TYK2 inhibitors

Abstract

The present disclosure relates to compounds of Formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) wherein all the variables are as defined herein. The compounds of the present disclosure are capable of inhibiting the activity of tyrosine kinase 2 (TYK2). The disclosure further provides methods of making the compounds of the disclosure and methods for their therapeutic use. Formula (I) imgabs0 #

Description

[0001] Related Applications

[0002] 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 expressly incorporated herein by reference. Background Art

[0003] Cytokines are small secreted proteins released by cells and have specific effects on cell-to-cell interactions and communication. Cytokine pathways mediate a wide range of biological functions, including many aspects of inflammation and immunity, primarily through extracellular signaling.

[0004] 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, the engagement of cytokines with cognate receptors triggers the activation of receptors associated with JAKs, which leads to tyrosine phosphorylation of JAK-mediated signal transducers and activators of transcription (STAT) proteins, and ultimately leads to transcriptional activation of specific gene sets (Schindler et al., 2007, J. Biol. Chem. 282: 20059-63). Many cytokines are known to activate the JAK family including the interferon (IFN) family (IFN-α, IFN-β, IFN-ω, Limitin, IFN-γ, IL-10, IL-19, IL-20, IL-22), glycoprotein (gp) 130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), γC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF) and G protein-coupled receptors (AT1).

[0005] TYK2 is important in the signaling of type I interferons (e.g., IFN-α), 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, WT & O'Shea, JJ, 2006, Immunity 25: 695-697). Consistent with this, primary cells derived from TYK2-deficient humans are defective in type I interferon, IL-6, IL-10, IL-12, and IL-23 signaling. TYK2 signals with other members of the JAK family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, TYK2 / JAK1 / JAK2.

[0006] Studies have shown that inappropriate JAK activity may be caused by mutation, overexpression or inappropriate regulation, abnormal or dysregulated regulation, and excessive or insufficient production of growth factors or cytokines, thereby triggering a variety of biological cellular responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility. Inappropriate JAK activity is involved in 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 nervous system and neurodegenerative disorders, such as Alzheimer's disease.

[0007] 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 that have entered development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also known as the JH1 or “Janus homology 1” domain), which prevents the catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and resulting pathway signaling (Bryan et al., J. Med. Chem. 2018, 61, 9030−9058).

[0008] Since the ATP active site is highly homologous throughout the kinome and in particular within the JAK family, achieving high selectivity for specific JAK family members while also maintaining selectivity within the kinome is a major challenge. As a result, many of the JAK inhibitors that have been developed are pan-JAK inhibitors or have modest selectivity for one or more JAK family members. While these inhibitors have shown promising results in the treatment of autoimmune diseases, adverse side effects have been observed that result in a narrow therapeutic index, indicating a need for improved treatments.

[0009] TYK2 has been shown to be important in the differentiation and function of multiple cell types that are important in inflammatory and autoimmune diseases, including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with a variety of autoimmune or inflammatory conditions.

[0010] There remains a need for potent compounds that exhibit high selectivity for TYK2 relative to other members of the JAK family. Summary of the invention

[0011] One aspect of the present disclosure is a compound of formula (I):

[0012]

[0013] (I)

[0014] or a pharmaceutically acceptable salt thereof, wherein:

[0015] Ring A and ring B together form a bicyclic heteroaromatic ring;

[0016] X1 is N or C;

[0017] X2 is N, NH or CR 2 ;

[0018] X3 is N or CR 3 ;

[0019] X4 is N or CR 4 ;

[0020] X5 is N or CH;

[0021] Y is CR 7 R 8 , O or NR 9 ;

[0022] R 1 and R 5 Each is independently selected from H, halogen, 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, wherein R 1 and R 5 C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each optionally substituted by one or more R 10 replace;

[0023] R 2 , R 3 and R 4 Each is independently selected from H, halo, -CN, -NR 1a R 1b 、-OR 1c , C 1-4 Alkyl and C 1-4 Haloalkyl;

[0024] R 6 is independently selected at each occurrence from H, halo, CN, -NR 1a R 1b 、-OR 1c 、-SO2R 1c or C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halo, CN, -NR 1a R 1b AND-OR 1c ; or two R 6 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered heterocycloalkyl or C 3-6 Cycloalkyl;

[0025] R 7 and R 8 Each is independently selected from H, halogen, CN, -NR 1a R 1b 、-OR 1c 、-SO2R 1c or C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halo, CN, -NR 1a R 1b AND-OR 1c , or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered heterocycloalkyl or C 3-6 Cycloalkyl;

[0026] R 9is H or C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halo, CN, -NR 1a R 1b AND-OR 1c ;

[0027] R 10 is independently selected at each occurrence from 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; wherein R 10 C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 4 to 7 membered monocyclic heterocycloalkyl and 5 to 6 membered heteroaryl are each optionally substituted with one or more substituents independently 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;

[0028] R 1a and R 1b Each independently is H or C 1-4 alkyl;

[0029] R 1c It is H, C 1-4 Alkyl or C 1-4 haloalkyl; and

[0030] r is 0 or an integer from 1 to 4.

[0031] In one aspect, 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.

[0032] Another aspect of the present disclosure is a method of inhibiting TYK2 activity in a subject in need thereof, 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.

[0033] In some aspects, the disclosure is a method of treating a disease or condition responsive to inhibition of TYK2 in a subject, 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.

[0034] 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 the manufacture of a medicament for inhibiting TYK2 activity. It also includes the use of at least one compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for the manufacture of a medicament for treating a disease or condition responsive to the inhibition of TYK2.

[0035] 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. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for use in treating a disease or condition responsive to inhibition of TYK2.

[0036] Other features and advantages will be apparent from the following detailed description of several embodiments, and from the appended claims. DETAILED DESCRIPTION

[0037] The compounds described herein or their pharmaceutically acceptable salts exhibit high potency against TYK2. In addition, the compounds disclosed herein or their pharmaceutically acceptable salts have high selectivity for inhibiting TYK2 compared to other members of the JAK family (such as JAK1, JAK2 and JAK3).

[0038] I. Definitions

[0039] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to the replacement of hydrogen groups in a given structure by groups of specified substituents. Specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise specified, the optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent at each position may be the same or different. In some embodiments, the optionally substituted group may be substituted by one or more substituents, each of which may be the same or different. In some embodiments, "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, "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.

[0040] As used herein, "halogen" or "halo" may be fluoro, chloro, bromo or iodo.

[0041] As used herein, "hydroxyl" or "hydroxy" refers to the group -OH.

[0042] As used herein, the number of carbon atoms in a group is indicated herein by the prefix "C x-xx ” where x and xx are integers. For example, “C 1-4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms.

[0043] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 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, alkyl is C 1-4 In some embodiments, the alkyl group is C 1-3 alkyl

[0044] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon group that may be straight or branched and has at least one carbon-carbon double bond. Alkenyl groups having 2 to 6 carbon atoms may be preferred. Alkenyl groups may contain 1, 2, or 3 or more carbon-carbon double bonds. Examples of alkenyl groups include vinyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, etc.

[0045] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halogen atom. 1-6 Haloalkyl groups may be preferred. 1-6 The haloalkyl group may be C 1-6 Monohaloalkyl, C 1-6 dihaloalkyl or C 1-6 Polyhalogenated alkyl (including C 1-6 perhaloalkyl). 1-6 A monohaloalkyl group may have one iodo, bromo, chloro or fluoro group within the alkyl group. 1-6 Dihaloalkyl and C 1-6 A polyhaloalkyl group may have two or more of the same halogenated atoms or a combination of different halogenated groups within the alkyl group. 1-6Polyhaloalkyl 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. 1-6 A perhaloalkyl group is a C 1-6 alkyl.

[0046] As used herein, the term "oxo" (=O) refers to an oxygen atom connected to a carbon or sulfur atom by a double bond. Examples include carbonyl, sulfinyl or sulfonyl (--C(O)--, --S(O)-- or --S(O)2--), such as a ketone, an aldehyde, or a portion of an acid, ester, amide, lactone or lactam group, etc.

[0047] As used herein, the terms "aryl", "aryl group", "aryl ring", "aromatic group" and "aromatic ring" are used interchangeably to refer to an aromatic 6- to 12-membered monocyclic or bicyclic carbon ring system. Examples of aryl systems include, but are not limited to, phenyl, naphthyl, and the like. 6-10 Aryl may be preferred.

[0048] As used herein, the terms "heteroaryl", "heteroaryl group", "heteroaromatic" and "heteroaromatic ring" are used interchangeably to refer to an aromatic 5 to 12 membered monocyclic or bicyclic ring system having at least one heteroatom (e.g., oxygen, sulfur, nitrogen or a combination thereof), wherein N may be oxidized (e.g., N(O)) or quaternized, and S may be optionally oxidized to sulfoxide and sulfone. Heteroaryls having 5 to 10 membered ring systems may be preferred. "Heteroaryl" includes heteroaromatic groups fused to phenyl or non-aromatic heterocycles, such as tetrahydrofuran, pyran, pyrrolidine, piperidine, and the like. Examples of heteroaryls include pyrrole, pyridyl, pyrazole, thienyl, furanyl, oxazolyl, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazolyl, triazinyl, pyrimidinyl, pyrazinyl, thiazolyl, indolyl, indazolyl, benzofuranyl, quinoxalinyl, and the like. In some embodiments, the heteroaryl group is selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, and pyrrole.

[0049] As used herein, the term "cycloalkyl" refers to a fully saturated monocyclic or bicyclic (e.g., fused, spiro or bridged) hydrocarbon group of 3-12 carbon atoms, 3-6 carbon atoms, or 5-7 carbon atoms. 3-8 Cycloalkyl groups may be preferred. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0050] As used herein, the term "heterocycloalkyl" refers to a fully saturated 4 to 12-membered monocyclic or bicyclic (e.g., fused) ring system with at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or a combination thereof). In some embodiments, heterocycloalkyl has 1, 2, 3, or 4 heteroatoms (preferably 1 or 2 heteroatoms). In some embodiments, heterocycloalkyl with a 4 to 10-membered ring system may be preferred. In some embodiments, heterocycloalkyl has 4 to 6 ring atoms (i.e., 4 to 6 heterocycloalkyls), wherein 1 or 2 heteroatoms are independently selected from oxygen and nitrogen. In some embodiments, heterocycloalkyl has 4 to 6 ring atoms, wherein 1 heteroatom is oxygen. In some embodiments, heterocycloalkyl is oxetane.

[0051] The phrase "pharmaceutically acceptable" means that the substance, composition or dosage form must be compatible chemically and / or toxicologically with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0052] Unless otherwise indicated, the term "compound of the present disclosure" refers to compounds described herein, such as compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (IIA), (IIB), (IIIA), (IIIB), (IVA) or (IVB) and all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitution). When there is a moiety capable of forming a salt, the salt (particularly a pharmaceutically acceptable salt) is also included. The compounds of the present disclosure may inherently or by design form salts, hydrates and solvates, polymorphs thereof.

[0053] As used herein, unless otherwise specified herein or clearly contradictory to the context, the terms "a / an", "the" and similar terms used in the context of the present disclosure (particularly in the context of the claims) should be interpreted as covering both the singular and the plural. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present disclosure and does not limit the scope of the present disclosure otherwise claimed.

[0054] In the case where the compounds provided herein have sufficient alkalinity or acidity to form stable non-toxic acid or base salts, it may be appropriate to prepare and administer the compounds in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as toluenesulfonates, mesylates, acetates, citrates, malonates, tartrates, succinates, benzoates, ascorbates, alpha-ketoglutarate or alpha-glycerophosphate. Inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates and carbonates.

[0055] Pharmaceutically acceptable salts can 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 providing a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

[0056] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases may include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts or magnesium salts. Salts derived from organic bases may include, but are not limited to, salts of primary, secondary or tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dienylamines, trialnylamines, 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 The invention also includes amines comprising cycloalkylamines, ... Non-limiting examples of amines may include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine or N-ethylpiperidine, etc. Other carboxylic acid derivatives, such as carboxylic acid amides (including formamide, lower alkyl formamide or dialkyl formamide, etc.) may be useful.

[0057] Those skilled in the art will recognize that the compounds of the present disclosure may contain chiral centers and may therefore exist in different stereoisomeric forms. As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure. It should be understood that substituents may be attached to the chiral centers of carbon atoms. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0058] Certain compounds described herein contain one or more asymmetric centers or axes, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- according to absolute stereochemistry. According to the present disclosure, any structure for which stereochemistry is not specified should be understood to include all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (e.g., racemic mixtures or enantiomerically enriched mixtures). How to prepare such optically active forms is well known in the art (e.g., by resolving racemic forms by recrystallization techniques, synthesizing from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases). In some embodiments, the compounds described herein are separated stereoisomers, wherein each of the compounds has a stereocenter, and the stereoisomer is in the R configuration. In other embodiments, the compounds described herein are separated stereoisomers, wherein each of the compounds has a stereocenter, and the stereoisomer is in the S configuration. In one embodiment, the compounds described herein are separated stereoisomers, wherein each of the compounds has two stereo centers, and the stereoisomers are in RR configuration. In one embodiment, the compounds described herein are separated stereoisomers, wherein each of the compounds has two stereo centers, and the stereoisomers are in RS configuration. In one embodiment, the compounds described herein are separated stereoisomers, wherein each of the compounds has two stereo centers, and the stereoisomers are in SR configuration. In one embodiment, the compounds described herein are separated stereoisomers, wherein each of the compounds has two stereo centers, and the stereoisomers are in SS configuration. In one embodiment, the compounds described herein each have one or two stereo centers and are racemic mixtures.

[0059] When a specific stereoisomer of a compound is depicted by name or structure, the stereochemical purity of that 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 percent of the desired stereoisomer relative to the combined weight of all stereoisomers.

[0060] When a specific enantiomer of a compound is depicted by name or structure, the stereochemical purity of that 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 percent of the desired enantiomer relative to the combined weight of all stereoisomers.

[0061] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further 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%. Stereoisomer purity means the weight percentage of the desired stereoisomer encompassed by the name or structure relative to the combined weight of all stereoisomers.

[0062] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has one chiral center, it is understood that the name or structure encompasses one enantiomer of the compound in pure or substantially pure form, as well as mixtures thereof (e.g., racemic mixtures of the compounds, and mixtures enriched in one enantiomer relative to its corresponding optical isomer).

[0063] Unless otherwise indicated, the compounds of the present disclosure are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separation on a chiral SFC or HPLC column (e.g., CHIRALPAK available from DAICEL Corp.) RTM and CHIRALCEL RTM) using an appropriate solvent or solvent mixture to achieve good separation). If the compound contains a double bond, the substituents may be in E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0064] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and, for example, the compound has at least two chiral centers, it is understood that the name or structure encompasses one stereoisomer in pure or substantially pure form as well as mixtures thereof (e.g., mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers are enriched relative to other stereoisomers).

[0065] The disclosed compounds can exist in tautomeric forms, and mixtures and individual single tautomers are desirable. All such forms are included within the scope of the present disclosure. In addition, some compounds may exhibit polymorphism. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via the migration of protons, such as keto-enol and imine-enamine isomerizations. The specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons in the bonding electrons.

[0066] In addition, the compounds of the present disclosure (including their salts) can also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds of the present disclosure can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present disclosure is intended to include both solvated forms and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its pharmaceutically acceptable salt) and one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field 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.

[0067] Compounds of the present disclosure containing groups capable of acting as donors and / or acceptors of hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from the compounds by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting or contacting the compound with the co-crystal former under crystallization conditions and isolating the co-crystals thus formed. Suitable co-crystal formers include those described in WO 2004 / 078163. Thus, the present disclosure further provides co-crystals comprising the compounds described herein.

[0068] In one embodiment, the present disclosure provides deuterated compounds disclosed herein, wherein any position or positions occupied by hydrogen may include an enrichment of deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 times (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium incorporation), at least 5500 times (82.5% deuterium incorporation), at least 6000 times (90% deuterium incorporation), at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporation), at least 6600 times (99% deuterium incorporation), or at least 6633.3 times (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all locations in its natural abundance.

[0069] II. Compounds of the Disclosure

[0070] In Embodiment 1, the compounds of the present disclosure are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as described above. In some embodiments, X5 is N.

[0071] (I).

[0072] In embodiment 2, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, X2 is NH or CR 2 ; and the remaining variables are as described in Embodiment 1. In some embodiments, X2 is NH or CH.

[0073] In embodiment 3, the compound is of formula (II), (III), (IV), (V), (VI) or (VII):

[0074] (II) (III) (IV)

[0075] (V) (VI) or (VII)

[0076] or a pharmaceutically acceptable salt thereof, and the variables in Formulas (II), (III), (IV), (V), (VI) and (VII) are as described in Embodiment 1.

[0077] In Embodiment 4, for a 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 variables are as described in Embodiment 1, 2 or 3.

[0078] In Embodiment 5, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, Y is O; and the remaining variables are as described in Embodiment 1, 2 or 3.

[0079] In Embodiment 6, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, Y is NR 9 ; and the remaining variables are as described in Embodiment 1, 2 or 3.

[0080] In Embodiment 7, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 1 is optionally replaced by 1, 2 or 3 R 10 substituted 5- to 6-membered heteroaryl; and the remainder of the variables are as described in Embodiment 1, 2, 3, 4, 5 or 6.

[0081] In Embodiment 8, for a 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 selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, pyridine, pyridazine, pyrimidine and pyrazine, wherein each heteroaryl is optionally substituted by 1, 2 or 3 R 10 and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6 or 7.

[0082] In Embodiment 9, for a 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 group selected from pyrazole, isoxazole, pyridine and pyridazine, wherein each heteroaryl group is optionally substituted by 1 or 2 R 10 and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6 or 7.

[0083] In Embodiment 10, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R1 is a 5- to 6-membered heteroaryl group selected from:

[0084] , , , ,

[0085] and ;

[0086] in represents the point of attachment to Ring B; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9.

[0087] In Embodiment 11, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 10 are independently selected from halo, -OR 1c , C 1-6 Alkyl and C 1-6 haloalkyl; and R 1c It is C 1-4 alkyl; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0088] In Embodiment 12, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 10 is independently selected from F, -OCH3, -CH3 and -CHF2; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

[0089] In Embodiment 13, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 2 , R 3 and R 4 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; and the remainder of the variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0090] In Embodiment 14, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 2 , R 3 and R 4is H; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13.

[0091] In Embodiment 15, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 5 H, halogen, C 1-4 Alkyl, C 1-4 haloalkyl or optionally substituted by 1, 2 or 3 R 10 substituted 5- to 6-membered heteroaryl; and the remainder of the variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14.

[0092] In Embodiment 16, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 5 is H; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0093] In Embodiment 17, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 7 and R 8 Each is independently selected from H, halogen, CN, -OR 1c 、-SO2R 1c and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents being independently selected from halo, CN and -OR 1c , or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group; and R 1c Is H or C 1-3 alkyl; and the remainder of the variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0094] In Embodiment 18, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 7 and R 8 Each is independently selected from H, F, CN, -OH, -OCH3, -SO2CH3, -CH3, -CHF2, -CF3, -CH2-CN, -CH2-O-CH3 and -CH2CH2-O-CH3, or R7 and R 8 Together with the carbon atom to which they are attached they form:

[0095] ; and the remaining variables are as described in embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17.

[0096] In Embodiment 19, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII), or a pharmaceutically acceptable salt thereof, r is 0, 1 or 2; and the remaining variables are as described in Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

[0097] In Embodiment 20, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 6 is independently selected at each occurrence from H, -OR 1c , C 1-4 haloalkyl and optionally substituted with CN 1-4 Alkyl, or two R 6 Together with the carbon atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group; and R 1c Is H or C 1-3 alkyl; and the remainder of the variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19.

[0098] In Embodiment 21, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 6 is independently selected at each occurrence from H, -OH, -OCH3, -CH2-CN and -CH3, or two R 6 Together with the carbon atom to which they are attached they form: ; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0099] In Embodiment 22, for a compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII) or a pharmaceutically acceptable salt thereof, R 1 is optionally replaced by 1, 2 or 3 R 10 Substituted 5- to 6-membered heteroaryl; R2 , R 3 and R 4 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; R 5 H, halogen, C 1-4 Alkyl, C 1-4 haloalkyl or optionally substituted by 1, 2 or 3 R 10 Substituted 5- to 6-membered heteroaryl; R 6 is independently selected at each occurrence from H, -OR 1c , C 1-4 haloalkyl and optionally substituted with CN 1-4 Alkyl, or two R 6 Together with the carbon atoms to which they are attached, they form a 4-membered heterocycloalkyl group; R 7 and R 8 Each is independently selected from H, halogen, CN, -OR 1c 、-SO2R 1c and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents being independently selected from halo, CN and -OR 1c , or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 4-membered heterocycloalkyl group; R 9 Is H or C 1-6 Alkyl; R 10 are independently selected from halo, -OR 1c , C 1-6 Alkyl and C 1-6 Haloalkyl; R 1a and R 1b Each independently is H or C 1-4 Alkyl; R 1c It is H, C 1-4 alkyl; and r is 0, 1 or 2; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5 or 6.

[0100] In Embodiment 23, for a 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 selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, pyridine, pyridazine, pyrimidine and pyrazine, wherein each heteroaryl is optionally substituted by 1, 2 or 3 R 10 Replacement; R 2 , R 3 and R 4 It is H; R 5 H, halogen, C 1-4Alkyl or C 1-4 Haloalkyl; R 6 is independently selected at each occurrence from H, -OR 1c , C 1-4 haloalkyl and optionally substituted with CN 1-4 Alkyl, or two R 6 Together with the carbon atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group; R 7 and R 8 Each is independently selected from H, halogen, CN, -OR 1c 、-SO2R 1c and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents being independently selected from halo, CN and -OR 1c , or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group; R 9 Is H or C 1-4 Alkyl; R 10 are independently selected from halo, -OR 1c , C 1-4 Alkyl and C 1-4 haloalkyl; and R 1c Is H or C 1-4 alkyl; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5 or 6.

[0101] In Embodiment 24, the compound is of Formula (IIA), (IIB), (IIIA), (IIIB), (IVA) or (IVB):

[0102] (IIA) (IIB), (IIIA),

[0103] (IIIB) (IVA) or (IVB),

[0104] or a pharmaceutically acceptable salt thereof; and the variables of Formula (IIA), (IIB), (IIIA), (IIIB), (IVA) and (IVB) are as described in Embodiment 1, 11, 12, 17, 18, 19, 20, 21, 22 or 23.

[0105] In Embodiment 25, 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 independently selected at each occurrence from H and C 1-4 Alkyl; R 7 and R 8 are each independently selected from H, halogen, CN and C 1-4 Alkyl; R 10 Selected from –OR 1c , C 1-4 Alkyl and C 1-4 Haloalkyl; R 1c It is C 1-4 alkyl; and r is 0, 1 or 2; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.

[0106] In Embodiment 26, 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 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; and r is 0, 1 or 2; and the remaining variables are as described in Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24.

[0107] In Embodiment 27, 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 is 0; and the remaining variables are as described in Embodiment 24, 25 or 26.

[0108] In embodiment 28, the compound is selected from any one of the following

[0109] (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]oct-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]oct-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]oct-3-yl)-3H-imidazo[4,5-b]pyridine; 7-((1R,5S)-8-(3-(difluoromethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]oct-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]oct-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] oct-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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile;.

[0110] (1R,3r)-3-(3-(2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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]oct-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 ]oct-8-yl)cyclobutane-1-carbonitrile; 2-(2-methoxypyridin-4-yl)-4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-1H-pyrrolo[2,3-b]pyridine; 4-(8-(3-(difluoromethyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]oct-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]oct-8-yl]oxetan-3-yl]ethyl 3-[3-[6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]oct-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]oct-8-yl]-1-(trifluoromethyl)cyclobutane-1-ol; 6-(1-methylpyrazol-4-yl)-4-[8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrrolo[1,2-b]pyridazine; 4-[8-(3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutane-1-carbonitrile; Azabicyclo[3.2.1]oct-3-yl]-6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine; 3-[3-[6-(1-methylpyrazol-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutan-1-ol; 4-(8-cyclobutyl-3,8-diazabicyclo[3.2.1]oct-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]pyridazine-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[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-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]heptane-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]oct-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]oct-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]oct-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]oct-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]oct-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]heptane-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]heptane-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]pyridazine-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 2-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile 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)cyclobutane-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)cyclobutane-1-ol; Rac-4-(8-((1S,2S)-2-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]oct-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]oct-3-yl]-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]oct-3-yl]pyrrolo[1,2-b]pyridazine; 3-[3-[6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutane-1-carbonitrile; 3-[3-[6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutane-1-carbonitrile; (6-pyridazin-4-ylpyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]cyclobutane-1-carbonitrile; 4-[8-(oxetane-3-yl)-3,8-diazabicyclo[3.2.1]oct-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]oct-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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile; (1S,3s)-3-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-3-(6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)cyclobutane-1-carbonitrile; )pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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]oct-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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile -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] oct-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-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]oct-8-yl) cyclobutane-1-carbonitrile or a pharmaceutically acceptable salt thereof. .

[0111] III. Pharmaceutical Compositions

[0112] 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.

[0113] As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, 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.), etc. and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pages 1289-1329). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical compositions is contemplated.

[0114] The formulation can be prepared using conventional dissolution and mixing procedures. For example, the raw drug substance (i.e., a compound of the present disclosure or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present disclosure are usually formulated into pharmaceutical dosage forms to provide a drug dosage that can be easily controlled and to provide patients with an elegant and easy-to-handle product.

[0115] The pharmaceutical composition (or preparation) for application can be packaged in a variety of ways according to the method for administering the drug. Generally, the article for distribution includes a container in which a pharmaceutical preparation in an appropriate form is placed. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-proof component to prevent inadvertent contact with the contents of the package. In addition, a label describing the contents of the container is also placed on the container. The label may also include appropriate warnings.

[0116] Pharmaceutical compositions containing compounds of the present disclosure are typically formulated for parenteral or oral administration.

[0117] For example, the pharmaceutical oral composition of the present disclosure can be prepared into 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 operations, such as sterilization, and / or can contain conventional inert diluents, lubricants or buffers and adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

[0118] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with

[0119] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0120] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, also

[0121] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; and, if necessary,

[0122] d) disintegrants, for example starch, agar, alginic acid or its sodium salt or an effervescent mixture; and / or

[0123] e) Absorbents, colorants, flavorings and sweeteners.

[0124] Tablets may be film-coated or enteric-coated according to methods known in the art.

[0125] Suitable compositions for oral administration include compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives, so as to provide pharmaceutically elegant and palatable preparations. Tablets may contain active ingredients mixed with nontoxic pharmaceutically acceptable excipients suitable for making tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; adhesives such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, and thereby provide sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g. calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g. peanut oil, liquid paraffin or olive oil).

[0126] Parenteral compositions (e.g., intravenous (IV) preparations) are aqueous isotonic solutions or suspensions. Parenteral compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and / or buffers for regulating osmotic pressure. In addition, they can also contain other therapeutically valuable substances. Compositions are usually prepared according to conventional mixing, granulation or coating methods, respectively, and contain about 0.1-75% or contain about 1-50% active ingredient.

[0127] IV. Uses of the Disclosed Compounds and Compositions

[0128] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to reduce or inhibit the activity of TYK2 or otherwise affect the properties and / or behavior of TYK2, for example, stability, phosphorylation, kinase activity, interaction with other proteins, etc.

[0129] In some embodiments, the present disclosure provides a method of inhibiting TYK2 activity in a subject in need thereof, 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.

[0130] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to a decrease, suppression, or significant reduction in the baseline activity of a biological activity or process.

[0131] One embodiment of the present disclosure is a method of treating a disease or condition responsive to inhibition of TYK2 in a subject, 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 condition responsive to inhibition of TYK2, wherein the disease or condition comprises inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoma, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain 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 diseases, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, 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.

[0132] The term "autoimmune disorder" includes diseases or disorders involving an inappropriate immune response to a natural antigen, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes, 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.

[0133] The term "inflammatory disorder" includes diseases or disorders involving acute or chronic inflammation, such as allergy, asthma, atopic dermatitis, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.

[0134] The term "cancer" includes diseases or disorders involving abnormal cell growth and / or proliferation, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumors, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability-high colorectal cancer).

[0135] As used herein, the terms "subject" and "patient" are used interchangeably and refer to mammals in need of treatment, such as humans, companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and experimental animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0136] As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the extent of a disease, disorder, or syndrome; alleviating or improving clinical symptoms or indicators associated with the disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0137] An effective dose of a compound provided herein or a pharmaceutically acceptable salt thereof administered to a subject may be 10 μg-500 mg.

[0138] Administration of a compound as described herein or a pharmaceutically acceptable salt thereof to a mammal includes any suitable delivery method. Administration of a compound as described herein or a pharmaceutically acceptable salt thereof to a mammal includes administration of a compound as described herein or a pharmaceutically acceptable salt thereof to the mammal externally, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternal, epidural, intravaginal, intravenous, intramuscularly, subcutaneously, intradermally or intravitreally. Administration of a compound as described herein or a pharmaceutically acceptable salt thereof to a mammal also includes administration of a compound as described herein or a pharmaceutically acceptable salt thereof to the mammal externally, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternal, epidural, intravaginal, intravenous, intramuscularly, subcutaneously, intradermally or intravitreally, which is metabolized to a compound as described herein or a pharmaceutically acceptable salt thereof in the body or on the surface of the body of the mammal externally, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternal, epidural, intravaginal, intravenous, intramuscularly, subcutaneously, intradermally or intravitreally.

[0139] Therefore, the compound as described herein or its pharmaceutically acceptable salt can be combined with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier and administered systemically, such as orally. They can be encapsulated in a hard or soft shell gelatin capsule, can be compressed into tablets, or can be directly blended with the food of the patient's diet. For oral therapeutic administration, the compound as described herein or its pharmaceutically acceptable salt can be combined with one or more excipients and can be used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups or glutinous rice paper capsules (wafers). Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the composition and preparation is of course variable, and can be conveniently between about 2% to about 60% of the weight of a given unit dosage form. The amount of the active compound in such a therapeutically useful composition can be such that an effective dosage level will be obtained.

[0140] Tablets, troches, pills, capsules, etc. may include the following: binders such as gum tragacanth, gum arabic, 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.

[0141] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts may be prepared in water optionally mixed with a nontoxic surfactant.

[0142] Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient, which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

[0143] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound in an appropriate solvent with various other ingredients listed above (as required), followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods may be vacuum drying and freeze drying techniques, which can produce a powder of the active ingredient plus any additional desired ingredients present in the previously sterile-filtered solution.

[0144] Exemplary solid carriers may include finely divided solids such as talc, clay, microcrystalline cellulose, silicon dioxide, alumina, etc. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends in which the compounds as described herein or pharmaceutically acceptable salts thereof may be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.

[0145] The useful dosage of the compound as described herein or its pharmaceutically acceptable salt can be determined by comparing their in vitro activity and in vivo activity in animal models. The method of extrapolating effective dosages in mice and other animals to humans is known in the art; for example, see U.S. Patent No. 4,938,949, which is incorporated by reference in its entirety.

[0146] The amount of a compound as described herein or a pharmaceutically acceptable salt thereof required for treatment may vary not only with the particular salt selected, but also with the route of administration, the nature of the disorder being treated, and the age and condition of the patient, and may ultimately be determined by the attending physician or clinician. However, in general, the dosage may be in the range of about 0.1 to about 10 mg / kg body weight per day.

[0147] The compound as described herein or a pharmaceutically acceptable salt thereof may conveniently be administered in unit dosage form; for example, each unit dosage form contains 0.01 to 10 mg or 0.05 to 1 mg of active ingredient. In some embodiments, a dose of 5 mg / kg or less may be appropriate.

[0148] The desired dose may conveniently be presented in a single dose or in divided doses administered at appropriate intervals.

[0149] The disclosed method may include a kit including a compound as described herein or a pharmaceutically acceptable salt thereof and explanatory materials, which may describe administering a compound as described herein or a pharmaceutically acceptable salt thereof or a composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof to a cell or subject. This should be interpreted as including other embodiments of kits known to those skilled in the art, such as a kit comprising a (such as sterile) solvent for dissolving or suspending a compound as described herein or a pharmaceutically acceptable salt thereof or a composition prior to administering a compound as described herein or a pharmaceutically acceptable salt thereof or a composition to a cell or subject. In some embodiments, the subject may be a human.

[0150] The disclosed compounds can be synthesized by synthetic routes including processes similar to those well known in the chemical arts, particularly in light of the description contained herein. Starting materials are generally available from commercial sources, such as Sigma-Aldrich, or are readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 editions) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplementary materials (also available via the Beilstein online database)). The protection of functional groups by protecting groups, the protecting groups themselves and their cleavage reactions are described, for example, in standard reference works, such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd 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.A characteristic of protecting groups is that they can be readily removed (ie without undesired secondary reactions), for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (eg by enzymatic cleavage).

[0151] Salts of compounds of the present disclosure having at least one salt-forming group can be prepared in a manner known to those skilled in the art. For example, acid addition salts of compounds of the present disclosure can be obtained in a conventional manner, such as by treating the compounds of the present disclosure with an acid or a suitable anion exchange reagent. Salts can be converted to free compounds according to methods known to those skilled in the art. Acid addition salts can be converted, for example, by treating with a suitable alkaline agent.

[0152] Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0153] For those compounds containing asymmetric carbon atoms, the compound exists in a single optically active isomeric form or as a mixture thereof, for example, as a racemic or diastereomeric mixture. Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art (such as by chromatography and / or fractional crystallization). Enantiomers can be separated in the following manner: by reacting with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or mosheoyl chloride) the enantiomeric mixture is converted into a diastereomeric mixture, the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Enantiomers can also be separated by using commercially available chiral HPLC columns.

[0154] The present disclosure further encompasses any variation of the processes of the present invention wherein the reaction components are used in the form of their salts or optically pure substances.The compounds and intermediates of the present disclosure may also be interconverted according to methods generally known to those skilled in the art.

[0155] For illustrative purposes, the reaction described below provides a possible approach for synthesizing compounds disclosed herein and key intermediates. For a more detailed description of each reaction step, see the following Examples section. Although specific starting materials and reagents are described in the scheme and discussed below, other starting materials and reagents can be easily replaced to provide multiple derivatives and / or reaction conditions. In addition, conventional chemical methods well known to those skilled in the art can be used according to the present disclosure to further modify many compounds in the compounds prepared by the following methods.

[0156] example

[0157] Unless otherwise stated, the compounds of the Examples described below were analyzed or purified according to one of the purification methods mentioned below.

[0158] abbreviation:

[0159] Aq. represents aqueous solution;

[0160] Bn represents benzyl;

[0161] Boc represents tert-butoxycarbonyl;

[0162] Boc2O represents di-tert-butyl dicarbonate;

[0163] br means width;

[0164] t-BuOH represents tert-butyl alcohol;

[0165] n-BuLi represents n-butyllithium;

[0166] ℃ means Celsius;

[0167] CDCl3 represents deuterated chloroform;

[0168] δ represents chemical shift;

[0169] d means double;

[0170] dd means double double;

[0171] DCM means dichloromethane;

[0172] DEA stands for diethylamine;

[0173] DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine;

[0174] DMA stands for N,N-dimethylacetamide;

[0175] DMF stands for N,N-dimethylformamide;

[0176] DMSO means dimethyl sulfoxide;

[0177] DMSO-d6 indicates hexadeuterated dimethyl sulfoxide;

[0178] Et represents ethyl;

[0179] EtOH indicates ethanol;

[0180] EtOAc means ethyl acetate;

[0181] Eq. means equivalent;

[0182] g means grams;

[0183] HCl means hydrochloric acid;

[0184] HCO2H represents formic acid

[0185] 1 H NMR denotes proton nuclear magnetic resonance;

[0186] H2O means water;

[0187] HPLC stands for high pressure liquid chromatography;

[0188] h means hour;

[0189] IPA stands for 2-propanol

[0190] K2CO3 represents potassium carbonate;

[0191] KF stands for potassium fluoride

[0192] KOH means potassium hydroxide;

[0193] L stands for liter;

[0194] LCMS stands for liquid chromatography mass spectrometry;

[0195] LDA stands for lithium diisopropylamide;

[0196] m means multiple;

[0197] M stands for mole;

[0198] Me represents methyl;

[0199] MeCN means acetonitrile;

[0200] MeI stands for methyl iodide

[0201] MeOH means methanol;

[0202] MeOH-d4 represents deuterated methanol;

[0203] mg means milligram;

[0204] MgSO4 means magnesium sulfate;

[0205] MHz stands for megahertz;

[0206] min means minute;

[0207] mL means milliliter;

[0208] mmol means millimole;

[0209] MS m / z indicates mass spectrum peak;

[0210] MsCl means methanesulfonyl chloride;

[0211] N2 represents nitrogen;

[0212] NaBH4 means sodium borohydride;

[0213] NaBH3CN represents sodium cyanoborohydride;

[0214] Na2CO3 represents sodium carbonate;

[0215] NaH means sodium hydride;

[0216] NaHCO3 means sodium bicarbonate;

[0217] NaIO4 represents sodium periodate;

[0218] NaOH means sodium hydroxide;

[0219] Na2SO4 means sodium sulfate;

[0220] NBS stands for N-bromosuccinimide;

[0221] NH3 represents ammonia;

[0222] NH4Cl represents ammonium chloride;

[0223] NH4OH is ammonium hydroxide;

[0224] NOE stands for Nuclear Overhauser Effect Spectroscopy;

[0225] PE stands for petroleum ether;

[0226] Pd(amphos)Cl2 stands for bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)

[0227] Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0);

[0228] Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride;

[0229] PdCl2(PPh3)2 represents bis(triphenylphosphine)palladium(II) dichloride;

[0230] Pd / C means palladium on carbon;

[0231] POCl3 represents phosphorus oxychloride;

[0232] q means quadruple;

[0233] rt means room temperature;

[0234] RuCl3 represents ruthenium(III) chloride;

[0235] s indicates single weight;

[0236] sat. means saturation;

[0237] SFC stands for supercritical fluid chromatography;

[0238] soln. means solution;

[0239] t means triple;

[0240] TBME means tert-butyl methyl ether;

[0241] TEA means triethylamine;

[0242] TFA denotes trifluoroacetic acid;

[0243] THF means tetrahydrofuran;

[0244] TLC means thin layer chromatography;

[0245] TsCl denotes p-toluenesulfonyl chloride;

[0246] TsOH represents p-toluenesulfonic acid

[0247] µL means microliter;

[0248] µmol means micromolar; and

[0249] RuPhos Pd G3 represents (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenylyl)[2-(2′-amino-1,1′-biphenylyl)]methanesulfonate palladium(II).

[0250] General Synthesis Methods

[0251] According to the first method, compounds of formula (I) can be prepared from compounds of formula (AII), (AIII), (AIV) and (AV) as shown in Scheme 1.

[0252] Solution 1

[0253]

[0254] LG1 and LG2 are suitable leaving groups, typically halogens (such as Cl, Br or I) or sulfonates, such as mesylate, tosylate or triflate.

[0255] W is boronic acid or a suitable boronic acid ester, such as boronic acid pinacol ester.

[0256] Compounds of formula (AIV) can be catalyzed by heat or transition metal catalysis using a suitable nucleophilic substitution reaction (such as S NAr) is prepared from a compound of formula (AII) and a compound of formula (AIII). Typical conditions include reacting an amine of formula (AIII) with a compound of formula (AII) in the presence of a suitable inorganic base, a suitable palladium catalyst, in the presence of a suitable phosphine ligand, in a suitable solvent at elevated temperature, optionally under microwave irradiation. Preferred conditions include reacting compounds of formula (AII) and (AIII) in the presence of RuPhosPdG3 or Xantphos, optionally in combination with Pd2(dba)3, in the presence of a suitable base such as K2CO3, K3PO4 or Cs2CO3, at 70°C to 110°C in a suitable solvent such as dioxane, THF or toluene, optionally under microwave irradiation. Alternatively, compounds of formula (AII) and (AIII) may be reacted together in the presence of a suitable base such as TEA, at 70°C to 110°C in a suitable aprotic solvent, optionally under microwave irradiation.

[0257] Compounds of formula (I) can be prepared from compounds of formula (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 reaction, optionally in the presence of microwave radiation. Preferred conditions include reacting compounds of formula (AIV) and (AV) in the presence of Pd(dppf)Cl or Pd(amphos)Cl and a suitable base such as NaCO, KCO or KF in a suitable solvent such as dioxane, optionally in the presence of water, at between 70°C and 100°C.

[0258] According to the second method, compounds of formula (I) can be prepared from compounds of formula (AII), (AVI), (AV), (AVII), (AVIII) and (AIX) as shown in Scheme 2.

[0259] Solution 2

[0260]

[0261] LG1 and LG2 are suitable leaving groups, typically halogens (such as Cl, Br or I) or sulfonates, such as mesylate, tosylate or triflate.

[0262] W is boronic acid or a suitable boric acid ester, such as pinacol borate.

[0263] PG is a typical amine protecting group such as carbamate, and preferably Boc.

[0264] Compounds of formula (AVII) can be catalyzed by heat or transition metal catalysis using a suitable nucleophilic substitution reaction (such as S N Ar) is prepared from a compound of formula (AII) and a compound of formula (AVI). Typical conditions include reacting an amine of formula (AVI) with a compound of formula (AII) in the presence of a suitable inorganic base, a suitable palladium catalyst, in the presence of a suitable phosphine ligand, in a suitable solvent at elevated temperature, optionally under microwave irradiation. Preferred conditions include reacting compounds of formula (AII) and (AVI) in the presence of RuPhosPdG3 or Xantphos, optionally in combination with Pd2(dba)3, in the presence of a suitable base such as K2CO3, K3PO4 or Cs2CO3, at 70°C to 110°C in a suitable solvent such as dioxane, THF or toluene, optionally under microwave irradiation. Alternatively, compounds of formula (AII) and (AVI) may be reacted together in the presence of a suitable base such as TEA, at 70°C to 110°C in an appropriate aprotic solvent, optionally under microwave irradiation.

[0265] Compounds of formula (AVIII) can be prepared from compounds of formula (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 reaction, optionally in the presence of microwave radiation. Preferred conditions include reacting compounds of formula (AV) and (AVII) in the presence of Pd(dppf)Cl or Pd(amphos)Cl and a suitable base such as NaCO, KCO or KF in a suitable solvent such as dioxane, optionally in the presence of water, at between 70°C and 100°C. The subsequent amine deprotection step preferably provides compounds of formula (AVIII) via a typical Boc removal reaction carried out under acidic conditions such as HCl or TFA in an aprotic solvent such as DCM at 0°C to room temperature.

[0266] Compounds of formula (I) can be prepared from compounds of formula (AVIII) and (AIX) using a reductive amination process in the presence of a suitable reducing agent in a suitable solvent at a temperature between 0°C and elevated temperature. Preferred conditions involve reacting an amine of formula (AVIII) with a ketone of formula (AIX) in the presence of a suitable reducing agent such as NaBHCN in a suitable protic solvent such as MeOH at a temperature between room temperature and reflux temperature, preferably at 50°C.

[0267] According to a third method, compounds of formula (I) can be prepared from compounds of formula (AIV), (AX) and (AXI) as shown in Scheme 3.

[0268] Solution 3

[0269]

[0270] LG1 and LG2 are suitable leaving groups, typically halogens (such as Cl, Br or I) or sulfonates, such as mesylate, tosylate or triflate.

[0271] W is boronic acid or a suitable boric acid ester, such as pinacol borate.

[0272] Compounds of formula (AIV) can be converted to compounds of formula (AX) using a boronate formation reaction by treatment with a suitable boronate ester such as (BPin) in the presence of a suitable inorganic base such as KCO or KOAc and a suitable catalyst such as Pd(dppf)Cl or Pd(dba) in a suitable non-polar solvent such as MeCN at temperatures between room temperature and elevated temperatures.

[0273] Compounds of formula (I) can be prepared from 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 reaction, optionally in the presence of microwave radiation. Preferred conditions include reacting compounds of formula (AX) and (AXI) in the presence of Pd(dppf)Cl or Pd(amphos)Cl and a suitable base (such as NaCO, KCO or KF) in a suitable solvent (such as dioxane), optionally in the presence of water, at 70°C to 100°C.

[0274] According to a fourth method, compounds of formula (I) can be prepared from compounds of formula (AVII), (AXII), (AXI), (AVIII) and (AIX) as shown in Scheme 4.

[0275] Solution 4

[0276]

[0277] LG1 and LG2 are suitable leaving groups, typically halogens (such as Cl, Br or I) or sulfonates, such as mesylate, tosylate or triflate.

[0278] W is boronic acid or a suitable boric acid ester, such as pinacol borate.

[0279] Compounds of formula (AVII) can be converted to compounds of formula (AXII) using a boronate formation reaction by treating with a suitable boronate ester (such as (BPin)2) 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) in a suitable non-polar solvent (such as MeCN) at room temperature to elevated temperatures.

[0280] Compounds of formula (AVIII) can be prepared from 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 reaction, optionally in the presence of microwave radiation. Preferred conditions include reacting compounds of formula (AXI) and (AXII) in the presence of Pd(dppf)Cl or Pd(amphos)Cl and a suitable base such as NaCO, KCO or KF in a suitable solvent such as dioxane, optionally in the presence of water, at 70°C to 100°C. The subsequent amine deprotection step is preferably carried out via an amine deprotection step in an aprotic solvent such as DCM at 0.05°C under acidic conditions such as HCl or TFA. ℃ A typical Boc removal reaction performed at room temperature provides compounds of formula (AVIII).

[0281] Compounds of formula (I) can be prepared from compounds of formula (AVIII) and (AIX) using a reductive amination process in the presence of a suitable reducing agent in a suitable solvent at a temperature between 0°C and elevated temperature. Preferred conditions involve reacting an amine of formula (AVIII) with a ketone of formula (AIX) in the presence of a suitable reducing agent such as NaBHCN in a suitable protic solvent such as MeOH at a temperature between room temperature and reflux temperature, preferably at 50°C.

[0282] According to a fifth method, wherein X2 and X3 are N and X1 is C, compounds of formula (I) can be prepared from compounds of formula (AIII), (AXIII), (AXIV), (AXV) and (AXVI) as shown in Scheme 5.

[0283] Solution 5

[0284]

[0285] LG is a suitable leaving group, typically a halogen (such as Cl, Br or I) or a sulfonate such as mesylate, tosylate or triflate.

[0286] Compounds of formula (AXIV) can be prepared by reacting compounds of formula (AIII) and (AXIII) in the presence of a suitable base and a suitable aprotic polar solvent at temperatures between 0°C and elevated temperatures. Preferred conditions include reacting compounds of formula (AIII) with compounds of formula (AXIII) in the presence of TEA in DMSO or DMF at ambient temperature to 90°C.

[0287] Compounds of formula (AXV) can generally be prepared from compounds of formula (AXIV) by reduction reaction in the presence of a suitable hydrogenation catalyst (such as Pd / C) in a suitable alcohol solvent (such as MeOH) under H2 atmosphere at room temperature.

[0288] Compounds of formula (I) can be prepared by condensation reaction of a diamine of formula (AXV) with an aldehyde of formula (AXVI) in the presence of a suitable acidic catalyst (such as TsOH) in a suitable polar aprotic solvent (such as DMF) at elevated temperature (such as between 50°C and 80°C).

[0289] According to the sixth method, a compound of formula (I) (B) (wherein R 6 One occurrence is CH2EWG) can be prepared from compounds of formula (AXIII) (or AVIII) and (AYY) as shown in Scheme 6.

[0290] Solution 6

[0291]

[0292] EWG is 6 An electron withdrawing group as defined in .

[0293] Compounds of formula (I) (B) can be prepared by reacting compounds of formula (AXIII) (or AVIII) and (AYY) in the presence of a suitable base and a suitable aprotic polar solvent at a suitable temperature, optionally in a sealed tube. Preferred conditions include reacting compounds of formula (AXIII) (or AVIII) with compounds of formula (AYY) in the presence of a DMSO or DMF solution of TEA in a sealed container at 90°C.

[0294] According to the seventh method, compounds of formula (AIII) can be prepared from compounds of formula (AXVIII), (AXIX), (AXX), (AXXI) and (AXXII) as shown in Scheme 7.

[0295] Solution 7

[0296]

[0297] LG is a suitable leaving group.

[0298] The compound of formula (AXX) can be prepared by the reaction of the amine of formula (AXIX) and the compound of formula (AXVIII) in the presence of a suitable base, in an aprotic solvent, at ambient temperature to an elevated temperature. Preferred conditions include reacting the compound of formula (AXVIII) with the compound of formula (AXIX) under reflux conditions in the presence of a MeCN solution of K2CO3. The compound of formula (AXXI) can be obtained after the functional group mutual conversion of the compound of formula (AXX) using the method selected by those skilled in the art. Specifically, the compound of formula (AXX) can be prepared using a suitable reducing agent (such as LiAlH4THF solution) using continuous and thorough hydride reduction. The intermediate alcohol is subsequently converted into a suitable leaving group LG, thereby obtaining a compound of formula (AXXI). The compound of formula (AXXII), wherein PG is benzyl, can be prepared by a compound of formula (AXXI) and benzylamine in the presence of a suitable base (such as K2CO3), in an aprotic solvent (such as MeCN), at ambient temperature to reflux temperature. Subsequent hydrogenolysis of the benzyl group (wherein PG is benzyl) in the presence of a suitable catalyst (such as Pd / C) in a suitable protic solvent (such as MeOH) under H2 at 50°C in an autoclave affords compounds of formula (AIII).

[0299] Compounds of formula (I) or (AIV) may be converted to alternative compounds of formula (I) or (AIV) by standard chemical transformations such as, for example, alkylation of heteroatoms (such as N) via reductive amination or halogenation (such as fluorination) using methods well known to those skilled in the art.

[0300] Compounds of formula (AII), (AIII), (AV), (AVI), (AVII), (AIX), (AXI), (AXIV) and (AXVII) are commercially available and can be prepared analogously to methods known in the literature or as described in the experimental part below.

[0301] Those skilled in the art will appreciate that it may be necessary to utilize an appropriate protecting group strategy to prepare compounds of formula (I). Typical protecting groups may include carbamates, and preferably Boc for protecting amines or tosyl for protecting imidazole N atoms.

[0302] Those skilled in the art will appreciate that it may be necessary to utilise appropriate functional group interconversion strategies in the preparation of intermediates to compounds of formula (I).

[0303] Silica gel chromatography was performed using a Teledyne ISCO Combiflash RF or Grace RevelerisX2 with ELSD purification system using 20-40 µM (particle size), 250-400 mesh or 400-632 mesh silica gel.

[0304] Analytical methods

[0305] ESI-MS:

[0306] ESI-MS data (also reported herein simply as MS) were recorded using a Waters system (Acquity HPLC and Micromass ZQ mass spectrometer); all masses reported are the m / z of the protonated parent ion unless otherwise noted.

[0307] LC / MS:

[0308] The sample was dissolved in a suitable solvent such as MeCN, DMSO or MeOH and then injected directly into the column using an automated sample processor. Analysis was performed using one of the following methods:

[0309] Analytical HPLC:

[0310] Acidic HPLC: performed on a Shimadza 20A instrument with an Ultimate C18 3.0 x 50 mm, 3 µm column, eluting with 2.75 mL / 4 L of TFA in water (solvent A) and 2.5 mL / 4 L of TFA in acetonitrile (solvent B).

[0311] Analytical LCMS:

[0312] Acidic LCMS: Performed on Shimadza 2010 series, Shimadza 2020 series or Waters Acquity UPLCBEH. (MS ionization: ESI) The instrument was equipped with a C18 column (2.1 mm x 30 mm, 3.0 mm or 2.1 mm x 50 mm, C18, 1.7 µm) and eluted with 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B).

[0313] SFC analysis separation:

[0314] Instrument: Waters UPC2 Analytical SFC (SFC-H). Column: ChiralCel OJ, 150×4.6 mm ID, 3µm. Mobile phase: A represents CO2, and B represents ethanol (0.05% DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35°C. Wavelength: 220 nm

[0315] Preparative HPLC purification:

[0316] The following codes refer to the preparative HPLC conditions used as indicated in the Examples and Preparations section. Individual gradients were optimized for each example as appropriate.

[0317] Table 1: HPLC conditions

[0318]

[0319] Preparative SFC purification

[0320] Instrument: MG III preparative SFC (SFC-1). 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: about 8 min.

[0321] Table 2: SFC purification conditions

[0322]

[0323] 1 H-NMR:

[0324] 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 expressed in Hertz (Hz). Splitting patterns describe apparent multiplicity and are indicated as s (singlet), d (double), t (triplet), dd (double double), dt (double triple), dq (double quadruple), m (multiple), br (broad).

[0325] Generally, the compounds described herein can be prepared according to the schemes provided below. The following examples are used to illustrate the present disclosure without limiting its scope. The following describes methods for preparing such compounds.

[0326] General Procedure

[0327] Preparation method:

[0328] Preparation 1.

[0329] 1-(Methoxymethyl)-3-oxocyclobutane-1-carbonitrile

[0330]

[0331] Part 1: Under an inert atmosphere, 3-methylenecyclobutane-1-carbonitrile (5 g, 53.7 mmol) was added dropwise to a stirred solution of LDA (60 mmol) in THF (50 mL) at -78°C, and the resulting mixture was stirred for 1 hour. Chloro(methoxy)methane (5.2 g, 64.6 mmol) was added dropwise at -78°C, and the reaction mixture was warmed to room temperature and stirred overnight. The resulting mixture was distributed between saturated NH4Cl solution (100 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine (100 mL), dried (Na2SO4) and evaporated to dryness in vacuo to give 1-(methoxymethyl)-3-methylenecyclobutane-1-carbonitrile (3.7 g), which was used without further purification.

[0332] Part 2: A single crystal of RuCl3 was added to a stirred solution of 1-(methoxymethyl)-3-methylenecyclobutane-1-carbonitrile (Preparation 1, Part 1, 3.7 g) and NaIO4 (23 g, 107.5 mmol) in a mixture of MeCN / CCl4 (40 mL, 1:1) and water (30 mL), and the mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was separated, washed with brine (20 mL), and dried (Na2SO4). 4. ) and evaporated to dryness in vacuo. The residue was purified by column chromatography (EtOAc / Hex, 1:4) to give 1-(methoxymethyl)-3-oxocyclobutane-1-carbonitrile (1.2 g, 16% over 2 steps). 1 H NMR (500MHz, DMSO-d6) δ: 3.65 (s, 2H), 3.61-3.48 (m, 2H), 3.46 (s, 3H), 3.38-3.28 (m, 2H).

[0333] Preparation 2

[0334] 1-(2-Methoxyethyl)-3-oxocyclobutane-1-carbonitrile

[0335]

[0336] The title compound was prepared from 3-methylenecyclobutane-1-carbonitrile and 1-bromo-2-methoxyethane using a method analogous to that described in Preparation 1. Yield: 1.5 g, 18% over 2 steps. 1 H NMR (400 MHz, CDCl6) δ: 3.67-3.55 (m, 4H), 3.35-3.23 (m, 5H), 2.11 (t, 2H).

[0337] Preparation 3

[0338] 3-Methylene-1-((methylsulfonyl)methyl)cyclobutane-1-carbonitrile

[0339]

[0340] Part 1: n-BuLi (2.5 M, 200 mL, 500 mmol) was added dropwise to a solution of 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 hours. The reaction mixture was cooled to -78 ° C, and a solution of 3-methylenecyclobutane-nitrile (40 g, 429.5 mmol) in THF (300 mL) was added dropwise, and the mixture was stirred for 1 hour. A solution of (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 NH4Cl aqueous solution and the organic phase was separated. The combined organics were dried (Na2SO4) and evaporated in vacuo to dryness. The residue was distilled (1 mBar, 50°C) to give 3-methylene-1-((methylthio)methyl)cyclobutane-1-carbonitrile (12 g).

[0341] Part 2: RuCl3 (0.1 g) was added to a solution of 3-methylene-1-((methylthio)methyl)cyclobutenenitrile (12 g, 78 mmol) in a mixture of MeCN / H2O (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 solids were 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-nitrile (5.05 g). 1 H 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).

[0342] Preparation 4

[0343] cis-1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-dicarboxylic acid diethyl ester

[0344]

[0345] Solid KCO (57.7 g, 418 mmol) was added to a stirred solution of 3,3-difluorocyclobutane-1-amine hydrochloride (20 g, 139 mmol) and diethyl 2,5-dibromoadipate (50.2 g, 139 mmol) in MeCN (250 mL), and the resulting mixture was heated at reflux for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (250 mL). The combined organics were washed with brine (200 mL), dried (Na2SO4) and evaporated to dryness in vacuo to give diethyl 1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-dicarboxylate as a mixture of diastereomers (40 g) which were separated by flash column chromatography (hexanes / MTBE gradient elution) to give cis diethyl 1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-dicarboxylate as a yellow oil (17.4 g, 40.9%).

[0346] Preparation 5

[0347] cis-(1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-diyl)dimethanol

[0348]

[0349] At 0 ° C, cis-1-(3,3-difluorocyclobutyl) pyrrolidine-2,5-dicarboxylic acid diethyl ester (preparation 4, 17.4 g, 57 mmol) in THF (40 mL) was added dropwise to LiAlH4(4.33 g, 114 mmol) in a stirred solution in THF (160 mL), and the resulting mixture was stirred for 16 hours. By dropwise addition of water (4.3 mL), 50% NaOH aqueous solution (4.3 g) and water (13 mL) were subsequently added to quench the reaction. Precipitation was removed by diatomite filtration and washed with THF. The filtrate was evaporated under reduced pressure, and the residue was dissolved in DCM (100 mL), dried (Na2SO4) and evaporated to obtain cis-(1-(3,3-difluorocyclobutyl) pyrrolidine-2,5-diyl) dimethanol (11 g, 87.4%).

[0350] Preparation 6

[0351] cis-1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-diyl)bis(methylene) dimethanesulfonate

[0352]

[0353] Methanesulfonyl chloride (14.25 g, 124.5 mmol) was added dropwise to a stirred solution of cis-(1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-diyl)dimethanol (Preparation 5, 11 g, 49.8 mmol) and TEA (20.8 mL, 149 mmol) in DCM (150 mL) at 0°C and stirring was continued at this temperature for 1 hour. The reaction mixture was diluted with H2O (200 mL) and DCM (100 mL). The combined organics were washed with aqueous Na2CO3, dried (Na2SO4) and evaporated under reduced pressure to give cis-1-(3,3-difluorocyclobutyl)pyrrolidine-2,5-diyl)bis(methylene) dimethanesulfonate (18.3 g, 97.3%).

[0354] Preparation 7

[0355] 3-Benzyl-8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octane

[0356]

[0357] Potassium carbonate (20.7 g, 150 mmol) and NaI (0.75 g, 5 mmol) are added to a stirred solution of cis-1-(3,3-difluorocyclobutyl) pyrrolidine-2,5-diyl)bis(methylene) dimethanesulfonate (preparation 6, 18.3 g, 48.5 mmol) and benzylamine (5.24 g, 49 mmol) in MeCN (250 mL), and the mixture is heated under reflux for 16 hours. The reaction mixture is diluted with water (250 mL) and extracted with EtOAc (2x 150 mL). The organic matter merged is washed with brine (150 mL), dried (Na2SO4) and evaporated in vacuo to dryness. The residue was purified by flash column chromatography (MTBE / MeOH; gradient elution) to give 3-benzyl-8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octane (4.8 g, 33.8%).

[0358] Preparation 8

[0359] 8-(3,3-Difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octane dihydrochloride

[0360]

[0361] By HCl Et o solution (20 weight %, 15 mL) add 3-benzyl-8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo [3.2.1] octane (preparation 7,4.8 g, 16.4 mmol) in MeOH (25 mL), and evaporate the solvent in vacuo. Residue is dissolved in MeOH (50 mL), and 10% Pd / C (1 g) is added, and the resulting mixture is stirred 64 hours in autoclave at 50 ° C under 50 atm H. Then the mixture is filtered through diatomite, and the filtrate is evaporated under reduced pressure, and the residue is ground with Et o (100 mL), to obtain 8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo [3.2.1] octane dihydrochloride (2.21 g, 48.8%). 1 H NMR (500 MHz, DMSO-d6) δ: 12.85 (s, 1H), 10.24 (s, 1H), 10.04 (s, 1H), 4.05 (s, 2H), 3.79-3.74 (m, 3H), 3.4-3.1 (m,4H), 2.94 (s, 2H), 2.28 (s, 4H).

[0362] Preparation 9

[0363] tert-Butyl 3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0364]

[0365] 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) was added DIPEA (146.1 mg, 1.13 mmol) and 4-chloro-3-nitropyridin-2-amine (163.5 mg, 0.942 mmol), and the reaction was stirred at 90° C. for 2 h. 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, 79.0% yield) as a yellow solid.

[0366] 1H 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).

[0367] Preparation 10

[0368] tert-Butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0369]

[0370] 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 15 psi of H2, and the reaction was stirred at 25°C for 1 hour. The reaction was filtered and the filtrate was concentrated in vacuo to give tert-butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (160.0 mg, 81.4% yield).

[0371] 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).

[0372] Preparation 11

[0373] 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

[0374]

[0375] To a solution of tert-butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 10, 150.0 mg, 0.470 mmol) in DMF (3.0 mL) were added TsOH (24.3 mg, 0.141 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (56.9 mg, 0.517 mmol), and the reaction was stirred at 80 °C for 2 h. The cooled reaction was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give 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 as a yellow solid (95.0 mg, 49.4% yield).

[0376] 1 H NMR (400 MHz, MeOH-d4) δ: 8.22 (s, 1H), 8.06 (s, 1H), 7.89-7.87 (m,1H), 6.50 (d, 1H), 4.64-4.38 (m, 4H), 3.98 (s, 3H), 3.21-3.18 (m, 2H), 2.00-1.98 (m, 4H), 1.51 (s, 9H).

[0377] Preparation 12

[0378] 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride

[0379]

[0380] To a solution of 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 (Preparation 11, 95.0 mg, 0.232 mmol) in DCM (2.0 mL) was added HCl / dioxane (4 M, 5.0 mL) and the reaction was stirred at 25 °C for 30 minutes. The mixture was evaporated under reduced pressure to give 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride (70.0 mg, 87.3% yield) as a yellow solid. LCMS m / z = 310.2 [M+H] + .

[0381] Preparation 13

[0382] 4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine

[0383]

[0384] NaH (1.75 g, 60% purity, 39.32 mmol) was added to a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 32.77 mmol) in DMF (80.0 mL) at 0 ° C, and the mixture was stirred at 20 ° C for 30 minutes, and then TsCl (9.4 g, 49.16 mmol) was added. The reactant was stirred at 20 ° C for 1 h, then quenched with water (30 mL), and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to obtain 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (6.1 g, 60.7% yield) as a white solid. 1 H NMR (400 MHz, CDCl3)δ: 8.29 (d, 1H), 8.04 (d, 2H), 7.75 (d, 1H), 7.26 (d, 2H), 7.17 (d, 1H), 6.68 (d, 1H), 2.36 (s, 3H).

[0385] Preparation 14

[0386] 4-Chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine

[0387]

[0388] To a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (preparation 13, 2.0 g, 6.52 mmol) in THF (50.0 mL) was added LDA (2 M, 3.91 mL) at -70 °C, and the solution was stirred for 30 minutes. I2 (2.0 g, 7.82 mmol) was added, and the reactant was stirred at 20 °C for 1 hour. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (800.0 mg, 28.4% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ: 8.27 (d, 1H), 8.09 (d, 2H), 7.28 (d, 2H), 7.15 (d, 1H), 7.10 (s, 1H), 2.38 (s, 3H).

[0389] Preparation 15

[0390] 4-Chloro-2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

[0391]

[0392] To a solution of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 14, 2.0 g, 4.62 mmol) in dioxane (20 mL) and H2O (2 mL) was added (2-methoxypyridin-4-yl)boronic acid (848.4 mg, 5.54 mmol), Pd(dppf)Cl2 (338.2 mg, 0.462 mmol) and K2CO3 (1.3 g, 9.24 mmol) at 25°C and the mixture was stirred at 100°C for 1.5 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x20 mL). The combined organics were washed with brine (30 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by SiO2 chromatography (15 / 1 to 2 / 1 PE / EtOAc) to give 4-chloro-2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 83.2%) as a yellow solid. LCMS m / z = 414.2 [M+H]+

[0393] Preparation 16

[0394] 4-Chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine

[0395]

[0396] To a solution of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 14, 500.0 mg, 1.16 mmol) in dioxane (3.0 mL) and H2O (0.3 mL) were added 1-methylpyrazole-4-boronic acid pinacol ester (289.6 mg, 1.39 mmol), K2CO3 (320.7 mg, 2.32 mmol), Pd(dppf)Cl2 (84.9 mg, 0.116 mmol), and the reaction was stirred at 100 °C for 3 h. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 1 / 1) to give 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (287.0 mg, 64.0% yield) as a yellow solid.

[0397] 1 H NMR (400 MHz, CDCl3) δ: 8.35-8.30 (m, 1H), 7.75-7.64 (m, 4H), 7.18-7.14 (m, 3H), 6.55 (s, 1H), 4.00 (s, 3H), 2.32 (s, 3H).

[0398] Preparation 17

[0399] 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

[0400]

[0401] To 4-chloro-2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (preparation 15,800 mg, 1.93 mmol) and 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (492.4 mg, 2.32 mmol) in t-BuOH (10 mL) solution at 25 ° C CsCO (1.3 g, 3.87 mmol) and RuPhosPdG (161.7 mg, 0.193 mmol), and the mixture was stirred at 110 ° C in microwave and N for 2 hours. The mixture was diluted with H O (10 mL) and extracted with EtOAc (3x 15 mL). The combined organic matter was washed with brine (15 mL), dried (NaSO) and evaporated in vacuo to dryness. The residue was purified by SiO2 chromatography (15 / 1 to 1 / 1 PE / EtOAc) to give 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 (800 mg, 70.5% yield) as a yellow solid. LCMS m / z = 590.3 [M+H] +

[0402] Preparation 18

[0403] 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

[0404]

[0405] 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) was 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 reactant was stirred at 110 ° C for 2 hours under microwave irradiation. The mixture was poured into water (20.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic layer was washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (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, 83.1% yield) as a yellow gum. LCMS m / z = 563.7 [M+H] + .

[0406] Preparation 19

[0407] 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

[0408]

[0409] To 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 NaOH (5 N, 0.1 mL), and the reactant was stirred at 50 ° C for 15 hours. The mixture was concentrated in vacuo, EtOAc was added, and the mixture was filtered. The filtrate was evaporated under reduced pressure to obtain 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, thick) as a yellow gum. LCMS m / z = 409.3 [M+H] + .

[0410] Preparation 20

[0411] 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride

[0412]

[0413] To 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 HCl / EtOAc (4 M, 2.0 mL) and the reaction was stirred at 20 °C for 1 hour. 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] + .

[0414] Preparation 21

[0415] 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride

[0416]

[0417] The title compound (80 mg) was prepared from 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 (Preparation 17, 100 mg, 0.170 mmol) as a yellow solid using a method similar to that described for Preparation 12. LCMS m / z = 490.2 [M+H] +

[0418] Preparation 22

[0419] 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride

[0420]

[0421] To a solution of 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 (preparation 17, 700 mg, 1.19 mmol) in EtOAc (5 mL), HCl / EtOAc (4 M, 0.3 mL) was added, and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC-1 (gradient 20-50%) to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (280 mg, 63.4%) as a yellow solid. LCMS m / z = 336.4 [M+H] +

[0422] Preparation 23

[0423] 1-(4-Bromo-1H-pyrrol-2-yl)ethan-1-one

[0424]

[0425] Amberlyst® 15 (3.97 g) was added to a solution of 1-(1H-pyrrole-2-yl) ethyl-1-one 1 (44 g, 403 mmol) in THF (442 mL) at room temperature, the mixture was cooled to -30 ° C, and NBS (71.8 g, 403 mmol) was added in batches. The resulting mixture was stirred for 2 h, then warmed to room temperature and filtered. The filtrate was diluted with a saturated aqueous sodium sulfite solution, and the resulting mixture was extracted with DCM (2x). The combined organics were evaporated to dryness in vacuo, and the residue was dissolved in TBME. The solution was washed with NaHCO (2x), brine, dried (Na2SO4) and concentrated under reduced pressure to obtain 1-(4-bromo-1H-pyrrole-2-yl) ethyl-1-one as a white solid, which was used without any further purification (76.2 g). LCMSm / z = 188.0 [M+H] + .

[0426] Preparation 24

[0427] (E)-1-(4-Bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one

[0428]

[0429] A solution of 1-(4-bromo-1H-pyrrole-2-yl)ethan-1-one (preparation 23, 76.2 g, 0.36 mol) in DMF-DMA (390 mL) was heated to 85 ° C overnight. The yellow suspension was diluted with heptane and the resulting solid was collected by filtration. The filter cake was washed with heptane and dried to give (E)-1-(4-bromo-1H-pyrrole-2-yl)-3-(dimethylamino)prop-2-ene-1-one (61.5 g, 69%) as a light brown solid. LCMS m / z = 243.1 [M+H] + .

[0430] Preparation 25

[0431] 6-Bromopyrrolo[1,2-b]pyridazin-4-ol

[0432]

[0433] Will KO t Bu (42.6 g, 379 mmol) was added in batches to a solution of (E)-1-(4-bromo-1H-pyrrole-2-yl)-3-(dimethylamino)prop-2-ene-1-one (preparation 24, 61.5 g, 253 mmol) in NMP (1.85 L), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled on an ice / water bath, and O-(4-nitrobenzoyl)hydroxylamine (69.1 g, 379 mmol) was added, and the resulting mixture was stirred at 0 ° C for 1 hour, and then stirred at room temperature overnight. The mixture was cooled to 0 ° C and saturated NH4Cl aqueous solution (500 mL) was added dropwise. The mixture was diluted with H2O (500 mL), pH was adjusted to 3-4 with 2N HCl aqueous solution, and extracted with TBME (3x). The combined organic matter was concentrated to half volume, and washed with H2O (2x), brine, and then evaporated in vacuo to dryness. The residue was filtered through a pad of silica (0-100% EtOAc / heptane) to give 6-bromopyrrolo[1,2-b]pyridazin-4-ol (58 g, 54%) which was used without any further purification. LCMS m / z = 213.0 [M+H] + .

[0434] Preparation 26

[0435] 6-Bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate

[0436]

[0437] Trifluoromethanesulfonic anhydride (88.3 g, 313 mmol) was added to a solution of 6-bromopyrrolo [1,2-b] pyridazine-4-ol (preparation 25, 58 g, about 140 mmol, about 50% pure) and TEA (32.5 g, 321 mmol) in DCM (870 mL) at 0 ° C, and the mixture was stirred for 1 hour under cooling, and then stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with Na2CO3 (2x), brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (0-2% TBME / heptane) to obtain trifluoromethanesulfonic acid 6-bromopyrrolo [1,2-b] pyridazine-4-yl ester (21.1 g, 43%) as a dark oil. LCMS m / z = 344.6 [M+H] + .

[0438] Preparation 27

[0439] tert-Butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0440]

[0441] A solution of 6-bromopyrrolo[1,2-b]pyridazine-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 (3x40 mL). The combined organics 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 (4.2 g, 70.3% yield) as a white solid. LCMS m / z = 409.2 [M+H] + .

[0442] Preparation 28

[0443] 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

[0444]

[0445] A mixture of tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 27, 1 eq, 25.42 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.5 eq, 38.13 mmol), KF (3.0 M, 1 eq, 25.4 mL) and Pd(amphos)Cl2 (1.80 g, 10 mol%) was suspended in dioxane (127 mL) and the reaction mixture was purged with N2 for 5 minutes and then heated to 60°C overnight. The cooled reaction was diluted with EtOAc (500 mL) and washed with saturated NH4Cl (2 x 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 by silica gel column chromatography (0-70% EtOAc / heptane) to give tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.9 g, 96.3%). LCMS m / z =409.3 [M+H] +

[0446] Preparation 29

[0447] 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride

[0448]

[0449] To a solution of tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 28, 1.83 g, 4.48 mmol) in DCM (18 mL) was added HCl (4 M, 11.2 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness in vacuo and dried under high vacuum to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride (1.685 g) as a light yellow solid. LCMS m / z = 309.2 [M+H] + .

[0450] Preparation 30

[0451] 4-(8-(2-((tert-butyldimethylsilyl)oxy)cyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

[0452]

[0453] NaBH3CN (273 mg, 4.35 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, 300 mg, 0.870 mmol) and 2-((tert-butyldimethylsilyl)oxy)cyclobutan-1-one (872 mg, 4.35 mmol) in MeOH (10 mL), and the mixture was stirred at 50° C. for 18 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (3× 20 mL). The combined organics were washed with brine (3 x 10 mL), dried (Na2SO4) and evaporated to dryness in vacuo to give 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 (428 mg) as a yellow oil which was used without further purification. LCMS m / z = 379.2 [M+H-TBS] + .

[0454] Preparation 31

[0455] 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-bromopyrrolo[1,2-b]pyridazine hydrochloride

[0456]

[0457] To a solution of tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 27, 2.3 g, 5.65 mmol) in DCM (20 mL) was added HCl / dioxane (4 M, 15 mL) and the resulting mixture was stirred at 25° C. for 3 hours. The reaction mixture was evaporated to dryness in vacuo to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-bromopyrrolo[1,2-b]pyridazine hydrochloride (3.5 g) as a white solid which was used without further purification.

[0458] Preparation 32

[0459] 3-(3-(6-Bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

[0460]

[0461] NaBHCN (914.3 mg, 14.55 mmol) was added to a solution of 4-(3,8-diazabicyclo [3.2.1] octane-3-yl)-6-bromopyrrolo [1,2-b] pyridazine hydrochloride (preparation 31, 1.0 g, 2.91 mmol) and 3-oxocyclobutane-1-carbonitrile (830.2 mg, 8.73 mmol) in MeOH (10 mL), and the mixture was stirred at 50 ° C for 4 hours. The mixture was evaporated to dryness in vacuo, and the residue was purified by preparative HPLC-3 (gradient 43-73%) to give 3-(3-(6-bromopyrrolo [1,2-b] pyridazine-4-yl)-3,8-diazabicyclo [3.2.1] octane-8-yl)cyclobutane-1-carbonitrile (210 mg, 18.7%) as a white solid. LCMS m / z = 386.1 [M+H] + .

[0462] Preparation 33

[0463] (1S,3s)-3-(3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile

[0464]

[0465] *Stereochemistry assigned by NOE studies

[0466] 3-(3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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]oct-8-yl)cyclobutane-1-carbonitrile (130 mg, 61.9%) as a white solid. 1H 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).

[0467] Preparation 34

[0468] 6-Bromo-4-(8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrrolo[1,2-b]pyridazine

[0469]

[0470] TEA (132 mg, 1.30 mmol) was added to a solution of 6-bromopyrrolo[1,2-b]pyridazine-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 hour. The mixture was poured into H2O (30 mL) and extracted with EtOAc (3x 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 give 6-bromo-4-(8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine (165 mg, 95.6%) as a brown oil. 1 H 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).

[0471] Preparation 35

[0472] 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

[0473]

[0474] A mixture of tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 27, 598.73 mg, 1.47 mmol), bis(pinacol)diboron (746.58 mg, 2.94 mmol), KOAc (432.80 mg, 4.41 mmol) and Pd(dppf)Cl2 (120.05 mg, 0.147 mmol) in MeCN (2.94 mL) was purged with N2 and stirred at 65 °C under N2 overnight. The mixture was cooled to room temperature, concentrated in vacuo, and the crude material was purified by column chromatography (heptane / EtOAc = 0-50%) to give 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 (560.0 mg, 83.8% yield). LCMS m / z = 455.3 [M+H] + .

[0475] Preparation 36

[0476] tert-Butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0477]

[0478] A mixture of 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(amphos)Cl2 (61.5 mg, 0.087 mmol) and KF (3.0 M, 1.24 mL) was dissolved in dioxane (6.20 mL) and 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 (2x) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by automated silica gel chromatography (10 to 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] + .

[0479] Preparation 37

[0480] tert-Butyl 3-(6-(pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0481]

[0482] A solution of 6-bromopyrrolo[1,2-b]pyridazine-4-yl trifluoromethanesulfonate (preparation 26, 150 mg, 0.368 mmol), 4-(tributyltinyl)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 at 150 ° C. for 1 hour under N2 in microwave. The mixture was poured into water (10 mL) and extracted with EtOAc (2x 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 to 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 (80 mg, 53.4%) as a yellow oil. 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).

[0483] Preparation 38

[0484] tert-Butyl 3-(6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0485]

[0486] To 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, 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 phase was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give 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] + .

[0487] Preparation 39

[0488] tert-Butyl 3-(6-(6-methylpyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0489]

[0490] To 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 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 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (3x 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 give tert-butyl 3-(6-(6-methylpyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 73.4%) as a yellow solid. LCMS m / z = 421.4. [M+H] + ; 1H 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).

[0491] Preparation 40

[0492] 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride

[0493]

[0494] To a solution of tert-butyl 3-(6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 38, 73.0 mg, 0.167 mmol) in DCM (1.50 mL) was added 4M HCl (334.5 uL) and the reaction was stirred at room temperature for 30 minutes. The mixture was evaporated under reduced pressure to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride. LCMS m / z = 337.2 [M+H] + .

[0495] Preparation 41

[0496] 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(pyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride

[0497]

[0498] The title compound (70 mg) was prepared from tert-butyl 3-(6-(pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 37, 80 mg, 0.197 mmol) as a yellow solid using a method similar to that described in Preparation 48. LCMS m / z = 307.2 [M+H] +

[0499] Preparation 42

[0500] 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(6-methylpyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride

[0501]

[0502] The title compound (70 mg) was prepared from tert-butyl 3-(6-(6-methylpyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 39, 70 mg, 0.166 mmol) as a brown solid using a method similar to that described in Preparation 48. LCMS m / z = 321.1 [M+H] +

[0503] Preparation 43

[0504] 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol

[0505]

[0506] To a solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol in dioxane (70 mL), EtOH (15 mL) and H2O (10 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.94 g, 9.34 mmol), Cs2CO3 (4.6 g, 14.02 mmol), Pd(dppf)Cl2 (341.9 mg, 0.467 mmol) and the mixture was stirred at 110°C under N2 for 15 hours. The reaction was diluted with H2O (50 mL) and extracted with EtOAc (3x 80 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (15:1 to 1:2 PE / EtOAc) to give 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (300 mg, 29.8%). 1 H NMR (500 MHz, DMSO-d6) δ: 11.65 (brs,1H), 8.01-7.99 (m, 1H), 7.83-7.80 (m, 2H), 7.76 (s, 1H), 7.06 (d, 1H), 3.83(s, 3H).

[0507] Preparation 44

[0508] 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine

[0509]

[0510] A solution of 6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-ol (Preparation 43, 300 mg, 1.39 mmol) in POCl3 (3 mL) was stirred at 100°C for 1 hour. The reaction mixture was evaporated and the residue was dissolved in DCM (20 mL) and the pH was adjusted to pH about 7 with aqueous NaHCO3. The organic layer was dried (Na2SO4) and evaporated to dryness in vacuo to give 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (300 mg, crude) as a white solid which was used in the next step without further purification. LCMS m / z = 234.0 [M+H] + .

[0511] Preparation 45

[0512] tert-Butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0513]

[0514] 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (363.4 mg, 1.71 mmol) was added to a solution of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (preparation 44, 200 mg, 0.856 mmol) and DIPEA (332 mg, 2.57 mmol) in DMF (5 mL), and the resultant was stirred at 25 ° C for 1 hour. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (2x 20 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (15:1 to 1:1, PE / EtOAc) to give 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 (210 mg, 59.9%) as a white solid. LCMS m / z = 410.2 [M+H] + .

[0515] Preparation 46

[0516] 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

[0517]

[0518] A solution of tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-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 hour. The mixture was evaporated to dryness to give 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 (180.0 mg) as a white solid which was used without further purification. LCMS m / z = 310.2 [M+H] + .

[0519] Preparation 47

[0520] 4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

[0521]

[0522] To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 13.02 mmol) in acetone (250 mL) was added TsCl (37.2 g, 195.4 mmol) and 2M NaOH (97.6 mL) at 0° C., and the reaction was stirred for 3 h at 25° C. The solid was filtered, washed with acetone / HO (v / v = 1 / 1), collected and dried under vacuum to give 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (45.6 g, 91.0% yield) as a white solid.

[0523] 1 H NMR (400 MHz, CDCl3) δ: 8.76 (s, 1H), 8.08 (d, 2H), 7.77 (d, 1H), 4.32 (d, 2H), 6.70 (d, 1H), 2.40 (s, 3H).

[0524] Preparation 48

[0525] 4-Chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

[0526]

[0527] To a solution of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (preparation 47, 10 g, 32.5 mmol) in THF (200 mL) was added LDA (2 M, 24.37 mL) dropwise at -78 ° C under N2, and the mixture was stirred at -78 ° C for 1 hour. A solution of I2 (10.7 g, 42.2 mmol) in THF (50 mL) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. The reactant was quenched with saturated NH4Cl aqueous solution (5.0 mL), diluted with H2O (10.0 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (10.0 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 3 / 1) to give 4-chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (6.0 g, 42.6% yield) as a yellow solid. LCMS m / z = 433.9 [M+H] + .

[0528] Preparation 49

[0529] 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

[0530]

[0531] At 25 ° C under N2, Pd (dppf) Cl2 (143.4 mg, 0.196 mmol) was added to a solution of 4-chloro-6-iodo-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine (Preparation 48, 850 mg, 1.96 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (612 mg, 2.94 mmol) and K3PO4 (832 mg, 3.92 mmol) in dioxane (3 mL) and H2O (0.3 mL), and the mixture was stirred at 30 ° C for 12 hours. The reactant was diluted with H2O (10 mL) and extracted with EtOAc (3x 10 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by SiO 2 column chromatography (15:1 to 1:1, PE / EtOAc) to give 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (210 mg, 27.6%) as a pink solid. 1 H NMR (500 MHz, CDCl3) δ: 8.79 (s, 1H), 7.77-7.74 (m,3H), 7.64 (s, 1H), 7.22 (d, 2H), 6.55 (s, 1H), 4.03 (s, 3H), 2.37 (s, 3H).

[0532] Preparation 50

[0533] tert-Butyl 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

[0534]

[0535] The title compound (230 mg, 75.4%) was prepared from tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 49) as a yellow gum using a method analogous to that described for Preparation 45. LCMS m / z = 564.7 [M+H] +

[0536] Preparation 51

[0537] 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

[0538]

[0539] 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 hours. The reaction was concentrated under reduced pressure and the residue was purified by SiO column chromatography (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 (149 mg, 93.2%) as a yellow gum. LCMS m / z = 410.2 [M+H] +

[0540] Preparation 52

[0541] 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride

[0542]

[0543] 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 analogous to that described for Preparation 46. Yield: 160 mg; LCMS m / z = 309.7 [M+H] + .

[0544] Preparation 53

[0545] 2-Bromo-8-hydroxyimidazo[1,2-b]pyridazine

[0546]

[0547] A mixture of 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine-7-carboxylic acid (Intermediate 1, Step 5, WO2014 / 039595, 300 mg, 1.16 mmol) in concentrated HCl (5 mL, 36% purity) was stirred at 100 °C for 15 hours. The cooled mixture was evaporated under reduced pressure, and the residue was purified by preparative HPLC-2 (gradient 17-47%) to give 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine (60.0 mg, 24.1% yield) as a white solid. LCMS m / z = 214.2, 216.2 [M+H] + .

[0548] Preparation 54

[0549] 2-Bromo-8-chloroimidazo[1,2-b]pyridazine

[0550]

[0551] 2-Bromo-8-hydroxyimidazo[1,2-b]pyridazine (Preparation 53, 20.0 mg, 0.093 mmol) and DIPEA (36.2 mg, 0.28 mmol) were slowly added to POCl3 (3.29 g, 21.46 mmol), and the reactants were stirred at 120°C for 3 hours. POCl3 (10.0 mL) was further added, and the reactants were stirred at 120°C for another 15 hours. The cooled reactants were concentrated in vacuo, quenched with H2O (1.0 mL), and then purified by preparative HPLC-2 (gradient 25-55%) to give 2-bromo-8-chloroimidazo[1,2-b]pyridazine (21.0 mg, 96.7% yield) as a yellow solid. LCMS m / z =234.0 [M+H] + .

[0552] Preparation 55

[0553] tert-Butyl 3-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0554]

[0555] 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), 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) were added, and the mixture was stirred at 130° C. for 1 hour under microwave irradiation. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EtOAc=15 / 1 to 3 / 1) to give tert-butyl 3-(2-bromoimidazo[1,2-b]pyridazine-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 67.8% yield) as a colorless gum. LCMS m / z = 410.1 [M+H] + .

[0556] Preparation 56

[0557] 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

[0558]

[0559] Following the procedure described in Preparation 28, 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, 69.8 % yield, 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. LCMS m / z = 410.2 [M+H] + .

[0560] Preparation 57

[0561] 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine hydrochloride

[0562]

[0563] To a solution of tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 56, 105.0 mg, 0.256 mmol) in DCM (2.0 mL) was added HCl / dioxane (4 M, 4 mL), and the mixture was stirred at 20° C. for 2 hours. The mixture was evaporated under reduced pressure to give 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine hydrochloride (89.0 mg, crude) as a yellow solid. LCMS m / z = 310.2 [M +H] + .

[0564] Example:

[0565] Examples 1 and 2

[0566] (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0567] and

[0568] *Relative stereochemistry arbitrarily specified

[0569] Part 1. NaBH3CN (27.3 mg, 0.434 mmol) was added to a solution of 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, 0.145 mmol) and 3,3-dimethylcyclobutan-1-one (78.9 mg, 0.723 mmol) in MeOH (2 mL), and the resulting mixture was stirred at 50°C for 18 hours. The mixture was concentrated and the residue was purified by preparative HPLC-3 (gradient 20-50%) to give 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 (21 mg, 36.1%) as a white solid. LCMS m / z = 403.2 [M+H] + .

[0570] Part 2. 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 (part 1, 21 mg, 0.0522 mmol) was separated by SFC chromatography (SFC-1, 45% EtOH) to give the title compound.

[0571] *Peak 1, Example 1; (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 (6.1 mg, 29%). LCMS m / z = 403.3 [M+H] + ; 1 H NMR (500 MHz, MeOH-d4) δ: 8.20 (s, 1H), 8.05 (s, 1H), 7.86 (d, 1H), 6.45 (d, 1H), 4.56-4.51(m, 2H), 3.98 (s, 3H), 3.37-3.31 (m,3H), 3.23-3.20 (m, 2H), 2.71-2.69 (m, 2H), 2.09-1.99 (m, 4H), 1.89-1.87 (m,2H), 1.54 (s, 3H).

[0572] *Peak 2, Example 2; (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 (6.2 mg, 29.5%). LCMSm / z = 403.3 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.20 (s, 1H), 8.06 (s, 1H), 7.86 (d, 1H), 6.45 (d, 1H), 4.62-4.55 (m, 2H), 3.98 (s, 3H), 3.36-3.29 (m,2H), 3.26-3.23 (m, 3H), 2.48-2.47 (m, 2H), 2.45-2.36 (m, 2H), 1.99-1.97 (m,2H), 1.89-1.87 (m, 2H), 1.56 (s, 3H).

[0573] Example 3 and Example 4

[0574] (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0575] and

[0576] *Relative stereochemistry arbitrarily specified

[0577] The title compound was prepared using a method analogous to that described in Example 1 and Example 2 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, 80 mg, 0.231 mmol) and 3-oxocyclobutane-1-carbonitrile.

[0578] *Peak 1, Example 3; (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 (10.6 mg, 26.5%). LCMS m / z =389.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 12.89 (brs, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.86-7.85 (m, 1H), 6.37-6.35 (m, 1H), 4.51-4.49 (m, 2H), 3.91 (s, 3H), 3.32-3.08 (m, 7H), 2.40-2.25 (m, 4H), 1.87-1.69 (m, 3H).

[0579] *Peak 2, Example 4; (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; (22.8 mg, 57%). LCMS m / z = 389.2 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.20 (s, 1H), 8.05 (s, 1H), 7.85 (d,1H), 6.45 (d, 1H), 4.57-4.54 (m 2H), 3.98 (s, 3H), 3.38-3.35 (m, 2H), 3.25-3.18 (m, 3H), 3.16-3.00 (m, 1H), 2.64-2.60 (m, 2H), 2.27-2.25 (m, 2H), 1.98-1.87 (m, 4H).

[0580] Example 5 and Example 6

[0581] 7-(8-((1r,3R)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]oct-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]oct-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

[0582] and

[0583] *Relative stereochemistry arbitrarily specified

[0584] The title compound was prepared using a method analogous to that described in Example 1 and Example 2 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.

[0585] *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)

[0586] *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] + ; 1H 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).

[0587] Example 7 and Example 8

[0588] (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

[0589] and

[0590] *Relative stereochemistry arbitrarily specified

[0591] Part 1. NaBH3CN (60.9 mg, 0.970 mmol) was added to a solution of 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, 0.145 mmol) and 2-((tert-butyldimethylsilyl)oxy)cyclobutan-1-one (323.8 mg, 1.62 mmol) in MeOH (5 mL) and the resulting mixture was stirred at 50°C for 18 hours. The reaction was diluted with H2O (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (15 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (DCM / MeOH, 10:1) to give 7-((1R,5S)-8-(2-((tert-butyldimethylsilyl)oxy)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (130 mg, 81.5%) as a yellow oil. LCMS m / z =494.4 [M+H] + .

[0592] Part 2. HCl / dioxane (4 M, 5 mL) was added to a solution of 7-((1R,5S)-8-(2-((tert-butyldimethylsilyl)oxy)cyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (Part 1, 130 mg, 0.263 mmol) in DCM (6 mL). The reaction mixture was evaporated to dryness in vacuo and the residue was purified by preparative HPLC-4 (gradient 15-45%) to give the isomeric title compounds.

[0593] *Peak 1, Example 7; (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 (29.5 mg, 29.5%) as a yellow solid. LCMS m / z = 380.0 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ: 12.84 (br, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 6.33 (d, 1H), 5.19-5.17 (m, 1H), 4.47-4.44 (m, 2H), 3.91 (s, 3H), 3.79-3.76 (m, 1H), 3.55-3.53 (m, 1H), 3.26-3.24(m, 1H), 3.10-3.07 (m, 2H), 2.76-2.74 (m, 1H), 2.00-1.92 (m, 3H), 1.79-1.76(m, 1H), 1.68-1.66 (m, 2H), 1.42-1.40 (m, 1H), 1.15-1.14 (m, 1H).

[0594] *Peak 2, Example 8; (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 (14.6 mg, 14.6%). LCMS m / z = 380.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 12.85 (br, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 6.35 (d, 1H), 4.62-4.61 (m, 1H), 4.53-4.50 (m, 2H),4.10-4.08 (m, 1H), 3.91 (s, 3H), 3.48-3.46 (m, 1H), 3.26-3.24 (m, 1H), 3.20-3.14 (m, 2H), 3.06-3.04 (m, 1H), 2.00-1.67(m, 6H).

[0595] Example 9

[0596] 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

[0597]

[0598] NaBH3CN (32.7 mg, 0.521 mmol) was added to a solution of 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, 30 mg, 0.087 mmol) and oxetan-3-one (62.5 mg, 0.868 mmol) in MeOH (5 mL), and the resulting mixture was stirred at 50°C for 16 hours. The mixture was concentrated and the residue was purified by preparative HPLC-3 (gradient 7-37%) to give 2-(1-methyl-1H-pyrazol-4-yl)-7-(8-(oxetane-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridine (5 mg, 15.8%) as a white solid. LCMS m / z = 366.2 [M+H] + ; 1 H NMR(400 MHz, MeOH-d4) δ: 8.18 (s, 1H), 8.03 (s, 1H), 7.84 (d, 1H), 6.44 (d, 1H), 4.78-4.75 (m, 4H), 4.61-4.59 (m, 4H), 3.96 (s, 3H), 3.81-3.78 (m, 1H), 3.28-3.26 (m, 2H), 1.97-1.89 (m, 4H).

[0599] Example 10

[0600] 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

[0601]

[0602] The title compound (39, 32.6%) 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, 100 mg, 0.289 mmol) and 3-(difluoromethyl)cyclobutan-1-one as a yellow solid using a method similar to that described in Example 9. LCMS m / z = 414.3 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ: 12.86 (br, 1H), 8.26 (s, 1H), 8.00 (s,1H), 7.85 (d, 1H), 6.33 (d, 1H), 6.19-5.94 (m, 1H), 4.21-4.19 (m, 2H), 3.92(s, 3H), 3.09-2.98 (m, 3H), 2.43-2.36 (m, 2H), 2.17-2.01 (m, 3H), 1.86-1.68(m, 6H).

[0603] Embodiment 11

[0604] 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

[0605]

[0606] Part 1. NaBH3CN (32.7 mg, 0.521 mmol) was added to a solution of 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, 100 mg, 0.289 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (742.5 mg, 4.34 mmol) in MeOH (6 mL), and the resulting mixture was stirred at 50°C for 36 hours. The reaction mixture was concentrated, and the residue was diluted with H2O (10 mL) and extracted with EtOAc (3x 5 mL). The combined extracts were washed with brine (15 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by SiO2 column chromatography (DCM / MeOH, 6:1 to 0:1) to give tert-butyl 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)azetidine-1-carboxylate (261.6 mg) as a yellow oil. LCMS m / z = 465.2 [M+H] +

[0607] Part 2. HCl / dioxane (4 M, 3 mL) was added to a solution of tert-butyl 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)azetidine-1-carboxylate (261.6 mg, 0.564 mmol), and the resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC-2 (gradient 5-35%) to give 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 (16 mg, 45.4% yield) as a white solid. LCMS m / z = 365.2 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.19 (s, 1H), 8.05 (s, 1H), 7.87 (d, 1H), 6.46 (d, 1H), 4.58-4.55(m, 2H), 3.98 (s, 3H), 3.98-3.86 (m, 2H), 3.79-3.74 (m, 2H), 3.60-3.58 (m,1H), 3.40-3.36 (m, 2H), 3.28-3.24 (m, 2H), 1.99-1.90 (m, 4H).

[0608] Example 12

[0609] 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

[0610]

[0611] To a mixture of 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 (Example 11, 70.6 mg, 0.176 mmol) in MeOH (3 mL) were added paraformaldehyde (39.6 mg, 0.440 mmol) and NaBH3CN (33.2 mg, 0.528 mmol), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC-5 (gradient 10-30%) to give 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 (16 mg, 45.4%) as a white solid. LCMS m / z = 379.2 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.36 (s, 1H), 8.13 (s, 1H), 7.92 (d, 1H), 6.77 (d, 1H), 4.60-4.55 (m, 2H), 4.43-4.25 (m, 2H), 4.11-4.07 (m, 2H), 3.99 (s, 3H), 3.62-3.51 (m, 5H), 3.06-2.99 (m, 3H), 2.01-1.99 (m, 2H), 1.89-1.81 (m, 2H).

[0612] Embodiment 13

[0613] 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

[0614]

[0615] NaBH3CN (67.6 mg, 1.08 mmol) was added to a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 22, 80 mg, 0.215 mmol) and 3-oxocyclobutane-1-carbonitrile (102.3 mg, 1.08 mmol) in MeOH (5 mL), and the resulting mixture was stirred at 50°C for 18 hours. The reaction mixture was concentrated and purified by preparative HPLC-3 (gradient 27-57%) to give 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 (44.9 mg, 50.4%) as a yellow solid. LCMS m / z = 415.3 [M+H] + ; 1 H NMR(400 MHz, CDCl3) δ: 8.21 (d, 1H), 8.11 (d, 1H), 7.29-7.27 (m, 1H), 7.16 (s,1H), 6.94 (s, 1H), 6.37 (d, 1H), 4.01 (s, 3H), 3.84-3.79 (m, 2H), 3.37-3.34(m, 4H), 3.08-3.06 (m, 1H), 2.81-2.60 (m, 1H), 2.58-2.51 (m, 2H), 2.37-2.33(m, 2H), 1.95-1.87 (m, 4H).

[0616] Example 14 and Example 15

[0617] (1S,3s)-3-(3-(2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0618] and

[0619] *Relative stereochemistry arbitrarily specified

[0620] The title compound was obtained by SFC chromatography (SFC-2) 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).

[0621] *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] + ; 1 HNMR (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).

[0622] *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 HNMR (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).

[0623] Example 16 and Example 17

[0624] (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0625] and

[0626] *Relative stereochemistry arbitrarily specified

[0627] Part 1. NaBH3CN (145.8 mg, 2.32 mmol) was added to a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 20 Sch-26-01, 160 mg, 0.519 mmol) and 3-oxocyclobutane-1-carbonitrile (353 mg, 3.71 mmol) in MeOH (6 mL), and the resulting mixture was stirred at 50°C for 40 hours. The reaction mixture was concentrated and purified by preparative HPLC-4 (gradient 21-51%) to give 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 (85 mg, 47.3%) as a white solid. LCMS m / z =388.1 [M+H] +

[0628] Part 2. The title compound was obtained from 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 (part 1) by SFC chromatography (SFC-1, 35% EtOH).

[0629] *Peak 1, Example 16. (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 (42.3 mg). LCMS m / z = 388.3[M+H] + ; 1H NMR (400 MHz, MeOH-d4) δ: 7.99 (s, 1H), 7.89 (s, 1H), 7.82 (d, 1H), 6.67 (s, 1H), 6.38 (d, 1H), 3.94 (s, 3H), 3.86-3.83 (m, 2H), 3.45-3.40 (m,3H), 3.25-3.21 (m, 3H), 2.49-2.37 (m, 4H), 2.01-1.87 (m, 4H).

[0630] * Peak 2, Example 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 (17.8 mg). LCMS m / z = 388.3[M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 7.99 (s, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 6.68 (s, 1H), 6.40 (d, 1H), 3.94 (s, 3H), 3.86-3.83 (m, 2H), 3.41-3.28 (m,2H), 3.17-3.25 (m, 3H), 3.00-2.98 (m, 1H), 2.65-2.58 (m, 2H), 2.27-2.25 (m,2H), 2.01-1.89- (m, 4H).

[0631] Embodiment 18

[0632] 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

[0633]

[0634] Part 1. NaBH3CN (67.6 mg, 1.08 mmol) was added to a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 21, 80 mg, 0.215 mmol) and oxetane-3-one (58.9 mg, 0.817 mmol) in MeOH (3 mL), and the resulting mixture was stirred at 50°C for 18 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative TLC (10:1 DCM / MeOH) to give 2-(2-methoxypyridin-4-yl)-4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (30 mg) as a white solid which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ: 8.21-8.16 (m, 2H),7.84-7.82 (m, 2H), 7.20-7.18 (m, 2H), 7.09-7.08 (m, 1H), 6.89 (s, 1H), 6.60(s, 1H), 6.43 (d, 1H), 4.75-4.73 (m, 2H), 4.58-4.55 (m, 2H), 4.01 (s, 3H), 3.70-3.65 (m, 1H), 3.64-3.56 (m, 2H), 3.33-3.32 (m, 2H), 3.30-3.20 (m, 2H),2.35 (s, 3H), 1.89-1.74 (m, 4H).

[0635] Part 2. 5 N NaOH (4.4 mg, 0.110 mmol) was added to a solution of 2-(2-methoxypyridin-4-yl)-4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Part 1, 30.0 mg, 0.055 mmol) in MeOH (2 mL), and the resulting mixture was stirred at 50 °C for 8 h. The reaction mixture was concentrated and purified by preparative HPLC-3 (gradient 23-52%) to give 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 (10 mg, 11.9% over 2 fractions) as a yellow solid. LCMS m / z = 392.2 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 8.21 (d, 1H), 8.08 (d, 1H), 7.24-7.23 (m, 1H), 7.10 (s, 1H), 6.95 (s, 1H), 6.37 (d, 1H), 4.77-4.75 (m, 2H), 4.63-4.61 (m,2H), 4.00 (s, 3H), 3.86-3.83 (m, 2H), 3.73-3.77 (m, 1H), 3.45-3.47 (m, 2H),3.29-3.40 (m, 2H), 1.87-1.96 (m, 4H).

[0636] Embodiment 19

[0637] 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

[0638]

[0639] NaBH3CN (46.2 mg, 0.735 mmol) was added to a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 21, 60 mg, 0.123 mmol) and 3-(difluoromethyl)cyclobutane-1-one (73.6 mg, 0.613 mmol) in MeOH (5 mL), and the resulting mixture was stirred at 50°C for 16 hours. The mixture was purified by preparative HPLC-3 (gradient 39-69%) to give 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 (5.5 mg, 10.2%) as a white solid. LCMS m / z = 440.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d3) δ: 11.98 (brs, 1H), 8.11 (d, 1H), 7.88 (d, 1H), 7.50 (d, 1H), 7.33 (d, 2H), 6.27 (d, 1H), 6.17-5.88 (m, 1H), 4.08-4.06 (m,1H), 3.84 (s, 3H), 3.77-3.74 (m, 2H), 3.14-3.10 (m, 3H), 3.01-2.96 (m, 1H),2.15-2.11 (m, 1H), 1.84-1.83 (m, 2H), 1.77-1.67 (m, 6H)

[0640] Embodiment 20

[0641] 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

[0642]

[0643] A mixture 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, 40 mg, 0.116 mmol), 2-(oxetanes-3-ylidene)acetonitrile (110 mg, 1.16 mmol) and TEA (117 mg, 1.16 mmol) in DMF (1 mL) was heated at 100 ° C for 24 hours in a sealed vial. The reaction mixture was cooled to room temperature, diluted with EtOAc and saturated NH4Cl aqueous solution and filtered through diatomaceous earth. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic matter was washed with brine, dried (MgSO4) and evaporated in vacuo to dryness. The residue was dissolved in DMSO (2 mL) and purified by PSR automated purification to give 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 (6.6 mg, 14.1%). LCMS m / z = 404.2 [M+H] + .

[0644] Example 21.

[0645] 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

[0646]

[0647] NaBH3CN (43.7 mg, 0.696 mmol) is 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-oxocyclobutanenitrile (110.3 mg, 1.16 mmol) in MeOH (2.3 mL), and the mixture is stirred at 50 ° C overnight. The reaction mixture is evaporated in vacuo to dryness and the residue is diluted with saturated NaHCO3 aqueous solution, H2O and EtOAc. The organic layer is separated and the aqueous layer is extracted with EtOAc (x2). The combined organics were dried (MgSO4) and evaporated to dryness in vacuo and purified by PSR automated 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] + .

[0648] Examples 22-26

[0649] The title compound was prepared using a method analogous to that described in Example 21 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.

[0650]

[0651]

[0652] Example 27 and Example 28

[0653] (1R,3r)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0654] and

[0655] *Relative stereochemistry arbitrarily specified

[0656] The title compound was 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).

[0657] *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).

[0658] *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] + ; 1 H 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).

[0659] Example 29 and Example 30

[0660] 4-(8-((1r,3R)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]oct-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]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

[0661] and

[0662] *Relative stereochemistry arbitrarily specified

[0663] The title compound was 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).

[0664] Peak 1, Example 29; 4-(8-((1r,3R)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine. Yield: 8.1 mg, 22.4%

[0665] Peak 2, Example 30; 4-(8-((1s,3S)-3-methoxycyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine. Yield: 9.4 mg, 26%

[0666] Example 31 and Example 32

[0667] (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

[0668] and

[0669] *Relative stereochemistry arbitrarily specified

[0670] The title compound was 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)cyclobutan-1-ol (Example 25) using SFC chromatography (SFC-5).

[0671] *Peak 1, Example 31; (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. Yield: 6.2 mg, 10.1%; LCMS m / z =379.3 [M+H] +

[0672] *Peak 2, Example 32; (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. Yield: 10.7 mg, 17.5%; LCMS m / z = 379.3 [M+H] +

[0673] Embodiment 33

[0674] 4-(8-(2-oxaspiro[3.3]hept-6-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

[0675]

[0676] NaBH3CN (27.3 mg, 0.435 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, 50 mg, 0.232 mmol) and 2-oxaspiro[3.3]heptan-6-one (110.3 mg, 1.16 mmol) in MeOH (5 mL), and the mixture was stirred overnight at 50° C. Additional 2-oxaspiro[3.3]heptan-6-one (81.3 mg, 0.725 μmol) and NaBH3CN (27.3 mg, 0.435 μmol) were added, and the reaction was stirred at 50° C. for 2 hours. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC-4 (gradient 23-53%) to give 4-(8-(2-oxaspiro[3.3]hept-6-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine (39.5 mg, 67.4%) as a yellow solid. LCMS m / z = 405.3 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 7.74 (d, 1H),7.69-7.72 (m, 2H), 7.55 (s, 1H), 6.52 (s, 1H), 5.71 (d, 1H), 4.70-4.73 (m,2H), 4.64-4.66 (m, 2H), 3.94 (s, 3H), 3.67-3.71 (m, 2H), 3.32-3.34 (m, 2H), 3.18-3.21 (m, 2H), 2.83-2.86 (m, 1H), 2.41-2.45 (m, 2H), 2.10-2.12 (m, 2H),1.86-1.96 (m, 4H).

[0677] Example 34 and Example 35

[0678] (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0679] and

[0680] *Relative stereochemistry arbitrarily specified

[0681] Part 1: NaBH3CN (24.5 mg, 0.389 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, 40 mg, 0.130 mmol) and 1-methyl-3-oxocyclobutane-1-carbonitrile (70.8 mg, 0.649 mmol) in MeOH (3 mL), and the mixture was stirred at 50 °C for 18 h. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC-4 (gradient 23-53%) to give 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 (35 mg, 67.2%) as a yellow solid. LCMSm / z = 402.3 [M+H] + .

[0682] Part 2: 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 (35.0 mg, 0.087 mmol) was purified by SFC chromatography (SFC-1, 55% IPA) to give:

[0683] *Peak 1, Example 34; (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 (16.5 mg, 47.1%) as a yellow solid; LCMS m / z = 402.3 [M+H] + ; 1H NMR (500 MHz, MeOH-d4) δ: 7.88 (s, 1H), 7.73-7.76 (m, 2H), 6.74 (d, 1H), 5.86 (d, 1H), 3.92 (s, 3H), 3.82-3.85 (m, 2H), 3.37-3.42 (m, 2H), 3.34-3.35 (m, 1H), 3.18-3.22 (m, 2H), 2.68-2.73 (m, 2H), 2.03-2.10 (m, 4H), 1.91-1.94 (m, 2H), 1.55 (s, 3H).

[0684] and

[0685] *Peak 2, Example 35; (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 (15.6 mg, 44.6%) as a yellow solid; LCMS m / z = 402.3 [M+H] + ; 1 H NMR (500 MHz, MeOH-d4) δ: 7.88 (s, 1H), 7.74-7.76 (m, 2H), 6.74 (s, 1H), 5.86 (d, 1H), 3.92 (s, 3H), 3.82-3.85 (m, 2H), 3.35-3.41 (m, 2H), 3.34-3.35 (m, 1H), 3.22-3.25 (m, 2H), 2.45-2.48 (m, 2H), 2.35-2.38 (m, 2H), 2.01-2.03 (m, 2H), 1.90-1.92 (m, 2H), 1.56 (s, 3H).

[0686] Example 36 and Example 37

[0687] 6-(1-methyl-1H-pyrazol-4-yl)-4-(8-((1s,3s)-3-(methylsulfonyl)cyclobutyl)-3,8-diazabicyclo[3.2.1]oct-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]oct-3-yl)pyrrolo[1,2-b]pyridazine

[0688] and

[0689] *Relative stereochemistry arbitrarily specified

[0690] The title compound was 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 3-(methylsulfonyl)cyclobutan-1-one using a procedure analogous to that described in Examples 34 and 35. SFC chromatography (SFC-1, 50% IPA).

[0691] *Peak 1, Example 36; 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 (56 mg, 70%) as a yellow solid; LCMS m / z = 441.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 8.08 (s, 1H), 7.93 (s,1H), 7.84-7.86 (m, 2H), 6.85 (s, 1H), 5.87 (s, 1H), 3.90 (s, 3H), 3.71-3.79(m, 3H), 3.38-3.40 (m, 2H), 3.08-3.17 (m, 3H), 2.94 (s, 3H), 2.42-2.44 (m,2H), 2.13-2.17 (m, 2H), 1.82-1.93 (m, 4H).

[0692] * Peak 2, Example 37; 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 (6 mg, 7.5%) as a yellow solid; LCMS m / z = 441.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 8.00 (s, 1H), 7.86 (s,1H), 7.76-7.78 (m, 2H), 6.78 (s, 1H), 5.81 (d, J=5.2 Hz, 1H), 3.87-3.88 (m,1H), 3.82 (s, 3H), 3.73-3.77 (m, 2H), 3.51-3.53 (m, 2H), 3.12-3.13 (m, 3H), 2.91 (s, 3H), 2.49-2.50 (m, 2H), 2.25-2.31 (m, 2H), 1.77-1.88 (m, 4H).

[0693] Example 38 and Example 39

[0694] (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0695] and

[0696] *Relative stereochemistry arbitrarily specified

[0697] The title compound was 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 1-(2-methoxyethyl)-3-oxocyclobutane-1-carbonitrile using a procedure analogous to that described in Example 34 and Example 35. SFC chromatography (SFC-1, 35% EtOH).

[0698] *Peak 1, Example 38; (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 (10.4 mg, 12%) as a white solid; LCMS m / z = 446.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ: 7.75 (d,1H), 7.69-7.71 (m, 2H), 7.56 (s, 1H), 6.51 (s, 1H), 5.71 (d, 1H), 3.94 (s,3H), 3.67-3.70 (m, 2H), 3.54-3.58 (m, 2H), 3.35 (s, 3H), 3.25-3.28 (m, 2H), 3.14-3.18 (m, 2H), 2.66-2.67 (m, 2H), 1.90-2.08 (m, 9H).

[0699] *Peak 2, Example 39; (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 (13.6 mg, 15.7%) as a white solid; LCMS m / z = 446.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.75(d, 1H), 7.68-7.71 (m, 2H), 7.56 (s, 1H), 6.51 (s, 1H), 5.72 (d, 1H), 3.94(s, 3H), 3.68-3.70 (m, 2H), 3.57-3.61 (m, 2H), 3.36 (s, 3H), 3.27-3.30 (m,2H), 3.19-3.22 (m, 2H), 3.09-3.11 (m, 1H), 2.40-2.51 (m, 4H), 2.01-2.05 (m,2H), 1.86-1.92 (m,4H).

[0700] Example 40 and Example 41

[0701] 4-(8-((S)-2-oxaspiro[3.3]hept-5-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine and 4-(8-((R)-2-oxaspiro[3.3]hept-5-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

[0702] and

[0703] *Stereochemistry arbitrarily specified

[0704] The title compound was 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-oxaspiro[3.3]heptan-5-one using a method similar to that described in Examples 34 and 35. SFC chromatography (SFC-6) gave:

[0705] *Peak 1, Example 40; 4-(8-((S)-2-oxaspiro[3.3]hept-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine (13 mg, 39.4%) as a yellow solid; LCMS m / z = 405.3 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 7.77 (d, 1H), 7.71-7.73 (m,2H), 7.58 (s, 1H), 6.56 (s, 1H), 5.74 (d, 1H), 5.30 (d, 1H), 4.62-4.66 (m,2H), 4.47-4.50 (m, 1H), 3.95 (s, 3H), 3.73-3.80 (m, 3H), 3.27-3.39 (m, 3H), 2.97-3.00 (m, 1H), 1.86-2.13 (m, 8H).

[0706] *Peak 1, Example 41; 4-(8-((R)-2-oxaspiro[3.3]hept-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine (9 mg, 27.3%) as a yellow solid; LCMS m / z = 405.3 [M+H] + ; 1H NMR (500 MHz, CDCl3) δ: 7.77 (d, 1H), 7.71-7.73 (m,2H), 7.58 (s, 1H), 6.56 (s, 1H), 5.74 (d, 1H), 5.29 (d, 1H), 4.62-4.66 (m,2H), 4.47-4.50 (m, 1H), 3.95 (s, 3H), 3.73-3.81 (m, 3H), 3.25-3.39 (m, 3H), 2.99-3.02 (m, 1H), 1.86-2.05 (m, 8H).

[0707] Example 42 and Example 43

[0708] (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0709] and

[0710] *Relative stereochemistry arbitrarily specified

[0711] The title compound was 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 1-(methoxymethyl)-3-oxocyclobutane-1-carbonitrile using a procedure analogous to that described in Examples 34 and 35. Chiral-SFC (DAICEL CHIRALPAK OD-H, 250 x 30 mm, 5 μm); 60% EtOH (+0.1% NH4OH) in CO2.

[0712] *Peak 1, Example 42; (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 (22.9 mg, 38.2%) as a pink solid; LCMS m / z = 432.3 [M+H] + ; 1H NMR (500 MHz, CDCl3) δ: 7.75(d, 1H), 7.69-7.71 (m, 2H), 7.56 (s, 1H), 6.51 (d, 1H), 5.71 (d, 1H), 3.94(s, 3H), 3.68-3.72 (m, 2H), 3.59 (s, 2H), 3.44 (s, 3H), 3.28-3.30 (m, 3H), 3.15-3.18 (m, 2H), 2.58-2.59 (m, 2H), 2.12-2.14 (m, 2H), 1.89-1.96 (m, 4H).

[0713] *Peak 2, Example 43; (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 (19.6 mg, 32.7%) as a pink solid; LCMS m / z = 432.3 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 7.76(d, 1H), 7.69-7.71 (m, 2H), 7.56 (s, 1H), 6.51 (s, 1H), 5.72 (d, 1H), 3.94(s, 3H), 3.68-3.71 (m, 2H), 3.55 (s, 2H), 3.46 (s, 3H), 3.21-3.30 (m, 4H), 3.05-3.10 (m, 1H), 2.39-2.46 (m, 4H), 1.88-1.93 (m, 4H).

[0714] Example 44 and Example 45

[0715] 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]oct-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]oct-8-yl)cyclobutyl)acetonitrile

[0716] and

[0717] *Relative stereochemistry arbitrarily specified

[0718] The title compound was 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 analogous to that described in Examples 34 and 35. SFC chromatography (SFC-3) gave:

[0719] *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 (27.9 mg) as a white solid; 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).

[0720] *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 (6.5 mg) as a white solid; LCMS m / z = 402.2 [M+H] + ; 1H 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).

[0721] Example 46, Example 47 and Example 48

[0722] 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 (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0723] and and

[0724] *Any specified structure

[0725] The title compound was 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 2,2-dimethyl-3-oxocyclobutane-1-carbonitrile using a procedure analogous to that described in Example 34 and Example 35. SFC chromatography (SFC-1, 55% EtOH).

[0726] Peak 1, 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, Example 46 (3.6, 8.4 mg), as a pink solid; LCMS m / z = 416.3 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 7.75 (d, 1H),7.69-7.71 (m, 2H), 7.56 (s, 1H), 6.52 (s, 1H), 5.70 (d, 1H), 3.94 (s, 3H),3.67-3.69 (m, 2H), 3.16-3.21 (m, 4H), 2.99-3.04 (m, 1H), 2.62-2.65 (m, 1H), 2.26-2.29 (m, 1H), 2.17-2.20 (m, 1H), 2.02-2.05 (m, 1H), 1.87-1.92 (m, 3H),1.35 (s, 3H), 1.27 (s, 3H)

[0727] Peak 2, (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, Example 47 (3.6, 8.4 mg), as a pink solid; LCMS m / z = 416.3 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 7.75 (d, 1H),7.69-7.71 (m, 2H), 7.56 (s, 1H), 6.51 (s, 1H), 5.71 (d, 1H), 3.94 (s, 3H),3.65-3.68 (m, 2H), 3.18-3.21 (m, 4H), 2.72-2.75 (m, 1H), 2.47-2.50 (m, 1H), 2.35-2.38 (m, 1H), 2.00-2.07 (m, 2H), 1.88-2.00 (m, 3H), 1.34 (s, 3H), 1.24(s, 3H).

[0728] Peak 3, (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, Example 48 (3.6, 8.4 mg), as a pink solid; LCMS m / z = 416.3 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 7.75 (d, 1H),7.69-7.71 (m, 2H), 7.55 (s, 1H), 6.51 (s, 1H), 5.71 (d, 1H), 3.94 (s, 3H),3.65-3.68 (m, 2H), 3.18-3.21 (m, 4H), 2.72-2.75 (m, 1H), 2.47-2.50 (m, 1H), 2.35-2.38 (m, 1H), 2.04-2.07 (m, 2H), 1.87-1.89 (m, 3H), 1.34 (s, 3H), 1.24(s, 3H).

[0729] Example 49 and Example 50

[0730] 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

[0731] and

[0732] *Relative stereochemistry arbitrarily specified

[0733] To a solution of 4-(8-(2-((tert-butyldimethylsilyl)oxy)cyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine (Preparation 30, 428 mg, 0.869 mmol) in DCM (5 mL) was added HCl / dioxane (4 M, 5 mL) and the mixture was stirred at 25° C. for 5 minutes. The mixture was evaporated to dryness in vacuo and the residue was purified by preparative HPLC-3 (gradient 30-60%) to give:

[0734] *Peak 1, Example 49; 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 (40.6 mg, 12.5%) as a brown solid; LCMS m / z = 379.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.70-7.75 (m, 3H), 7.56 (s, 1H), 6.53 (s, 1H), 5.71 (d, 1H), 4.07-4.10 (m, 1H), 3.94 (s, 3H), 3.61-3.72 (m, 3H), 3.24-3.33 (m, 3H), 2.85-2.88 (m, 1H), 2.21-2.24 (m, 1H), 1.86-2.08 (m, 6H), 1.38-1.52 (m, 1H).

[0735] *Peak 2, Example 50; 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 (34.3 mg, 10.5%); LCMS m / z = 379.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.70-7.78 (m, 3H), 7.57 (s, 1H), 6.52(s, 1H), 5.73 (d, 1H), 4.13-4.16 (m, 1H), 3.94 (s, 3H), 3.68-3.79 (m, 2H), 3.13-3.39 (m, 5H), 1.85-2.06 (m, 8H).

[0736] Embodiment 51

[0737] 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

[0738]

[0739] NaH (9.5 mg, 0.238 mmol, 60% purity) was added to a mixture of 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 (Example 49, 30.0 mg, 0.079 mmol) in THF (2 mL) at 0° C. and stirred for 10 minutes. CH3I (33.8 mg, 0.23b mmol) was added thereto, and the mixture was stirred at 20° C. for 18 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC-3 (gradient 32-62%) to give 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 (8.1 mg, 26%) as a white solid. LCMS m / z = 393.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ:7.74 (d, 1H), 7.71-7.69 (m, 2H), 7.56 (s, 1H), 6.53 (s, 1H), 5.70 (d, 1H), 3.94 (s, 3H), 3.73-3.66 (m, 3H), 3.55-3.53 (m, 1H), 3.32-3.23 (m, 6H), 2.95-2.92 (m, 1H), 2.14-1.86 (m, 6H), 1.54-1.36 (m, 2H).

[0740] Embodiment 52

[0741] 4-(8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine

[0742]

[0743] To a solution of 6-bromo-4-(8-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazine (Preparation 34, 165 mg, 0.333 mmol) in dioxane (5 mL) and H2O (0.5 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (103.7 mg, 0.498 mmol), K2CO3 (91.8 mg, 0.665 mmol) and Pd(dppf)Cl2 (24.3 mg, 0.033 mmol), and the mixture was stirred under N2 at 70°C for 1 h. The mixture was evaporated to dryness in vacuo and the residue was purified by preparative HPLC-6 (gradient 44-59%) to give 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 (80 mg, 60.4%) as a yellow solid. LCMS m / z = 399.1[M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.74 (d, 1H), 7.70-7.68 (m, 2H), 7.54 (s,1H), 6.50 (s, 1H), 5.70 (d, 1H), 3.92 (s, 3H), 3.70-3.67 (m, 2H), 3.30-3.28(m, 2H), 3.20-3.16 (m, 2H), 2.93-2.91 (m, 1H), 2.71-2.68 (m, 2H), 2.46-2.42(m, 2H), 1.99-1.89 (m, 4H).

[0744] Embodiment 53

[0745] 6-(6-methoxypyridazin-4-yl)-4-(8-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrrolo[1,2-b]pyridazine

[0746]

[0747] The title compound was prepared from 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride (Preparation 40) and oxetane-3-one using a method similar to that used in Example 9. Purification was performed using preparative HPLC-3 (gradient 30-51%) to give 6-(6-methoxypyridazin-4-yl)-4-(8-(oxetane-3-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyrrolo[1,2-b]pyridazine (6.2 mg, 23.6%) as a white solid. 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).

[0748] Examples 54-57

[0749] The title compound was prepared using a procedure analogous to that described in Example 9 from the appropriate amine and ketone.

[0750]

[0751]

[0752] Example 58 and Example 59

[0753] (1R,3r)-3-(3-(6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0754] and

[0755] *Relative stereochemistry arbitrarily specified

[0756] Part 1. To a solution of 3-(3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile (Preparation 32, 70 mg, 0.181 mmol) in dioxane (3 mL) and H2O (0.3 mL) under N2 were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (56.8 mg, 0.272 mmol), K2CO3 (50.1 mg, 0.362 mmol) and Pd(dppf)Cl2 (13.3 mg, 0.0181 mmol), and the mixture was stirred at 100°C for 1 h. The mixture was concentrated and purified by preparative HPLC-3 (gradient 36-66%) to give 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 (25 mg, 34.7%) as a white solid. LCMS m / z = 389.3[M+H] + .

[0757] Part 2. 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 (Part 1, 25 mg) was purified by SFC chromatography (SFC-7) to give:

[0758] *Peak 1, Example 58; (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 (5.5 mg, 22%); LCMS m / z = 389.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.94 (s, 1H), 7.80 (d, 1H), 6.80 (s, 1H), 6.23(s, 1H), 5.73 (d, 1H), 3.71-3.75 (m, 3H), 3.31-3.36 (m, 3H), 3.15-3.23 (m,3H), 2.48-2.50 (m, 2H), 2.34 (s, 3H), 2.30-2.32 (m, 1H), 1.88-1.98 (m, 4H).

[0759] *Peak 2, Example 59; (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 (8.2 mg, 32.8%); LCMS m / z = 389.3[M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.94 (s, 1H), 7.81 (d, 1H), 6.80 (s, 1H), 6.23 (s, 1H), 5.74 (d, 1H), 3.69-3.75 (m, 3H), 3.21-3.31 (m, 4H), 3.02-3.06(m, 1H), 2.78-2.81 (m, 1H), 2.54-2.57 (m, 2H), 2.34 (s, 3H), 2.30-2.32 (m,1H), 1.87-1.95 (m, 4H).

[0760] Embodiment 60

[0761] (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

[0762]

[0763] To a solution of (1S,3s)-3-(3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)cyclobutane-1-carbonitrile (Preparation 33, 20 mg, 0.052 mmol) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.3 mg, 0.104 mmol) in dioxane (1 mL) and H2O (0.1 mL) were added Pd(dppf)Cl2 (3.8 mg, 0.0052 mmol) and KF (9.0 mg, 0.155 mmol), and the mixture was stirred at 70 °C under N2 for 2 h. The mixture was evaporated to dryness in vacuo and the residue was purified by preparative HPLC-3 (gradient 43-73%) to give (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 (12.1 mg, 55.2%) as a white solid. LCMS m / z = 424.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.98 (s, 1H), 7.87 (s, 1H), 7.79-7.77 (m, 2H), 7.37-7.06 (m, 1H), 6.55 (s, 1H), 5.74 (d,1H), 3.71-3.68 (m, 2H), 3.31-3.22 (m, 2H), 3.19-3.06 (m, 2H), 3.04-3.02 (m,1H), 2.81-2.78 (m, 1H), 2.56-2.53 (m, 2H), 2.35-2.30 (m, 2H), 1.94-1.88 (m,4H).

[0764] Example 61 and Example 62

[0765] (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0766] and

[0767] *Relative stereochemistry arbitrarily specified

[0768] The title compound was prepared using a method analogous to that described in Example 1 and Example 2 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.

[0769] Part 1. Preparative HPLC-3 (gradient 23-53%) to give 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 (45 mg, 26.7%) as a white solid; LCMS m / z = 389.2 [M+H] + .

[0770] Part 2. The compound from Part 1 was further purified by SFC chromatography (SFC-1, 40% IPA) to give the title compound as a white solid.

[0771] *Peak 1, Example 61; (1S,3s)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-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] + ; 1 H 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).

[0772] *Peak 2, Example 62; (1R,3r)-3-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine-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 H 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).

[0773] Example 63 and Example 64

[0774] (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]oct-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]oct-8-yl)cyclobutane-1-carbonitrile

[0775] and

[0776] *Relative stereochemistry arbitrarily specified

[0777] The title compound was prepared using a method analogous to that described in Example 1 and Example 2 from 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (Preparation 52) and 3-oxocyclobutane-1-carbonitrile.

[0778] Part 1. Preparative HPLC-3 (gradient 17-47%) to give 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 (81 mg, 48.1%) as a white solid. LCMS m / z = 389.1 [M+H] + .

[0779] Part 2. The compound from Part 1 was further purified by SFC chromatography (SFC-1, 50% EtOH) to give the title compound as a white solid.

[0780] *Peak 1, Example 63; (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 (24.1 mg, 26.4%). LCMS m / z =389.2 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.09 (s, 1H), 7.98 (s, 1H), 7.88 (s,1H), 6.74 (s, 1H), 4.43-4.40 (m, 2H), 3.94 (s, 3H), 3.42-3.36 (m, 6H), 2.51-2.39 (m, 4H), 1.98-1.96 (m, 2H), 1.73-1.72 (m, 2H).

[0781] *Peak 2, Example 64; (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 (9.8 mg, 12.1%). LCMS m / z =389.2 [M+H] + ; 1H NMR (400 MHz, MeOH-d4) δ: 8.10 (s, 1H), 7.98 (s, 1H), 7.88 (s,1H), 6.74 (s, 1H), 4.46-4.42 (m, 2H), 3.94 (s, 3H), 3.48-3.40 (m, 4H), 3.27-3.25 (m, 1H), 3.03-3.01 (m, 1H), 2.66-2.64 (m, 2H), 2.35-2.30 (m, 2H), 2.00-1.97 (m, 2H), 1.78-1.75 (m, 2H).

[0782] Example 65 and Example 66

[0783] (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-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]oct-8-yl)cyclobutane-1-carbonitrile

[0784] and

[0785] *Relative stereochemistry arbitrarily specified

[0786] The title compound was prepared using a method analogous to that described in Example 1 and Example 2 from 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine hydrochloride (Preparation 57) and 3-oxocyclobutane-1-carbonitrile.

[0787] Part 1, preparative HPLC-3 (gradient 28-58%) to give 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 (140 mg, 51.9%) as a white solid.

[0788] Part 2, the compound of Part 1 was further purified by SFC chromatography (SFC-1, 45% IPA) to give the title compound as a white solid.

[0789] *Peak 1, Example 65; (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, yield: 25 mg, 17.9%; LCMS m / z =389.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.87 (d, 1H), 7.82-7.81 (m, 2H), 7.75 (s, 1H), 5.88 (d, 1H), 4.65-4.62 (m, 2H), 3.94 (s, 3H), 3.35-3.32 (m, 2H), 3.30-3.22 (m, 2H), 3.07-3.02 (m, 1H), 2.82-2.77 (m, 1H), 2.57-2.50 (m, 2H), 2.36-2.33 (m, 2H), 1.89 (s, 4H).

[0790] *Peak 2, Example 66; (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, yield: 65 mg, 46.3%; LCMS m / z =389.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.87 (d, 1H), 7.83-7.82 (m, 2H), 7.75 (s, 1H), 5.89 (d, 1H), 4.67-4.64 (m, 2H), 3.94 (s, 3H), 3.34-3.23 (m, 6H), 2.50-2.34 (m, 4H), 1.93-1.91 (m, 4H).

[0791] Biological assays

[0792] The compounds of the present disclosure were evaluated for their ability to inhibit TYK2, JAK1, JAK2, and JAK3 activity as summarized below in Table 3. The inhibitory properties of the compounds of the present disclosure described herein can be demonstrated by testing according to any of the following protocols.

[0793] The kinase activity of 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, 50 µM of JAK3-342 (sequence ALVDGYFRLTT (SEQ ID NO: 1)) peptide was phosphorylated using 4 nM of recombinant JAK1 kinase domain in the presence of 35 µM ATP. The catalytic activity of recombinant JAK2, JAK3, and TYK2 kinase domains (0.2 nM, 0.3 nM, and 2 nM, respectively) was evaluated by the phosphorylation state of JAK3-974 (50 µM; sequence LPLDKDYYVVR (SEQ ID NO: 2)) peptide with the addition of ATP (15 μM, 4 μM, and 10 μM, respectively). Reactions were run for 100 minutes, and catalytic activity was quantified by first depleting unused ATP and converting hydrolyzed ADP to ATP to generate luminescence in the luciferase reaction; this is the basis of the ADP-Glo ​​platform. Compounds were tested at 10 µM or 1 µM top concentrations, with 11 points of 3-fold dilutions. Data were normalized and a 4-parameter logistic model was used to fit the percent activity of the compound versus log concentration to generate curves and IC50 values.

[0794] Table 3: Experimental data

[0795]

[0796]

Claims

1. A compound of formula (I): (I)， or a pharmaceutically acceptable salt thereof, wherein: Ring A and ring B together form a bicyclic heteroaromatic ring; X1 is N or C; X2 is N, NH or CR 2 ; X3 is N or CR 3 ; X4 is N or CR 4 ; X5 is N or CH; Y is CR 7 R 8 、 O or NR 9 ; R 1 and R 5 Each is independently selected from H, halogen, 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, wherein R 1 and R 5 The C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each optionally substituted by one or more R 10 replace; R 2 , R 3 and R 4 Each is independently selected from H, halo, -CN, -NR 1a R 1b 、-OR 1c , C 1-4 Alkyl and C 1-4 Haloalkyl; R 6 is independently selected at each occurrence from H, halo, CN, -NR 1a R 1b 、-OR 1c 、-SO2R 1c or C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halo, CN, -NR 1a R 1b AND-OR 1c ; or two R 6 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered heterocycloalkyl or C 3-6 Cycloalkyl; R 7 and R 8 Each is independently selected from H, halogen, CN, -NR 1a R 1b 、-OR 1c 、-SO2R 1c or C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halo, CN, -NR 1a R 1b AND-OR 1c , or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 3- to 6-membered heterocycloalkyl or C 3-6 Cycloalkyl; R 9 is H or C optionally substituted by one or more substituents 1-6 Alkyl, the substituents are independently selected from halo, CN, -NR 1a R 1b AND-OR 1c ; R 10 is independently selected at each occurrence from 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; wherein R 10 The C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 4 to 7 membered monocyclic heterocycloalkyl and 5 to 6 membered heteroaryl are each optionally substituted with one or more substituents independently 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 Each independently is H or C 1-4 alkyl; R 1c It is H, C 1-4 Alkyl or C 1-4 haloalkyl; and r is 0 or an integer from 1 to 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X2 is NH or CR 2 .

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

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

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

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

7. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein R 1 is optionally replaced by 1, 2 or 3 R 10 Substituted 5- to 6-membered heteroaryl.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein 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 by 1, 2 or 3 R 10 replace.

9. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5- to 6-membered heteroaryl selected from pyrazole, isoxazole, pyridine and pyridazine, each of which is optionally substituted by 1 or 2 R 10 replace.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 1 is a 5- to 6-membered heteroaryl group selected from: 、 、 、 、 and ; in Indicates the point of attachment to ring B.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 10 are independently selected from halo, -OR 1c , C 1-6 Alkyl and C 1-6 haloalkyl; and R 1c It is C 1-4 alkyl.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 10 Independently selected from F, -OCH3, -CH3 and -CHF2.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 and R 4 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 2 , R 3 and R 4 It's H.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R 5 H, halogen, C 1-4 Alkyl, C 1-4 haloalkyl or optionally substituted by 1, 2 or 3 R 10 Substituted 5- to 6-membered heteroaryl.

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

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein: R 7 and R 8 Each is independently selected from H, halogen, CN, -OR 1c 、-SO2R 1c and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents being independently selected from halo, CN and -OR 1c , or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group; and R 1c Is H or C 1-3 alkyl.

18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Each is 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 atom to which they are attached they form: 。 19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1 or 2.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein: R 6 is independently selected at each occurrence from H, -OR 1c , C 1-4 haloalkyl and optionally substituted with CN 1-4 Alkyl, or two R 6 Together with the carbon atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group; and R 1c Is H or C 1-3 alkyl.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 6 is independently selected at each occurrence from H, -OH, -OCH3, -CH2-CN and -CH3, or two R 6 Together with the carbon atom to which they are attached they form: 。 22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: R 1 is optionally replaced by 1, 2 or 3 R 10 substituted 5- to 6-membered heteroaryl; R 2 , R 3 and R 4 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; R 5 H, halogen, C 1-4 Alkyl, C 1-4 haloalkyl or optionally substituted by 1, 2 or 3 R 10 substituted 5- to 6-membered heteroaryl; R 6 is independently selected at each occurrence from H, -OR 1c , C 1-4 haloalkyl and optionally substituted with CN 1-4 Alkyl, or two R 6 Together with the carbon atoms to which they are attached, they form a 4-membered heterocycloalkyl group; R 7 and R 8 Each is independently selected from H, halogen, CN, -OR 1c 、-SO2R 1c and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents being independently selected from halo, CN and -OR 1c , or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 4-membered heterocycloalkyl group; R 9 Is H or C 1-6 alkyl; R 10 are independently selected from halo, -OR 1c , C 1-6 Alkyl and C 1-6 Haloalkyl; R 1a and R 1b Each independently is H or C 1-4 alkyl; R 1c It is H, C 1-4 Alkyl; and r is 0, 1, or 2.

23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein: 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 by 1, 2 or 3 R 10 replace; R 2 , R 3 and R 4 It is H; R 5 H, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; R 6 is independently selected at each occurrence from H, -OR 1c , C 1-4 haloalkyl and optionally substituted with CN 1-4 Alkyl, or two R 6 Together with the carbon atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group; R 7 and R 8 Each is independently selected from H, halogen, CN, -OR 1c 、-SO2R 1c and C optionally substituted by one or more substituents 1-6 Alkyl, the substituents being independently selected from halo, CN and -OR 1c , or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 4- to 6-membered heterocycloalkyl group; R 9 Is H or C 1-4 alkyl; R 10 are independently selected from halo, -OR 1c , C 1-4 Alkyl and C 1-4 haloalkyl; and R 1c Is H or C 1-4 alkyl.

24. A compound as described in any one of claims 1 to 4 and 7 to 23, wherein the compound is composed of Formula (IIA), (IIB), (IIIA), (IIIB), (IVA) or (IVB): (IIA)、 (IIB)、 (IIIA)、 (IIIB) (IVA) or (IVB), or a pharmaceutically acceptable salt thereof.

25. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 and 7 to 24, wherein: R 6 is independently selected at each occurrence from H and C 1-4 alkyl; R 7 and R 8 are each independently selected from H, halogen, CN and C 1-4 alkyl; R 10 Select from -OR 1c , C 1-4 Alkyl and C 1-4 Haloalkyl; R 1c It is C 1-4 Alkyl; and r is 0, 1, or 2.

26. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 and 7 to 24, wherein: R 6 is H or CH3; R 7 and R 8 Each independently selected from H, F, CH3 and CN; R 10 is selected from the group consisting of CH3, CHF2 and OCH3; and r is 0, 1, or 2.

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

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

29. A method of inhibiting tyrosine kinase 2 (TYK2) activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound as described in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 28.

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

31. The method of claim 30, wherein the disease or condition is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoma, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, kidney disease, inflammation, 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, menstrual pain, 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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