TYK2 inhibitor

Abstract

The present disclosure relates to a compound of formula (I), JPEG2025521886000126.jpg7055 or a pharmaceutically acceptable salt thereof, wherein all variable elements are as defined herein, to the compound or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure are capable of inhibiting the activity of tyrosine kinase 2 (TYK2). The present disclosure further provides methods for preparing the compounds of the present disclosure and methods for their therapeutic use.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 357,762, filed on July 1, 2022. The entire contents of the foregoing application are hereby expressly incorporated by reference herein.

Background Art

[0002] Cytokines are small molecular weight secreted proteins released by cells and have specific effects on cell-cell interactions and communication. The cytokine pathway mediates a wide range of biological functions, including many aspects of inflammation and immunity, mainly through extracellular signal transduction.

[0003] Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of cytoplasmic protein kinases associated with cytokine receptors and plays a central role in mediating cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1, and Yamaoka et al., Genome Biology 2004, 5, 253). The JAK family also includes JAK1, JAK2, and JAK3. More specifically, binding of cytokines to their cognate receptors causes activation of the associated JAKs, which leads to JAK-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately to activation of transcription of specific gene sets (Schindler et al, 2007, J. Biol. Chem. 282:20059-63). A number of cytokines known to activate the JAK family include the interferon (IFN) family (IFN-alpha, IFN-beta, IFN-omega, limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp)130 family (IL-6, IL-11, OSM, LlF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), the gammaC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), the IL-3 family (IL-3, IL-5, GM-CSF), the single-chain family (EPO, GH, PRL, TPO), the receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and the G protein-coupled receptor (AT1).

[0004] TYK2 is important in the signaling of type I interferons (e.g., IFN-alpha), IL-6, IL-10, IL-12, and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutic Targets, 2014, 18, 5, 571-580, Kisseleva et al., 2002, Gene 285:1-24, and Watford, W.T. & O’Shea, J.J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from TYK2-deficient humans are defective in the signaling of type I interferons, IL-6, IL-10, IL-12, and IL-23. TYK2 signals together with other members of the JAK family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, TYK2 / JAK1 / JAK2.

[0005] Studies have shown that inappropriate JAK activity results from mutations, overexpression, or inappropriate regulation, dysregulation, or deregulation, as well as overproduction or underproduction of growth factors or cytokines, and can thus cause various biological cell responses related to cell proliferation, cell differentiation, cell function, survival, apoptosis, and cell motility. Inappropriate JAK activity has been associated with many diseases including, but not limited to, cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease.

[0006] Small molecule JAK inhibitors have emerged as a major therapeutic advance in the treatment of autoimmune diseases. To date, all known small molecule JAK inhibitors in development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (also called the JH1 or “Janus homology 1” domain) of the JAK protein, preventing the kinase's catalytic activity by interfering with ATP, downstream phosphorylation, and the resulting pathway signaling (Bryan et al., J. Med. Chem. 2018, 61, 9030-9058).

[0007] Due to the high homology of the ATP active site throughout the kinome, especially within the JAK family, achieving high selectivity for specific JAK family members while maintaining selectivity within the kinome is a significant challenge. As a result, many of the JAK inhibitors developed are either pan-JAK inhibitors or moderately selective for one or more JAK family members. While these inhibitors have shown promising results in the treatment of autoimmune diseases, undesirable side effects leading to a narrow therapeutic index have been observed, suggesting a need for improved therapies.

[0008] TYK2 has been shown to be important in the differentiation and function of multiple cell types important in inflammatory and autoimmune diseases, including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with multiple autoimmune or inflammatory conditions.

[0009] There remains a need for potent compounds that show high selectivity for TYK2 compared to other members of the JAK family. SUMMARY OF THE INVENTION

[0010] One aspect of the present disclosure is a compound of formula (I):

Chemical formula

[0011] In one aspect, the present disclosure is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0012] Another aspect of the present disclosure is a method of inhibiting TYK2 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0013] In some aspects, the present disclosure is a method of treating a disease or disorder that is responsive to inhibition of TYK2 in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0014] The present disclosure also includes the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for manufacturing a medicament for inhibiting TYK2 activity. The use of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for manufacturing a medicament for treating a disease or disorder that is responsive to inhibition of TYK2 is also included.

[0015] The present disclosure also provides a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in inhibiting TYK2 activity. A compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a disease or disorder that is responsive to inhibition of TYK2 is also provided.

[0016] Other features or advantages will become apparent from the following detailed description of some embodiments and from the appended claims as well.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The compounds described herein or pharmaceutically acceptable salts thereof exhibit high potency against TYK2. In addition, the compounds of the present disclosure or pharmaceutically acceptable salts thereof have high selectivity for TYK2 inhibition compared to other members of the JAK family such as JAK1, JAK2, and JAK3.

[0018] I. DEFINITIONS As used herein, the phrase “optionally substituted” is used synonymously with the phrase “substituted or unsubstituted”. In general, the term “optionally substituted” refers to the replacement of a hydrogen radical in a given structure with a radical of a specified substituent. Specific substituents are described in the definitions as well as in the description of the compounds and their examples. Unless otherwise specified, an optionally substituted group may have substituents at each substitutable position of the group, and where two or more positions in any given structure may be substituted with two or more substituents selected from the specified group, the substituents may be the same or different at all positions. In some embodiments, an optionally substituted group may be substituted with one or more substituents, each of which may be the same or different. In some embodiments, the “one or more” substituents may be 1, 2, 3, 4, 5, 6, etc. substituents, each of which may be the same or different. In some embodiments, the “one or more” substituents may be 1 to 6, 1 to 4, 1 to 3, or 1 to 2 substituents, each of which may be the same or different.

[0019] As used herein, “halogen” or “halo” may be fluorine, chlorine, bromine, or iodine.

[0020] As used herein, "hydroxyl" or "hydroxy" refers to an -OH group.

[0021] As used herein, the number of carbon atoms in a group is specified herein by the prefix "C" x-xx ", where x and xx are integers. For example, "C" 1-4 alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0022] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. An alkyl group having 1 to 6 carbon atoms, i.e., C 1-6 alkyl may be preferred. Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and neopentyl. In some embodiments, the alkyl group is C 1-4 alkyl. In some embodiments, the alkyl group is C 1-3 alkyl.

[0023] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon group having at least one carbon-carbon double bond, which may be straight-chain or branched. An alkenyl group having 2 to 6 carbon atoms may be preferred. The alkenyl group may contain one, two or three carbon-carbon double bonds, or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

[0024] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which at least one of the hydrogen atoms is replaced by a halo atom. A haloalkyl group having 1 to 6 carbon atoms, i.e., C 1-6 haloalkyl may be preferred. C 1-6 haloalkyl is C 1-6 monohaloalkyl, C1-6 Dihaloalkyl or C 1-6 C containing perhaloalkyl 1-6 It may be polyhaloalkyl. C 1-6 Monohaloalkyl may have one iodine, bromo, chloro, or fluoro in the alkyl group. C 1-6 Dihaloalkyl and C 1-6 The polyhaloalkyl group may have two or more of the same halo atoms or a combination of different halo groups in the alkyl group. Usually, the C 1-6 The polyhaloalkyl group contains 2 to 14 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. C 1-6 The perhaloalkyl group refers to a C 1-6 alkyl group in which all hydrogen atoms are replaced by halo atoms.

[0025] As used herein, the term "oxo" (=O) refers to an oxygen atom bonded to a carbon or sulfur atom by a double bond. Examples include carbonyl, sulfinyl, or sulfonyl groups (-C(O)-, -S(O)-, or -S(O)2-), such as part of a ketone, aldehyde, or acid, ester, amide, lactone, or lactam group.

[0026] As used herein, the terms "aryl", "aryl group", "aryl ring", "aromatic group" and "aromatic ring" are used synonymously and refer to a 6- to 12-membered aromatic monocyclic or bicyclic carbocyclic system. Examples of aryl systems include, but are not limited to, phenyl, naphthyl, etc. An aryl group having a 6- to 10-membered ring system, i.e., C 6-10 aryl may be preferred.

[0027] As used herein, the terms "heteroaryl", "heteroaryl group", "heteroaromatic", and "heteroaromatic ring" are used synonymously for the purpose of referring to an aromatic monocyclic or bicyclic ring system having 5 to 12 members, having at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or combinations thereof), wherein the N can be oxidized (e.g., N(O)) or can be quaternized, and the S can optionally be oxidized to sulfoxide and sulfone. A heteroaryl group having a 5- to 10-membered ring system may be preferred. "Heteroaryl" includes heteroaromatic groups fused to a phenyl group or a non-aromatic heterocycle, such as tetrahydrofuran, pyran, pyrrolidine, piperidine, etc. Examples of heteroaryl include pyrrole, pyridyl, pyrazole, thienyl, furanyl, oxazolyl, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, indolyl, indazolyl, benzofuranyl, quinoxalinyl, and the like. In some embodiments, heteroaryl is selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, and pyrrole.

[0028] As used herein, the term "cycloalkyl" refers to a completely saturated monocyclic or bicyclic (e.g., fused, cyclic or bridged) hydrocarbon group having 3 to 12 carbon atoms, 3 to 6 carbon atoms or 5 to 7 carbon atoms. A cycloalkyl group having 3 to 8 carbons, i.e., C 3-8 cycloalkyl may be preferred. C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] As used herein, the term "heterocycloalkyl" refers to a fully saturated monocyclic or bicyclic (e.g., fused) ring system of 4 to 12 members having at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or combinations thereof). In some embodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatoms (preferably 1 or 2 heteroatoms). In some embodiments, a heterocycloalkyl group having a 4 to 10 membered ring system may be preferred. In some embodiments, the heterocycloalkyl group has 4 to 6 ring atoms (i.e., a 4 to 6 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen). In some embodiments, the heterocycloalkyl group has 4 to 6 ring atoms containing 1 heteroatom which is oxygen. In some embodiments, the heterocycloalkyl group is oxetane.

[0030] The phrase "pharmaceutically acceptable" indicates that a substance, composition or dosage form must be chemically and / or toxicologically compatible with the other ingredients in the formulation and / or the mammal being treated thereby.

[0031] Unless otherwise specified, the term "compounds of the present disclosure" refers to the compounds described herein, e.g., compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (IIA), (IIB), (IIIA), (IIIB), (IVA) or (IVB), and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotope-labeled compounds (including deuterium substitution). When moieties capable of forming salts are present, salts, particularly pharmaceutically acceptable salts, are likewise included. The compounds of the present disclosure may inherently or by design form their salts, hydrates and solvates, polymorphs.

[0032] As used herein, the terms "a", "an", "the" and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to include both the singular and the plural forms unless otherwise indicated herein or clearly contradicted by the context. The use of all examples or exemplary language provided herein (e.g., "such as") is merely intended to better illustrate the present disclosure and does not limit the scope of the present disclosure unless otherwise claimed.

[0033] When the compounds provided herein are sufficiently basic or acidic to form stable, non-toxic acid or base salts, the preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed using acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.

[0034] Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid to obtain a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) salts or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be produced.

[0035] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts or magnesium salts. Examples of salts derived from organic bases include primary amines, secondary amines or tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed amines of diamines and triamines, wherein at least two of the substituents on the amine may be different and they may be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl, etc., and salts of mixed amines, but are not limited thereto. Also included are amines in which two or three substituents together with the amino nitrogen form a heterocycloalkyl group or a heteroaryl group.Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine, etc. Other carboxylic acid derivatives, such as carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, etc., including carboxylic acid amides may be useful.

[0036] It will be understood by those skilled in the art that the compounds of the present disclosure may have chiral centers and thus may exist in different stereoisomeric forms. As used herein, the terms "optical isomers" or "stereoisomers" refer to any of the various stereoisomeric structures that may exist for a given compound of the present disclosure. It is understood that substituents may be attached at the chiral centers of carbon atoms. Accordingly, the present disclosure encompasses enantiomers, diastereomers, or racemates of the compounds.

[0037] Some of the compounds described herein contain one or more chiral centers or axes and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- from the perspective of absolute stereochemistry. According to the present disclosure, any structure without specifying stereochemistry is understood to include all various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, and mixtures thereof (e.g., racemic mixtures or mixtures enriched in enantiomers). Methods for preparing such optically active forms (e.g., resolution of racemates by recrystallization techniques, synthesis from optically active starting materials by chiral synthesis, or chromatographic separation using a chiral stationary phase) are well known in the art. In some embodiments, the compounds described herein are isolated stereoisomers, where each compound has one chiral center and the stereoisomer is in the R configuration. In other embodiments, the compounds described herein are isolated stereoisomers, where each compound has one chiral center and the stereoisomer is in the S configuration. In one embodiment, the compounds described herein are isolated stereoisomers, where each compound has two chiral centers and the stereoisomer is in the RR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, where each compound has two chiral centers and the stereoisomer is in the RS configuration. In one embodiment, the compounds described herein are isolated stereoisomers, where each compound has two chiral centers and the stereoisomer is in the SR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, where each compound has two chiral centers and the stereoisomer is in the SS configuration. In one embodiment, the compounds described herein are racemic mixtures, each having one or two chiral centers.

[0038] When a specific stereoisomer of a compound is indicated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the weight percentage of the desired stereoisomer relative to the total weight of all stereoisomers.

[0039] When a specific enantiomer of a compound is indicated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the weight percentage of the desired enantiomer relative to the total weight of all stereoisomers.

[0040] The stereochemistry of the disclosed compound is named or depicted in structure, and when the named or depicted structure encompasses two or more stereoisomers (e.g., in the case of a pair of diastereomers, etc.), it should be understood that one of the included stereoisomers or any mixture of the included stereoisomers is included. Further, it should be understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. Stereoisomeric purity means the weight percentage of the desired stereoisomer included by name or structure relative to the total weight of all stereoisomers.

[0041] When the disclosed compound is named or depicted in structure without indicating stereochemistry and the compound has one chiral center, its name or structure should be understood to include one enantiomer of the compound in pure or substantially pure form, and mixtures thereof (such as a racemic mixture of the compound and a mixture in which one enantiomer is enriched compared to its corresponding optical isomer).

[0042] Unless otherwise specified, the compounds of the present disclosure are intended to encompass all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. The optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques (e.g., chiral SFC or by using an appropriate solvent or solvent mixture to achieve good separation on HPLC chromatography columns such as CHIRALPAK RTM and CHIRALCEL RTM etc.). When a compound contains a double bond, the substituents can be in the E configuration or the Z configuration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have the cis configuration or the trans configuration. All tautomeric forms are also intended to be included.

[0043] If the disclosed compounds are described by name or by structure without indicating stereochemistry, and, for example, if the compound has at least two chiral centers, the name or structure is to be understood to include one stereoisomer in pure or substantially pure form, and mixtures thereof (mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers are enriched compared to other stereoisomer(s), etc.).

[0044] The disclosed compounds may exist in tautomeric forms, and mixtures and separated individual tautomers are contemplated. All such forms are included within the scope of the present disclosure. In addition, some compounds may exhibit polymorphism. The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) involve interconversion by the movement of a proton, e.g., keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety where the proton can move between two ring nitrogens. Valence tautomers involve interconversion by some rearrangement of bonding electrons.

[0045] Furthermore, the compounds of the present disclosure (including their salts) can also be obtained in the form of their hydrates or can contain other solvents used in their crystallization. The compounds of the present disclosure can form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design, and thus the present disclosure is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0046] Compounds of the present disclosure containing groups that can act as hydrogen bond donors and / or acceptors can form co-crystals with suitable co-crystallization agents. These co-crystals can be prepared from the compounds by known co-crystallization procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting the compound with the co-crystallization agent under crystallization conditions in solution and isolating the co-crystals thus formed. Suitable co-crystallization agents include those described in WO 2004 / 078163. Accordingly, the present disclosure further provides co-crystals comprising the compounds described herein.

[0047] In one embodiment, the present disclosure provides a deuterated compound disclosed herein, where any or more positions occupied by hydrogen can include enrichment with deuterium in excess of the natural abundance of deuterium. For example, one or more hydrogen atoms are at least 3340 times higher in abundance than the natural abundance of deuterium, replaced with deuterium at an abundance of 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). In one embodiment, hydrogen is present at its natural abundance at all positions.

[0048] II. Compounds of the Present Disclosure In a first embodiment, the compound of the present disclosure is represented by formula (I) or a pharmaceutically acceptable salt thereof, and the variable elements are as described above. In some embodiments, X5 is N.

Chemical Formula

[0049] In a second embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, X2 is NH or CR 2 and the remaining variable elements are as described in the first embodiment. In some embodiments, X2 is NH or CH.

[0050] In a third embodiment, the compound is of formula (II), (III), (IV), (V), (VI) or (VII):

Chemical Formula

[0051] In the fourth embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, Y is CR 7 R 8 and the remaining variable elements are as described in the first, second or third embodiment.

[0052] In the fifth embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, Y is O, and the remaining variable elements are as described in the first, second or third embodiment.

[0053] In the sixth embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, Y is NR 9 and the remaining variable elements are as described in the first, second or third embodiment.

[0054] In the seventh embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 1 is a 5- to 6-membered heteroaryl optionally substituted with one, two or three R 10 and the remaining variable elements are as described in the first, second, third, fourth, fifth or sixth embodiment.

[0055] In the eighth embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 1is a 5- or 6-membered heteroaryl selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, pyridine, pyridazine, pyrimidine and pyrazine, each of which is optionally substituted with one, two or three R 10 and the remaining variable elements are as described in the first, second, third, fourth, fifth, sixth or seventh embodiment.

[0056] In a ninth embodiment, for a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 1 is a 5- or 6-membered heteroaryl selected from pyrazole, isoxazole, pyridine and pyridazine, each of which is optionally substituted with one or two R 10 and the remaining variable elements are as described in the first, second, third, fourth, fifth, sixth or seventh embodiment.

[0057] In a tenth embodiment, for a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 1 is

Chemical formula

Chemical formula

[0058] In an eleventh embodiment, for a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 10 is halo, -OR 1c , C 1-6 alkyl and C1-6 independently selected from haloalkyl, R 1c is C 1-4 alkyl, and the remaining variable elements are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0059] In the twelfth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, R 10 is independently selected from F, -OCH3, -CH3 and -CHF2, and the remaining variable elements are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0060] In the thirteenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, R 2 R 3 and R 4 are each independently H, halo, C 1-4 alkyl and C 1-4 haloalkyl, and the remaining variable elements are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0061] In the fourteenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, R 2 R 3 and R 4 are H, and the remaining variable elements are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0062] In the fifteenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, R5 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl or a 5- to 6-membered heteroaryl optionally substituted with one, two or three R 10 and the remaining variable elements are as described in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, or 14th embodiment.

[0063] In the 16th embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 5 is H and the remaining variable elements are as described in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, or 15th embodiment.

[0064] In the 17th embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 7 and R 8 are each independently H, halo, CN, -OR 1c -SO2R 1c and are optionally substituted with one or more substituents independently selected from halo, CN, and -OR 1c alkyl selected from C 1-6 alkyl, or R 7 and R 8 together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl, and R 1c is H or C 1-3 alkyl and the remaining variable elements are as described in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, or 16th embodiment.

[0065] In the 18th embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R7 and R 8 are each independently selected from H, F, CN, -OH, -OCH3, -SO2CH3, -CH3, -CHF2, -CF3, -CH2-CN, -CH2-O-CH3, and -CH2CH2-O-CH3; or R 7 and R 8 together with the carbon atoms to which they are attached. [ka] and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0066] In a nineteenth embodiment, for compounds of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharma- ceutically acceptable salt thereof, r is 0, 1 or 2, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0067] In a twentieth embodiment, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharma- ceutically acceptable salt thereof, R 6 For each occurrence, independently, H,-OR 1c , C 1-4 C optionally substituted with haloalkyl and CN 1-4 alkyl, or two R 6 together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl; R 1c is H or C 1-3 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0068] In the 21st embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 6 is, each occurrence, independently selected from H, -OH, -OCH3, -CH2-CN, and -CH3, or two Rs 6 together with the carbon atom to which they are attached,

Chemical formula

[0069] In the 22nd embodiment, for the compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 1 is a 5- to 6-membered heteroaryl optionally substituted with one, two or three Rs 10 , Rs 2 , Rs 3 , and Rs 4 are each independently selected from H, halo, C 1-4 alkyl and C 1-4 haloalkyl, Rs 5 is H, halo, C 1-4 alkyl, C 1-4 haloalkyl or a 5- to 6-membered heteroaryl optionally substituted with one, two or three Rs 10 , Rs 6 is, each occurrence, independently selected from H, -OR 1c , C 1-4 haloalkyl and C 1-4 alkyl optionally substituted with CN, or two Rs 6 together with the carbon atom to which they are attached, form a 4-membered heterocycloalkyl, Rs 7 and Rs 8 are each independently selected from H, halo, CN, -OR 1c , -SO2R1c and halo, CN, and -OR 1c optionally substituted with one or more substituents independently selected from C 1-6 alkyl, or R 7 and R 8 together with the carbon atom to which they are attached form a 4-membered heterocycloalkyl, R 9 is H or C 1-6 alkyl, R 10 is halo, -OR 1c C 1-6 alkyl and C 1-6 haloalkyl, independently selected from R 1a and R 1b are each independently H or C 1-4 alkyl, R 1c is H, C 1-4 alkyl, r is 0, 1 or 2, and the remaining variable elements are as described in the first, second, third, fourth, fifth, or sixth embodiments.

[0070] In the 23rd embodiment, for the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), or pharmaceutically acceptable salts thereof, R 1 is a 5- to 6-membered heteroaryl selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, pyridine, pyridazine, pyrimidine and pyrazine, each of which is optionally substituted with one, two or three R 10 and R 2 R 3 and R 4 are H, R 5 is H, halo, C 1-4 alkyl or C 1-4 haloalkyl, R 6 is, each occurrence, independently selected from H, -OR 1c C 1-4 haloalkyl and CN, optionally substituted C 1-4 alkyl, or two R 6together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl, and R 7 and R 8 are each independently H, halo, CN, -OR 1c , -SO2R 1c , and are each independently selected from one or more substituents selected from halo, CN, and -OR 1c and are optionally substituted C 1-6 alkyl, or R 7 and R 8 together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl, R 9 is H or C 1-4 alkyl, R 10 is halo, -OR 1c , C 1-4 alkyl and C 1-4 haloalkyl, R 1c is H or C 1-4 alkyl, and the remaining variable elements are as described in the first, second, third, fourth, fifth, or sixth embodiments.

[0071] In the twenty-fourth embodiment, the compound is of formula (IIA), (IIB), (IIIA), (IIIB), (IVA) or (IVB):

Chemical formula

[0072] In the twenty-fifth embodiment, for a compound of formula (I), (II), (IIA), (IIB), (III), (IIIA), (IIIB), (IV), (IVA), (IVB), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 6 is, each occurrence independently, H and C 1-4Selected from alkyl, R 7 and R 8 are each independently H, halo, CN, and C 1-4 selected from alkyl, R 10 is -OR 1c , C 1-4 alkyl, and C 1-4 selected from haloalkyl, R 1c is C 1-4 alkyl, r is 0, 1 or 2, and the remaining variable elements are as described in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, or 24th embodiments.

[0073] In the 26th embodiment, for the compound of formula (I), (II), (IIA), (IIB), (III), (IIIA), (IIIB), (IV), (IVA), (IVB), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, R 6 is H or CH3, R 7 and R 8 are each independently selected from H, F, CH3 and CN, R 10 is selected from CH3, CHF2 and OCH3, r is 0, 1 or 2, and the remaining variable elements are as described in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, or 24th embodiments.

[0074] In the 27th embodiment, for the compound of formula (I), (II), (IIA), (IIB), (III), (IIIA), (IIIB), (IV), (IVA), (IVB), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, r is 0, and the remaining variable elements are as described in the 24th, 25th, or 26th embodiments.

[0075] In the 28th embodiment, a compound selected from any one of the following: (1R,3r)-1-Methyl-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-1-Methyl-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1R,3r)-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, 7-(8-((1r,3R)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine, 7-(8-((1s,3S)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine, (1RS,2RS)-2-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol, (1RS,2SR)-2-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol, 2-(1-methyl-1H-pyrazol-4-yl)-7-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridine, 7-((1R,5S)-8-(3-(difluoromethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1] (Octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine, 7-(8-(azetidin-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride, 2-(1-methyl-1H-pyrazol-4-yl)-7-(8-(1-methylazetidin-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridine trifluoroacetate, 3-(3-(2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3S)-3-(3-(2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile. (1R,3r)-3-(3-(2-(2-Methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-3-(3-(2-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-3-(3-(2-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, 2-(2-Methoxypyridin-4-yl)-4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine, 4-(8-(3-(Difluoromethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine, 2-[3-[3-[6-(1-Methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]oxetan-3-yl]acetonitrile, 3-[3-[6-(1-Methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclobutane-1-carbonitrile, 3-[3-[6-(1-Methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-1-(trifluoromethyl)cyclobutan-1-ol, 6-(1-Methylpyrazol-4-yl)-4-[8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrrolo[1,2-b]pyridazine, 4-[8-(3-Methoxycyclobutyl)-3,8-diazabicyclo[3.2.1][Octan-3-yl]-6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine, 3-[3-[6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclobutan-1-ol, 4-(8-cyclobutyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine, (1R,3r)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-carbonitrile, (1S,3s)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-carbonitrile, 4-(8-((1r,3R)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine, 4-(8-((1s,3S)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine, (1R,3r)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol, (1S,3s)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol, 6-(1-methylpyrazol-4-yl)-4-[8-(2-oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrrolo[1,2-b]pyridazine, (1r,3r)-1-methyl-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1] (Octan-8-yl)cyclobutane-1-carbonitrile, (1S,3S)-1-methyl-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, 6-(1-methyl-1H-pyrazol-4-yl)-4-(8-((1S,3S)-3-(methylsulfonyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine, 6-(1-methyl-1H-pyrazol-4-yl)-4-(8-((1R,3R)-3-(methylsulfonyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine, (1R,3R)-1-(2-methoxyethyl)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3S)-1-(2-methoxyethyl)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, 4-(8-((S)-2-oxaspiro[3.3]heptan-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine, 4-(8-((R)-2-oxaspiro[3.3]heptan-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine, (1S,3S)-1-(methoxymethyl)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1R,3R)-1-(methoxymethyl)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1] (Octan-8-yl)cyclobutane-1-carbonitrile, 2-((1S,3S)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutyl)acetonitrile, 2-((1R,3R)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutyl)acetonitrile, Rac-(1R,3R)-2,2-dimethyl-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1R,3S)-2,2-dimethyl-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3R)-2,2-dimethyl-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, rac-(1S,2S)-2-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol, rac-(1R,2S)-2-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol, Rac-4-(8-((1S,2S)-2-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine, 4-[8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1] [3-Octanyl]-6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine, 6-(6-methoxypyridazin-4-yl)-4-[8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrrolo[1,2-b]pyridazine, 3-[3-[6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclobutane-1-carbonitrile, 3-[3-(6-pyridazin-4-ylpyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclobutane-1-carbonitrile, 4-[8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-pyridazin-4-ylpyrrolo[1,2-b]pyridazine, 3-[3-[6-(6-methylpyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]cyclobutane-1-carbonitrile, (1R,3r)-3-(3-(6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-3-(3-(6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-3-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1R,3r)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1) (Octan-8-yl)cyclobutane-1-carbonitrile, (1R,3r)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, (1S,3s)-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]oct. (Octan-8-yl)cyclobutane-1-carbonitrile, and (1R,3r)-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

[0076] III. Pharmaceutical Compositions In another embodiment, the disclosure is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0077] As used herein, the term "pharmaceutically acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and the like, generally recognized as safe (GRAS) as known to those of ordinary skill in the art, and combinations thereof (see, e.g., Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Its use in therapeutic or pharmaceutical compositions is contemplated, except where any conventional carrier is incompatible with the active ingredient.

[0078] Formulations can be prepared using conventional dissolution and mixing procedures. For example, bulk drug substance (i.e., the compounds of the present disclosure or stabilized forms of the compounds (e.g., complexes with cyclodextrin derivatives or other known complexing agents)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compounds of the present disclosure are typically formulated into pharmaceutical dosage forms in order to provide a drug with an easily adjustable dosage and to provide a product that is simple and easy to handle for the patient.

[0079] Pharmaceutical compositions (or formulations) for use can be packaged in a variety of ways depending on the method used to administer the drug. Generally, articles for distribution include a container in which a pharmaceutical formulation in a suitable form is disposed. Suitable containers are known to those of ordinary skill in the art and include, for example, bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container can also include an anti-tampering mechanism to prevent inadvertent access to the contents of the package. In addition, the container has a label thereon that describes the contents of the container. The label can also include appropriate warnings.

[0080] Pharmaceutical compositions containing the compounds of the present disclosure are generally formulated for use in parenteral or oral administration.

[0081] For example, the oral pharmaceutical composition of the present disclosure can be made in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical processes such as sterilization, and / or contain conventional inert diluents, lubricants, or buffering agents, in addition to adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffer solutions.

[0082] Generally, the pharmaceutical composition contains the active ingredient a) diluents such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol, also in the case of tablets c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired d) disintegrants such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) absorbents, colorants, flavors and sweeteners, and is a tablet or gelatin capsule.

[0083] Tablets can be film-coated or enteric-coated according to methods known in the art.

[0084] Compositions suitable for oral administration include tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or the compounds of the present disclosure in the form of syrups or elixirs. Compositions intended for oral use are prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives in order to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time delay substances such as glyceryl monostearate or glyceryl distearate may be used. Preparations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium such as peanut oil, liquid paraffin, or olive oil.

[0085] The parenteral composition (e.g., intravenous (IV) formulation) is an aqueous isotonic solution or suspension. The parenteral composition can be sterilized and / or can contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for adjusting osmotic pressure, and / or buffers. In addition, they can also contain other therapeutically valuable substances. The compositions are generally prepared by conventional mixing, granulating, or coating methods respectively and contain from about 0.1% to 75% or from about 1% to 50% of the active ingredient.

[0086] IV. USES OF THE COMPOUNDS AND COMPOSITIONS OF THE DISCLOSURE The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to decrease or inhibit the activity of TYK2 or otherwise affect the properties and / or behavior of TYK2, such as stability, phosphorylation, kinase activity, interaction with other proteins, etc.

[0087] In some embodiments, the disclosure provides a method of inhibiting TYK2 activity in a subject in need of inhibiting TYK2 activity, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0088] As used herein, the terms "inhibit", "inhibition", or "inhibiting" refer to a reduction or suppression of the baseline activity of a biological activity or biological process, or a significant decrease.

[0089] One embodiment of the present disclosure is a method of treating a disease or disorder that is responsive to the inhibition of TYK2 in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the methods described herein treat a disease or disorder that is responsive to the inhibition of TYK2, where the disease or disorder includes, but is not limited to, inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular diseases, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, head trauma, neurodegeneration, liver diseases, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, autoimmune diseases, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, flushing, eczema, psoriasis, atopic dermatitis, and sunburn.

[0090] The term "autoimmune disorder" includes diseases or disorders associated with an inappropriate immune response to a native antigen, such as, but not limited to, acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, diabetes type 1, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjögren's syndrome, temporal arteritis, and Wegener's granulomatosis.

[0091] The term "inflammatory disorder" includes diseases or disorders associated with acute or chronic inflammation, such as allergies, asthma, atopic dermatitis, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, such as Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.

[0092] The term "cancer" includes diseases or disorders associated with abnormal cell growth and / or proliferation, such as glioma, thyroid cancer, breast cancer, lung cancer (such as small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, cholangiocarcinoma, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (such as anaplastic large cell lymphoma), leukemia (such as acute myeloid leukemia, T cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (such as high-frequency microsatellite instability colorectal cancer).

[0093] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as a human, companion animal (such as a dog, cat, etc.), livestock (such as a cow, pig, horse, sheep, goat, etc.), and laboratory animal (such as a rat, mouse, guinea pig, etc.). Typically, the subject is a human in need of treatment.

[0094] As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect can be therapeutic and includes partially or completely reducing the degree of a disease, disorder, or syndrome; remitting or improving clinical symptoms or indicators associated with the disorder; or partially or substantially achieving one or more of the results of delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0095] The effective dose of the compounds provided herein, or pharmaceutically acceptable salts thereof, administered to a subject can be from 10 μg to 500 mg.

[0096] Administration of the compounds described herein or pharmaceutically acceptable salts thereof to a mammal includes any suitable delivery method. Administration of the compounds described herein or pharmaceutically acceptable salts thereof to a mammal involves administering the compounds described herein or pharmaceutically acceptable salts thereof to the mammal locally, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Also, administration of the compounds described herein or pharmaceutically acceptable salts thereof to a mammal involves administering to the mammal a compound that is metabolized in the body or on the body surface of the mammal to the compounds described herein or pharmaceutically acceptable salts thereof locally, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.

[0097] Accordingly, the compounds described herein or pharmaceutically acceptable salts thereof can be administered systemically orally, for example, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an absorbable edible carrier. They can be encapsulated in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the compounds described herein or pharmaceutically acceptable salts thereof can be combined with one or more excipients and used in the form of tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers that are orally ingestible. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentages of the compositions and preparations can of course vary and can conveniently be about 2 to about 60% by weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions can be such that an effective dosage level is achieved.

[0098] Tablets, troches, pills, capsules, etc. may contain the following: binders such as tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; or sweeteners such as sucrose, fructose, lactose, or aspartame, or flavoring agents.

[0099] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water and optionally mixed with a non-toxic surfactant.

[0100] Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions containing the active ingredient, or sterile powders containing the active ingredient suitable for the extemporaneous preparation of injectable or infusible sterile solutions or dispersions. In all cases, the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.

[0101] Sterile injection solutions can be prepared by incorporating the required amount of the active compound into a suitable solvent containing the various other ingredients listed above, followed by filter sterilization if necessary. In the case of sterile powders for the preparation of sterile injection solutions, the preferred methods of preparation can be vacuum drying and freeze-drying techniques that can yield a powder of the active ingredient and any additional desired ingredients present in a previously sterile-filtered solution.

[0102] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohol, or glycol, or water-alcohol / glycol mixtures in which the compounds described herein or their pharmaceutically acceptable salts can be dissolved or dispersed at effective levels, optionally with the aid of a non-toxic surfactant.

[0103] Useful dosages of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known to those of skill in the art, see, for example, U.S. Patent No. 4,938,949, which is incorporated herein by reference in its entirety.

[0104] The amount of the compound described herein or its pharmaceutically acceptable salt required for use in therapy can vary not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and can ultimately be at the discretion of the attending physician or clinician. However, in general, the dosage can be in the range of about 0.1 to about 10 mg / kg body weight per day.

[0105] The compounds described herein or their pharmaceutically acceptable salts can conveniently be administered in unit dosage forms containing, for example, from 0.01 to 10 mg, or from 0.05 to 1 mg of the active ingredient per unit dosage form. In some embodiments, dosages of 5 mg / kg or less may be suitable.

[0106] The desired dosage can conveniently be provided as a single dose, or as divided doses administered at appropriate intervals.

[0107] The methods of the present disclosure can include a kit, the kit including the compound described herein or its pharmaceutically acceptable salt, and instructional materials that can describe administering to a cell or subject the compound described herein or its pharmaceutically acceptable salt or a composition comprising the compound described herein or its pharmaceutically acceptable salt. This is to be construed as encompassing other embodiments of kits known to those of skill in the art, such as kits including a solvent (e.g., a sterile solvent) for dissolving or suspending the compound described herein or its pharmaceutically acceptable salt, or the composition, prior to administering the compound described herein or its pharmaceutically acceptable salt, or the composition, to a cell or subject. In some embodiments, the subject can be a human.

[0108] The compounds of the present disclosure can be synthesized by synthetic routes that include processes similar to those well known in the chemical arts, particularly in view of the descriptions contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich or can be readily prepared using methods known to those of skill in the art (e.g., generally by the methods described in Louis F. Fieser and Mary F. Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin (also available via the Beilstein online database) including appendices).The protection of functional groups by protecting groups, the protecting groups themselves, and their cleavage reactions are described in standard reference books such as, for example, J.F.W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, and H.-D. Jakubke and H. Jeschkeit, “Aminosauren, Peptide, Proteine” (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982. The characteristics of the protecting groups are, for example, that they can be readily removed by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g., enzymatic cleavage) (i.e., no unwanted secondary reactions occur).

[0109] Salts of the compounds of the present disclosure having at least one salt-forming base can be prepared by methods known to those skilled in the art. For example, acid addition salts of the compounds of the present disclosure are obtained according to convention, for example, by treating the compound with an acid or a suitable anion exchange reagent. The salts can be converted to the free compound according to methods known to those skilled in the art. Acid addition salts can be converted, for example, by treatment with a suitable basic agent.

[0110] Any of the resulting mixtures of isomers can be separated into pure or substantially pure geometric isomers or optical isomers, diastereomers, racemates, etc. by, for example, chromatography and / or fractional crystallization based on the physicochemical differences of the components.

[0111] In compounds containing an asymmetric carbon atom, the compound exists in individual optically active isomeric forms or as mixtures thereof, for example, as a racemic mixture or a mixture of diastereomers. A mixture of diastereomers can be separated into their individual diastereoisomers based on their physicochemical differences by methods known to those skilled in the art, for example, by chromatography and / or fractional recrystallization. Enantiomers can be separated by converting a mixture of enantiomers into a mixture of diastereomers by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using commercially available chiral HPLC columns.

[0112] This disclosure further includes any variant forms of the processes herein in which the reaction components are used in the form of their salts or optically pure materials. The compounds and intermediates of this disclosure can also be converted into each other according to methods widely known to those skilled in the art.

[0113] For illustrative purposes, the reactions described below provide possible routes for synthesizing the major intermediates as well as the compounds of this disclosure. For a more detailed description of the individual reaction steps, refer to the Examples section below. Specific starting materials and reagents are shown in the schemes and described below, but other starting materials and reagents can be readily substituted to provide various derivatives and / or reaction conditions. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

Examples

[0114] The compounds of the examples described below were analyzed or purified according to one of the purification methods mentioned below, unless otherwise stated.

[0115] Abbreviations: Aq. means an aqueous solution, Bn means benzyl, Boc means tert-butoxycarbonyl, Boc2O means di-tert-butyl dicarbonate, br means broad, t-BuOH means tert-butanol, n-BuLi means n-butyllithium, ℃ means degrees Celsius, CDCl3 means deuterated chloroform, δ means chemical shift, d means doublet, dd means doublet of doublets, DCM means dichloromethane, DEA means diethylamine, DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine, DMA means N,N-dimethylacetamide, DMF means N,N-dimethylformamide, DMSO means dimethyl sulfoxide, DMSO-d6 means hexadeuterodimethyl sulfoxide, Et means ethyl, EtOH means ethanol, EtOAc means ethyl acetate, Eq. means equivalent, g means gram, HCl means hydrochloric acid, HCO2H means formic acid, 11H NMR means proton nuclear magnetic resonance, H2O means water, HPLC means high performance liquid chromatography, h means time, IPA means 2-propanol, K2CO3 means potassium carbonate, KF means potassium fluoride, KOH means potassium hydroxide, L means liter, LCMS means liquid chromatography mass spectrometry, LDA means lithium diisopropylamide, m means multiplet, M means mole, Me means methyl, MeCN means acetonitrile, MeI means iodomethane, MeOH means methanol, MeOH-d4 means deuteromethanol, mg means milligram, MgSO4 means magnesium sulfate, MHz means megahertz, mins means minutes, mL means milliliter, mmol means millimole, MS m / z means mass spectrum peak, MsCl means methanesulfonyl chloride, N2 means nitrogen, NaBH4 means sodium borohydride, NaBH3CN means sodium cyanoborohydride, Na2CO3 means sodium carbonate, NaH means sodium hydride, NaHCO3 means sodium bicarbonate, NaIO4 means sodium periodate, NaOH means sodium hydroxide, Na2SO4 means sodium sulfate, NBS means N-bromosuccinimide, NH3 means ammonia, NH4Cl means ammonium chloride, NH4OH is ammonium hydroxide, NOE means nuclear Overhauser effect spectroscopy, PE means petroleum ether, Pd(amphos)Cl2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium(0), Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), PdCl2(PPh3)2 means bis(triphenylphosphine)palladium(II) dichloride, Pd / C means palladium on carbon, POCl3 means phosphorus oxychloride, q means quartet, rt means room temperature, RuCl3 means ruthenium(III) chloride, s means singlet, sat. means saturated, SFC means supercritical fluid chromatography, soln. means solution, t means triplet, TBME means tert-butyl methyl ether, TEA means triethylamine, TFA means trifluoroacetic acid, THF means tetrahydrofuran, TLC means thin layer chromatography, TsCl means para-toluenesulfonyl chloride, TsOH means para-toluenesulfonic acid, μL means microliter, μmol means micromole, and RuPhos Pd G3 means (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate.

[0116] General synthetic methods According to the first process, the compound of formula (I) can be prepared from the compounds of formula (AII), (AIII), (AIV) and (AV) exemplified in Scheme 1.

[0117] Scheme 1 [Chemical formula] LG1 and LG2 are suitable leaving groups, typically a halogen such as Cl, Br, or I, or a sulfonate such as mesylate, tosylate or triflate. W is a suitable boronate ester such as boric acid or pinacol boronate ester.

[0118] The compound of formula (AIV) is obtained from the compound of formula (AII) and the compound of formula (AIII) under thermal or transition metal catalyst conditions, S NIt may also be prepared using a suitable nucleophilic substitution reaction such as Ar. Typical conditions include the reaction of an amine of formula (AIII) and a compound of formula (AII) in a suitable solvent, at a high temperature, optionally under microwave irradiation, in the presence of a suitable palladium catalyst in the presence of a suitable inorganic base and a suitable phosphine ligand. Preferred conditions include the reaction of compounds of formulas (AII) and (AIII) in a suitable solvent such as dioxane, THF or toluene, at 70 °C to 110 °C, optionally under microwave irradiation, in the presence of RuPhos Pd G3 or xantphos, optionally in combination with Pd2(dba)3, in the presence of a suitable base such as K2CO3, K3PO4 or Cs2CO3. Alternatively, the compounds of formulas (AII) and (AIII) can be reacted together in a suitable aprotic solvent, at 70 °C to 110 °C, optionally under microwave irradiation, in the presence of a suitable base such as TEA.

[0119] The compound of formula (I) can be prepared from compounds of formulas (AIV) and (AV) by a palladium-catalyzed cross-coupling reaction such as the Suzuki reaction. Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand in the presence of an inorganic base, in a suitable solvent, at room temperature to the reflux temperature of the reactants, optionally in the presence of microwave irradiation. Preferred conditions include the reaction of compounds of formulas (AIV) and (AV) in a suitable solvent such as dioxane, optionally in the presence of water, at 70 °C to 100 °C, in the presence of Pd(dppf)Cl2 or Pd(amphos)Cl2 and a suitable base such as Na2CO3, K2CO3 or KF.

[0120] According to a second process, the compound of formula (I) can be prepared from compounds of formulas (AII), (AVI), (AV), (AVII), (AVIII) and (AIX) exemplified in Scheme 2.

[0121] Scheme 2

Chemical formula

[0122] The compound of formula (AVII) can be prepared from the compound of formula (AII) and the compound of formula (AVI) under thermal catalyst or transition metal catalyst conditions using a suitable nucleophilic substitution reaction such as S N Ar. Typical conditions include the reaction of the amine of formula (AVI) and the compound of formula (AII) in a suitable solvent at high temperature, optionally under microwave irradiation, in the presence of a suitable palladium catalyst in the presence of a suitable inorganic base and a suitable phosphine ligand. Preferred conditions include the reaction of the compounds of formula (AII) and (AVI) in the presence of a suitable base such as K2CO3, K3PO4 or Cs2CO3, in a suitable solvent such as dioxane, THF or toluene, at 70 °C to 110 °C, optionally under microwave irradiation, in the presence of RuPhos Pd G3 or xantphos, optionally in combination with Pd2(dba)3. Alternatively, the compounds of formula (AII) and (AVI) can be reacted together in a suitable aprotic solvent at 70 °C to 110 °C, optionally under microwave irradiation, in the presence of a suitable base such as TEA.

[0123] The compound of formula (AVIII) can be prepared from the compounds of formulas (AV) and (AVII) by a palladium-catalyzed cross-coupling reaction such as the Suzuki reaction. Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand in the presence of an inorganic base, in a suitable solvent, at room temperature to the reflux temperature of the reactants, optionally in the presence of microwave irradiation. Preferred conditions include the reaction of the compounds of formulas (AV) and (AVII) in a suitable solvent such as dioxane, optionally in the presence of water, at 70 °C to 100 °C, in the presence of Pd(dppf)Cl2 or Pd(amphos)Cl2 and a suitable base such as Na2CO3, K2CO3 or KF. The subsequent amine deprotection step preferably provides the compound of formula (AVIII) under acidic conditions such as HCl or TFA in an aprotic solvent such as DCM at 0 °C to room temperature, typically by the typical removal of the Boc reaction.

[0124] The compound of formula (I) may be prepared from the compounds of formulas (AVIII) and (AIX) using a reductive amination process in a suitable solvent, at a temperature from 0 °C to a high temperature, in the presence of a suitable reducing agent. Preferred conditions include reacting the amine of formula (AVIII) with the ketone of formula (AIX) in a suitable protic solvent such as MeOH, in the presence of a suitable reducing agent such as NaBH3CN, at a temperature from room temperature to the reflux temperature, preferably at 50 °C.

[0125] According to a third process, the compound of formula (I) can be prepared from the compounds of formulas (AIV), (AX) and (AXI) exemplified in Scheme 3.

[0126] Scheme 3

Chemical formula

[0127] The compound of formula (AIV) may be converted to the compound of formula (AX) using a boronate ester formation reaction achieved by treatment with a suitable boronate such as (BPin)2 in a suitable nonpolar solvent such as MeCN at room temperature to high temperature in the presence of a suitable inorganic base such as K2CO3 or KOAc and a suitable catalyst such as Pd(dppf)Cl2 or Pd2(dba)3.

[0128] The compound of formula (I) can be prepared from the compounds of formula (AX) and (AXI) using a palladium-catalyzed cross-coupling reaction such as the Suzuki reaction. Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand in the presence of an inorganic base, in a suitable solvent, at room temperature to the reflux temperature of the reactants, optionally in the presence of microwave irradiation. Preferred conditions include the reaction of the compounds of formula (AX) and (AXI) in a suitable solvent such as dioxane, optionally in the presence of water, at 70 °C to 100 °C in the presence of Pd(dppf)Cl2 or Pd(amphos)Cl2 and a suitable base such as Na2CO3, K2CO3 or KF.

[0129] According to a fourth process, the compound of formula (I) can be prepared from the compounds of formula (AVII), (AXII), (AXI), (AVIII) and (AIX) exemplified in Scheme 4.

[0130] Scheme 4 [Chemical formula] LG1 and LG2 are suitable leaving groups and are typically a halogen such as Cl, Br, or I, or a sulfonate such as mesylate, tosylate or triflate. W is a boronic acid or a suitable boronate ester such as a boronic acid pinacol ester.

[0131] The compound of formula (AVII) may be converted to the compound of formula (AXII) using a boronate ester formation reaction achieved by treatment with a suitable boronate such as (BPin)2 in a suitable nonpolar solvent such as MeCN, at room temperature to high temperature, in the presence of a suitable inorganic base such as K2CO3 or KOAc and a suitable catalyst such as Pd(dppf)Cl2 or Pd2(dba)3.

[0132] The compound of formula (AVIII) can be prepared from the compounds of formula (AXI) and (AXII) using a palladium-catalyzed cross-coupling reaction such as the Suzuki reaction. Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand in the presence of an inorganic base, in a suitable solvent, at room temperature to the reflux temperature of the reactants, optionally in the presence of microwave irradiation. Preferred conditions include the reaction of the compounds of formula (AXI) and (AXII) in a suitable solvent such as dioxane, optionally in the presence of water, at 70 °C to 100 °C, in the presence of Pd(dppf)Cl2 or Pd(amphos)Cl2 and a suitable base such as Na2CO3, K2CO3 or KF. A subsequent amine deprotection step provides the compound of formula (AVIII) under acidic conditions such as HCl or TFA in an aprotic solvent such as DCM at 0 °C to room temperature, preferably by typical removal of the Boc reaction.

[0133] The compound of formula (I) may be prepared from the compounds of formula (AVIII) and (AIX) using a reductive amination process in a suitable solvent, at a temperature of 0 °C to high temperature, in the presence of a suitable reducing agent. Preferred conditions include reacting the amine of formula (AVIII) with the ketone of formula (AIX) in a suitable protic solvent such as MeOH, at a temperature of room temperature to reflux temperature, preferably 50 °C, in the presence of a suitable reducing agent such as NaBH3CN.

[0134] According to a fifth process, the compound of formula (I) in which X2 and X3 are N and X1 is C can be prepared from the compounds of formula (AIII), (AXIII), (AXIV), (AXV) and (AXVI) exemplified in Scheme 5.

[0135] Scheme 5 [Chemical formula] LG is a suitable leaving group and is typically a halogen such as Cl, Br, or I, or a sulfonate such as mesylate, tosylate, or triflate.

[0136] The compound of formula (AXIV) may be prepared by reacting the compounds of formulas (AIII) and (AXIII) at 0 °C to a high temperature in the presence of a suitable base and a suitable aprotic polar solvent. Preferred conditions include the reaction of the compound of formula (AIII) with the compound of formula (AXIII) at ambient temperature up to 90 °C in the presence of TEA in DMSO or DMF.

[0137] The compound of formula (AXV) may be prepared by a reduction reaction from the compound of formula (AXIV), typically in the presence of a suitable hydrogenation catalyst such as Pd / C, in a suitable alcoholic solvent such as MeOH, at room temperature under an atmosphere of H2.

[0138] The compound of formula (I) may be prepared by a condensation reaction from the diamine of formula (AXV) and the aldehyde of formula (AXVI), typically in the presence of a suitable acidic catalyst such as TsOH, in a suitable polar aprotic solvent such as DMF, at a high temperature such as between 50 °C and 80 °C.

[0139] According to the sixth process, one occurrence of R 6 in which is CH2EWG, the compound of formula (I)(B) can be prepared from the compounds of formulas (AXIII) (or AVIII) and (AYY) exemplified in Scheme 6.

[0140] Scheme 6 [Chemical formula] EWG is an electron-withdrawing group defined within R 6 as defined herein.

[0141] The compound of formula (I)(B) may be prepared by reacting a compound of formula (AXIII) (or AVIII) and (AYY) at a suitable temperature, optionally in a sealed tube, in the presence of a suitable base and a suitable aprotic polar solvent. Preferred conditions include reacting a compound of formula (AXIII) (or AVIII) with a compound of formula (AYY) in a sealed container at 90 °C in the presence of TEA in DMSO or DMF.

[0142] According to a seventh process, the compound of formula (AIII) can be prepared from compounds of formula (AXVIII), (AXIX), (AXX), (AXXI) and (AXXII) illustrated in Scheme 7.

[0143] Scheme 7 [Chemical formula] LG is a suitable leaving group.

[0144] The compound of formula (AXX) may be prepared by reacting an amine of formula (AXIX) with a compound of formula (AXVIII) in an aprotic solvent in the presence of a suitable base at ambient temperature to high temperature. Preferred conditions include reacting a compound of formula (AXVIII) with a compound of formula (AXIX) in MeCN under reflux in the presence of K2CO3. The compound of formula (AXXI) may be obtained after functional group interconversion of the compound of formula (AXX) using a method selected by those skilled in the art. In particular, the compound of formula (AXX) may be prepared using successive complete hydride reduction with a suitable reducing agent such as LiAlH4 in THF. Subsequently, the intermediate alcohol is converted to a suitable leaving group LG to obtain the compound of formula (AXXI). The compound of formula (AXXII) in which PG is benzyl may be prepared from the compound of formula (AXXI) and benzylamine in an aprotic solvent such as MeCN at ambient temperature to reflux temperature in the presence of a suitable base such as K2CO3. Thereafter, the benzyl group (wherein PG is benzyl) is hydrogenolyzed in an autoclave at 50 °C under H2 in a suitable protic solvent such as MeOH in the presence of a suitable catalyst such as Pd / C to obtain the compound of formula (AIII).

[0145] Compounds of formula (I) or (AIV) can be converted into alternative compounds of formula (I) or (AIV) using methods well known to those skilled in the art, via standard chemical transformations, such as alkylation of heteroatoms such as N via reductive amination, or halogenation such as fluorination.

[0146] Compounds of formula (AII), (AIII), (AV), (AVI), (AVII), (AIX), (AXI), (AXIV) and (AXVII) are commercially available and can be prepared, for example, by methods known in the literature or by the methods described in the Examples section below.

[0147] Those skilled in the art will understand that it may be necessary to utilize suitable protecting group strategies for the preparation of compounds of formula (I). Typical protecting groups can include carbamates, and preferably Boc for the protection of amines, or tosyl groups for the protection of imidazole N atoms.

[0148] Those skilled in the art will understand that it may be necessary to utilize suitable functional group interconversion strategies for the intermediate intermediates for the preparation of compounds of formula (I).

[0149] Chromatography on silica gel was carried out using either a Teledyne ISCO Combiflash RF or a Grace Reveleris X2 equipped with an ELSD purification system, using silica gel with a particle size of 20 - 40 μm, 250 - 400 mesh, or 400 - 632 mesh.

[0150] Analytical methods ESI-MS: ESI-MS data (also simply reported as MS in this specification) were recorded using a Waters System (Acquity HPLC and Micromass ZQ mass spectrometer), and all masses reported are the m / z of the protonated parent ion, unless otherwise recorded.

[0151] LC / MS: Dissolve the sample in a suitable solvent such as MeCN, DMSO, or MeOH and inject it directly onto the column using an automated sample handler. Analysis was performed using one of the following methods:

[0152] HPLC for analysis: Acidic HPLC: Performed on a Shimadza 20A instrument equipped with an Ultimate C18 3.0×50 mm, 3 μm column, eluted with 2.75 mL / 4 L aqueous TFA solution (solvent A) and 2.5 mL / 4 L acetonitrile solution of TFA (solvent B).

[0153] LCMS for analysis: Acidic LCMS: Performed on a Shimadza 2010 series, Shimadza 2020 series, or Waters Acquity UPLC BEH equipped with a C18 column (2.1 mm×30 mm, 3.0 mm or 2.1 mm×50 mm, C18, 1.7 μm) (MS ionization: ESI) instrument, eluted with 1.5 mL / 4 L aqueous TFA solution (solvent A) and 0.75 mL / 4 L acetonitrile solution of TFA (solvent B).

[0154] SFC analysis separation: Instrument: Waters UPC2 analytical SFC (SFC-H). Column: ChiralCel OJ, 150×4.6 mm I.D., 3 μm. Mobile phase: CO2 for A, ethanol (0.05% DEA) for B. Gradient: 40% B. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35 °C. Wavelength: 220 nm

[0155] Preparative HPLC purification: The following codes refer to the preparative HPLC conditions used as shown in the Examples and Preparation sections. The individual gradients were optimized for each example as appropriate. [Table 1]

[0156] Preparative SFC purification Machine: MG III Fractionation SFC (SFC-1). The column, mobile phase, and gradient are shown in Table 3. Flow rate: 40 mL / min. Back pressure: 100 bar. Column temperature: 38 °C. Wavelength: 220 nm. Cycle time: approximately 8 minutes.

Table 2

[0157] 1 H-NMR: The NMR spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance III 400 MHz, Varian-400 VNMRS, or Varian-400 MR. Chemical shifts are expressed in parts per million (ppm). Coupling constants (J) are in Hertz (Hz). Splitting patterns represent the apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), dd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), m (multiplet), br (broad).

[0158] Typically, the compounds described herein can be prepared according to the schemes provided below. The following examples serve to illustrate the disclosure without limiting the scope of the disclosure. Thereby, a method for preparing such compounds will be described.

[0159] General procedure Preparation method: Preparation 1 1-(Methoxymethyl)-3-oxocyclobutane-1-carbonitrile

Chem.

[0160] Preparation 2 1-(2-Methoxyethyl)-3-oxocyclobutane-1-carbonitrile

Chemical formula

[0161] Preparation 3 3 - Methylene - 1 - ((methylsulfonyl)methyl)cyclobutane - 1 - carbonitrile [Chemical Structure] Part 1: n - BuLi (2.5 M, 200 mL, 500 mmol) was added dropwise to diisopropylamine (52.15 g, 515.4 mmol) in THF (1500 mL) at 0 °C, and the resulting mixture was stirred at the same temperature for 0.5 h. The reaction mixture was cooled to -78 °C, and 3 - methylenecyclobutanecarbonitrile (40 g, 429.5 mmol) in THF (300 mL) was added dropwise, and the mixture was stirred for 1 h. (Chloromethyl)(methyl)sulfane (49.8 g, 515.4 mmol) in THF (300 mL) was added dropwise, and the reaction mixture was stirred overnight. The reaction was quenched with an aqueous NH4Cl solution, and the organic phase was separated. The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was distilled (1 mbar, 50 °C) to give 3 - methylene - 1 - ((methylthio)methyl)cyclobutane - 1 - carbonitrile (12 g). Part 2: RuCl3 (0.1 g) was added to a solution of 3 - methylene - 1 - ((methylthio)methyl)cyclobutenecarbonitrile (12 g, 78 mmol) in a MeCN / H2O mixture (400 mL), and the solution was cooled to 0 °C. Sodium periodate (90 g, 468 mmol) was added in portions, and the resulting mixture was stirred at room temperature overnight. The solid was removed by filtration, and the filtrate was evaporated to dryness in vacuo. The residue was washed with EtOAc, and the solvent was evaporated under reduced pressure. The residue was recrystallized from MeCN / IPS to give 3 - methylene - 1 - ((methylsulfonyl)methyl)cyclobutane - 1 - carbonitrile (5.05 g). 1 1H NMR (400 MHz, DMSO - d6) δ: 4.05 (s, 2H), 3.87 - 3.75 (m, 2H), 3.67 - 3.58 (m, 2H), 3.13 (s, 3H).

[0162] Preparation 4 cis-Diethyl 1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-dicarboxylate

Chem.

[0163] Preparation 5 cis-(1-(3,3-Difluorocyclobutyl)pyrrolidine-2,5-diyl)dimethanol

Chem.

[0164] Preparation 6 cis 1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-diyl)bis(methylene) dimethanesulfonate

Chem.

[0165] Preparation 7 3-Benzyl-8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octane

Chem.

[0166] Preparation 8 8-(3,3-Difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octane dihydrochloride

Chemical formula

[0167] Preparation 9 tert-Butyl 3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical formula] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200.0 mg, 0.942 mmol) in DMF (5.0 mL) were added DIPEA (146.1 mg, 1.13 mmol) and 4-chloro-3-nitropyridin-2-amine (163.5 mg, 0.942 mmol), and the reaction mixture was stirred at 90 °C for 2 hours. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1) to give tert-butyl 3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260.0 mg, yield 79.0%) as a yellow solid. 1 H NMR (400 MHz, MeOH-d4) δ: 7.78 (d, 1H), 6.48 (d, 1H), 4.25 (s, 2H), 3.20 - 3.14 (m, 4H), 1.93 - 1.81 (m, 4H), 1.49 (s, 9H).

[0168] Preparation 10 tert-Butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical formula] To a solution of tert-butyl 3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 9, 215.0 mg, 0.615 mmol) in MeOH (3.0 mL) was added Pd / C (39.3 mg, 0.037 mmol, 10% purity) under H2 at 15 psi, and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford tert-butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160.0 mg, 81.4% yield) as a yellow solid. 1 H NMR (500 MHz, MeOH-d4) δ: 7.39 - 7.37 (m, 1H), 6.47 - 6.45 (m, 1H), 4.29 (s, 2H), 3.00 - 2.84 (m, 4H), 2.08 - 1.98 (m, 4H), 1.49 (s, 9H).

[0169] Preparation 11 tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Chemical formula

[0170] Preparation 12 7-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride

Chemical Structure

[0171] Preparation 13 4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

Chemical Structure

[0172] Preparation 14 4-Chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine

Chemical formula

[0173] Preparation 15 4-Chloro-2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

Chemical formula

[0174] Preparation 16 4-Chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

Chemical formula

[0175] Preparation 17 tert-Butyl 3-(2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Chemical Structure

[0176] Preparation 18 tert-Butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical Structure] To a solution of 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 16, 250.0 mg, 0.646 mmol) in t-BuOH (5.0 mL) were added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (137.2 mg, 0.646 mmol), Ruphos Pd G3 (54.1 mg, 0.065 mmol), and Cs2CO3 (421.1 mg, 1.29 mmol), and the reaction mixture was stirred at 110 °C for 2 h under microwave irradiation. The mixture was poured into water (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1 to 1 / 2) to give tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (302.0 mg, yield 83.1%) as a yellow rubbery solid. LCMS m / z = 563.7 [M+H] + .

[0177] Preparation 19 tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical formula] A solution of tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 18, 280.0 mg, 0.498 mmol) in MeOH (4.0 mL) was added with NaOH (5N, 0.1 mL), and the reaction mixture was stirred at 50 °C for 15 h. The mixture was concentrated in vacuo, EtOAc was added, and the mixture was filtered. The filtrate was evaporated under reduced pressure to give tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (215.0 mg, crude) as a yellow rubbery solid. LCMS m / z = 409.3 [M+H] + .

[0178] Preparation 20 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride [Chemical formula] A solution of tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 19, 215.0 mg, 0.526 mmol) in EtOAc (2.0 mL) was added with HCl / EtOAc (4M, 2.0 mL), and the reaction mixture was stirred at 20 °C for 1 h. The mixture was evaporated under reduced pressure to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (173 mg, 95.3%) as a yellow solid. LCMS m / z = 309.1 [M+H] + .

[0179] Preparation 21 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride

Chem.

[0180] Preparation 22 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride

Chem.

[0181] Preparation 23 1-(4-Bromo-1H-pyrrol-2-yl)ethan-1-one

Chem.

[0182] Preparation 24 (E)-1-(4-Bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one

Chemical Structure

[0183] Preparation 25 6-Bromopyrrolo[1,2-b]pyridazin-4-ol

Chemical Structure

[0184] Preparation 26 6-Bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate [Chemical formula] Trifluoromethanesulfonic anhydride (88.3 g, 313 mmol) was added at 0 °C to a solution of 6-bromopyrrolo[1,2-b]pyridazin-4-ol (Preparation 25, 58 g, about 140 mmol, about 50% purity) and TEA (32.5 g, 321 mmol) in DCM (870 mL), and the mixture was stirred for 1 hour while cooling and then at room temperature for 2 hours. The mixture was diluted with DCM, washed with Na2CO3 (2 times), brine, dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (0 - 2% TBME / heptane) to give 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate as a dark oil (21.1 g, 43%). LCMS m / z = 344.6 [M+H] + .

[0185] Preparation 27 tert-Butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical formula] A solution of 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate (Preparation 26, 5.0 g, 14.49 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.4 g, 15.9 mmol), and TEA (2.2 g, 21.7 mmol) in NMP (50 mL) was stirred at 100 °C for 30 minutes. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (60 mL), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (0 - 20% EtOAc / PE) to give tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (4.2 g, yield 70.3%). LCMS m / z = 409.2 [M+H] + .

[0186] Preparation 28 tert-Butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical formula] tert-Butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 27, 1 equivalent, 25.42 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 equivalents, 38.13 mmol), KF (3.0 M, 1 equivalent, 25.4 mL), and a mixture of Pd(amphos)Cl2 (1.80 g, 10 mol%) were suspended in dioxane (127 mL), the reaction mixture was purged with N2 for 5 minutes, and then heated at 60 °C overnight. The cooled reaction was diluted with EtOAc (500 mL) and washed with saturated NH4Cl (2 × 200 mL), water (200 mL), and brine (200 mL). The combined organics were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified using silica gel column chromatography (0 - 70% EtOAc / heptane) to afford tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.9 g, 96.3%). LCMS m / z = 409.3 [M+H] +

[0187] Preparation 29 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridine hydrochloride

Chemical Structure

[0188] Preparation 30 4-(8-(2-((tert-Butyldimethylsilyl)oxy)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

Chemical formula

[0189] Preparation 31 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-bromopyrrolo[1,2-b]pyridazine hydrochloride

Chem.

[0190] Preparation 32 3-(3-(6-Bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chem.

[0191] Preparation 33 (1S,3s)-3-(3-(6-Bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile [Chemical formula] 3-(3-(6-Bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile (Preparation 32, 210 mg, 0.544 mmol) was separated by SFC-1 (45% EtOH) to give (1S,3s)-3-(3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile as a white solid (130 mg, 61.9%). 1 H NMR (400 MHz, CDCl3) δ: 7.77 (d, 1H), 7.62 (s, 1H), 6.50 (s, 1H), 5.74 (d, 1H), 3.64 - 3.60 (m, 2H), 3.28 - 3.02 (m, 5H), 2.85 - 2.78 (m, 1H), 2.76 - 2.53 (m, 2H), 2.48 - 2.31 (m, 2H), 2.00 - 1.89 - 2 (m, 4H).

[0192] Preparation 34 6-Bromo-4-(8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine [Chemical formula] TEA (132 mg, 1.30 mmol) was added to a solution of 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate (Preparation 26, 150 mg, 0.435 mmol) and 8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octane dihydrochloride (Preparation 8, 119.6 mg, 0.435 mmol) in DMF (5 mL), and the mixture was stirred at 90 °C for 1 h. The mixture was poured into H2O (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (30 mL), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by column chromatography (0 - 16% EtOAc / PE) to afford 6-bromo-4-(8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine as a brown oil (165 mg, 95.6%). 1 1H NMR (500 MHz, CDCl3) δ: 7.77 (d, 1H), 7.61 (d, 1H), 6.51 (d, 1H), 5.74 (d, 1H), 3.64 - 3.62 (m, 2H), 3.30 - 3.28 (m, 2H), 3.19 - 3.16 (m, 2H), 2.92 - 2.90 (m, 1H), 2.73 - 2.71 (m, 2H), 2.46 - 2.43 (m, 2H), 1.99 - 1.86 (m, 4H).

[0193] Preparation 35 tert-Butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Chemical Structure

[0194] Preparation 36 tert-Butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical Structure] tert-Butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 35, 563.4 mg, 1.24 mmol), 3,5-dichloropyridazine (277.1 mg, 1.86 mmol), Pd(dppf)Cl2 (61.5 mg, 0.087 mmol) and KF (3.0 M, 1.24 mL) were dissolved in dioxane (6.20 mL). The reaction mixture was purged with N2 for 5 minutes and then heated to 80 °C for 4 hours. The cooled mixture was diluted with EtOAc, washed with NH4Cl (twice) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel chromatography (10 - 55% EtOAc / heptane) to give tert-butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (287 mg, 52.5%) as a yellow solid. LCMS m / z = 441.2 [M+H] + .

[0195] Preparation 37 tert-Butyl 3-(6-(pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical formula] A solution of 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate (Preparation 26, 150 mg, 0.368 mmol), 4-(tributylstannyl)pyridazine (204 mg, 0.552 mmol), CuCl (4.4 mg, 0.0442 mmol), CsF (167.8 mg, 1.10 mmol) and Pd(PPh3)4 (42.6 mg, 0.0368 mmol) in DMF (5 mL) was heated under N2 at 150 °C for 1 h under microwave irradiation. The mixture was poured into water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (2 × 10 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (PE / EtOAc = 20 / 1 - 1 / 1) to give tert-butyl 3-(6-(pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (80 mg, 53.4%). 1 H NMR (400 MHz, CDCl3) δ: 9.47 (s, 1H), 9.13 (d, 1H), 8.08 (d, 1H), 7.87 (d, 1H), 7.62 - 7.64 (m, 1H), 6.82 (d, 1H), 5.84 (d, 1H), 4.44 - 4.53 (m, 2H), 3.60 - 3.74 (m, 2H), 3.27 - 3.36 (m, 2H), 1.98 - 2.09 (m, 4H), 1.50 (s, 9H).

[0196] Preparation 38 tert-Butyl 3-(6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical Structure] To tert-butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 36, 46 mg, 0.104 mmol) in MeOH / DMSO (504 μL / 500 μL) was added NaOMe (25 wt% in MeOH, 239 μL, 1.04 mmol), and the reaction was heated to 50 °C overnight. The cooled reaction was diluted with saturated aqueous NH4Cl and EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure to afford tert-butyl 3-(6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LCMS m / z = 437.3 [M+H] + .

[0197] Preparation 39 tert-butyl 3-(6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical formula] A solution of tert-butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 36, 100 mg, 0.227 mmol) and methylboronic acid (20.4 mg, 0.340 mmol) in dioxane (10 mL) and H2O (1 mL) was added with K2CO3 (94.0 mg, 0.680 mmol) and Pd(dppf)Cl2 (16.6 mg, 0.0227 mmol) at 25 °C, and the resulting mixture was stirred at 100 °C for 16 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by column chromatography (PE / EtOAc = 15 / 1 to 1 / 1) to afford tert-butyl 3-(6-(6-methylpyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (70 mg, 73.4%). LCMS m / z = 421.4 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 9.31 (s, 1H), 8.06 (d, 1H), 7.86 (d, 1H), 7.48 (s, 1H), 6.81 (s, 1H), 5.83 (d, 1H), 4.44 - 4.49 (m, 2H), 3.65 - 3.80 (m, 2H), 3.25 - 3.30 (m, 2H), 2.76 (s, 3H), 2.06 - 2.10 (m, 4H), 1.50 (s, 9H).

[0198] Preparation 40 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride

Chemical Structure

[0199] Preparation 41 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(pyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride

Chem.

[0200] Preparation 42 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(6-methylpyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride

Chem.

[0201] Preparation 43 6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol

Chemical Structure

[0202] Preparation 44 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine

Chem.

[0203] Preparation 45 tert-Butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Chem.

[0204] Preparation 46 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride [Chemical Structure] A solution of tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 45, 200 mg, 0.488 mmol) in HCl / EtOAc (4 M, 5.0 mL) was stirred at 25 °C for 1 h. The mixture was evaporated to dryness to afford 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride as a white solid (180.0 mg), which was used without further purification. LCMS m / z = 310.2 [M+H] + .

[0205] Preparation 47 4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

Chemical formula

[0206] Preparation 48 4-Chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

Chemical formula

[0207] Preparation 49 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

Chemical Structure

[0208] Preparation 50 tert-Butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Chemical Structure

[0209] Preparation 51 tert-Butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemical formula] K2CO3 (161.8 mg, 1.17 mmol) was added to a solution of tert-butyl (1R,5S)-3-(6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 50, 220 mg, 0.390 mmol) in MeOH (8 mL), and the mixture was stirred at 50 °C for 4 h. The reaction was concentrated under reduced pressure, and the residue was purified by column chromatography on SiO2 (25% - 100% EtOAc / PE) to give tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow rubbery solid (149 mg, 93.2%). LCMS m / z = 410.2 [M+H] +

[0210] Preparation 52 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride [Chemical formula] The title compound was prepared from tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 51, 140 mg, 0.341 mmol) using a method similar to that described for Preparation 46. Yield: 160 mg; LCMS m / z = 309.7 [M+H] + .

[0211] Preparation 53 2-Bromo-8-hydroxyimidazo[1,2-b]pyridazine

Chem.

[0212] Preparation 54 2-Bromo-8-chloroimidazo[1,2-b]pyridazine

Chem.

[0213] Preparation 55 tert-Butyl 3-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemistry] To a solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine (Preparation 54, 21.0 mg, 0.090 mmol) in n-BuOH (3.0 mL) were added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.9 mg, 0.117 mmol) and DIPEA (46.7 mg, 0.361 mmol), and the mixture was stirred at 130 °C for 1 h under microwave irradiation. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1 - 3 / 1) to afford tert-butyl 3-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, yield 67.8%) as a colorless rubbery solid. LCMS m / z = 410.1 [M+H] + .

[0214] Preparation 56 tert-Butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [Chemistry] tert-Butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a white solid (105 mg, yield 69.8%) from tert-butyl 3-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 55) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the procedure described in Preparation 28. LCMS m / z = 410.2 [M+H] + .

[0215] Preparation 57 8-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine hydrochloride

Chem.

[0216] Examples 1 and 2 (1R,3r)-1-Methyl-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1S,3s)-1-methyl-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chem.

[0217] Examples 3 and 4 (1R,3r)-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1S,3s)-3-(3-(2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chemical Structure

[0218] Examples 5 and 6 7-(8-((1r,3R)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine and 7-(8-((1s,3S)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine [Chemical formula] The title compound was prepared from 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride (Preparation 12, 50 mg, 0.162 mmol) and 3-methoxycyclobutan-1-one using a method similar to the method described for Examples 1 and 2. *Peak 1, Example 5; 7-(8-((1r,3R)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (9.3 mg, 27.8%). LCMS m / z = 394.3 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 8.08 (s, 1H), 8.01 (s, 2H), 6.34 (d, 1H), 4.60 - 4.58 (m, 2H), 4.09 - 4.06 (m, 1H), 3.99 (s, 3H), 3.41 - 3.34 (m, 4H), 3.27 (s, 3H), 3.23 - 3.21 (m, 1H), 2.22 - 2.14 (m, 4H), 1.95 - 1.86 (m, 4H) *Peak 2, Example 6; 7-(8-((1s,3S)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (19.8 mg, 59.6%). LCMS m / z = 389.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 8.02 (s, 1H), 8.00 - 7.98 (m, 1H), 6.33 (d, 1H), 4.58 - 4.56 (m, 2H), 3.99 (s, 3H), 3.65 - 3.62 (m, 1H), 3.39 - 3.34 (m, 4H), 3.25 (s, 3H), 2.53 - 2.51 (m, 1H), 2.50 - 2.49 (m, 2H), 1.95 - 1.85 (m, 6H).

[0219] Examples 7 and 8 (1RS,2RS)-2-(3-(2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol and (1RS,2SR)-2-(3-(2-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol

Chem.

[0220] Example 9 2-(1-Methyl-1H-pyrazol-4-yl)-7-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridine

Chemical Structure

[0221] Example 10 7-((1R,5S)-8-(3-(Difluoromethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Chem.

[0222] Example 11 7-(8-(Azetidin-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride

Chem.

[0223] Example 12 2-(1-Methyl-1H-pyrazol-4-yl)-7-(8-(1-methylazetidin-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridine trifluoroacetate

Chemical Structure

[0224] Example 13 3-(3-(2-(2-Methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chem.

[0225] Examples 14 and 15 (1S,3s)-3-(3-(2-(2-Methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1R,3r)-3-(3-(2-(2-Methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile [Chemical Structure] The title compound was obtained from 3-(3-(2-(2-Methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile (Example 13) by SFC chromatography (SFC-2). * Peak 1, Example 14. (1S,3s)-3-(3-(2-(2-Methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, LCMS m / z = 415.3 [M+H] + ; 11H NMR (500 MHz, CDCl3) δ: 8.15 (d, 1H), 7.92 (br d, 1H), 7.14 (dd, 1H), 7.00 (s, 1H), 6.88 (s, 1H), 6.30 (d, 1H), 3.80 (br d, 2H), 3.41 - 3.25 (m, 5H), 3.16 - 3.09 (m, 1H), 2.45 (ddd, 2H), 2.34 - 2.22 (m, 2H), 1.99 - 1.90 (m, 3H), 1.79 (br d, 4H). *Peak 2, Example 15. (1R,3r)-3-(3-(2-(2-Methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile, LCMS m / z = 415.3 [M+H] + ; 1 1H NMR (500 MHz, CDCl3) δ: 8.24 (d, 1H), 8.10 (d, 1H), 7.23 (dd, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 6.37 (d, 1H), 4.03 (s, 3H), 3.81 (br d, 2H), 3.40 - 3.32 (m, 4H), 3.10 (s, 1H), 2.84 (s, 1H), 2.65 - 2.51 (m, 2H), 2.43 - 2.30 (m, 2H), 1.91 (br s, 4H).

[0226] Examples 16 and 17 (1S,3s)-3-(3-(2-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1R,3r)-3-(3-(2-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chemical Structure

[0227] Example 18 2-(2-Methoxypyridin-4-yl)-4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine

Chemical Structure

[0228] Example 19 4-(8-(3-(Difluoromethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine

Chemical Structure

[0229] Example 20 2-(3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)oxetan-3-yl)acetonitrile

Chem.

[0230] Example 21 3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile [Chemical formula] NaBH3CN (43.7 mg, 0.696 mmol) was added to a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride (Preparation 29, 80 mg, 0.232 mmol) and 3-oxocyclobutanecarbonitrile (110.3 mg, 1.16 mmol) in MeOH (2.3 mL), and the mixture was stirred at 50 °C overnight. The reaction mixture was evaporated to dryness in vacuo, and the residue was diluted with saturated aqueous NaHCO3, H2O, and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 times). The combined organics were dried (MgSO4), evaporated to dryness in vacuo, and purified by PSR automatic purification to give 3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile. LCMS m / z = 388.2 [M+H] + .

[0231] Examples 22 - 26 The title compounds were prepared from 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride (Preparation 29) and the appropriate ketone using a method similar to that described for Example 21. [Table 3-1] [Table 3-2]

[0232] Examples 27 and 28 (1R,3r)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1S,3s)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile [Chemical formula] The title compounds were obtained from 3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile (Example 21) using SFC chromatography (SFC-3). *Peak 1, Example 27; (1R,3r)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile. Yield: 67.9 mg, 15.1%; LCMS m / z = 388.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.76 - 7.70 (m, 3H), 7.56 (s, 1H), 6.51 (d, 1H), 5.71 (d, 1H), 3.94 (s, 3H), 3.72 - 3.69 (m, 2H), 3.37 - 3.30 (m, 3H), 3.18 - 3.15 (m, 3H), 2.49 - 2.46 (m, 2H), 2.34 - 2.30 (m, 2H), 1.94 - 1.92 (m, 4H). *Peak 2, Example 28; (1S,3s)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile. Yield: 157.3 mg, 35%; LCMS m / z = 388.3 [M+H] + ; 11H NMR (400 MHz, CDCl3) δ: 7.76 - 7.70 (m, 3H), 7.56 (s, 1H), 6.51 (s, 1H), 5.71 (d, 1H), 3.94 (s, 3H), 3.79 - 3.69 (m, 2H), 3.30 - 3.28 (m, 2H), 3.20 - 3.17 (m, 2H), 3.06 - 3.01 (m, 1H), 2.80 - 2.76 (m, 1H), 2.56 - 2.53 (m, 2H), 2.35 - 2.29 (m, 2H), 1.90 - 1.88 (m, 4H).

[0233] Examples 29 and 30 4-(8-((1r,3R)-3-Methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine and 4-(8-((1s,3S)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine [Chemical formula] The title compounds were obtained from 4-(8-(3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine (Example 24) using SFC chromatography (SFC-4). Peak 1, Example 29; 4-(8-((1r,3R)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine. Yield: 8.1 mg, 22.4% Peak 2, Example 30; 4-(8-((1s,3S)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine. Yield: 9.4 mg, 26%

[0234] Examples 31 and 32 (1R,3r)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol and (1S,3s)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol

Chem.

[0235] Example 33 4-(8-(2-Oxaspiro[3.3]heptan-6-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

Chem.

[0236] Examples 34 and 35 (1r,3r)-1-Methyl-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1s,3s)-1-Methyl-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chem.

[0237] Examples 36 and 37 6-(1-Methyl-1H-pyrazol-4-yl)-4-(8-((1s,3s)-3-(methylsulfonyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine and 6-(1-Methyl-1H-pyrazol-4-yl)-4-(8-((1r,3r)-3-(methylsulfonyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine

Chem.

[0238] Examples 38 and 39 (1r,3r)-1-(2-Methoxyethyl)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1s,3s)-1-(2-Methoxyethyl)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chemical Structure

[0239] Examples 40 and 41 4-(8-((S)-2-Oxaspiro[3.3]heptan-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine and 4-(8-((R)-2-oxaspiro[3.3]heptan-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

Chem.

[0240] Examples 42 and 43 (1s,3s)-1-(Methoxymethyl)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1r,3r)-1-(methoxymethyl)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chemical formula

[0241] Examples 44 and 45 2-((1s,3s)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutyl)acetonitrile and 2-((1r,3r)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutyl)acetonitrile [Chemical formula] The title compounds were obtained from 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride (Preparation 29) and 2-(3-oxocyclobutyl)acetonitrile using a method similar to the method described for Example 34 and Example 35. The following were obtained by SFC chromatography (SFC-3): * Peak 1, Example 44; 2-((1s,3s)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutyl)acetonitrile as a white solid (27.9 mg); LCMS m / z = 402.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.74 (d, J = 5.6 Hz, 1H), 7.69 - 7.71 (m, 2H), 7.56 (s, 1H), 6.52 (d, J = 1.6 Hz, 1H), 5.70 (d, J = 1.6 Hz, 1H), 3.94 (s, 3H), 3.67 - 3.70 (m, 2H), 3.20 - 3.32 (m, 2H), 3.15 - 3.18 (m, 2H), 2.90 - 2.93 (m, 1H), 2.49 - 2.51 (m, 2H), 2.37 - 2.41 (m, 3H), 1.86 - 1.94 (m, 4H), 1.70 - 1.73 (m, 2H). *Peak 2, Example 45; 2-((1r,3r)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutyl)acetonitrile as a white solid (6.5 mg); LCMS m / z = 402.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.74 - 7.79 (m, 3H), 7.56 (s, 1H), 6.52 (d, J = 1.6 Hz, 1H), 5.71 (d, J = 5.6 Hz, 1H), 3.94 (s, 3H), 3.69 - 3.72 (m, 2H), 3.21 - 3.32 (m, 2H), 3.15 - 3.19 (m, 3H), 2.52 (s, 1H), 2.49 - 2.51 (m, 2H), 2.18 - 2.52 (m, 2H), 1.85 - 2.04 (m, 6H).

[0242] Examples 46, 47 and 48 Rac-(1R,3R)-2,2-Dimethyl-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1R,3S)-2,2-Dimethyl-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1S,3R)-2,2-Dimethyl-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chemical formula

[0243] Examples 49 and 50 Rac-(1S,2S)-2-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol and rac-(1R,2S)-2-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutan-1-ol

Chemical Structure

[0244] Example 51 Rac-4-(8-((1S,2S)-2-Methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

Chem.

[0245] Example 52 4-(8-(3,3-Difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

Chem.

[0246] Example 53 6-(6-Methoxypyridazin-4-yl)-4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine [Chemical formula] The title compound was prepared from 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride (Preparation 40) and oxetan-3-one using a method similar to the method used in Example 9. Purification using preparative HPLC-3 (gradient 30-51%) gave 6-(6-methoxypyridazin-4-yl)-4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine as a white solid (6.2 mg, 23.6%). LCMS m / z = 393. [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 8.05 (d, 1H), 7.95 (d, 1H), 7.82 (d, 1H), 7.07 (d, 1H), 6.72 (d, 1H), 5.77 (d, 1H), 4.73 - 4.77 (m, 2H), 4.57 - 4.61 (m, 2H), 3.82 (s, 3H), 3.69 - 3.73 (m, 3H), 3.26 - 3.34 (m, 4H), 1.89 - 1.98 (m, 4H).

[0247] Examples 54 to 57 The title compound was prepared from the appropriate amine and ketone using a method similar to the method described for Example 9.

Table 4-1

Table 4-2

Table 4-3

Table 4-4

[0248] Examples 58 and 59 (1R,3r)-3-(3-(6-(3-Methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1S,3s)-3-(3-(6-(3-Methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chem.

[0249] Example 60 (1S,3s)-3-(3-(6-(1-(Difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chemical Structure

[0250] Examples 61 and 62 (1S,3s)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1R,3r)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile [Chemical Formula] The title compound was prepared from 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 46) and 3-oxocyclobutane-1-carbonitrile using a method similar to the method described for Examples 1 and 2. Part 1. 3-((1R,5S)-3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile was obtained as a white solid by preparative HPLC-3 (gradient 23 - 53%) (45 mg, 26.7%); LCMS m / z = 389.2 [M+H] + . Part 2. The compound of Part 1 was further purified by SFC-chromatography (SFC-1, 40% IPA) to obtain the title compound as a white solid. *Peak 1, Example 61; (1S,3s)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile (22 mg, 48.9%). LCMS m / z = 389.1 [M+H] + ; 11H NMR (400 MHz, MeOH-d4) δ: 7.88 (s, 1H), 7.78 - 7.76 (m, 3H), 7.04 (s, 1H), 4.55 - 4.52 (m, 2H), 3.91 (s, 3H), 3.45 - 3.23 (m, 4H), 3.21 - 3.19 (m, 1H), 3.04 - 2.99 (m, 1H), 2.66 - 2.62 (m, 2H), 2.32 - 2.27 (m, 2H), 1.99 - 1.96 (m, 2H), 1.73 - 1.70 (m, 2H). *Peak 2, Example 62; (1R,3r)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile (10.5 mg, 23.3%). LCMS m / z = 389.2 [M+H] + ; 1 1H NMR (400 MHz, MeOH-d4) δ: 7.88 (s, 1H), 7.77 - 7.75 (m, 3H), 7.04 (s, 1H), 4.54 - 4.50 (m, 2H), 3.91 (s, 3H), 3.42 - 3.36 (m, 5H), 3.29 - 3.27 (m, 1H), 2.52 - 2.47 (m, 2H), 2.46 - 2.37 (m, 2H), 1.98 - 1.94 (m, 2H), 1.70 - 1.68 (m, 2H).

[0251] Examples 63 and 64 (1R,3r)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1S,3s)-3-(3-(6-(1-Methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chemical Structure

[0252] Examples 65 and 66 (1S,3s)-3-(3-(2-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile and (1R,3r)-3-(3-(2-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

Chemical formula

[0253] Biological Assay As summarized in Table 3 below, the compounds of the present disclosure were evaluated for their ability to inhibit TYK2, JAK1, JAK2, and JAK3 activities. The inhibitory properties of the compounds of the present disclosure described herein can be demonstrated by testing according to any of the following protocols.

[0254] The kinase activity of the recombinantly produced catalytic kinase (also known as JH1) domains of human JAK1, JAK2, JAK3, and TYK2 was evaluated in a plate-based assay using the ADP-Glo™ Kinase Assay platform. Specifically, 4 nM of the recombinant JAK1 kinase domain was used to phosphorylate 50 μM of the JAK3-342 (sequence ALVDGYFRLTT (SEQ ID NO: 1)) peptide in the presence of 35 μM of ATP. The catalytic activities of the recombinant JAK2, JAK3, and TYK2 kinase domains (0.2, 0.3, and 2 nM, respectively) were evaluated by the phosphorylation status of the JAK3-974 (50 μM; sequence LPLDKDYYVVR (SEQ ID NO: 2)) peptide with added ATP (15, 4, and 10 μM, respectively). The reaction was allowed to proceed for 100 minutes, and the catalytic activity was quantified by first depleting the unspent ATP, converting the hydrolyzed ADP to ATP, and causing luminescence in a luciferase reaction, which is the basis of the ADP-Glo platform. Compounds were tested at 11-point three-fold dilutions at either a maximum concentration of 10 μM or 1 μM. The data were normalized and the percent activity versus the log concentration of the compound was fit using a four-parameter logistic model to generate curves and IC50 values.

Table 5-1

Table 5-2

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof [wherein, ring A and ring B together form a bicyclic heteroaryl ring, X １ is N or C, X ２ is N, NH or CR ２ and X ３ is N or CR ３ and X ４ is N or CR ４ and X ５ is N or CH, Y is CR ７ R ８ , O or NR ９ and R １ and R ５ are each independently selected from H, halo, CN, -NR １ａ R １ｂ , -OR １ｃ , C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, and the C １ alkyl, the C ５ cycloalkyl, the C １－６ aryl, the 4- to 10-membered heterocycloalkyl, and the 5- to 10-membered heteroaryl represented by R ３－８ and R ６－１０ are each optionally substituted with one or more R １０ . R ２ 、 R ３ 、 and R ４ are each independently H, halo, -CN, -NR １ａ R １ｂ , -OR １ｃ , C １－４ alkyl and C １－４ haloalkyl, and are selected from R ６ is, for each occurrence, independently, H, halo, CN, -NR １ａ R １ｂ , -OR １ｃ , -SO ２ R １ｃ or halo, CN, -NR １ａ R １ｂ , and -OR １ｃ and is optionally substituted with one or more substituents independently selected from C １－６ alkyl, or two Rs ６ together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl or C ３－６ cycloalkyl, R ７ and R ８ are each independently H, halo, CN, -NR １ａ R １ｂ , -OR １ｃ , -SO ２ R １ｃ or halo, CN, -NR １ａ R １ｂ , and -OR １ｃ optionally substituted with one or more substituents independently selected from C １－６ alkyl selected, or R ７ and R ８ together with the carbon atom to which they are attached form a 3- to 6-membered heterocycloalkyl or C ３－６ cycloalkyl, R ９ is C alkyl optionally substituted with one or more substituents independently selected from H or halo, CN, -NR １ａ R １ｂ , and -OR １ｃ １－６ and is optionally substituted with one or more substituents independently selected from H or halo, CN, -NRR, and -OR and is optionally substituted with one or more substituents independently selected from H or halo, CN, -NR R １０ each occurrence independently represents halo, -CN, -NR １ａ R １ｂ , -OR １ｃ , -C(O)OR １ｃ , C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ６－１０ aryl, 4- to 7-membered monocyclic heterocycloalkyl, or 5- to 6-membered heteroaryl; R １０ The C represented by １－６ Alkyl, the C １－６ Haloalkyl, the C ３－６ Cycloalkyl, the C ６－１０ Aryl, said 4- to 7-membered monocyclic heterocycloalkyl, and said 5- to 6-membered heteroaryl are each optionally selected from halo, C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, -NR １ａ R １ｂ , -OR １ｃ and 4- to 6-membered monocyclic heterocycloalkyl; R １ａ and R １ｂ are each independently H or C １－４ alkyl, R １ｃ is H, C １－４ alkyl or C １－４ haloalkyl, and r is an integer of 0 or 1 to 4].

2. X ２ is NH or CR ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein the compound is represented by formula (II), (III), (IV), (V), (VI) or (VII): 【Chemical 2】 or a pharmaceutically acceptable salt thereof.

4. Y is CR ７ R ８ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is CR

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is O.

6. Y is NR ９ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is NR

7. R １ is a 5- to 6-membered heteroaryl optionally substituted with one, two or three Rs １０ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R １ is a 5- or 6-membered heteroaryl selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, pyridine, pyridazine, pyrimidine and pyrazine, each of which is optionally substituted with one, two or three R １０ groups, the compound according to claim 7, or a pharmaceutically acceptable salt thereof.

9. R １ is a 5- or 6-membered heteroaryl selected from pyrazole, isoxazole, pyridine and pyridazine, each of which is optionally substituted with one or two R １０ and the compound according to claim 7, or a pharmaceutically acceptable salt thereof.

10. R １ is [Chemical Formula 3] a 5- to 6-membered heteroaryl selected from, wherein represents the point of attachment to ring B, the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. [Chemical Formula 4]

11. R １０ is halo, -OR １ｃ C １－６ alkyl and C １－６ is independently selected from haloalkyl, R １ｃ is C １－４ alkyl, the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R １０ is independently selected from F, -OCH ３ , -CH ３ and -CHF ２ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R ２ 、 R ３ 、 and R ４ are each independently H, halo, C １－４ alkyl and C １－４ haloalkyl, a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. R ２ 、R ３ 、and R ４ is H, a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. R ５ is H, halo, C １－４ alkyl, C １－４ haloalkyl or a 5- to 6-membered heteroaryl optionally substituted with one, two or three R １０ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R is H, halo, C

16. R ５ The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R is H.

17. R ７ and R ８ are each independently H, halo, CN, -OR １ｃ , -SO ２ R １ｃ , and are optionally substituted with one or more substituents independently selected from halo, CN, and -OR １ｃ selected from C １－６ alkyl, or R ７ and R ８ together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl, R １ｃ is H or C １－３ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

18. R ７ and R ８ are each independently H, F, CN, -OH, -OCH ３ , -SO ２ CH ３ , -CH ３ , -CHF ２ , -CF ３ , -CH ２ -CN, -CH ２ -O-CH ３ , and -CH ２ CH ２ -O-CH ３ selected from, or R ７ and R ８ together with the carbon atom to which they are attached, 【Chemical Formula 5】 forming, the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1 or 2.

20. R ６ is, for each occurrence, independently H, -OR １ｃ , C １－４ alkyl optionally substituted with haloalkyl and CN, or C １－４ alkyl selected therefrom, or two Rs ６ together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl R １ｃ is H or C １－３ The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

21. R ６ is, for each occurrence and independently, H, -OH, -OCH ３ , -CH ２ -CN, and -CH ３ is selected from, or two Rs ６ together with the carbon atom to which they are attached 【Chemical Formula 6】 forming, the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

22. R １ is a 5- to 6-membered heteroaryl optionally substituted with one, two or three R １０ groups R ２ , R ３ , and R ４ are each independently selected from H, halo, C １－４ alkyl and C １－４ haloalkyl, R ５ is H, halo, C １－４ alkyl, C １－４ haloalkyl or a 5- to 6-membered heteroaryl optionally substituted with one, two or three Rs １０ and is R ６ is, for each occurrence, independently H, —OR １ｃ , C １－４ alkyl optionally substituted with haloalkyl and CN, or C １－４ alkyl selected from, or two Rs ６ together with the carbon atom to which they are attached form a 4-membered heterocycloalkyl, R ７ and R ８ are each independently H, halo, CN, -OR １ｃ , -SO ２ R １ｃ , and are optionally substituted with one or more substituents independently selected from halo, CN, and -OR １ｃ selected from C １－６ alkyl, or R ７ and R ８ together with the carbon atom to which they are attached form a 4-membered heterocycloalkyl R ９ is H or C １－６ and is alkyl, R １０ is selected independently from halo, -OR １ｃ , C １－６ alkyl and C １－６ haloalkyl, R １ａ and R １ｂ are each independently H or C １－４ alkyl, R １ｃ is H, C １－４ alkyl, and The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1 or 2.

23. R １ is a 5- or 6-membered heteroaryl selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, pyridine, pyridazine, pyrimidine and pyrazine, each of which is optionally substituted with one, two or three R １０ and is optionally substituted with R ２ 、R ３ 、and R ４ are H, R ５ is H, halo, C １－４ alkyl or C １－４ haloalkyl, and R ６ which, for each occurrence, is independently H, -OR １ｃ C １－４ alkyl optionally substituted with haloalkyl and CN, or C １－４ alkyl selected therefrom, or two Rs ６ together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl, R ７ and R ８ are each independently H, halo, CN, -OR １ｃ , -SO ２ R １ｃ , and halo, CN, and -OR １ｃ optionally substituted with one or more substituents independently selected from C １－６ alkyl, or R ７ and R ８ together with the carbon atom to which they are attached form a 4- to 6-membered heterocycloalkyl, R ９ is H or C １－４ is alkyl, R １０ is selected independently from halo, -OR １ｃ , C １－４ alkyl and C １－４ haloalkyl, R １ｃ is H or C １－４ alkyl, the compound according to claim 22, or a pharmaceutically acceptable salt thereof.

24. The compound according to any one of claims 1 to 4 and 7 to 23, wherein the compound is represented by formula (IIA), (IIB), (IIIA), (IIIB), (IVA) or (IVB): 【Chemical Formula 7】 or a pharmaceutically acceptable salt thereof.

25. R ６ is, for each occurrence, independently selected from H and C １－４ alkyl R ７ and R ８ are each independently selected from H, halo, CN, and C １－４ alkyl, R １０ is -OR １ｃ C １－４ alkyl, and C １－４ haloalkyl, and is selected from R １ｃ is C １－４ alkyl, and The compound according to any one of claims 1 to 4 and 7 to 24, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1 or 2.

26. R ６ is H or CH ３ and R ７ and R ８ are each independently selected from H, F, CH ３ and CN, R １０ is selected from CH ３ , CHF ２ and OCH ３ and is selected from The compound according to any one of claims 1 to 4 and 7 to 24, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1 or 2.

27. The compound according to any one of claims 24 to 26, or a pharmaceutically acceptable salt thereof, wherein r is 0.

28. A pharmaceutical composition comprising the compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. A method for inhibiting tyrosine kinase 2 (TYK2) activity in a subject in which it is necessary to inhibit TYK2 activity, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 28.

30. A method for treating a disease or disorder that is responsive to inhibition of tyrosine kinase 2 (TYK2) in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 28.

31. The method according to claim 30, wherein the disease or disorder is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, head trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, and sunburn.

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