile Int61, [11961 52-518] Ala 539 539 156 z o ^Z^Z 54741542ctdopropylmorpholine- 4carbonyl)pyridin-2yl]amino]-3methylimidazo[4,5b]pyridin-54l]oxH4methylpi ridin-2-ca rbo nitrile Int 61, [10637 34-79- 1] Ala 511 511 IF-2019-17407397-APN-ANP#INP?15 Page 429 of 545 IF-2019-17407397-APN-ANP#INPI Page 430 of 545 j Comp # Structure Name SM Mtd PM Month 157 J -< O Z A ^z^z 4-methi l-5-[3-methi 1-71(5—[(3R>—3—propa n-2llmorfolin-4carbonylJplridin-2ll ]amino]imldazo[4,5b]plridin-5-yljoxypyridin—2car bon it ri Io Int61, [74572 -01-3] Ala 513 513 158 -0' V “ ^Ζ^,Ζ 4-methyl-5 -[3-methyl-7[[5—{2—oxa—5— azabicyclo[2.2.1]heptan-5carbonyl)pyridin-2yl]amino]imidazo[4,5bjpyridin-5-!]oxypyridine-2carbonitrile Int 61 , [31560 -06-21 Ala 483 483 159 z o %0R<T ^z^z S-[7-[[5H3cyclopropylmorpholine-4carbonyl)pyridin-2yl]aminol-3methylimidazo[4,5b]pyridin—5—yljoxy—4 — methylpyridine-2-carbonitrile Int 61, [26066 7-057] Ala 511 511 IF-2019-17407397-APN-ANP#INP?16 Page 431 of 545 IF-2019-17407397-APN-ANP#INPI Page 432 of 545 Comp # Structure Name SM Mtd PM Month 160 z o -ti2 O z λ o \__ \X / / Z 4-[6-[ [5-{&-da no-4methylpyridin—3—yl)oxy—3— methylimidazo [4.5b] pyridin-7yljaminojpyridin—3— ca rbon II] morph Ün-2carbonitrile Int 61, [12057 51-070] Ala 496 496 161 z O I φ >φ \0 11 H ' ^Z^Z 4—Methyl— 5—{3-methyl—7—[5— ((3aS,6aS}—l—methyl— hexahydro-pyrrolo[3,4b]pyrrole-5-carbonyl)pyridine n-2-i la mi no]-3 Himidazo [4,5-b]pyridin-5yloxy}-pyridin-2carbonitrile Int 61, [87721 2-981) Ala 510 510 162 Z^Z* Í-X XX Q< & O o z z 4-[6-[[5- (6-cyano-4methylplridin—3—yljoxy—3—methylimldazo[4,5b]pyridin-7yljamino]pyridin-3carbonyl]morpholín-3ca rbo nitrile Int 61, [97039 -63-9] Ala 496 496 IF-2019-17407397-APN-ANP#INP?17 Page 433 of 545 IF-2019-17407397-APN-ANP#INPI Page 434 of 545 Comp It Structure Name SM Mtd PM Month 163 r VA OH Nx JL 'N^NH NCtx Λα 5H7-[[6-[(2R}-2(hydroxymethyl)morpholin-4yljplridazin-3-yljamino]—3methylimidazo[4,5b ] pyridine n—5—i 1 ] ο χϊ—4— methylpyridin-2-carbonitrile Int 3, Int 68 B2a 474 474 164 D D _ Ο-A ^'N 4-m ethyl-5-[3-methyl-7[[6-(27,3,3,5,5,6,6octa deirterio mo rfolli n-4yl)pyridazin-3yl]amino]imidazo[4 ,5b]pyridirt—5—iljoxt—pyridin— 2-ca rbo nitrile Int 3, Int 69 B2a 452 452 165 OH N. 1 'N^NH ΝΥχ Λα Y^O-'Si^N 5-[7-[[ 6-[{2S}-2(hydroxymethyl)morpholin-4yl]pyridazin-3-yl]amino]-3methylimidazo[4,5bjpyridtn—5—yl]oxy—4—methylpyridin-2-carbonitrile Int 3, Int 70 B2a 474 474 166 °^Ί ,..L n. *N^NH ν°ίΛ Λλ 5-[7-[[6-[(2S,65)-2,6dimethylmorpholirr-4lljpyridazin-3-yl]amino]-3methylimidazo[ 4,5b]pyridi n-5-yl]oxy-4methylpyridin-2-carbonitrile Int 3, Int 71 B2a 472 472 IF-2019-17407397-APN-ANP#INP? 18 Page 435 of 545 IF-2019-17407397-APN-ANP#INPI Page 436 of 545 Comp # Structure Name 5M Mtd PM Month 167 11 | N'N^NH N Yi iX 4-m ethyl-543-m eti 1-7[ [6-{1,4-oxaze pa n-4yljpyridazin-3yl]amino]imidazo[4,5bjpirldin-5-yljoxypyridin-2carbonitrile Int 3, Int 72 B2a 458 458 168 'zf^zr' 0 λ • ·<ζ> 2m °A / 5-[7-[[6-[(2R,6R)-2,6dimethylmorpholin-4yl]pyridazin-3 -yl]amino]-3methyl i midazo [4,5— bjpyridin-5-yl]oxy-4methylpyridin-2-carbonitrile Int 3, Int 73 B2a 472 472 169 X o / Co — / ”z ZRp 547-((642 (hydroxymethyl)morpholin-4yl]pyridazirt—3—yljamino]—3— methylimidazo[4,5b] pyridin—5—yljoxy—4— methylpyridin-2-carbonitrile Int 3, Int 74 B2a 474 474 170 z^z- x_H z —<z z RR \ V o — z 4-methyl-5-[3-methyl-7[[648-0X3-3azabicyclo[3.2.1]octan-3yljpyridazin—3— yl]amino]imidazo(4,5bjpyridin—5 —»1]oxypyridine—2— carbonitrile Int 3, Int 75 B2a 470 470 IF-2019-17407397-APN-ANP#INP? 1θ Page 437 of 545 IF-2019-17407397-APN-ANP#INPI Page 438 of 545 Comp # Structure Name SM Mtd PM Month 171 z ~ ° o o y-fi 4~[64 [5-{&-cia η 0-4— methylpyridin-3-yljoxl-3methylimidazo(4,5bjpyridin—7— yl]amino ]pyridazin-3- 11] m o rfo lin-2-ca rbonitri lo Int 3, Int 76 B2a 468 469 172 Nx jL NCxA 4—methyl—5—[3-methyl—7— ([G-í(2R>- 2methylmorpholyrY-4H]pyridazin—3— njamino]imidazo[4,5bjplridin-5-yljoxypyridin-2carbonitrile Int 3, Int 77 B2a 458 458 173 4v, i n JL 'Sr'SiH NCY1 ΛΪ5 4-m ethyl-5-[3- m ethyl-7[[6-[(2R)-2-propa n-2ylmorpholin—4-yl]pyridazin3-¡l]amino]Ím¡dazo[4,5bjpyridin—5—yljoxtpyridin—2— carbonitrile Int 3, Int 78 B2a 486 486 174 °7S N^N-AlH Ν°ϋ Ji¿5 4-methi l-5-[3-meti 1-7[[6-[(lS,4S}-2-oxa—5azabÍclclo[2.2 .1]heptan-5yljpyridazin-3¡l]amino]imidazo[4,5b]pyridin—5—yljoxyptridin—2— carbonitrile Int 3, Int 79 B2a 455 456 IF-2019-17407397-APN-ANP#INP?20 Page 439 of 545 IF-2019-17407397-APN-ANP#INPI Page 440 of 545 Co mp ft Structure Name SM Mtd PM Month 175 N*nXnH NCtX χχν 5-[7-[[6-{2,2dimethylmorpholine—4íljpyr...

Claims

1. A compound according to formula I (FORMULA I) wherein Cy is phenyl, or a 5- to 6-membered heteroaryl comprising one, two, or three N atoms; L1 is a single bond, -O-, -C(=O)O-; -S(O)2-, -NR 6a -, -C(=O)NR 6b -, -S(O)2NR 6c -, -C(=O)NR 6d S(O)2-; R1 is: H, C1-6 alkyl optionally substituted with one or more independently selected ◦ OH, ◦ halo, ◦ C1-4 alkoxy, ◦ -NR 7a R 7b , ◦ -C(=O)OH-, ◦ -C(=O)NR 7c R 7d , ◦ -C(=O)O C1-4 alkyl, or ◦ 4-8 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, S and O; C3-7 cycloalkyl optionally substituted with one or more OH, C1-4 alkoxy, or 4-9 membered monocyclic or spirobicyclic or bridged or fused bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N,S and O; said heterocycloalkyl is optionally substituted with one or more independently selected R11 groups; each R11 is independently: OH, CN, halo, oxo, -NR8aR8b, C3-7 cycloalkyl, C1-4 alkyl optionally substituted with one or more independently selected halo, OH, C1-4 alkoxy, -NR9aR9b, C1-4 alkoxy optionally substituted with a C1-4 alkoxy, 4-7 membered monocyclic heterocycloalkyl comprising one, two or three independently selected heteroatoms of N, S and O, -C(=O)O C1-4 alkyl, or -NR8c C(=O)O C1-4 alkyl; R2 is halo, CN, or C1-4 alkyl; subscript n is 0, or 1; L2 is O, or -NR4-, R3 is C1-6 alkyl optionally substituted with one or more independently selected ◦ halo, or ◦ C3-7 cycloalkyl, - Phenyl substituted with an R5a group and one or two independently selected R5b groups, - 6-membered heteroaryl comprising one or two N atoms,substituted with an R 5a group and one or two independently selected R 5b groups, - 4- to 10-membered monocyclic or fused, bridging, or spiro bicyclic heterocycloalkyl comprising one or two independently selected heteroatoms of N, S, and O, optionally substituted with one, two, or three independently selected groups of R 5a and R 5b, or - 4- to 10-membered monocyclic or fused, bridging, or spiro bicyclic cycloalkyl, optionally substituted with one, two, or three independently selected groups of R 5a and R 5b, R 4 is - H, - C1-4 alkyl optionally substituted with one or more independently selected groups of OH or C1-4 alkoxy or - C3-7 cycloalkyl; R 5a is -CN, -SO2-C1-4 alkyl, or -CF3; each R 5b is independently selected from halo, C1-4 alkyl and C3-7 cycloalkyl; each R 7a and R 7b is independently selected from -H, and C1-4 alkyl optionally substituted with one -NR 10a R 10b; and each R 6a , R 6b , R 6c , R 6d , R 7c , R 7d ,R8a, R8b, R8c, R9a, R9b, R10a, and R10b are independently selected from H, and C1-4 alkyl; or a pharmaceutically acceptable salt thereof, or a solvate or the solvate of a pharmaceutically acceptable salt thereof. Fourteen claims follow.