TYK2 inhibitors

Abstract

The present disclosure relates to a compound of formula (I'), or a pharma- ceutically acceptable salt thereof, in which all variables are as defined in this application. The compounds of the present disclosure are capable of inhibiting the activity of tyrosine kinase 2 (TYK2). The present disclosure further provides methods for preparing the compounds of the present disclosure, and methods for their therapeutic use. TIFF2024502601000345.tif8851

Description

[Technical Field]

[0001] Related Applications Under 35 U.S.C. §119(e), this application claims the benefit of and priority to the filing date of U.S. Provisional Application No. 63 / 134,786, filed January 7, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Cytokines are small secreted proteins released by cells that have specific effects on cell-cell interactions and communication. Cytokine pathways mediate a wide range of biological functions, including many aspects of inflammation and immunity, primarily through extracellular signaling.

[0003] Tyrosine kinase 2 (TYK2) is a cytoplasmic protein kinase that associates with cytokine receptors and is a member of the Janus kinases (JAKs) that play 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, engagement of a cytokine with its cognate receptor triggers activation of the JAK-associated receptor, which leads to JAK-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately to transcriptional activation of a specific set of genes (Schindler et al., 2007, J. Biol. Chem. 282:20059-63). Numerous cytokines are known to activate the JAK family, including the interferon (IFN) family (IFN-alpha, IFN-beta, IFN-omega, limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp)130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), the gamma C family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), the IL-3 family (IL-3, IL-5, GM-CSF), the single-chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G protein-coupled receptors (AT1).

[0004] TYK2 is important in the signal transduction of type I interferons (e.g., IFN-alpha), IL-6, IL-10, IL-12, and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutic Targets, 2014, 18, 5, 571-580; Kisseleva et al., 2002, Gene 285:1-24; and Watford, W.T. & O'Shea, J.J., 2006, Immunity 25:695-697). Consistent with this, primary cells 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, and TYK2 / JAK1 / JAK2.

[0005] Research has shown that inappropriate JAK activity can result from mutation, overexpression, or inappropriate regulation, dysregulation, or deregulation, as well as excessive or underproduction of growth factors or cytokines, thereby causing various biological cellular responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell mobility. 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 neurological and neurodegenerative diseases such as Alzheimer's disease.

[0006] Small molecule JAK inhibitors have emerged as a major therapeutic advance in the treatment of autoimmune diseases. To date, all known small molecule JAK inhibitors that have progressed into development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site in the catalytic domain (JH1, also known as the "Janus Homology 1" domain) of JAK proteins, preventing 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).

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

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

[0009] There remains a need for potent compounds that exhibit high selectivity for TYK2 over other members of the JAK family. Summary of the Invention

[0010] One aspect of the present disclosure is a compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof, wherein: provided that the ring containing X1, X2, X3, X4, X5, X6, and X7 is a bicyclic heteroaryl ring; [ka] is a single bond or a double bond, X1 is N, NH, or CR 1 and X2 is N or CR 2 and X3 is N or CR 3 and X4 is N or CR 4 and X5, NR 5 or CR 5 and X6 and X7 are both C, or one of X6 and X7 is N and the other is C; Y is C(O) or S(O)2; R 1 , R 2 , R 3 , and R 4 each independently, if present, is H, halo, -CN, or -NR 1a R 1b , -OR 1c , C 1-4 Alkyl, and C 1-4 haloalkyl; R 5 H, halo, CN, -NR 1a R 1b , -OR 1c , C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 7-membered partially saturated heterocyclyl, and 5- to 10-membered heteroaryl; R 5 C represented by 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 The aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each optionally contain one or more R 7 is replaced by R 6 But H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; R 6 C represented by 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 The aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each optionally contain one or more R 8 is replaced by R 7 are, at each occurrence independently, halo, -CN, oxo (=O), -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, and 5- to 6-membered heteroaryl; R 7 C represented by 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 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 8 However, for each occurrence, independently, halo,-NR 1a R 1b , -OR 1c , -CN, C 1-6 Alkyl, C 1-3 Hydroxyalkyl, -C(=O)OR 1c , and C 1-6 haloalkyl; R 1a and R 1b are each independently H or C 1-4 is alkyl, R 1c But H, C 1-4 Alkyl, or C 1-4 is haloalkyl, m is 0 or an integer of 1 to 6, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

[0016] Other features or advantages will become apparent from the following detailed description of several embodiments and the appended claims. DETAILED DESCRIPTION OF THE INVENTION

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

[0018] In a first embodiment, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables shown in formula (I') are as defined above.

[0019] In a second embodiment, the compounds of the present disclosure are represented by formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein X1 is N and X2 is CR 2 or X2 is N and X1 is CR 1 and the definitions for the other variables are as defined in the first embodiment.

[0020] In a third embodiment, the compound of the present disclosure is represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR 1 and X2 is N, with the definitions for the other variables as defined in the second embodiment.

[0021] In a fourth embodiment, the compound of the present disclosure is represented by formula (I') or (I), or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 each independently, if present, is H, halo, -NH, -OH, C 1-4 Alkyl, or C 1-4haloalkyl, and the definitions for the other variables are as defined in the first, second, or third embodiment.

[0022] In a fifth embodiment, the compound of the present disclosure is represented by the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions for the variables set forth in formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X) are as defined in the first embodiment.

[0023] In a sixth embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), or a pharmaceutically acceptable salt thereof, wherein Y is S(O)2, and the definitions for the other variables are as defined in the first, second, third, fourth, or fifth embodiment.

[0024] In a seventh embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), or a pharmaceutically acceptable salt thereof, wherein Y is C(O), and the definitions for the other variables are as defined in the first, second, third, fourth, or fifth embodiment.

[0025] In an eighth embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), or a pharmaceutically acceptable salt thereof, wherein R 3 If present, H, halo, C 1-4 Alkyl, or C 1-4haloalkyl, and the definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0026] In a ninth embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, halo, if present, and the definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0027] In a tenth embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), or a pharmaceutically acceptable salt thereof, wherein: R 5 But C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 7-membered partially saturated heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; 3-8 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 7-membered partially saturated heterocyclyl, 5- or 6-membered monocyclic heteroaryl, and 8- to 10-membered bicyclic heteroaryl each optionally contain one, two, or three R 7 is replaced by R 7 are, at each occurrence independently, halo, -CN, oxo (=O), -NR 1a R 1b , -OR 1c , -C(O)OR 1c , C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, 1-4 Alkyl, C 1-4Haloalkyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocycloalkyl, each optionally selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, -NR 1a R 1b , -OR 1c and 4-6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; The definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0028] In an eleventh embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), or a pharmaceutically acceptable salt thereof, wherein: R 5 is a 5- or 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl, and the 5- or 6-membered monocyclic heteroaryl and the 8- to 10-membered bicyclic heteroaryl each optionally contain 1, 2, or 3 R 7 is replaced by R 7 However, for each occurrence, independently, halo, -CN, -NR 1a R 1b , -OR 1c , -C(O)OR 1c , C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocycloalkyl, each optionally selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, -NR 1a R1b , -OR 1c and 4-6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; The definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0029] In a twelfth embodiment, the compound of the present disclosure is as defined in the eleventh embodiment, or a pharmaceutically acceptable salt thereof; R 5 is a 5- or 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, S, and N, and the 5- or 6-membered monocyclic heteroaryl is selected from 1, 2, or 3 R 7 is optionally replaced by

[0030] In a thirteenth embodiment, the compound of the present disclosure is as defined in the eleventh embodiment, or a pharmaceutically acceptable salt thereof; R 5 is a 5-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, S, and N, and the 5-membered monocyclic heteroaryl is selected from 1, 2, or 3 R 7 is optionally replaced by

[0031] In a fourteenth embodiment, the compound of the present disclosure is as defined in the thirteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein the five-membered monocyclic heteroaryl is pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, or pyrrole, each of which is selected from the group consisting of one, two, or three R 7 is optionally replaced by

[0032] In a fifteenth embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), or a pharmaceutically acceptable salt thereof, wherein R 7 However, for each occurrence, independently, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, 1-4 Alkyl, C 3-6 The cycloalkyl, and 4- to 6-membered monocyclic heterocycloalkyl are each optionally substituted with one or two substituents independently selected from halo, and 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, and the definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0033] In a sixteenth embodiment, the compound of the present disclosure is represented by the formula: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 9a But C 1-4 Alkyl, C 3-6 cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, 1-4 Alkyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocycloalkyl, each optionally selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, -NR 1a R 1b, -OR 1c and 4-6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; R 9b and R 9c However, independently, H, C 1-4 Alkyl, or C 1-4 haloalkyl, and the definitions for the other variables are as defined in the first embodiment.

[0034] In a seventeenth embodiment, the compound of the present disclosure is as defined in the sixteenth embodiment, or a pharmaceutically acceptable salt thereof, and R 9a But -CH3, -CH2CH3, [ka] and R 9b and R 9c One of the groups is H and the other is H, —CH3, —CHF2, or —CF3.

[0035] In an eighteenth embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), (VIIIA), (IXA), and (XA), or a pharmaceutically acceptable salt thereof, wherein R 6 But C 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-8 bicyclic cycloalkyl, a 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, or a 5- to 8-membered bicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, 1-4 Alkyl, C 3-6 Monocyclic cycloalkyl, C 5-8The bicyclic cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, and 5- to 8-membered bicyclic heterocycloalkyl are each optionally selected from halo, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-3 Hydroxyalkyl, -C(=O)OR 1c , and C 1-4 substituted with 1 to 3 substituents independently selected from alkoxy; 1c But H or C 1-3 alkyl, and the definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0036] In a nineteenth embodiment, the compound of the present disclosure is as defined in the eighteenth embodiment, or a pharmaceutically acceptable salt thereof, and R 6 But halo, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-3 Hydroxyalkyl, -C(=O)OR 1c , and C 1-4 C optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy 3-6 is a monocyclic cycloalkyl, and R 1c But H or C 1-3 It is alkyl.

[0037] In a twentieth embodiment, the compound of the present disclosure is as defined in the nineteenth embodiment, or a pharmaceutically acceptable salt thereof, and R 6 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is selected from halo, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-3 Hydroxyalkyl, -C(=O)OR 1c , and C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; R 1c But H or C1-3 It is alkyl.

[0038] In a twenty-first embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), (VIIIA), (IXA), and (XA), or a pharmaceutically acceptable salt thereof, wherein m is 0 and the definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0039] In a twenty-second embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), (VIIIA), (IXA), and (XA), or a pharmaceutically acceptable salt thereof, wherein m is 1 and the definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0040] In a twenty-third embodiment, the compound of the present disclosure is represented by any one of formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), (VIIIA), (IXA), and (XA), or a pharmaceutically acceptable salt thereof, wherein -(CH) m -R 6 But CH3, -CH2CH3, [ka] and the definitions for the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0041] In a twenty-fourth embodiment, the compound of the present disclosure is represented by the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 6 But halo, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-3 Hydroxyalkyl, -C(=O)OR 1c , and C 1- 4 optionally substituted with one or two substituents independently selected from alkoxy 3-6 is a monocyclic cycloalkyl, and R 1c But H or C 1-3 alkyl, and R 9a But C 1-4 alkyl, and the definitions for the other variables are as defined in the first embodiment.

[0042] In a 25th embodiment, the compound of the present disclosure is as defined in the 24th embodiment, or a pharmaceutically acceptable salt thereof, and R 6 But, Halo, C 1-4 Alkyl, and C 1-4 C optionally substituted with 1 or 2 substituents independently selected from haloalkyl 3-6 is a monocyclic cycloalkyl, and R 9a But C 1-3 It is alkyl.

[0043] In a 26th embodiment, the compound of the present disclosure is as defined in the 24th embodiment, or a pharmaceutically acceptable salt thereof, and R 6 But, Halo, C 1-4 Alkyl, and C 1-4cyclopropyl optionally substituted with one or two substituents independently selected from haloalkyl; R 9a But C 1-3 It is alkyl.

[0044] In a twenty-seventh embodiment, the compound of the present disclosure is selected from Examples 1-252 set forth below, or a pharmaceutically acceptable salt thereof.

[0045] 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 a hydrogen radical in a given structure with the radical of a specified substituent. Specific substituents are set forth in the definitions and descriptions of the compounds and their examples. Unless otherwise indicated, an 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 with more than one substituent selected from a specified group, the substituents may be the same or different at all positions.

[0046] As used herein, "halogen" or "halo" may be fluorine, chlorine, bromine, or iodine.

[0047] As used herein, "hydroxyl" or "hydroxy" refers to the group --OH.

[0048] 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 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0049] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Alkyl groups having 1 to 6 carbons, i.e., C 1-6Alkyl may be preferred. Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, and neopentyl. In some embodiments, an alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 It is alkyl.

[0050] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon group, which may be linear or branched, having at least one carbon-carbon double bond. Alkenyl groups having 2 to 6 carbon atoms may be preferred. Alkenyl groups may contain one, two, or three or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

[0051] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., an -O-alkyl group, where alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. Preferably, alkoxy groups have about 1 to 6 carbons.

[0052] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which at least one of the hydrogen atoms is replaced by a halo atom. Haloalkyl groups having 1 to 6 carbons, i.e., C 1-6 Haloalkyl may be preferred. 1-6 Haloalkyl is C 1-6 Monohaloalkyl, C 1-6 Dihaloalkyl, or C 1-6 C containing perhaloalkyl 1-6 It may be a polyhaloalkyl.1-6 A monohaloalkyl can have one iodo, bromo, chloro, or fluoro within the alkyl group. 1-6 Dihaloalkyl and C 1-6 Polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically, C 1-6 Polyhaloalkyl groups contain 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 Perhaloalkyl groups are C alkyl groups in which all hydrogen atoms have been replaced with halo atoms. 1-6 Refers to an alkyl group.

[0053] As used herein, the term "hydroxyalkyl" refers to an alkyl group, as defined herein, in which at least one of the hydrogen atoms is replaced by a hydroxy group. Non-limiting examples of hydroxy-substituted C1-4 alkyl include hydroxy-methyl, dihydroxy-methyl, pentahydroxy-ethyl, dihydroxyethyl, and dihydroxypropyl.

[0054] 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 groups (--C(O)--, --S(O)--, or --S(O)--), such as a ketone, aldehyde, or part of an acid, ester, amide, lactone, or lactam group.

[0055] 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 carbocyclic ring system. Examples of aryl systems include, but are not limited to, phenyl, naphthyl, and the like. Aryl groups having 6- to 10-membered ring systems, i.e., C 6-10 Aryl may be preferred.

[0056] 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 can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxides and sulfones. Heteroaryl groups having 5- to 10-membered ring systems may be preferred. "Heteroaryl" includes heteroaromatic groups fused to a phenyl group or non-aromatic heterocycles such as tetrahydrofuran, pyran, pyrrolidine, and piperidine. Examples of heteroaryl include pyrrole, pyridyl, pyrazole, thienyl, furanyl, oxazolyl, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, indolyl, indazolyl, benzofuranyl, quinoxalinyl, and the like. In some embodiments, heteroaryl is selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, and pyrrole.

[0057] As used herein, the term "cycloalkyl" refers to a fully saturated monocyclic or bicyclic (e.g., fused, spiro, or bridged) hydrocarbon group of 3 to 12 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms. Cycloalkyl groups having 3 to 8 carbons, i.e., C 3-8 Cycloalkyl may be preferred. 3-8Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0058] As used herein, the term "heterocycloalkyl" refers to a fully saturated 4- to 12-membered monocyclic or bicyclic (e.g., fused) ring system having at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or a combination thereof). Heterocycloalkyl groups having 4- to 10-membered ring systems may be preferred.

[0059] As used herein, the term "partially saturated heterocyclyl" refers to an unsaturated non-aromatic 5- to 12-membered monocyclic or bicyclic ring system having at least one heteroatom (e.g., oxygen, sulfur, nitrogen, or a combination thereof), where C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. In one embodiment, the partially saturated heterocyclyl is pyridinone.

[0060] The phrase "pharmaceutically acceptable" indicates that the substance, composition, or dosage form must be chemically and / or toxicologically compatible with the formulation, including other ingredients, and / or with the mammal being treated therewith.

[0061] Unless otherwise specified, the term "compounds of the present disclosure" refers to compounds of Formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), (VIIIA), (IXA), (XA), or (IVB), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitution), and inherently formed moieties (e.g., polymorphs, solvates, and / or hydrates). Where moieties capable of forming salts exist, salts, particularly pharmaceutically acceptable salts, are also included. Compounds of the present disclosure, including their salts, hydrates, and solvates, may inherently or by design form polymorphs.

[0062] As used herein, the terms "a," "an," "the," and similar terms used within the context of this disclosure (particularly within the context of the claims) are intended to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples provided herein, or exemplary language (e.g., "such as"), is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the unclaimed disclosure.

[0063] When the compounds provided herein are sufficiently basic or acidic to form stable non-toxic acid or base salts, the preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate. Inorganic salts, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate, may also be formed.

[0064] 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 that provides 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 made.

[0065] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, or magnesium salts. Salts derived from organic bases include, but are not limited to, alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, di-alkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkanes, trisubstituted cycloalkanes, cycloalkanes, di-alkenylamines, tri-alkenylamines, substituted cycloalkanes, disubstituted cycloalkanes, tri-substituted cycloalkanes, cycloalkanes, di-alkenylamines, tri-substituted cycloalkanes, cycloalkanes, di-substituted cycloalkane ... Included are salts of primary, secondary, or tertiary amines such as arylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed di- and triamines in which at least two of the substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl. Also included are amines in which two or three substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group.Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine. Other carboxylic acid derivatives may be useful, such as carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides.

[0066] Those skilled in the art will recognize that the compounds of the present disclosure may contain chiral centers and therefore may 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 is understood that a substituent may be attached to a chiral center of a carbon atom. Thus, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0067] Certain compounds described herein contain one or more asymmetric centers or axes and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-. According to the present disclosure, any structure that does not specify stereochemistry is understood to encompass all various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by resolution of racemic forms by chromatographic separation using chiral stationary phases) are well known in the art. In some embodiments, the compounds described herein are isolated stereoisomers in which each of the compounds has one stereocenter and the stereoisomer is in the R configuration. In other embodiments, the compounds described herein are isolated stereoisomers in which each of the compounds has one stereocenter and the stereoisomer is in the S configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each of which has two stereocenters and the stereoisomers are in the RR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each of which has two stereocenters and the stereoisomers are in the RS configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each of which has two stereocenters and the stereoisomers are in the SR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each of which has two stereocenters and the stereoisomers are in the SS configuration. In one embodiment, the compounds described herein each have one or two stereocenters and are racemic mixtures.

[0068] When a specific stereoisomer of a compound is indicated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the percent by weight of the desired stereoisomer relative to the combined weight of all stereoisomers.

[0069] When a specific enantiomer of a compound is designated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the percent by weight of the desired enantiomer relative to the combined weight of all stereoisomers.

[0070] 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%. Stereoisomeric purity refers to the percent by weight of the desired stereoisomer encompassed by the name or structure relative to the combined weight of all stereoisomers.

[0071] When the disclosed compounds are named or depicted by a structure that does not indicate 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, including racemic mixtures of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer.

[0072] Unless otherwise specified, the compounds of the present disclosure are meant 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., separated on chiral SFC or HPLC chromatography columns such as CHIRALPAK® and CHIRALCEL®, available from DAICEL Corp., using an appropriate solvent or mixture of solvents to achieve good resolution). When a compound contains a double bond, the substituent can be in the E- or Z-configuration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0073] Where the disclosed compounds are named or depicted by structures that do not depict stereochemistry, for example, where 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, including mixtures of stereoisomers and mixtures of stereoisomers in which one or more stereoisomers are enriched relative to the other(s).

[0074] The compounds of the present disclosure may exist in tautomeric forms and mixtures, and separate individual tautomers are contemplated. All such forms are encompassed 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 are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0075] Furthermore, the compounds of the present disclosure, including their salts, may also be obtained in the form of their hydrates, or may include other solvents used in their crystallization. The compounds of the present disclosure may inherently or by design form solvates with pharmaceutically acceptable solvents (including water), and therefore the present disclosure is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its pharmaceutically acceptable salts) with one or more solvent molecules. For example, such solvent molecules, such as water, ethanol, etc., are commonly used in the pharmaceutical field and are known to be harmless to the recipient. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0076] Compounds of the present disclosure that contain groups capable of acting as hydrogen bond donors and / or acceptors may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from the compounds by known co-crystal formation procedures. Such procedures include grinding, heating, co-heating, co-melting, or contacting in solution the compound with a co-crystal former under crystallization conditions and isolating the co-crystal formed thereby. Suitable co-crystal formers include those described in WO2004 / 078163. Accordingly, the present disclosure further provides co-crystals comprising the compounds described herein.

[0077] In one embodiment, the present disclosure provides a deuterated compound disclosed herein, wherein any or more positions occupied by hydrogen may contain an enrichment with deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance of at least 3340 times the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all positions at its natural abundance.

[0078] In another embodiment, the present disclosure is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0079] As used herein, the term "pharmaceutically acceptable carrier" includes, as would be known to those skilled in the art, generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Any conventional carrier is contemplated for use in therapeutic or pharmaceutical compositions, except insofar as it is incompatible with the active ingredient.

[0080] The formulation can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the 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 compound of the present disclosure is typically formulated into a pharmaceutical dosage form to provide an easily controllable dosage of the drug and provide patients with a simple and easy-to-use product.

[0081] Pharmaceutical compositions (or formulations) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution can include a container having the pharmaceutical formulation disposed therein in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container can also include a tamper-evident assembly to prevent inadvertent access to the contents of the package. In addition, the container has a label disposed thereon that describes the contents of the container. The label can also include appropriate warnings.

[0082] Pharmaceutical compositions containing the compounds of the present disclosure are generally formulated for use in parenteral or oral administration.

[0083] For example, the pharmaceutical oral compositions of the present disclosure may be configured in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0084] Typically, a pharmaceutical composition contains: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; also in tablets c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; optionally d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) Tablets or gelatin capsules containing absorbents, coloring agents, flavoring agents, and sweeteners.

[0085] Tablets may be film coated or enteric coated according to methods known in the art.

[0086] Compositions suitable for oral administration include the 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 can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically simple and palatable preparation. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; 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, thereby providing a sustained effect over a longer period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.The preparation for oral use can be presented as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0087] Parenteral compositions (e.g., intravenous (IV) formulations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents, or emulsifiers, solution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically useful substances. The compositions generally contain about 0.1 to 75%, or about 1 to 50%, of the active ingredient, prepared according to conventional mixing, granulating, or coating methods, respectively.

[0088] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to decrease or inhibit the activity of TYK2 or to affect the properties and / or behavior of TYK2, such as stability, phosphorylation, kinase activity, interaction with other proteins, etc.

[0089] 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.

[0090] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0091] One embodiment of the present disclosure is a method of treating a disease or disorder 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 disorder responsive to inhibition of TYK2, including inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain trauma, neurodegeneration, liver disease, and 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, muscle pain, endotoxic 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 redness, eczema, psoriasis, atopic dermatitis, and sunburn.

[0092] The term "autoimmune disorder" includes diseases or disorders involving an inappropriate immune response to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid 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, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis.

[0093] The term "inflammatory disorder" includes diseases or disorders involving acute or chronic inflammation, such as allergies, 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.

[0094] 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 tumor, pancreatic cancer, cholangiocarcinoma, 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 carcinoma).

[0095] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as humans, companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0096] As used herein, the terms "treating" or "treatment" refer to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partial or substantial achievement of one or more of the following results: partially or completely reducing the severity of a disease, disorder, or syndrome; alleviating or ameliorating clinical symptoms or signs associated with a disorder; or slowing, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0097] An effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, to be administered to a subject can be from 10 μg to 500 mg.

[0098] Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal includes any suitable delivery method. Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal includes administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Administering a compound described herein or a pharmaceutically acceptable salt thereof to a mammal also includes administering a compound that is metabolized into a compound described herein or a pharmaceutically acceptable salt thereof to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.

[0099] Thus, the compounds described herein or their pharmaceutically acceptable salts can be systemically administered orally in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the compounds described herein or their pharmaceutically acceptable salts can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the compositions and preparations can, of course, vary and can conveniently be about 2 to about 60% by weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level will be obtained.

[0100] The tablets, troches, pills, capsules, etc. may contain: a binder such as tragacanth, acacia, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; or a sweetening agent such as sucrose, fructose, lactose, or aspartame, or a flavoring agent.

[0101] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

[0102] Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions, or sterile powders containing the active ingredient adapted 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.

[0103] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients as listed above, as needed, followed by filter sterilization. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying techniques, which can obtain a powder of the active ingredient and any additional desired ingredients present in a previously sterile-filtered solution.

[0104] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols, or glycols, or water-alcohol / glycol blends, in which the compounds described herein or pharmaceutically acceptable salts thereof can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.

[0105] Useful doses of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated by reference in its entirety.

[0106] The amount of a compound described herein or a pharmaceutically acceptable salt thereof required for therapeutic use may vary depending not only on the particular salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician. Generally, however, dosages may range from about 0.1 to about 10 mg / kg of body weight per day.

[0107] The compounds described herein, or pharmaceutically acceptable salts thereof, may be conveniently administered in unit dosage form, for example, containing 0.01 to 10 mg, or 0.05 to 1 mg of active ingredient per unit dosage form. In some embodiments, dosages of 5 mg / kg or less may be suitable.

[0108] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0109] The disclosed methods may include kits containing a compound described herein or a pharmaceutically acceptable salt thereof and instructions that may describe administering the compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, to a cell or a subject. This should be construed to include other embodiments of kits known to those skilled in the art, such as kits that include a solvent (such as sterile) for dissolving or suspending the compound described herein or a pharmaceutically acceptable salt thereof, or the composition, prior to administering the compound described herein or a pharmaceutically acceptable salt thereof, or the composition, to a cell or a subject. In some embodiments, the subject may be a human.

[0110] The compounds of the present disclosure can be synthesized by synthetic routes, including processes similar to those well known in the chemical arts, especially in light of the description contained herein.Starting materials are generally available from commercial sources such as Sigma-Aldrich, or can be easily prepared using methods well known to those skilled in the art (for example, by the methods outlined in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967-1999 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplementary documents (also available through Beilstein online database)).For details of protecting groups, the protecting groups themselves, and the protection of functional groups by their cleavage reactions, see, for example, J.F.W.M. McOmie, "Protective Groups in Organic Chemistry," Plenum Press, London and New York, 1973; T.W. Greene and P.G.W. Muts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York, 1999; "The Peptides," Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York, 1981; "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, Fourth Edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart, 1974; and H.-D. Jakubke and H. Jeschkeit, "Aminosaurens, Peptides, Proteins" (Amino Protecting groups are described in standard reference works such as "Protective Groups for the Synthesis of Novel Protecting Groups," "Proteins and Their Applications," Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982. A characteristic of a protecting group is that it can be easily removed (i.e., without the occurrence of undesired secondary reactions), for example, by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g., enzymatic cleavage).

[0111] The salt of the compound of the present disclosure that has at least one salt-forming group can be prepared in a manner known to those skilled in the art.For example, the acid addition salt of the compound of the present disclosure can be obtained in a conventional manner, for example, by treating the compound with an acid or suitable anion exchange reagent.Salt can be converted into free compound according to the method known to those skilled in the art.For example, acid addition salt can be converted by treating with suitable basic agent.

[0112] Any resulting isomeric mixtures can be separated on the basis of the physical chemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0113] For those compounds containing asymmetric carbon atoms, the compounds exist in individual optically active isomeric forms or as mixtures thereof, such as racemic or diastereomeric mixtures. Diastereomeric mixtures can be separated into their individual diastereoisomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reacting it with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Moschel's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using commercially available chiral HPLC columns.

[0114] The present disclosure further includes any variations of the present processes in which the reaction components are used in the form of their salts or optically pure materials. The compounds and intermediates of the present disclosure can also be converted into each other according to methods generally known to those skilled in the art.

[0115] The reactions described below for illustrative purposes provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. While specific starting materials and reagents are shown in the schemes and discussed below, other starting materials and reagents may be readily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0116] Example Unless otherwise stated, the compounds of the examples were analyzed or purified according to one of the purification methods mentioned below.

[0117] Chromatography on silica gel was performed using either Teledyne ISCO Combiflash RF or Grace Reveleris X2 with ELSD purification systems, using 20–40 μM (particle size), 250–400 mesh, or 400–632 mesh silica gel.

[0118] Analysis method ESI-MS data (also reported herein simply as MS) were recorded using a Waters System (Acquity HPLC and Micromass ZQ mass spectrometer), and all masses reported are the m / z of the protonated parent ion unless otherwise noted.

[0119] LC / MS: The sample is dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and injected directly onto the column using an automated sample preparation device. Analysis using one of the following methods: The present disclosure further includes any variations of the present processes in which the reaction components are used in the form of their salts or optically pure materials. The compounds and intermediates of the present disclosure can also be converted into each other according to methods generally known to those skilled in the art.

[0120] Analytical HPLC: Acidic HPLC: performed on a Shimadza 20A instrument equipped with an ultimate C18 3.0 x 50 mm, 3 μm column eluted with 2.75 mL / 4 L TFA in water (solvent A) and 2.5 mL / 4 L TFA in acetonitrile (solvent B).

[0121] Analytical LCMS: Acidic LCMS: Shimadza 2010 series, Shimadza 2020 series, or Waters Acquity UPLC BEH (MS ionization: ESI) instruments were equipped with a C18 column (2.1 mm × 30 mm, 3.0 mm or 2.1 mm × 50 mm, C18, 1.7 μm) eluted with 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B).

[0122] SFC analysis separation: Instrument: Waters UPC2 analytical SFC (SFC-H). Column: ChiralCel OJ, 150 x 4.6 mm ID, 3 μm. Mobile phase: CO2 in A, ethanol in B (0.05% DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35 °C. Wavelength: 220 nm.

[0123] Preparative HPLC purification: 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 where necessary. [Table 1]

[0124] Preparative SFC purification Instrument: MG III preparative SFC (SFC-1). Column: ChiralCel OJ, 250 x 30 mm ID, 5 μm. Mobile phase: CO2 in A, ethanol in B (0.1% NH3H2O). Gradient: B 50%. Flow rate: 40 mL / min. Back pressure: 100 bar. Column temperature: 38 °C. Wavelength: 220 nm. Cycle time: approximately 8 min.

[0125] 1 H-NMR: NMR spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance III 400 MHz, Varian-400 VNMRS, or Varian-400 MR. Chemical shifts are expressed in parts per million (ppm). Coupling constants (J) are in hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), dd (double doublet), dt (double triplet), dq (double quartet), m (multiplet), or br (broad line).

[0126] Typically, the compounds described herein can be prepared according to the schemes provided below. The following examples serve to illustrate the present disclosure without limiting its scope. Methods for preparing such compounds are described below.

[0127] Abbreviations used are those conventional in the art or are as follows: Aq. means aqueous, Bn means benzyl Boc means tert-butoxycarbonyl; BocO means di-tert-butyl dicarbonate, br means wide line, n-BuOH means butan-1-ol, t-BuOH means tertiary butanol, n-BuLi means n-butyllithium; °C means degrees Celsius CDCl3 means deuterated chloroform; δ means chemical shift, d means double line, dd means double double line, DCM means dichloromethane DEA stands for diethylamine DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine DMF means N,N-dimethylformamide DMSO means dimethyl sulfoxide DMSO-d6 means hexadeuterial dimethyl sulfoxide; Et means ethyl, TEA means triethylamine EtOH means ethanol, EtOAc means ethyl acetate Eq. means equivalent, g stands for grams HATU means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCl means hydrochloric acid HCO2H means formic acid 1 H NMR means proton nuclear magnetic resonance; H2O means water, HOAt means 1-hydroxy-7-azabenzotriazole; HPLC stands for high pressure liquid chromatography h stands for hours, IPA stands for 2-propanol K2CO3 means potassium carbonate, KF means potassium fluoride KOH means potassium hydroxide L stands for liters LCMS means liquid chromatography mass spectrometry m means multiplet, M means mole Me means methyl, MeCN means acetonitrile; MeI means methane iodide MeOH means methanol, MeOH-d4 means deuterium-methanol, mg means milligrams MgSO4 means magnesium sulfate, MHz stands for megahertz mins means minutes, mL means milliliters mmol means millimole, MS m / z means mass spectrum peak; MsCl means methanesulfonyl chloride; N2 means nitrogen, NaBH4 means sodium borohydride Na2CO3 means sodium carbonate, NaH means sodium hydride NaHCO3 means sodium bicarbonate NaOH means sodium hydroxide Na2SO4 means sodium sulfate, NH3 means ammonia, NH4Cl means ammonium chloride, NH4OH is ammonium hydroxide, PE means petroleum ether Pd(OAc)2 means palladium acetate; Pd(amphos)Cl2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium(0), Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4 means tetrakis(triphenylphosphine)palladium(0); PdCl2(PPh3)2 means Pd / C means q means quartet, rt means room temperature; RT means retention time; s means single track, sat. means saturated, SFC stands for supercritical fluid chromatography SiliaMetS DMT means 2,4,6-trimercaptotriazine functionalized silica gel; SM means starting material; soln. means solution, t means triple line, T3P® means propylphosphonic anhydride solution; TEA means triethylamine TFA means trifluoroacetic acid THF means tetrahydrofuran; TLC means thin layer chromatography TsOH means para-toluenesulfonic acid; μL means microliters μmol means micromolar XPhos Pd G3 means (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II); RuPhos Pd G3 means (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II)

[0128] General Procedure Preparation method: Preparation 1 6-Bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine [ka] A solution of 6-bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (3.0 g, 14.0 mmol) in POCl3 (50 mL) was stirred at 100 °C for 3 h. The reaction mixture was evaporated in vacuo, the residue was dissolved in DCM (60 mL), and the pH was adjusted to approximately 7 with aqueous NaHCO3. The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (20-35% EtOAc / PE) to give 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine as a white solid (2.6 g, 80%). LCMS m / z = 231.5 [M+H] + .

[0129] Preparation 2 tert-Butyl 3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A solution of 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (Preparation 1, 7.0 g, 30.1 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.39 g, 30.1 mmol), and DIPEA (11.7 g, 90.3 mmol) in DMF (60 mL) was stirred for 2 h at 50° C. The reaction mixture was diluted with EtOAc / heptane (1:1.500 mL) and washed with saturated aqueous NH4Cl (2 x 200 mL), HO (200 mL), and brine (200 mL). The combined organics were washed with brine (60 mL), dried (MgSO4) and evaporated to dryness in vacuo to give tert-butyl 3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (10.38 g, 84%), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ: 7.85-7.82 (m, 1H), 7.59-7.54 (m, 1H), 6.72-6.71 (m, 1H), 4.50-4.38 (m, 4H), 3.45-3.39 (m, 2H), 1.98-1.96 (m, 2H), 1.75-1.73 (m, 2H), 1.49 (s, 9H).

[0130] Preparation 3 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-bromopyrrolo[2,1-f][1,2,4]triazine hydrochloride [ka] To a solution of tert-butyl 3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 2, 2.5 g, 6.12 mmol) in DCM (25 mL) was added HCl / dioxane (4 M, 20 mL) and the mixture was stirred for 30 minutes at 25° C. The reaction mixture was evaporated to dryness in vacuo to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-bromopyrrolo[2,1-f][1,2,4]triazine hydrochloride as a yellow solid (2.05 g), which was used without further purification. 1 H NMR (500MHz, DMSO-d6) δ: 9.63 (br, 1H), 9.40 (br, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.20 (s, 1H), 4.62-4.58 (m, 2H), 4.17-4.15 (m, 2H), 3.66-3.63 (m, 2H), 2.00-1.97 (m, 2H), 1.82-1.82 (m, 2H).

[0131] Preparation 4 tert-Butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of tert-butyl 3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 2, 10.38 g, 25.42 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (9.31 g, 38.13 mmol), KF (3.0 M, 25.4 mL), and Pd(amphos)Cl (1.80 g, 2.54 mmol) was suspended in dioxane (127 mL), and the reaction mixture was sparged with N 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 using silica gel column chromatography (0-70% EtOAc / heptane) to give tert-butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.9 g, 96.3%). 1 H NMR (500 MHz, CDCl3) δ: 7.99 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.74 (d, 1H), 7.22 (t, 1H), 6.78 (s, 1H), 4.59-4.43 (m, 4H), 3.46-3.39 (m, 2H), 2.00-1.98 (m, 2H), 1.81-1.77 (m, 2H), 1.50 (s, 9H).

[0132] Preparation 5 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 [ka] To a solution of tert-butyl 3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 2, 1.60 g, 3.92 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.63 g, 7.84 mmol) in DMSO (10 mL) was added Pd(dppf)Cl (573 mg, 0.784 mmol), KCO (1.08 g, 7.84 mmol), and the reaction was stirred at 110 °C for 5 h. The mixture was diluted with HO (60 mL) and extracted with EtOAc (4 × 60 mL). The combined organics were washed with brine (4 × 30 mL), dried (NaSO), and evaporated to dryness. The residue was purified by silica gel column chromatography (0-50% EtOAc / PE) 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 as a white solid (800 mg, 49.7% yield). LCMS m / z = 410.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.79 (s, 1H), 7.62-7.61 (m, 2H), 7.49 (s, 1H), 6.66 (s, 1H), 4.51-4.32 (m, 4H), 3.88 (s, 3H), 3.40-3.38 (m, 2H), 1.93-1.90 (m, 2H), 1.72-1.71 (m, 2H), 1.44 (s, 9H).

[0133] Preparation 6 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride [ka] To a solution of tert-butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 4, 2.47 g, 5.54 mmol) in DCM (22 mL) was added the HCl / dioxane solution and the reaction was stirred at room temperature for 5 hours. The mixture was evaporated to dryness in vacuo to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride, which was used without further purification. LCMS m / z=346.0 [M+H] + .

[0134] Preparation 7 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 [ka] The title compound was prepared from tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 5) using a method similar to that described for Preparation 6. LCMS m / z=310.0 [M+H] + .

[0135] Preparation 8 (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone [ka] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-bromopyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 3, 2.0 g, 5.80 mmol) in DCM (30 mL) was added cyclopropanecarbonyl chloride (910 mg, 8.70 mmol) and DIPEA (2.3 g, 17.4 mmol), and the reaction was stirred for 1 h at 25° C. The reaction mixture was poured into HO (20 mL) and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (20 mL), dried (NaSO) and evaporated to dryness to give (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone as a yellow solid (1.9 g, 87% yield), which was used without further purification. 1 H NMR (500MHz, CDCl3) δ: 7.86 (s, 1H), 7.59 (d, 1H), 6.71 (d, 1H), 4.86-4.45 (m, 4H), 3.56-3.42 (m, 2H), 1.98-1.91 (m, 1H), 1.77-1.72 (m, 4H), 1.09-1.03 (m, 2H), 0.85-0.82 (m, 2H).

[0136] Preparation 9 tert-Butyl 8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] To a solution of (1S,2R)-2-fluorocyclopropanecarboxylic acid (2.70 g, 25.9 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.00 g, 23.6 mmol), and TEA (11.92 g, 117.75 mmol) in EtOAc (47 mL) was added 50 wt% T3P in EtOAc (30.0 g, 47.1 mmol). The reaction was stirred at room temperature for 5 minutes and then heated at 60 °C for 5 hours. The reaction mixture was cooled to room temperature and diluted with HO, 0.5 N NaOH, and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated to dryness in vacuo to give tert-butyl 8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (7.03 g), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ: 4.90-4.43 (m, 4H), 3.83-3.65 (m, 2H), 3.07-2.74 (m, 3H), 1.93-1.40 (m, 5H), 1.35 (s, 9H).

[0137] Preparation 10 (3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride [ka] To a solution of tert-butyl 8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Preparation 9, 246.0 mg, 0.825 mmol) in EtOAc (3.0 mL) was added HCl / EtOAc (4 M, 3.0 mL) and the reaction was stirred at 18 °C for 3 h. The mixture was evaporated under reduced pressure to give (3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride as a pale yellow solid (150.0 mg, crude). LCMS m / z = 199.2 [M+H] + .

[0138] Preparation 11 (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] DIPEA (4.52 g, 35 mmol) was added to a suspension of 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (Preparation 1, 2.71 g, 11.7 mmol) and (3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride (Preparation 10, 2.74 g, 11.67 mmol) in DMF (23 mL), and the reaction was heated to 90 °C overnight. The cooled mixture was diluted with EtOAc / heptane (1:1) and washed with aqueous NH4Cl (3 times). The combined organics were dried over (MgSO4) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc / heptane) to give (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (2.76 g, 60%). LCMS m / z=394.0 [M+H] + .

[0139] Preparation 12 ((1S,2R)-2-Fluorocyclopropyl)(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] A mixture of (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 11, 500 mg, 1.27 mmol), bis(pinacolato)diboron (645 mg, 2.54 mmol), KOAc (374 mg, 3.81 mmol), and Pd(dppf)Cl.DCM (103.7 mg, 0.127 mmol) in MeCN (2.5 mL) was purged with N and stirred at 65 °C under N for 24 h. The reaction mixture was evaporated to dryness, and the residue was purified by silica gel column chromatography (0-90% EtOAc / heptane) to give ((1S,2R)-2-fluorocyclopropyl)(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (526 mg, 93.9%). LCMS m / z=442.1 [M+H] + .

[0140] Preparation 13 Cyclopropyl(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 8, 100 mg, 0.266 mmol) and bis(pinacolato)diboron (81 mg, 0.319 mmol) in toluene (5 mL) was added KOAc (52.2 mg, 0.532 mmol). Pd(dppf)Cl (19.5 mg, 0.0265 mmol) was then added under N, and the mixture was stirred at 90 °C for 16 h. The cooled reaction mixture was purified by column chromatography (5-50% EtOAc / PE) to give cyclopropyl(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow solid (50 mg), which was used without further purification. LCMS m / z=424.1 [M+H] + .

[0141] Preparation 14 (3-(6-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone [ka] To a solution of (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 8, 100 mg, 0.266 mmol) in MeCN (2.66 mL) was added F-TEDA (94.16 mg, 0.266 mmol) at 0 °C, and the mixture was stirred for 0.5 h. The reaction mixture was concentrated in vacuo to give crude (3-(6-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (18.0 mg, 17.2% yield), which was purified by silica gel column (heptane / EtOAc = 1:1). LCMS m / z=396.1[M+H] + .

[0142] Preparation 15 1-(Difluoromethyl)-4-iodo-1H-imidazole [ka] To a solution of 4-iodo-1H-imidazole (500 mg, 2.58 mmol) in DMF (20 mL) was added sodium 2-chloro-2,2-difluoroacetate (1.18 g, 7.73 mmol) and CsCO (2.52 g, 7.73 mmol), and the reaction was stirred at 120 °C for 4 h. The reaction was filtered, and the filtrate was diluted with HO (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organics were washed with HO (3 × 20 mL), brine (20.0 mL), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by column chromatography (10% EtOAc / PE) to afford 1-(difluoromethyl)-4-iodo-1H-imidazole as a colorless oil (131 mg, 20.8%). 1 H NMR (500 MHz, CDCl3) δ: 7.71 (d, 1H), 7.32 (s, 1H), 7.04 (t, 1H).

[0143] Preparation 16 4-Bromo-3-fluoro-1-methyl-1H-pyrazole [ka] A mixture of NaH (48.5 mg, 1.21 mmol, 60% purity) and 4-bromo-3-fluoro-1H-pyrazole (100 mg, 0.606 mmol) in THF (5 mL) was stirred at 25 °C for 10 min. MeI (129 mg, 0.909 mol) was added and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with NH4Cl (saturated, 10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo to give 4-bromo-3-fluoro-1-methyl-1H-pyrazole (72 mg, 66.3%). LCMS m / z = 179.2 [M+H] + .

[0144] Preparation 17 Cyclopropyl(3-(6-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (100 mg, 0.267 mmol) in DMSO (2 mL) was added (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 8, 81.6 mg, 0.292 mmol), KCO (73.5 mg, 0.532 mmol), and Pd(dppf)Cl (19.5 mg, 0.027 mmol) under N and the reaction was stirred at 90 °C for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (10 mL), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by preparative TLC (50% EtOAc / PE) to give cyclopropyl(3-(6-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow oil (105 mg, 88% yield). 1 H NMR (500 MHz, CDCl3) δ: 7.94 (d, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.07 (d, 1H), 5.75-5.71 (m, 1H), 4.88-4.60 (m, 4H), 4.10-4.08 (m, 1H), 3.80-3.75 (m, 1H), 3.57-3.49 (m, 2H), 2.50-2.46 (m, 1H), 2.16-2.10 (m, 3H), 1.93-1.90 (m, 2H), 1.80-1.73 (m, 4H), 1.68-1.65 (m, 1H), 1.10-1.04 (m, 2H), 0.86-0.81 (m, 2H).

[0145] Preparation 18 (3-(6-(2H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone hydrochloride [ka] To a solution of cyclopropyl(3-(6-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 17, 100 mg, 0.223 mmol) in DCM (5 mL) was added HCl / dioxane (4 M, 5 mL) and the mixture was stirred at 25° C. for 30 min. The reaction mixture was evaporated to dryness in vacuo to give (3-(6-(2H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone hydrochloride as a yellow solid (90 mg), which was used without further purification. 1 H NMR (500 MHz, DMSO-d6) δ: 8.20 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.39 (s, 1H), 4.83-4.68 (m, 4H), 3.75-3.70 (m, 2H), 2.03-1.70 (m, 5H), 0.83-0.74 (m, 4H).

[0146] Preparation 19 2-(azetidin-1-yl)-4-chloropyridine [ka] To a suspension of 2,4-dichloropyridine (500 mg, 3.38 mmol) and azetidine hydrochloride (316.1 mg, 3.38 mmol) in DMSO (5 mL) was added K2CO3 (1.40 g, 10.1 mmol) and the mixture was heated to 100 °C. The cooled reaction was diluted with EtOAc (5 mL) and washed with aqueous NH4Cl (3 times). The combined organics were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by silica gel column (0-50% EtOAc / heptane) to give 2-(azetidin-1-yl)-4-chloropyridine (133 mg, 23.3%). LCMS m / z = 169.0 [M+H] + .

[0147] Preparation 20 4-chloro-2-(3,3-difluoroazetidin-1-yl)pyridine [ka] The title compound was prepared from 2,4-dichloropyridine and 3,3-difluoroazetidine hydrochloride using a method similar to that described in Preparation 19 (37 mg, 5.4%). LCMS m / z=205.0 [M+H] + .

[0148] Preparation 21 1-(4-Bromo-1H-pyrrol-2-yl)ethan-1-one [ka] Amberlyst® 15 (3.97 g) was added to a room temperature solution of 1-(1H-pyrrol-2-yl)ethan-1-one 1 (44 g, 403 mmol) in THF (442 mL), the mixture was cooled to −30° C., and NBS (71.8 g, 403 mmol) was added portionwise. The resulting mixture was stirred for 2 hours, then warmed to room temperature and filtered. The filtrate was diluted with saturated aqueous sodium sulfite, and the resulting mixture was extracted with DCM (twice). The combined organics were evaporated to dryness in vacuo, and the residue was dissolved in TBME. The solution was washed with NaHCO (twice), brine, dried (NaSO), and concentrated under reduced pressure to give 1-(4-bromo-1H-pyrrol-2-yl)ethan-1-one (76.2 g) as a white solid, which was used without further purification. LCMS m / z=188.0 [M+H] + .

[0149] Preparation 22 (E)-1-(4-Bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one [ka] A solution of 1-(4-bromo-1H-pyrrol-2-yl)ethan-1-one (Preparation 21, 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 (£)-1-(4-bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one as a light brown solid (61.5 g, 69%). LCMS m / z=243.1 [M+H] + .

[0150] Preparation 23 6-Bromopyrrolo[1,2-b]pyridazin-4-ol [ka] KO tBu (42.6 g, 379 mmol) was added portionwise to a solution of (E)-1-(4-bromo-1H-pyrrol-2-yl)-3-(dimethylamino)prop-2-en-1-one (Preparation 22, 61.5 g, 253 mmol) in NMP (1.85 L), and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled on an ice / water bath, and O-(4-nitrobenzoyl)hydroxylamine (69.1 g, 379 mmol) was added. The resulting mixture was stirred at 0 °C for 1 h and then at room temperature overnight. The mixture was cooled to 0 °C, and saturated aqueous NH 4 Cl (500 mL) was added dropwise. The mixture was diluted with HO (500 mL), the pH adjusted to 3–4 with 2 N aqueous HCl, and extracted with TBME (3×). The combined organics were concentrated to half the volume, washed with HO (2×), brine, and then evaporated to dryness in vacuo. 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 further purification. LCMS m / z=213.0 [M+H] + .

[0151] Preparation 24 6-Bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate [ka] Trifluoromethanesulfonic anhydride (88.3 g, 313 mmol) was added to a solution of 6-bromopyrrolo[1,2-b]pyridazin-4-ol (Preparation 23, 58 g, ca. 140 mmol, ca. 50% purity) and TEA (32.5 g, 321 mmol) in DCM (870 mL) at 0 °C. The mixture was stirred with cooling for 1 h and then at room temperature for 2 h. The mixture was diluted with DCM, washed with Na2CO3 (twice), brine, dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (0-2% TBME / heptane) to give 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate as a dark oil (21.1 g, 43%). LCMS m / z = 344.6 [M+H] +.

[0152] Preparation 25 tert-Butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A solution of 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate (Preparation 24, 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 min. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×40 mL). The combined organics were washed with brine (60 mL), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (0-20% EtOAc / PE) to give tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (4.2 g, 70.3% yield). LCMS m / z = 409.2 [M+H] + .

[0153] Preparations 26-29 Following a procedure similar to that described in Preparation 4, the compounds in the following table were prepared from tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 25) and the appropriate boronic acid. [Table 2-1] [Table 2-2]

[0154] Preparation 30 tert-Butyl 3-(6-(3-fluoro-2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 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 25, 80.0 mg, 0.196 mmol) in dioxane (5.0 mL) and water (0.5 mL) was added (3-fluoro-2-methoxypyridin-4-yl)boronic acid (50.4 mg, 0.295 mmol), KCO (81.4 mg, 0.589 mmol), and Pd(dppf)Cl (14.4 mg, 0.020 mmol), and the mixture was stirred at 100 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give tert-butyl 3-(6-(3-fluoro-2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (70.0 mg, 78.6% yield). 1 H NMR (400 MHz, CDCl3) δ ppm: 8.13 (s, 1H), 7.90 (d, 1H), 7.85 (d, 1H), 7.18-7.15 (m, 1H), 6.87 (s, 1H), 5.80 (d, 1H), 4.41-4.35 (m, 2H), 4.07 (s, 3H), 3.74-3.60 (m, 2H), 3.24-3.10 (m, 2H), 2.05-1.98 (m, 4H), 1.49 (s, 9H).

[0155] Preparation 31 tert-Butyl 3-(6-(2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Following the procedure described in Preparation 30, tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 25) and (2-methoxypyridin-4-yl)boronic acid gave tert-butyl 3-(6-(2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 90 mg, 84.2%, as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ: 8.16 (d, 1H), 7.97 (d, 1H), 7.83 (d, 1H), 7.13-7.15 (m, 1H), 6.99 (s, 1H), 6.76 (s, 1H), 5.79 (d, 1H), 4.51-4.43 (m, 2H), 3.98 (s, 3H), 3.80-3.73 (m, 2H), 3.23-3.15 (m, 2H), 2.07-1.98 (m, 4H), 1.50 (s, 9H).

[0156] Preparation 32 tert-Butyl 3-(6-(5-fluoro-2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Following a procedure similar to that described in Preparation 30, tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 25) and (5-fluoro-2-methoxypyridin-4-yl)boronic acid gave tert-butyl 3-(6-(5-fluoro-2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 62.4 mg, 70% yield, as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm : 8.13 (d, 1H), 8.05 (d, 1H), 7.85 (d, 1H), 7.02 (d, 1H), 6.85 (s, 1H), 5.80 (d, 1H), 4.46-4.40 (m, 2H), 3.96 (s, 3H), 3.81-3.68 (m, 2H), 3.35-3.20 (m, 2H), 2.07-1.98 (m, 4H), 1.51 (s, 9H).

[0157] Preparation 33 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride [ka] To 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 (Preparation 26, 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 as a pale yellow solid (1.685 g). LCMS m / z=309.2 [M+H] + .

[0158] Preparation 34 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride [ka] To a solution of tert-butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 27, 154 mg, 0.346 mmol) in DCM (2.4 mL) was added a solution of 4 M HCl / dioxane, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness in vacuo to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride, which was used without further purification. LCMS m / z=345.0 [M+H] + .

[0159] Preparations 35-39 Following a procedure similar to that described in Preparation 34, the compounds in the following table were obtained from the appropriate Boc-protected compounds. [Table 3-1] [Table 3-2]

[0160] Preparation 40 (3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] To a suspension of 6-bromopyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate (Preparation 24, 5.80 g, 16.8 mmol) and (3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride (Preparation 10, 3.95 g, 16.8 mmol) in DMF (33.62 mL) was added DIPEA (6.52 g, 50.4 mmol) and the mixture was warmed to 90 °C overnight. The reaction was cooled to room temperature, diluted with EtOAc / heptane (1:1), and washed with aqueous NH4Cl (3 times). The combined organics were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc / heptane) to give (3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (4.19 g, 63.4%). LCMS m / z=393.0 [M+H] + .

[0161] Preparation 41 ((1S,2R)-2-Fluorocyclopropyl)(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]octan-8-yl)methanone [ka] A mixture of (3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 40, 499 mg, 1.27 mmol), bis(pinacolato)diboron (645 mg, 2.54 mmol), KOAc (374 mg, 3.81 mmol), and Pd(dppf)Cl.DCM (104 mg, 0.127 mmol) in MeCN (2.5 mL) was purged with N and stirred at 65 °C under N for 24 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by silica gel column chromatography (0-90% EtOAc / heptane) to give ((1S,2R)-2-fluorocyclopropyl)(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]octan-8-yl)methanone (420 mg, 75%). LCMS m / z=441.2 [M+H] + .

[0162] Preparation 42 tert-Butyl 3-(6-vinylpyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 25, 1.20 g, 2.95 mmol), potassium vinyltrifluoroborate (790.3 mg, 5.90 mmol), Pd(Amphos)Cl (208.9 mg, 0.295 mmol), and KF (3.0 M, 2.95 mL) in dioxane (5.90 mL) was purged with N for 5 minutes and then heated to 80 °C overnight. The cooled mixture was adsorbed onto silica gel and purified by column chromatography (0-80% EtOAc:heptane) to give tert-butyl 3-(6-vinylpyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (552.0 mg, 52.8% yield). LCMS m / z = 355.2 [M+H] + .

[0163] Preparation 43 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(2,2-difluorocyclopropyl)pyrrolo[1,2-b]pyridazine [ka] A mixture of tert-butyl 3-(6-vinylpyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 42, 100 mg, 0.282 mmol), (bromodifluoromethyl)trimethylsilane (114.6 mg, 0.564 mmol), and tetrabutylammonium bromide (2.73 mg, 0.009 mmol) in toluene (0.56 mL) was stirred at 110 °C for 6 h. The cooled mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phase was washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc / heptane, 0% to 100%) to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(2,2-difluorocyclopropyl)pyrrolo[1,2-b]pyridazine, 58.0 mg, yield 67.6%.

[0164] Preparation 44 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 [ka] A mixture of tert-butyl 3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 25, 598.73 mg, 1.47 mmol), bis(pinacolato)diboron (746.58 mg, 2.94 mmol), KOAc (432.80 mg, 4.41 mmol), and Pd(dppf)Cl (120.05 mg, 0.147 mmol) in MeCN (2.94 mL) was purged with N and stirred at 65 °C under N 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 as a white solid (560.0 mg, 83.8% yield). LCMS m / z = 455.3 [M+H] + .

[0165] Preparation 45 tert-Butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 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 44, 563.4 mg, 1.24 mmol), 3,5-dichloropyridazine (277.1 mg, 1.86 mmol), Pd(amphos)Cl (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 N for 5 minutes and then heated to 80 °C for 4 hours. The cooled mixture was diluted with EtOAc, washed with NHCl (twice) and brine, dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by automated silica gel chromatography (10-55% EtOAc / heptane) to afford tert-butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (287 mg, 52.5% yield). LCMS m / z = 441.2 [M+H] + .

[0166] Preparation 46 tert-Butyl 3-(6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To tert-butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 45, 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 (2×). The combined organic layers were washed with brine, dried (MgSO), 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] + .

[0167] Preparation 47 tert-Butyl 3-(6-(6-(dimethylamino)pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] N-Methylmethanamine (2 M in THF, 4.54 mL) and NMP (1.51 mL) were added to tert-butyl 3-(6-(6-chloropyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 45, 100.0 mg, 0.227 mmol) in a microwave vial. The vial was sealed and heated to 170 °C under microwave irradiation for 6 h. The cooled mixture was concentrated in vacuo, and BocO (99 mg, 0.454 mmol) and DMAP (8.31 mg, 0.068 mmol) were added, and the reaction was stirred at room temperature for 1.5 h. The reaction was diluted with water and EtOAc, the layers were separated, and the aqueous solution was extracted with EtOAc (3 x). The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography on silica gel (10-90% [3:1 EtOAc / EtOH] / heptane) to quantitatively afford tert-butyl 3-(6-(6-(dimethylamino)pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 102 mg. LCMS m / z=450.3 [M+H] + .

[0168] Preparation 48 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride [ka] 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 46, 73.0 mg, 0.167 mmol) in DCM (1.50 mL) was added 4 M 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]+ .

[0169] Preparation 49 5-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazin-6-yl)-N,N-dimethylpyridazin-3-amine hydrochloride [ka] 5-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazin-6-yl)-N,N-dimethylpyridazin-3-amine hydrochloride was prepared from tert-butyl 3-(6-(6-(dimethylamino)pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 47) according to the procedure described in Preparation 48. LCMS m / z=350.2 [M+H] + .

[0170] Preparation 50 tert-Butyl 3-(6-bromo-3-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 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 25, 300 mg, 0.737 mmol) in MeCN (7.37 mL) was added F-TEDA (260.9 mg, 0.737 mmol) at 0 °C, and the reaction was stirred for 30 minutes. The reaction mixture was concentrated in vacuo and purified by silica gel column (heptane / EtOAc = 1:1) to give tert-butyl 3-(6-bromo-3-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (88.0 mg, 28.1% yield). LCMS m / z = 425.1, 427.1 [M + H] + .

[0171] Preparation 51 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-bromo-3-fluoropyrrolo[1,2-b]pyridazine hydrochloride [ka] To a solution of tert-butyl 3-(6-bromo-3-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 50, 88.0 mg, 0.207 mmol) in DCM (1.03 mL) was added 4 M HCl:dioxane (0.52 mL) and the reaction was stirred for 2 hours. The mixture was evaporated under reduced pressure to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-bromo-3-fluoropyrrolo[1,2-b]pyridazine hydrochloride, 67.0 mg.

[0172] Preparation 52 (3-(6-bromo-3-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone [ka] To a solution of cyclopropanecarboxylic acid (23.92 mg, 0.278 mmol), 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-bromo-3-fluoropyrrolo[1,2-b]pyridazine hydrochloride (Preparation 51, 67.0 mg, 0.185 mmol), and TEA (93.74 mg, 0.926 mmol) in DMF (0.926 mL) was added 50 wt% T3P® (235.79 mg, 370.54 μmol, 50% solution in EtOAc), and the reaction was stirred at room temperature for 5 minutes and then heated at 60° C. for 5 hours. The reaction mixture was cooled to room temperature and diluted with water, 0.5 N NaOH, and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give (3-(6-bromo-3-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (24.0 mg, 32.9% yield). LCMS m / z=395.1 [M+H] + .

[0173] Preparation 53 (3-(6-(2,5-dihydrofuran-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] Following a procedure similar to that described in Preparation 4, (3-(6-(2,5-dihydrofuran-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone, 31 mg, 31.9% yield, was prepared from (3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 40) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane. LCMS m / z=383.1 [M+H]+ .

[0174] Preparation 54 tert-Butyl 3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 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 hours. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EtOAc = 2 / 1) to afford tert-butyl 3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (260.0 mg, 79.0% yield). 1 H NMR (400 MHz, MeOH-d4) δ: 7.78 (d, 1H), 6.48 (d, 1H), 4.25 (s, 2H), 3.20-3.14 (m, 4H), 1.93-1.81 (m, 4H), 1.49 (s, 9H).

[0175] Preparation 55 tert-Butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 54, 215.0 mg, 0.615 mmol) in MeOH (3.0 mL), Pd / C (39.3 mg, 0.037 mmol, 10% purity) was added under 15 psi of H and the reaction was stirred at 25° C. for 1 hour. The reaction was filtered and the filtrate concentrated in vacuo to afford 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). 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).

[0176] Preparation 56 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 [ka] To a solution of tert-butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 55, 150.0 mg, 0.470 mmol) in DMF (3.0 mL) was 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 column chromatography on silica gel (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). 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).

[0177] Preparations 57-65 Following a procedure similar to that described in Preparation 56, the compounds in the following table were prepared from tert-butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 55) and the appropriate aldehyde (RCOH). [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0178] Preparation 66 tert-Butyl 3-(2-(2-cyanopyridin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(2-(2-chloropyridin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 59, 220.0 mg, 0.50 mmol) in DMF (2.0 mL) was added Zn(CN) (175.7 mg, 1.5 mmol), DPPF (55.3 mg, 0.010 mmol), Pd(dba) (45.7 mg, 0.050 mmol) and the reaction was stirred at 150 °C under microwave irradiation for 2 h. The cooled mixture was concentrated in vacuo, and the crude material was purified by column chromatography on silica gel (DCM / MeOH=10 / 1) to give tert-butyl 3-(2-(2-cyanopyridin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110.0 mg, 51.1% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 8.83 (d, 1H), 8.49 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 6.50 (d, 1H) 5.07-4.49 (m, 4H), 3.46-3.43 (m, 2H), 2.06-1.93 (m, 4H), 1.53 (s, 9H).

[0179] Preparation 67 tert-Butyl (3-(2-(1-fluorocyclopropyl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) [ka] Part A: To a solution of 1-fluorocyclopropane-1-carboxylic acid (65.2 mg, 0.626 mmol) in DMF (2.0 mL) was added HATU (119.4 mg, 0.313 mmol) and the solution was stirred for 15 minutes. TEA (95.0 mg, 0.939 mmol) and tert-butyl 3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 55, 100.0 mg, 0.313 mmol) were added and the reaction was stirred at 20 °C for 20 hours. The reaction was diluted with HO (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine (2 × 10 mL), dried over NaSO, and the mixture was filtered. The filtrate was evaporated under reduced pressure to give tert-butyl 3-(2-amino-3-(1-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (100.0 mg, crude).

[0180] Part B: To a solution of tert-butyl 3-(2-amino-3-(1-fluorocyclopropane-1-carboxamido)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 0.1 mmol) in DMF (2.0 mL), CsF (13.0 mg, 0.197 mmol) was added, and the reaction was stirred at 100° C. for 2 h. The cooled mixture was concentrated in vacuo, and the residue was purified by preparative HPLC-4 (gradient 37-67%) to afford tert-butyl (3-(2-(1-fluorocyclopropyl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) as a white oil (25.0 mg, 65.4% yield). 1H NMR (400 MHz, CDCl3) δ: 8.04 (s, 1H), 6.35 (s, 1H), 4.65-4.35 (m, 5H), 3.24-3.23 (m, 2H), 2.04-1.91 (m, 5H), 1.65-1.57 (m, 9H), 1.33-1.25 (m, 1H), 0.87-0.82 (m, 1H).

[0181] Preparation 68 2-Chloro-5-fluoro-3-nitropyridin-4-amine [ka] 2-Chloro-5-fluoropyridin-4-amine (1.1 g, 7.51 mmol) was carefully added to concentrated H2SO4 (15 mL) at 0-5 °C (ice bath) with stirring, followed by the slow addition of KNO3 (1.59 g, 15.76 mmol) while maintaining the internal temperature below 5 °C. The reaction was stirred at 0-5 °C for 1 h and at 20 °C for an additional 20 h. The mixture was poured into ice water, and the solid was filtered, collected, and dried in vacuo. The solid was dissolved in concentrated H2SO4 (10 mL), and the solution was stirred at 20 °C for 20 h. The reaction was poured into ice water (30 mL), adjusted to pH 7 with NH3.H2O, and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and evaporated under reduced pressure to give 2-chloro-5-fluoro-3-nitropyridin-4-amine as a yellow solid (970.0 mg, 67.4% yield). 1 H NMR (500 MHz, CDCl3) δ: 8.07 (s, 1H), 5.87 (br s, 2H).

[0182] Preparation 69 5-Fluoro-N2-(4-methoxybenzyl)-3-nitropyridine-2,4-diamine [ka] To a solution of 2-chloro-5-fluoro-3-nitropyridin-4-amine (Preparation 68, 960.0 mg, 5.01 mmol) in DMSO (10.0 mL) was added TEA (1.52 g, 15.03 mmol) and 4-methoxybenzylamine (1.37 g, 10.02 mmol), and the reaction was stirred at 150 °C for 2 h. The cooled mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1 to 10 / 1) to give 5-fluoro-N-(4-methoxybenzyl)-3-nitropyridine-2,4-diamine as a yellow solid (850.0 mg, 66.4% yield). 1 H NMR (500 MHz, CDCl3) δ: 8.78 (br s, 1H), 7.93 (d, 1H), 7.28 (d, 2H), 7.90-7.87 (m, 2H), 4.68 (d, 2H), 3.80 (s, 3H).

[0183] Preparation 70 4-chloro-5-fluoro-N-(4-methoxybenzyl)-3-nitropyridin-2-amine [ka] To a solution of 5-fluoro-N-(4-methoxybenzyl)-3-nitropyridine-2,4-diamine (Preparation 69, 1.2 g, 4.11 mmol) in MeCN (15.0 mL) was added t-BuNO (635.7 mg, 6.17 mmol) and CuCl (610.3 mg, 6.17 mmol), and the reaction was stirred at 70 °C for 3 h. The cooled mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1 to 10 / 1) to give 4-chloro-5-fluoro-N-(4-methoxybenzyl)-3-nitropyridin-2-amine as a yellow solid (850.0 mg, 66.4% yield). 1 H NMR (500 MHz, CDCl3) δ: 8.57 (s, 1H), 7.15 (d, 2H), 6.82-6.78 (m, 2H), 5.31 (s, 2H), 3.76 (s, 3H).

[0184] Preparation 71 tert-Butyl 3-(5-fluoro-2-((4-methoxybenzyl)amino)-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of 4-chloro-5-fluoro-N-(4-methoxybenzyl)-3-nitropyridin-2-amine (Preparation 70, 200.0 mg, 0.642 mmol) in DMSO (6.0 mL) was added DIPEA (248.8 mg, 1.92 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (149.8 mg, 0.706 mmol), and the reaction was stirred at 50 °C for 20 h. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE / EtOAc=20 / 1 to 10 / 1) to give tert-butyl 3-(5-fluoro-2-((4-methoxybenzyl)amino)-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (850.0 mg, 66.4% yield). 1 H NMR (400 MHz, CDCl3) δ: 8.37 (d, 1H), 7.15 (d, 2H), 6.80 (d, 2H), 5.27 (s, 2H), 4.30-4.20 (m, 2H), 3.76 (s, 3H), 3.38-3.36 (m, 2H), 2.98-2.96 (m, 2H), 1.93-1.90 (m, 4H), 1.49 (s, 9H).

[0185] Preparation 72 tert-Butyl 3-(2,3-diamino-5-fluoropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(5-fluoro-2-((4-methoxybenzyl)amino)-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 71, 290.0 mg, 0.595 mmol) in EtOH (10.0 mL), Pd / C (30.0 mg, 10% purity) was added, and the reaction was stirred at 50 °C under 50 psi of H for 20 hours. The mixture was filtered, and the filter cake was washed several times with EtOH. The filtrate was evaporated under reduced pressure to give tert-butyl 3-(2,3-diamino-5-fluoropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown solid (190.0 mg, 94.7% yield). LCMS m / z = 338.2 [M+H] + .

[0186] Preparation 73 tert-Butyl 3-(6-fluoro-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(2,3-diamino-5-fluoropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 72, 50.0 mg, 0.148 mmol) in DMF (1.0 mL) was added TsOH (7.7 mg, 0.044 mmol) and 3-fluoro-1-methyl-1H-pyrazole-4-carbaldehyde (38.0 mg, 0.296 mmol) and the reaction was stirred at 50° C. for 20 h. The mixture was concentrated in vacuo, and the crude was purified by preparative TLC (DCM / MeOH=10 / 1) to give tert-butyl 3-(6-fluoro-2-(3-fluoro-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 brown oil (25 mg, 37.9% yield). LCMS m / z=446.2 [M+H] + .

[0187] Preparation 74 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine hydrochloride [ka] 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 56, 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 as a yellow solid (70.0 mg, 87.3% yield). LCMS m / z=310.2 [M+H] + .

[0188] Preparations 75-84 Following a procedure similar to that described in Preparation 74, the compounds in the following table were prepared from the corresponding Boc-protected imidazo[4,5-b]pyridines (SM). [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0189] Preparation 85 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(tetrahydrofuran-3-yl)-3H-imidazo[4,5-b]pyridine 1,1,1-trifluoroacetate [ka] TFA (745.0 mg, 6.53 mmol) was added dropwise to a solution of tert-butyl 3-(2-(tetrahydrofuran-3-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 65, 40.0 mg, 0.10 mmol) in DCM (2.0 mL), and the reaction was stirred at 25° C. for 1 hour. The reaction was evaporated under reduced pressure to give 7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(tetrahydrofuran-3-yl)-3H-imidazo[4,5-b]pyridine 1,1,1-trifluoroacetate as a yellow solid (41.2 mg, crude). LCMS m / z=300.2 [M+H] + .

[0190] Preparation 86 2-Bromo-7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine [ka] To a solution of 2-bromo-7-chloro-3H-imidazolo[4,5-b]pyridine (200 mg, 0.860 mmol) in THF (5.0 mL) was added NaH (34.4 mg, 0.860 mmol, 60% purity) and SEMCl (157.8 mg, 0.946 mmol), and the reaction was stirred at 20 °C for 2 h. The reaction was quenched with aqueous NH4Cl (2.0 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1 to 3 / 1) to give 2-bromo-7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine as a yellow solid (150 mg, 48.1% yield). 1H NMR (400 MHz, CDCl3) δ: 7.88 (d, 1H), 7.22 (d, 1H), 5.96 (s, 2H), 3.69-3.67 (m, 2H), 1.01-0.96 (m, 2H), -0.01--0.02 (m, 9H).

[0191] Preparation 87 4-(7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)morpholine [ka] A mixture of 2-bromo-7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (Preparation 86, 135 mg, 0.372 mmol), morpholine (32.4 mg, 0.372 mmol), and DIPEA (48.1 mg, 372 mmol) in n-BuOH (5 mL) was stirred at 50° C. for 12 hours. The reaction was concentrated in vacuo, and the residue was purified by chromatography on silica gel (PE / EtOAc = 5 / 1 to 3 / 1) to give 4-(7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)morpholine as a yellow solid (52 mg, 37.9% yield). 1 H NMR (400 MHz, CDCl3) δ: 8.00-7.93 (m, 1H), 7.10 (d, 1H), 5.42 (s, 2H), 3.85-3.79 (m, 6H), 3.63-3.62 (m, 4H), 0.91-0.90 (m, 2H), -0.03--0.09 (m, 9H).

[0192] Preparation 88 tert-Butyl 3-(2-morpholino-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of 4-(7-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yl)morpholine (Preparation 87, 42 mg, 0.114 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.2 mg, 0.114 mmol), Ruphos Pd G3 (9.5 mg, 0.0114 mmol), and K2CO3 (31.5 mg, 0.228 mmol) in toluene (4 mL) was stirred at 120 °C under N2 and microwave irradiation for 1.5 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 5 / 1) to give tert-butyl 3-(2-morpholino-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (25 mg, 40.3% yield). LCMS m / z = 545.3 [M+H] + .

[0193] Preparation 89 4-(7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)morpholine hydrochloride [ka] A mixture of tert-butyl 3-(2-morpholino-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 88, 25 mg, 0.046 mmol) in HCl / MeOH (4 M, 3 mL) was stirred at 30° C. for 2 hours. The mixture was evaporated under reduced pressure to give 4-(7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)morpholine hydrochloride as a white solid (13 mg, crude). LCMS m / z=315.2 [M+H] + .

[0194] Preparation 90 (3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone [ka] To a solution of 4-chloro-3-nitropyridin-2-amine (80.0 mg, 0.461 mmol) in DMF (3.0 mL) was added DIPEA (119.1 mg, 0.922 mmol) and 8-cyclopropanecarbonyl-3,8-diazabicyclo[3.2.1]octane hydrochloride (99.9 mg, 0.461 mmol), and the reaction was stirred at 50 °C for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1 to 0 / 1) to give (3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone as a yellow oil (120.0 mg, 82.0% yield). LCMS m / z = 318.2 [M+H] + .

[0195] Preparation 91 (3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] To a solution of tert-butyl 8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Preparation 9, 150.0 mg, 0.639 mmol) in DMF (2.0 mL) was added DIPEA (101 mg, 0.783 mmol) and 4-chloro-3-nitropyridin-2-amine (110.9 mg, 0.639 mmol), and the reaction was stirred at 90 °C for 4 h. The cooled mixture was diluted with water (8.0 mL) and extracted with EtOAc (10.0 mL × 4), and the combined organic phases were washed with brine (8.0 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (EtOAc) to give (3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone as a yellow oil (107.0 mg, 49.9% yield). 1 H NMR (400 MHz, MeOH-d4) δ: 7.82-7.80 (m, 1H), 6.51-6.49 (m, 1H), 4.73-4.60 (m, 5H), 3.28-3.17 (m, 2H), 2.50-2.48 (m, 1H), 2.05-1.90 (m, 4H), 1.29-1.22 (m, 2H).

[0196] Preparation 92 Cyclopropyl(3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of (3-(2-amino-3-nitropyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 90, 120.0 mg, 0.378 mmol) in MeOH (8.0 mL) was added Pd / C (30.0 mg, 0.028 mmol, 10% purity) and the reaction was stirred at 25° C. for 1 h. The mixture was filtered and the filter cake was washed with MeOH. The filtrate was evaporated under reduced pressure to give cyclopropyl(3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow oil (85.0 mg, crude). LCMS m / z=288.2 [M+H] + .

[0197] Preparation 93 (3-(2,3-Diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] (3-(2,3-Diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 91) following the procedure described in Preparation 92 gave (3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone as a brown solid. LCMS m / z=306.2 [M+H] + .

[0198] Preparation 94 tert-Butyl 2-(7-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)morpholine-4-carboxylate [ka] To a solution of (3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 93, 70.0 mg, 0.229 mmol) and tert-butyl 2-formylmorpholine-4-carboxylate (49.4 mg, 0.229 mmol) in DMF (3.0 mL) was added TsOH (11.8 mg, 0.069 mmol) and the reaction was stirred at 80° C. for 1 h. The cooled mixture was concentrated in vacuo and the crude was purified by preparative TLC (DCM / MeOH=10 / 1) to give tert-butyl 2-(7-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)morpholine-4-carboxylate as a purple solid (100.0 mg, crude). LCMS m / z=501.2 [M+H] + .

[0199] Preparation 95 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine [ka] 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 2 M 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 as a white solid (45.6 g, 91.0% yield). 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).

[0200] Preparation 96 4-chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine [ka] To a solution of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 95, 10 g, 32.5 mmol) in THF (200 mL) at −78 °C, LDA (2 M, 24.37 mL) was added dropwise under N , and the mixture was stirred at −78 °C for 1 h. A solution of I (10.7 g, 42.2 mmol) in THF (50 mL) was added dropwise, and the mixture was stirred at −78 °C for 1 h. The reaction was quenched using saturated aqueous NH Cl (5.0 mL), diluted with HO (10.0 mL), and extracted with EtOAc (20 mL × 3). The combined organic extracts were washed with brine (10.0 mL), dried over Na SO , filtered, and the filtrate was concentrated in vacuo. The crude material was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 3 / 1) to give 4-chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid (6.0 g, 42.6% yield). LCMS m / z = 433.9 [M+H] + .

[0201] Preparation 97 tert-Butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 6.59 mmol) in DMF (30 mL) was added DIPEA (2.6 g, 19.77 mmol) and 4-chloro-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 96, 3.7 g, 8.57 mmol), and the reaction was stirred for 2 h at 30° C. The reaction was diluted with HO (30.0 mL) and extracted with EtOAc (30 mL × 4), and the combined organic extracts were washed with brine (120 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 3 / 1) to give tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (4.0 g, quantitative yield). 1 H NMR (500 MHz, CDCl3) δ: 8.34 (s, 1H), 8.10 (d, 2H), 7.29 (d, 2H), 6.93 (s, 1H), 4.32-4.26 (m, 4H), 3.39-3.31 (m, 2H), 2.38 (s, 3H), 1.97-1.93 (m, 2H), 1.71-1.68 (m, 2H), 1.48 (s, 9H).

[0202] Preparation 98 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride [ka] To a solution of tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97, 732.0 mg, 1.13 mmol) in DCM (10.0 mL) was added HCl / dioxane (4 M, 7.3 mL) and the reaction was stirred at 25 °C for 1 h. The mixture was evaporated under reduced pressure to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride as a yellow solid (732.0 mg, crude). LCMS m / z = 510.1 [M+H] + .

[0203] Preparation 99 Cyclopropyl(3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (Preparation 98, 732.0 mg, crude) in DCM (5.0 mL) was added cyclopropanecarbonyl chloride (287.3 mg, 2.75 mmol) and DIPEA (710.3 mg, 5.50 mmol) and the reaction was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1 to 1 / 1) to give cyclopropyl(3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow oil (290.0 mg, 27.4% yield). LCMS m / z = 578.5 [M+H] + .

[0204] Preparation 100 Cyclopropyl(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of cyclopropyl(3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 99, 140.0 mg, 0.242 mmol) in DMSO (3.0 mL) was added 1-(difluoromethyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (88.8 mg, 0.364 mmol), KCO (67.0 mg, 0.485 mmol), Pd(dppf)Cl (17.7 mg, 0.024 mmol), and the mixture was stirred at 90 °C under N for 1 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1 to 1 / 1) to give cyclopropyl(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow gum (93.0 mg, 67.6% yield). LCMS m / z = 568.4 [M+H] + .

[0205] Preparation 101 Cyclopropyl(3-(6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Following the procedure described in Preparation 100, cyclopropyl(3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 99) and 1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave cyclopropyl(3-(6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, 93.2 mg, 72.3% yield, as a colorless oil. LCMS m / z=532.2 [M+H] + .

[0206] Preparation 102 tert-Butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97, 200.0 mg, 0.328 mmol) in DMSO (2.0 mL) was added 1-(difluoromethyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (96.1 mg, 0.394 mmol), KCO (90.7 mg, 0.656 mmol), and Pd(dppf)Cl (24.0 mg, 0.033 mmol), and the reaction was stirred at 85 °C for 1 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown oil (200.0 mg, crude), LCMS m / z=600.2 [M+H] + .

[0207] Preparations 103-109 Following a procedure similar to that described in Preparation 102, the compounds in the following table were prepared from tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97) and the appropriate boronic acid or boronic ester (RBY). [Table 6-1] [Table 6-2] [Table 6-3]

[0208] Preparation 110 tert-Butyl 3-(6-(5-fluoropyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a mixture of tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97, 27.7 mg, 0.197 mmol), (5-fluoropyridin-3-yl)boronic acid (100.0 mg, 0.164 mmol), and KPO (104.5 mg, 0.492 mmol) in dioxane (5.0 mL) and water (0.5 mL), Pd(dppf)Cl (12.0 mg, 0.016 mmol) was added and the reaction was stirred at 85 °C under N for 1 h. The cooled mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic phase was washed with brine (45 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 3 / 1) to give tert-butyl 3-(6-(5-fluoropyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil (92.7 mg, 97.6% yield). LCMS m / z = 579.4 [M+H] + .

[0209] Preparation 111 tert-Butyl 3-(6-(2-methylpyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97, 200.0 mg, 0.328 mmol), (2-methylpyridin-4-yl)boronic acid (67.4 mg, 0.492 mmol), CsCO (213.8 mg, 0.656 mmol), and Pd(OAc) (7.4 mg, 0.033 mmol) in dioxane (5.0 mL) and HO (0.5 mL) was stirred at 90 °C under N for 12 h. The cooled mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give tert-butyl 3-(6-(2-methylpyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown oil (118.0 mg, crude). LCMS m / z = 575.3 [M+H] + .

[0210] Preparation 112 tert-Butyl (3-(6-(3-fluoropyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a 0° C. solution of 2,2,6,6-tetramethylpiperidine (509.9 mg, 3.61 mmol) in THF (12.0 mL) was added n-BuLi (2.5 M, 1.44 mL) and the solution was stirred at 0° C. for 20 min, then cooled to −78° C. A solution of 3-fluoropyridine (318.6 mg, 3.28 mmol) in THF (3.0 mL) was added slowly and the mixture was stirred for 1 h, then a solution of ZnBr (960.7 mg, 4.27 mmol) in THF (9.0 mL) was added and the reaction was allowed to warm to 20° C. over 2 h. tert-Butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97, 200.0 mg, 0.328 mmol) and Pd(PPh3)4 (37.9 mg, 0.033 mmol) were added, and the reaction was heated to 60 °C and stirred for 1 h. Pd(Amphos)Cl2 (23.2 mg, 0.033 mmol) was added, and the mixture was stirred at 60 °C for 18 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL × 3), and the combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 2 / 1) to give tert-butyl (3-(6-(3-fluoropyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) as a pale yellow oil (83.5 mg, 44.0% yield). LCMS m / z = 579.3 [M+H] + .

[0211] Preparation 113 tert-Butyl 3-(6-(pyridazin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97, 148.6 mg, 0.244 mmol), 4-(tributylstannyl)pyridazine (90.0 mg, 0.244 mmol), and Pd(PPh3)4 (56.4 mg, 0.049 mmol) in THF (3.0 mL) was stirred at 110 °C under microwave irradiation for 2 h. The cooled mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1 to 1 / 4) to give tert-butyl 3-(6-(pyridazin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (82.0 mg, 59.9% yield). LCMS m / z = 562.2 [M+H] + .

[0212] Preparation 114 tert-Butyl (3-(6-(2-cyanopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) [ka] To a solution of tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97, 100.0 mg, 0.164 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (45.3 mg, 0.197 mmol) in DMSO (5.0 mL) was added KCO (68.0 mg, 0.492 mmol) and Pd(dppf)Cl (12.0 mg, 0.016 mmol) and the reaction was stirred at 85 °C for 16 h. The cooled mixture was diluted with water (15.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phase was washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE / EtOAc = 3 / 1 to 4 / 3) to give tert-butyl 3-(6-(2-cyanopyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (50.0 mg, 70.6% yield). LCMS m / z = 432.3 [M+H] + .

[0213] Preparation 115 tert-Butyl (3-(6-(6-cyanopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Following the procedure described in Preparation 114, tert-butyl 3-(6-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 97) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile gave tert-butyl (3-(6-(6-cyanopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 63.9 mg, 90.3% yield, as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ: 9.15 (s, 1H), 8.36 (s, 1H), 8.16-8.14 (m, 1H), 7.80 (d, 1H), 6.99 (s, 1H), 4.50-4.49 (m, 4H), 3.56-3.47 (m, 2H), 2.03-2.01 (m, 2H), 1.81-1.79 (m, 2H), 1.52 (s, 9H).

[0214] Preparation 116 tert-Butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 102, 200.0 mg, 0.333 mmol) in MeOH (5.0 mL) was added KCO (138.3 mg, 1.00 mmol) and the reaction was stirred at 50° C. for 1 h. The mixture was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1 to 0 / 1) to give tert-butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (95.0 mg, 63.9% yield). LCMS m / z = 446.1 [M+H] + .

[0215] Preparations 117-125 Following a procedure similar to that described in Preparation 116, the compounds in the following table were prepared from the appropriate tosyl-protected pyrrolo[2,3-d]pyrimidine (SM). [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0216] Preparation 126 tert-Butyl 3-(6-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl (3-(6-(3-fluoropyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 112, 83.5 mg, 0.144 mmol) in MeOH (3.0 mL) was added KCO (59.8 mg, 0.433 mmol) and the reaction was stirred at 20 °C for 3 h. The mixture was diluted with water (8 mL) and EtOAc (10 mL) was added. × 4), and the combined organic phases were washed with brine (8 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude was purified by preparative TLC (PE / EtOAc = 1 / 3) to give tert-butyl 3-(6-(3-fluoropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid (34.9 mg, 57.0% yield). LCMS m / z = 425.2 [M+H] + .

[0217] Preparation 127 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 [ka] To a solution of 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 (Preparation 103, 316.7 mg, 0.562 mmol) in MeOH (10.0 mL), KCO (310.6 mg, 2.25 mmol) was added and the reaction was stirred at 25 °C for 16 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (15.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phase was washed with brine (60.0 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give tert-butyl 3-(6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (150.0 mg, 65.2% yield). LCMS m / z=410.2 [M+H] + .

[0218] Preparation 128 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride [ka] To a solution of tert-butyl 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 116, 95.0 mg, 0.213 mmol) in DCM (5.0 mL) was added HCl / EtOAc (4 M, 5.0 mL) and the reaction was stirred at 20° C. for 30 minutes. The mixture was evaporated under reduced pressure to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride as a yellow solid (90.0 mg, crude).

[0219] Preparations 129-141 Following a procedure similar to that described in Preparation 128, the compounds in the following table were prepared from the appropriate Boc-protected pyrrolo[2,3-d]pyrimidine (SM). [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5]

[0220] Preparation 142 4-Bromo-5-fluoro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.33 mmol), DMAP (28.4 mg, 0.233 mmol), and TEA (588 mg, 5.81 mmol) in DCM (5 mL) was added benzenesulfonyl chloride (411 mg, 2.33 mmol), and the reaction was stirred for 2 h at 15° C. The mixture was concentrated under reduced pressure to give a residue that was purified by column chromatography (15–25% EtOAc / PE) to give 4-bromo-5-fluoro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a white solid (720 mg, 87%). 1 H NMR (500 MHz, CDCl3) δ: 8.25 (s, 1H), 8.16-8.18 (m, 2H), 7.84 (d, 1H), 7.59-7.61 (m, 1H), 7.49-7.52 (m, 2H), 6.65 (d, 1H).

[0221] Preparation 143 4-Bromo-5-fluoro-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-bromo-5-fluoro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (Preparation 142, 750 mg, 2.11 mmol) in THF (5 mL) was added LDA (2 M, 2.11 mL) dropwise over 30 min at −78° C. To this was added a solution of I (1.1 g, 4.22 mmol) in THF (5 mL) dropwise, and the mixture was stirred at −78° C. for 2 h. The reaction was quenched with aqueous NH4Cl (5 mL) and extracted with EtOAc (10 mL × 2). The combined organics were washed with brine (5 mL × 2), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by column chromatography (15-25% EtOAc / PE) to give 4-bromo-5-fluoro-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a white solid (650 mg, 64%). 1 H NMR (400 MHz, CDCl3) δ: 8.18 (s, 1H), 7.59-7.63 (m, 2H), 7.51-7.53 (m, 3H), 7.04 (s, 1H).

[0222] Preparation 144 4-Bromo-5-fluoro-2-(2-methoxypyridin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine [ka] A mixture of 4-bromo-5-fluoro-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (Preparation 143, 500 mg, 1.04 mmol), (2-methoxypyridin-4-yl)boronic acid (159 mg, 1.04 mmol), Pd(dppf)Cl (76.1 mg, 0.104 mmol), and KPO (441 mg, 2.08 mmol) in dioxane (5 mL) and HO (1 mL) was stirred at 30 °C under N for 2 h. The reaction was evaporated to dryness in vacuo, and the residue was purified by chromatography on silica gel (15-25% EtOAc / PE) to give 4-bromo-5-fluoro-2-(2-methoxypyridin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a white solid (260 mg, 54%). 1 H NMR (500 MHz, CDCl3) δ: 8.31 (s, 1H), 8.27 (d, 1H), 7.93-7.95 (m, 2H), 7.56-7.58 (m, 1H), 7.44-7.47 (m, 2H), 7.07 (dd, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 4.03 (s, 3H).

[0223] Preparation 145 tert-Butyl 3-(5-fluoro-2-(2-methoxypyridin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of 4-bromo-5-fluoro-2-(2-methoxypyridin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (Preparation 144, 260 mg, 0.562 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (119 mg, 0.562 mmol), CsCO (366 mg, 1.12 mmol), and Ruphos Pd G (47.0 mg, 0.056 mmol) in toluene (3 mL) was stirred at 110 °C under N in a microwave for 2 h. The reaction was evaporated to dryness in vacuo and the residue was purified by chromatography on silica gel (20-50% EtOAc / PE) to give tert-butyl 3-(5-fluoro-2-(2-methoxypyridin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (145 mg, 43%). 1 H NMR (400 MHz, CDCl3) δ: 8.23 ​​(d, 1H), 8.13 (d, 1H), 7.94 (d, 2H), 7.53-7.55 (m, 1H), 7.41-7.45 (m, 2H), 7.05-7.07 (m, 1H), 6.88 (s, 1H), 6.64 (s, 1H), 4.25-4.31 (m, 2H), 4.02 (s, 3H), 3.46-3.47 (m, 4H), 1.92-1.93 (m, 4H), 1.56 (s, 9H).

[0224] Preparation 146 tert-Butyl 3-(5-fluoro-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(5-fluoro-2-(2-methoxypyridin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 145, 145 mg, 0.244 mmol) in MeOH (5 mL) was added 5N NaOH (19.5 mg, 0.488 mmol) and the resulting mixture was stirred at 50° C. for 2 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by chromatography on silica gel (50–75% EtOAc / PE) to give tert-butyl 3-(5-fluoro-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (82 mg, 74%). 1 H NMR (400 MHz, CDCl3) δ: 10.76 (br s, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 7.20 (d, 1H), 7.05 (s, 1H), 6.98 (s, 1H), 4.32-4.33 (m, 2H), 4.02 (s, 3H), 3.52-3.72 (m, 4H), 2.02-2.05 (m, 4H), 1.52 (s, 9H).

[0225] Preparation 147 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride [ka] A mixture of tert-butyl 3-(5-fluoro-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 146, 82 mg, 0.181 mmol) in HCl / dioxane (4 M, 3 mL) was stirred at 15° C. for 2 hours. The reaction was concentrated under reduced pressure to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride as a yellow solid (55 mg, 78%), which was used without further purification. LCMS m / z=354.4 [M+H] + .

[0226] Preparation 148 4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine Sch15-04 [ka] To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 32.77 mmol) in DMF (80.0 mL) was added NaH (1.75 g, 60% purity, 39.32 mmol) at 0 °C. The mixture was stirred at 20 °C for 30 min, and then TsCl (9.4 g, 49.16 mmol) was added. The reaction was stirred at 20 °C for 1 h, then quenched with water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 5 / 1) to give 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid (6.1 g, 60.7% yield). 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).

[0227] Preparation 149 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 148, 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 min. I2 (2.0 g, 7.82 mmol) was added and the reaction was stirred at 20 °C for 1 h. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 5 / 1) to give 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a white solid (800.0 mg, 28.4% yield). 1 H NMR (400 MHz, 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).

[0228] Preparation 150 4-chloro-1-tosyl-2-(tributylstannyl)-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 149, 2.0 g, 6.52 mmol) in THF (15.0 mL) was added LDA (2 M, 3.91 mL) at -70 °C and the solution was stirred for 30 min. BuSnCl (1.59 g, 4.89 mmol) was added and the reaction was warmed to 25 °C and stirred for 1 h. The mixture was quenched with aqueous KF (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE / EtOAc=20 / 1 to 5 / 1) to give 4-chloro-1-tosyl-2-(tributylstannyl)-1H-pyrrolo[2,3-b]pyridine as a colorless oil (3.2 g, 82.4% yield). 1 H NMR (500 MHz, CDCl3) δ: 8.18 (d, 1H), 7.98 (d, 2H), 7.25 (d, 2H), 7.11 (d, 1H), 6.77 (s, 1H), 2.37 (s, 3H), 1.61-1.58 (m, 6H), 1.41-1.37 (m, 6H), 1.29-1.25 (m, 6H), 0.94-0.90 (m, 9H).

[0229] Preparation 151 4-chloro-2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-1-tosyl-2-(tributylstannyl)-1H-pyrrolo[2,3-b]pyridine (Preparation 150, 500.0 mg, 0.839 mmol) in toluene (10.0 mL) was added 4-bromo-5-fluoro-1-methyl-1H-pyrazole (180.3 mg, 1.01 mmol) and PdCl(PPh) (58.9 mg, 0.084 mmol), and the reaction was stirred at 120 °C for 18 h. The cooled mixture was concentrated in vacuo, and the crude material was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 2 / 1) to give 4-chloro-2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a yellow gum (52.0 mg, 15.3% yield). LCMS m / z=405.0[M+H] + .

[0230] Preparation 152 4-Bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] LDA (2 M, 140.7 mL) was added dropwise to a −78 °C mixture of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (52.0 g, 187.57 mmol) in THF (600.0 mL) under N2, and the mixture was stirred for 1.5 h. A solution of (PhSO2)2NF (88.72 g, 281.35 mmol) in THF (100.0 mL) was added dropwise, and the reaction was stirred at −78 °C for 1 h. The mixture was quenched with NH4Cl (sat, 100 mL) and extracted with EtOAc (50 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with PE to give 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a yellow oil (5.10 g, crude).

[0231] Preparation 153 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] n-BuLi (2.5 M, 4.9 mL) was added dropwise to a −78° C. mixture of 4-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Preparation 152, 4.8 g, 8.13 mmol) in THF (60.0 mL) under N2, and the solution was stirred for 30 min. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.03 g, 16.26 mmol) was added dropwise, and the reaction was stirred at 20° C. for 12 h. The mixture was quenched with NH4Cl (saturated, 30 mL), extracted with EtOAc (30 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc=10 / 1) to give 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a yellow oil (940.0 mg, yield 33.8%). 1 H NMR (400 MHz, CDCl3) δ: 7.62 (d, 1H), 5.34 (s, 2H), 3.61 (t, 2H), 1.32 (s, 12H), 0.81 (t, 2H), -0.02 (s, 9H).

[0232] Preparation 154 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 149, 500.0 mg, 1.16 mmol) in dioxane (3.0 mL) and HO (0.3 mL) was added 1-methylpyrazole-4-boronic acid pinacol ester (289.6 mg, 1.39 mmol), KCO (320.7 mg, 2.32 mmol), Pd(dppf)Cl (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 column chromatography on silica gel (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 as a yellow solid (287.0 mg, yield 64.0%). 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).

[0233] Preparations 155-159 Following a procedure similar to that described in Preparation 154, prepare the compounds in the following table from 4-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 149) and the appropriate boronic acid or boronic ester (R-BY). [Table 9-1] [Table 9-2]

[0234] Preparation 160 4-chloro-2-(3-fluoro-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] A solution of 4-chloro-2-(3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 155, 50.0 mg, 0.096 mmol) in TFA (1.0 mL) and DCM (5.0 mL) was stirred at 30 °C for 1 h. The mixture was concentrated in vacuo, the residue was dissolved in MeOH (3 mL), NH 3 .HO was added until pH 8-9, and the mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc = 3 / 1) to give 4-chloro-2-(3-fluoro-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a colorless oil (25.0 mg, crude). 1 H NMR (500 MHz, CDCl3) δ: 9.85 (br s, 1H), 8.36 (d, 1H), 7.82-7.79 (m, 3H), 7.23-7.19 (m, 3H), 6.72 (s, 1H), 2.35 (s, 3H).

[0235] Preparation 161 4-chloro-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ka] NaH (81.6 mg, 2.04 mmol, 60% purity) was added to a 0° C. mixture of 4-chloro-2-(3-fluoro-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 160, 400.0 mg, 1.02 mmol) in THF (15.0 mL), the solution was stirred for 10 min, then CHI (217.2 mg, 1.53 mmol) was added and the reaction was stirred for 1 h at 20° C. The mixture was quenched with NH4Cl (sat. 5 mL), extracted with EtOAc (10 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc=3 / 1) to give 4-chloro-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (150.0 mg, crude).

[0236] Preparation 162 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 [ka] To a solution of 4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Preparation 154, 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 CsCO3 (421.1 mg, 1.29 mmol), and the reaction was stirred at 110 °C for 2 h under microwave irradiation. The mixture was poured into water (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1 to 1 / 2) to give tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow gum (302.0 mg, 83.1% yield). LCMS m / z = 563.7 [M+H] + .

[0237] Preparations 163-168 Following a procedure similar to that described in Preparation 162, the compounds in the following table were prepared from the appropriate chloropyrrolo[2,3-b]pyridine and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [Table 10-1] [Table 10-2] [Table 10-3]

[0238] Preparation 169 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 [ka] 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 162, 280.0 mg, 0.498 mmol) in MeOH (4.0 mL) was added NaOH (5 N, 0.1 mL) and the reaction 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 give tert-butyl 3-(2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow gum (215.0 mg, crude). LCMS m / z=409.3[M+H] + .

[0239] Preparation 170 tert-Butyl 3-(2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(2-(5-fluoro-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 164, 190.0 mg, 0.327 mmol) in MeOH (10.0 mL) was added NaOH (5 M, 0.327 mL) and the reaction was stirred at 50° C. for 6 hours. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude was purified by preparative TLC (EtOAc) to give tert-butyl 3-(2-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil (110.0 mg, 78.8% yield). LCMS m / z=427.3 [M+H] + .

[0240] Preparations 171-174 Following a procedure similar to that described in Preparation 170, the compounds in the following table were prepared from the appropriate tosyl-protected pyrrolo[2,3-d]pyridine. [Table 11-1] [Table 11-2]

[0241] Preparation 175 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride [ka] 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 162, 200.0 mg, 0.355 mmol) in DCM (5.0 mL) was added 4 M HCl / dioxane (5.0 mL) and the reaction was stirred for 30 minutes at 25° C. 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)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride as a yellow oil (180.0 mg, crude). 1 H NMR (500MHz, DMSO-d6) δ: 9.96 (br s, 1H), 9.73 (s, 1H), 8.12 (d, 1H), 7.94 (s, 1H), 7.62-7.58 (m, 3H), 7.37-7.32 (m, 2H), 7.02 (s, 1H), 6.91 (d, 1H), 4.03-3.92 (m, 2H), 3.64 (s, 3H), 3.61-3.59 (m, 2H), 3.50-3.43 (m, 2H), 2.35 (s, 3H), 2.02-1.89 (m, 4H).

[0242] Preparation 176 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride [ka] 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride was obtained from tert-butyl 3-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 163) according to the procedure described in Preparation 175, as a yellow oil, 120 mg. LCMS m / z=499.2 [M+H] + .

[0243] Preparation 177 Cyclopropyl(3-(2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 175, 180.0 mg, 0.361 mmol) in DCM (5.0 mL) was added TEA (73.0 mg, 0.721 mmol) and cyclopropanecarbonyl chloride (56.6 mg, 0.541 mmol), and the reaction was stirred for 2 h at 25° C. The mixture was poured into water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give cyclopropyl(3-(2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow oil (180.0 mg, crude). LCMS m / z=531.2 [M+H] + .

[0244] Preparation 178 Cyclopropyl(3-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Following the procedure described in Preparation 177, 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 176) gave cyclopropyl(3-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow oil, 90 mg, crude. LCMS m / z=567.3 [M+H] + .

[0245] Preparation 179 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride [ka] 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 169, 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 as a yellow solid (173.0 mg, 95.3% yield). LCMS m / z=309.1 [M+H] + .

[0246] Preparation 180~184 Following a procedure similar to that described in Preparation 179, the compounds in the following table were prepared from the appropriate Boc-protected pyrrolo[2,3-b]pyridine. [Table 12-1] [Table 12-2] Preparation 185 tert-Butyl 3-(3-bromo-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 [ka] 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 162, 650.0 mg, 1.16 mmol) in DCM (20.0 mL) was added NBS (215.9 mg, 1.21 mmol) and the mixture was stirred at 20° C. for 3 h. The mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 2 / 1) to give tert-butyl 3-(3-bromo-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 as a white oil (700.0 mg, yield 94.5%). 1H NMR (500 MHz, CDCl3) δ: 8.28 (d, 1H), 7.76 (d, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.19 (d, 1H), 6.76 (d, 1H), 4.35-4.25 (m, 2H), 4.03 (s, 3H), 3.45-3.36 (m, 2H), 3.04-2.95 (m, 2H), 2.37 (s, 3H), 2.35-2.22 (m, 2H), 1.95-1.86 (m, 2H), 1.47 (s, 9H).

[0247] Preparation 186 tert-Butyl 3-(3-cyano-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 [ka] To a solution of tert-butyl 3-(3-bromo-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 185, 200.0 mg, 0.312 mmol) in DMF (3.0 mL) was added Zn(CN) (146.4 mg, 1.25 mmol), Pd(dba) (28.6 mg, 0.031 mmol), and dppf (34.6 mg, 0.062 mmol) under N, and the reaction was stirred at 150 °C under microwave irradiation for 2 h. The cooled reaction was diluted with HO (10.0 mL), extracted with EtOAc (2 × 10.0 mL), and washed with brine (2 × 10.0 mL). The combined organic phase was dried over NaSO, concentrated under reduced pressure, and purified by column chromatography (PE / EtOAc = 15 / 1 to 1 / 1) to give tert-butyl 3-(3-cyano-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 as a yellow solid (60.0 mg, 32.8% yield). 1 H NMR (400 MHz, CDCl3) δ: 8.29 (d, 1H), 7.88-7.82 (m, 3H), 7.76 (s, 1H), 7.23 (d, 2H), 6.71 (d, 1H), 4.38-4.31 (m, 2H), 4.04 (s, 3H), 3.56-3.41 (m, 2H), 3.21-2.95 (m, 2H), 2.37 (s, 3H), 2.36-2.15 (m, 2H), 1.95-1.88 (m, 2H), 1.46 (s, 9H).

[0248] Preparation 187 tert-Butyl 3-(3-methyl-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 [ka] To a solution of tert-butyl 3-(3-bromo-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 185, 600.0 mg, 0.935 mmol) in dioxane (4.0 mL) and HO (0.4 mL), methylboronic acid (67.2 mg, 1.12 mmol), KCO (258.5 mg, 1.87 mmol), and Pd(dppf)Cl (68.4 mg, 0.094 mmol) were added, and the reaction was stirred at 100 °C under N for 3 h. The cooled mixture was quenched with water (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a mixture of tert-butyl 3-(3-methyl-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 and 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 (450 mg) as a yellow oil, which was used without further purification. LCMS m / z=563.2, 577.2 [M+H] + .

[0249] Preparation 188 tert-Butyl 3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] A mixture of tert-butyl 3-(3-methyl-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, 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 187, 400 mg), and 5 N NaOH (109.2 mg, 2.73 mmol) in MeOH (10.0 mL) was stirred for 14 hours at 50° C. The mixture was concentrated in vacuo, treated with HO, and extracted with EtOAc (3×30 mL). The organic layer was evaporated under reduced pressure to give a mixture of tert-butyl 3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 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 as a brown solid (280.0 mg, crude). LCMS m / z=409.2, 423.3 [M+H] + .

[0250] Preparation 189 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride [ka] To a solution of tert-butyl 3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 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 188, 280.0 mg, crude) in DCM (20.0 mL) was added HCl / EtOAc (4 M, 3.0 mL) and the reaction was stirred at 20° C. for 30 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC-9 (gradient 0-25%) to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride as a white solid (100 mg). LCMS m / z=323.2 [M+H] + .

[0251] Preparation 190 2-Bromo-8-hydroxyimidazo[1,2-b]pyridazine [ka] 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 h. The cooled mixture was evaporated under reduced pressure, and the residue was purified by preparative HPLC-8 (gradient 17-47%) to give 2-bromo-8-hydroxyimidazo[1,2-b]pyridazine as a white solid (60.0 mg, 24.1% yield). LCMS m / z = 214.2, 216.2 [M+H] + .

[0252] Preparation 191 2-Bromo-8-chloroimidazo[1,2-b]pyridazine [ka] 2-Bromo-8-hydroxyimidazo[1,2-b]pyridazine (Preparation 190, 20.0 mg, 0.093 mmol) and DIPEA (36.2 mg, 0.28 mmol) were slowly added to POCl (3.29 g, 21.46 mmol), and the reaction was stirred at 120 °C for 3 h. Additional POCl (10.0 mL) was added, and the reaction was stirred at 120 °C for an additional 15 h. The cooled reaction was concentrated in vacuo, quenched with HO (1.0 mL), and then purified by preparative HPLC-8 (gradient 25-55%) to give 2-bromo-8-chloroimidazo[1,2-b]pyridazine as a yellow solid (21.0 mg, 96.7% yield). LCMS m / z = 234.0 [M+H] + .

[0253] Preparation 192 tert-Butyl 3-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine (Preparation 191, 21.0 mg, 0.090 mmol) in n-BuOH (3.0 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (24.9 mg, 0.117 mmol) and DIPEA (46.7 mg, 0.361 mmol), and the mixture was stirred under microwave irradiation at 130 °C for 1 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1 to 3 / 1) to give tert-butyl 3-(2-bromoimidazo[1,2-b]pyridazin-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] + .

[0254] Preparation 193 tert-Butyl 3-(2-bromo-7-fluoroimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 192, 155 mg, 0.380 mmol) in MeCN (3 mL) was added Select-F (201.7 mg, 0.569 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (5:1 PE / EtOAc) to give tert-butyl 3-(2-bromo-7-fluoroimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (50 mg, 31%). LCMS m / z = 428.1 [M+H] + .

[0255] Preparation 194 tert-Butyl 3-(2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 192, 20.0 mg, 0.049 mmol) in dioxane (3.0 mL) and water (0.3 mL) was added (2-methoxypyridin-4-yl)boronic acid (7.5 mg, 0.049 mmol), KCO (13.5 mg, 0.098 mmol), and Pd(dppf)Cl (3.6 mg, 0.005 mmol) and the reaction was stirred at 100 °C under N for 15 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1 to 3 / 1) to give tert-butyl 3-(2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a colorless gum (15.0 mg, 70.2% yield). LCMS m / z = 437.2 [M+H] + .

[0256] Preparation 195 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 [ka] Following the procedure described in Preparation 194, tert-butyl 3-(2-bromoimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 192) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave 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, 105 mg, 69.8% yield, as a white solid. LCMS m / z=410.2 [M+H] + .

[0257] Preparation 196 tert-Butyl 3-(7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3-(2-bromo-7-fluoroimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 193, 60 mg, 0.141 mmol) in dioxane (4 mL) and HO (0.4 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35.1 mg, 0.169 mmol), Pd(dppf)Cl (10.3 mg, 0.014 mmol), and KCO (38.9 mg, 0.282 mmol), and the mixture was stirred at 100 °C under N for 3 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative TLC (3:1 PE / EtOAc) to give tert-butyl 3-(7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (20 mg, 33.2%). LCMS m / z=428.3 [M+H] + .

[0258] Preparation 197 tert-Butyl 3-(7-fluoro-2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Following the procedure described in Preparation 196, tert-butyl 3-(2-bromo-7-fluoroimidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 193) and 2-methoxypyridin-4-ylboronic acid gave tert-butyl 3-(7-fluoro-2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 20 mg, 37.5%, as a white solid. LCMS m / z=455.2 [M+H] + .

[0259] Preparation 198 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazine hydrochloride [ka] A solution of tert-butyl 3-(2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 194, 15.0 mg, 0.034 mmol) in HCl / dioxane (4 M, 3 mL) 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-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazine hydrochloride as a yellow solid (12.0 mg, crude). LCMS m / z=337.2 [M+H] + .

[0260] Preparation 199 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine hydrochloride [ka] To a solution of 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 (Preparation 195, 105.0 mg, 0.256 mmol) in DCM (2.0 mL) was added HCl / dioxane (4 M, 4.0 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 as a yellow solid (89.0 mg, crude). LCMS m / z=310.2 [M+H] + .

[0261] Preparation 200 (3-(2-Bromopyrazolo[1,5-a]pyrimidin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] To a suspension of 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (495.3 mg, 2.13 mmol) and (3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride (Preparation 10, 500 mg, 2.13 mmol) in DMF (4.26 mL) was added DIPEA (1.12 mL, 6.39 mmol) and the reaction was stirred at 90 °C overnight. The reaction was cooled to room temperature, diluted with EtOAc / heptane (1:1), and washed with aqueous NH Cl (3 times). The organic solution was dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:heptane 0-100%) to give (3-(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone, 732 mg, 87.2% yield.

[0262] Preparation 201 7-Chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-b]pyridine [ka] To a mixture of 7-chloro-1H-pyrazolo[4,3-b]pyridine (500.6 mg, 3.26 mmol) in THF (136 mL) was added 3,4-dihydro-2H-pyran (822.7 mg, 9.78 mmol) and D(+)-10-camphorsulfonic acid (75.73 mg, 0.326 mmol), and the reaction was stirred at 70 °C for 14 h. The cooled mixture was washed with saturated aqueous NaHCO and the layers were separated. The aqueous phase was extracted with EtOAc, and the combined organics were washed with HO, brine, dried over NaSO, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (10–60% EtOAc / hexanes) to afford 7-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-b]pyridine, 164.0 mg, 21.2% yield. LCMS m / z=238.0[M+H] +

[0263] Preparation 202 ((1S,2R)-2-Fluorocyclopropyl)(3-(2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] A mixture of 7-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-b]pyridine (Preparation 201, 100.0 mg, 0.421 mmol), (3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride (Preparation 10, 148.1 mg, 0.631 mmol), Pd(dba) (24.19 mg, 0.042 mmol), CsCO (274.2 mg, 0.841 mmol), and (S)-BINAP (52.4 mg, 0.084 mmol) in toluene (1.05 mL) was heated to 90 °C and stirred for 16 h. The cooled reaction was diluted with EtOAc, washed with NH4Cl (aq), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (0-100% EtOAc / heptane) to afford ((1S,2R)-2-fluorocyclopropyl)(3-(2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, 123 mg, 73.2% yield. LCMS m / z=400.1 [M+H] +

[0264] Preparation 203 (3-(2H-pyrazolo[4,3-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride [ka] To a solution of ((1S,2R)-2-fluorocyclopropyl)(3-(2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[4,3-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 202, 123 mg, 0.308 mmol) in MeOH (1.54 mL) was added 4 M HCl / dioxane (0.770 mL) and the reaction was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure to give (3-(2H-pyrazolo[4,3-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride. LCMS m / z=316.0 [M+H] + [Example]

[0265] Example 1. (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] T3P® (50 wt% in EtOAc, 1.67 mg, 2.62 mmol) was added to a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 6, 500 mg, 1.31 mmol), (1S,2R)-2-fluorocyclopropanecarboxylic acid (204 mg, 1.96 mmol), and TEA (663 mg, 6.55 mmol) in DMF (6.5 mL), and the mixture was stirred at room temperature for 60 minutes. The reaction mixture was diluted with 1:1 EtOAc:heptane and washed with 0.5 N NaOH, HO, saturated NH4Cl, and brine. The combined organics were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified by SiO2 (12 g, 0-70% 3:1 EtOAc:IPA-heptane) to give (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (321 mg, 56.8%). LCMS m / z = 432.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 8.61 (d, 1H), 8.22 (d, 1H), 8.16 (s, 1H), 7.89 (d, 1H), 7.84 (t, 1H), 7.36 (br d, 1H), 4.94 (br s, 1H), 4.83 (br d, 2H), 4.65 (br d, 4H), 2.57-2.67 (m, 1H), 1.96-2.09 (m, 1H), 1.78-1.91 (m, 2H), 1.72 (br d, 1H), 1.35-1.51 (m, 1H), 1.17-1.28 (m, 1H).

[0266] Examples 2 to 27. The title compounds were prepared from the appropriate amines and carboxylic acids using methods similar to those described in Example 1. Compounds were purified by preparative HPLC-1 (except as noted in the table). Amine-1: 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 (Preparation 7), Amine-2: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (Preparation 8) ]triazine (Preparation 6), Amine-3: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine (Preparation 33), Amine-4: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b] Pyridazine (Preparation 34), Amine-5: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine (Preparation 35), Amine-6: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-cyclopropylpyrrolo[1,2-b]pyridazine (Preparation 36) , Amine-7: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(3-fluoro-2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazine (Preparation 37), Amine-8: 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(5-fluoro-2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazine (Preparation 38). [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9] [Table 13-10] [Table 13-11] [Table 13-12] [Table 13-13]

[0267] Examples 28 and 29. (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1r,3r)-3-(trifluoromethyl)cyclobutyl)methanone and (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1s,3s)-3-(trifluoromethyl)cyclobutyl)methanone [ka] *Arbitrarily assigned stereochemistry Chiral SFC separation of Example 14 (CHIRALPAK IC 30 x 250 mm, 5 μm; 0.1% DEA in 35% MeOH+CO2) afforded the title compound.

[0268] Peak 1*: (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1r,3r)-3-(trifluoromethyl)cyclobutyl)methanone (Example 28), LCMS m / z=496.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 8.60 (s, 1H), 8.21 (s, 1H), 8.15 (d, 1H), 7.99-7.70 (m, 2H), 7.34 (d, 1H), 4.73-4.67 (m, 1H), 4.65-4.52 (m, 2H), 4.34-4.27 (m, 1H), 3.53-3.44 (m, 1H), 3.43-3.32 (m, 2H), 3.17-3.03 (m, 1H), 2.65-2.56 (m, 1H), 2.49-2.42 (m, 1H), 2.38-2.28 (m, 2H), 1.99-1.88 (m, 1H), 1.85-1.76 (m, 1H), 1.76-1.63 (m, 2H).

[0269] Peak 2*: (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1s,3s)-3-(trifluoromethyl)cyclobutyl)methanone (Example 29), LCMS m / z=496.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 8.01-7.70 (m, 2H), 7.34 (d, 1H), 4.72-4.51 (m, 3H), 4.35 (br d, 1H), 3.46-3.34 (m, 2H), 3.32-3.22 (m, 1H), 3.22-3.10 (m, 1H), 2.43-2.22 (m, 4H), 1.98-1.88 (m, 1H), 1.86-1.62 (m, 3H).

[0270] Examples 30 to 37. [ka] The title compound was prepared using the one-step library protocol described below.

[0271] In a 2-dram reaction vial equipped with a stir bar, a stock solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 6, 95.5 mg, 0.25 mmol), T3P® (50 wt% in EtOAc, 175 mg, 0.55 mmol), and DIPEA (129 mg, 1 mmol) was added to the appropriate carboxylic acid (RCOH, 0.3 mmol) in EtOAc (1 mL) and DMF (0.3 mL). The vial was sealed and heated to 50 °C overnight. The reaction was concentrated (Genevac), and HO (2 mL) and EtOAc (3 mL) were added. The organic layer was removed, and the aqueous layer was extracted with EtOAc (2 mL). The combined organics were evaporated (Genevac) and the residue was dissolved in DMSO (1.5 mL), filtered and purified by preparative HPLC-2 (gradient 5-65%). [Table 14-1] [Table 14-2] [Table 14-3]

[0272] Example 37. ((1S,2R)-2-Fluorocyclopropyl)(3-(2-(2-methoxypyridin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] A mixture of (3-(2H-pyrazolo[4,3-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone hydrochloride (Preparation 203, 30.0 mg, 0.085 mmol), 4-bromo-2-methoxypyridine (24.1 mg, 0.128 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (4.85 mg, 0.034 mmol), CuI (1.62 mg, 0.0085 mmol), and K3PO4 (90.5 mg, 0.426 mmol) in toluene (0.284 mL) was degassed for 10 minutes, and the reaction was heated at 100 °C overnight. The cooled mixture was diluted with EtOAc and washed with water (3 times) and brine. The combined organics were dried and evaporated to dryness in vacuo. The residue was diluted with EtOAc, washed with NH4Cl, dried (MgSO4), and evaporated to dryness in vacuo. The residue was purified by preparative HPLC-MS purification to give ((1S,2R)-2-fluorocyclopropyl)(3-(2-(2-methoxypyridin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (6 mg, 16.7%). LCMS m / z = 423.1 [M+H] + . 1 H NMR (500 MHz, CDCl3) δ 9.17 (s, 1H), 8.34-8.43 (m, 2H), 8.17 (br t, J=6.41 Hz, 1H), 7.39 (br d, J=4.88 Hz, 1H), 6.44 (br s, 1H), 4.87-5.02 (m, 2H), 4.80-4.86 (m, 1H), 4.72-4.78 (m, 1H), 4.67-4.71 (m, 1H), 4.06 (s, 3H), 3.87 (br d, J=12.82 Hz, 2H), 3.59-3.69 (m, 1H), 2.19-2.33 (m, 2H), 1.44-1.57 (m, 4H).

[0273] Example 38. Rac-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2S)-2-(hydroxymethyl)cyclopropyl)methanone [ka] Part A. T3P® (50 wt% in EtOAc, 902 mg, 2.84 mmol) was added to a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 6, 653 mg, 1.89 mmol), (1S,2S)-2-methoxycarbonylcyclopropanecarboxylic acid (286 mg, 1.98 mmol), and TEA (765 mg, 7.56 mmol) in EtOAc (3.5 mL), and the mixture was stirred at room temperature for 5 minutes and then at 40° C. for 3 hours. The reaction mixture was diluted with HO, 0.5 N NaOH, and EtOAc. The layers were separated, and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), and evaporated to dryness in vacuo. The residue was purified over SiO2 (12 g, 10-80% EtOAc:heptane) to give (1S,2S)-2-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopropane-1-carboxylate (rac-methyl ester) as an off-white foam (594 mg, 67%). LCMS m / z = 472.0 [M+H] + .

[0274] To rac-methyl (1S,2S)-2-[3-[6-[1-(difluoromethyl)pyrazol-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carbonyl]cyclopropanecarboxylate (Part A, 50 mg, 0.106 mmol) in MeOH (1 mL) was added NaBH (12 mg, 0.318 mmol) at room temperature, and the resulting solution was stirred at room temperature for 2 h. The mixture was heated to 50 °C for 1 h, additional NaBH (40.1 mg, 1.06 mmol) was added, and the reaction was stirred at room temperature overnight. Further NaBH (40.1 mg, 1.06 mmol) and MeOH were added and stirred at room temperature for 5 h. The reaction was quenched with HO (2 mL) and diluted with EtOAc. The organic layer was removed and the aqueous layer was extracted with EtOAc (2x). The combined organics were evaporated to dryness and the residue was purified by chromatography (SiO2; 30-100% EtOAc / heptane) to give rac-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-(hydroxymethyl)cyclopropyl)methanone as a white solid (23 mg, 46.5% yield). LCMS m / z = 444.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 7.99 (s, 1H), 7.91-7.82 (m, 2H), 7.74 (br s, 1H), 7.21 (t, 1H), 6.78 (d, 1H), 4.93-4.60 (m, 3H), 4.60-4.46 (m, 1H), 3.92-3.71 (m, 1H), 3.66-3.32 (m, 3H), 2.23-2.05 (m, 2H), 2.02-1.88 (m, 2H), 1.86-1.67 (m, 3H), 1.39-1.30 (m, 1H), 0.94-0.76 (m, 1H).

[0275] Examples 39 and 40. (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2S)-2-(hydroxymethyl)cyclopropyl)methanone and (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1R,2R)-2-(hydroxymethyl)cyclopropyl)methanone [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from (1S,2S)-2-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopropane-1-carboxylate (Example 38, 20 mg) by chiral SFC (LUX Cellulose-4 30 × 250 mm, 5 μm; 0.1% DEA in 40% MeOH+CO).

[0276] Peak 1; Example 39; (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2S)-2-(hydroxymethyl)cyclopropyl)methanone (8 mg). LCMS m / z = 444.0 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 7.99-7.70 (m, 2H), 7.36 (br s, 1H), 4.83-4.73 (m, 1H), 4.71-4.60 (m, 3H), 4.59-4.47 (m, 1H), 3.58-3.35 (m, 3H), 3.29-3.20 (m, 1H), 2.09-1.93 (m, 1H), 1.93-1.75 (m, 3H), 1.74-1.65 (m, 1H), 1.47-1.36 (m, 1H), 1.06-0.93 (m, 1H), 0.80-0.66 (m, 1H)

[0277] Peak 2; Example 40; (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1R,2R)-2-(hydroxymethyl)cyclopropyl)methanone (2.6 mg). LCMS m / z=444.0 [M+H] + .

[0278] Example 41. 1-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propan-1-one [ka] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine (Preparation 6, 25 mg, 0.066 mmol) in DMF (2 mL) was added propionic acid (5.9 mg, 0.098 mmol), HATU (37.5 mg, 0.098 mmol), and DIPEA (25.4 mg, 0.196 mmol), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was purified by preparative HPLC-3 (gradient 27-57%) to give 1-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propan-1-one as an off-white solid (6.7 mg, 26.4%). LCMS m / z = 402.1 [M+H] + . 1 H NMR (400 MHz, MeOH-d4) δ: 8.36 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.47 (t, 1H), 7.17 (s, 1H), 4.81-4.78 (m, 1H), 4.76-4.65 (m, 2H), 4.53-4.50 (m, 1H), 3.45-3.41 (m, 2H), 2.53-2.43 (m, 2H), 2.10-1.80 (m, 4H), 1.17 (t, 3H).

[0279] Examples 42 to 72. Using a method similar to that described in Example 41, the title compounds were prepared from either pyrazole-1,4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 6) or pyrazole-2,4-(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 7) and the appropriate carboxylic acid. Table 15-1 Table 15-2 Table 15-3 Table 15-4 Table 15-5 Table 15-6 Table 15-7 Table 15-8 Table 15-9 Table 15-10 Table 15-11 Table 15-12 Table 15-13 Table 15-14 Table 15-15 Table 15-16

[0280] Example 73. (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1R,2R)-2-fluorocyclopropyl)methanone [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from rac-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1R,2R)-2-fluorocyclopropyl)methanone (Example 46) by chiral HPLC (Diacel Chiralpak AD; 30 × 250 mm, 10 μm; 55% EtOH + 0.1% NH OH).

[0281] Peak 1; Example 73; LCMS m / z = 432.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 8.60 (d, 1H), 8.21 (d, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.84 (t, 1H), 7.36 (d, 1H), 5.03-4.84 (m, 1H), 4.77-4.54 (m, 4H), 3.51-3.47 (m, 2H), 2.31-2.06 (m, 1H), 1.90-1.53 ​​(m, 5H), 1.09-1.02 (m, 1H).

[0282] Example 74. (1R,2R)-2-(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-carbonyl)cyclopropane-1-carbonitrile [ka] *Arbitrarily assigned stereochemistry rac-(1S,2S)-2-(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-carbonyl)cyclopropane-1-carbonitrile was isolated by chiral HPLC (Diacel Chiralcel OJ-H; 30 × 250 mm, 5 μm; 40% MeOH + 0.1% NH4OH). The title compound was obtained from (Example 66).

[0283] Peak 2; Example 74; LCMS m / z = 403.1 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 7.88 (s, 1H), 7.76-7.80 (m, 3H), 7.07.08 (m, 1H), 4.64-4.77 (m, 4H), 3.90 (s, 3H), 3.43-3.52 (m, 2H), 2.76-2.79 (m, 1H), 1.93-2.12 (m, 5H), 1.47-1.52 (m, 2H).

[0284] Examples 75 and 76. (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1R,2S)-2-fluorocyclopropyl)methanone and (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from Rac-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1R,2S)-2-fluorocyclopropyl)methanone (Example 54) by chiral HPLC (Diacel Chiralpak AD; 30 × 250 mm, 10 μm; 55% EtOH + 0.1% NH OH).

[0285] Peak 1; Example 75; LCMS m / z = 432.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 8.58 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.80 (t, 1H), 7.32 (d, 1H), 4.93-4.49 (m, 5H), 3.44-3.42 (m, 2H), 2.62-2.54 (m, 1H), 2.03-1.67 (m, 4H), 1.41-1.17 (m, 2H).

[0286] Peak 2; Example 76; LCMS m / z = 432.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 8.58 (d, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.80 (t, 1H), 7.33 (d, 1H), 4.93-4.50 (m, 5H), 3.44-3.42 (m, 2H), 2.62-2.54 (m, 1H), 2.00-1.67 (m, 4H), 1.41-1.17 (m, 2H).

[0287] Example 77. ((R)-2,2-Difluorocyclopropyl)(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from (2,2-difluorocyclopropyl)(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Example 49) by chiral HPLC (Diacel Chiralpak AD-H; 30 × 250 mm, 5 μm; 40% EtOH + 0.1% NH OH).

[0288] Peak 2; Example 77; LCMS m / z = 450.2 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 8.00 (s, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.22 (t, 1H), 6.77 (s, 1H), 4.96-4.82 (m, 2H), 4.65-4.62 (m, 1H), 4.52-4.57 (m, 1H), 3.54-3.57 (m, 1H), 3.44-3.47 (m, 1H), 2.57-2.60 (m, 1H), 1.83-2.29 (m, 6H).

[0289] Example 78. (1R,2R)-2-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopropane-1-carbonitrile [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from Rac-(1S,2S)-2-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclopropane-1-carbonitrile (Example 53) by chiral HPLC (Diacel Chiralpak AD-H; 30 × 250 mm, 5 μm; 40% EtOH + 0.1% NH OH).

[0290] Peak 2; Example 78; LCMS m / z = 439.1 [M+H] + ; 1 H NMR (500 MHz, MeOH-d4) δ: 8.29 (s, 1H), 7.97 (d, 1H), 7.84 (s, 1H), 7.74 (d, 1H), 7.39 (t, 1H), 7.13 (d, 1H), 4.73-4.58 (m, 4H), 3.37-3.35 (m, 2H), 2.72-2.69 (m, 1H), 2.10-1.84 (m, 5H), 1.44-1.39 (m, 2H).

[0291] Examples 79 and 80. ((1R,2R)-2-Fluorocyclopropyl)(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)methanone and ((1S,2S)-2-Fluorocyclopropyl)(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)methanone [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from Rac-((1R,2R)-2-fluorocyclopropyl)(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)methanone (Example 60) by chiral HPLC (Diacel Chiralpak AD-H; 30 × 250 mm, 5 μm; 55% EtOH + 0.1% NH OH).

[0292] Peak 1; Example 79; LCMS m / z = 396.1 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 7.86 (d, 1H), 7.68-7.70 (m, 2H), 7.55 (s, 1H), 6.72 (d, 1H), 4.75-4.96 (m, 3H), 4.55-4.61 (m, 2H), 3.94 (s, 3H), 3.58-3.60 (m, 1H), 3.41-3.45 (m, 1H), 1.83-2.15 (m, 6H), 1.09-1.12 (m, 1H).

[0293] Peak 2; Example 80; LCMS m / z = 396.1 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 7.86 (d, 1H), 7.68-7.69 (m, 2H), 7.55 (s, 1H), 6.71 (d, 1H), 4.81-4.96 (m, 3H), 4.74-4.79 (m, 2H), 3.94 (s, 3H), 3.57-3.60 (m, 1H), 3.40-3.45 (m, 1H), 1.83-2.05 (m, 6H), 1.09-1.12 (m, 1H).

[0294] Examples 81 and 82. ((1R,2S)-2-Fluorocyclopropyl)(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)methanone and ((1S,2R)-2-Fluorocyclopropyl)(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)methanone [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from Rac-((1R,2S)-2-fluorocyclopropyl)(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)methanone (Example 61) by chiral HPLC (Diacel Chiralpak AD; 30 × 250 mm, 10 μm; 50% EtOH + 0.1% NH OH).

[0295] Peak 1; Example 81; LCMS m / z = 396.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.87 (s, 1H), 7.70-7.68 (m, 2H), 7.56 (s, 1H), 6.71 (d, 1H), 4.84-4.78 (m, 3H), 4.58-4.57 (m, 2H), 3.95 (s, 3H), 3.57-3.42 (m, 2H), 2.23-2.16 (m, 2H), 2.12-2.11 (m, 2H), 1.86-1.83 (m, 1H), 1.49-1.44 (m, 2H).

[0296] Peak 2; Example 82; LCMS m / z = 396.1 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, 1H), 7.69 (s, 2H), 7.55 (s, 1H), 6.72 (s, 1H), 4.84-4.78 (m, 3H), 4.58-4.57 (m, 2H), 3.95 (s, 3H), 3.57-3.44 (m, 2H), 2.23-2.21 (m, 2H), 2.11-1.83 (m, 3H), 1.50-1.43 (m, 1H).

[0297] Examples 83 and 84. ((S)-2,2-Difluorocyclopropyl)(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)methanone and ((R)-2,2-Difluorocyclopropyl)(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)methanone [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from (2,2-difluorocyclopropyl)(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)methanone (Example 63) by chiral HPLC (Diacel Chiralpak AD; 30 × 250 mm, 10 μm; 40% IPA + 0.1% NH OH).

[0298] Peak 1; Example 83; LCMS m / z = 414.0 [M+H] + ; 1H NMR (500 MHz, MeOH-d4) δ: 7.90 (d, 1H), 7.83-7.81 (m, 2H), 7.79 (d, 1H), 7.09 (s, 1H), 4.84-4.77 (m, 2H), 4.75-4.67 (m, 2H), 3.91 (s, 3H), 3.56-3.65 (m, 2H), 3.08-3.01 (m, 1H), 2.19-2.04 (m, 2H), 2.00-1.90 (m, 2H), 1.89-1.78 (m, 2H), 1.36-1.30 (m, 1H).

[0299] Peak 2; Example 84; LCMS m / z = 414.0 [M+H] + ; 1 H NMR (500 MHz, MeOH-d4) δ: 7.90 (d, 1H), 7.83-7.81 (m, 2H), 7.79 (d, 1H), 7.09 (s, 1H), 4.86-4.77 (m, 2H), 4.75-4.64 (m, 2H), 3.92 (s, 3H), 3.46-3.31 (m, 2H), 3.08-3.01 (m, 1H), 2.20-2.03 (m, 2H), 2.00-1.90 (m, 2H), 1.89-1.83 (m, 2H), 1.36-1.30 (m, 1H).

[0300] Example 85. (1R,2S)-2-(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-carbonyl)cyclopropane-1-carbonitrile [ka] *Arbitrarily assigned stereochemistry The title compound was obtained from rac-(1R,2S)-2-(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-carbonyl)cyclopropane-1-carbonitrile (Example 65) by chiral HPLC (Diacel Chiralpak AD; 30 × 250 mm, 10 μm; 55% EtOH + 0.1% NHOH).

[0301] Peak 1; Example 85; LCMS m / z = 403.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.88 (s, 1H), 7.71-7.70 (m, 2H), 7.56 (s, 1H), 6.72 (s, 1H), 5.01-4.83- (m, 2H), 4.62-4.55 (m, 2H), 3.96 (s, 3H), 3.71-3.61 (m, 1H), 3.43 (t, 1H), 2.33-2.29 (m, 1H), 2.04-1.99 (m, 1H), 1.92-1.86 (m, 5H), 1.41-1.38 (m, 1H)

[0302] Example 86. 1-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethan-1-one [ka] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 6, 20.0 mg, 0.052 mmol) in DMF (2 mL) was added DIPEA (6.7 mg, 0.052 mmol) and 2,2,2-trifluoroacetic anhydride (11.0 mg, 0.052 mmol) and the mixture was stirred at 30° C. for 1 h. The mixture was purified by preparative HPLC-5 (gradient 38-68%) to give 1-(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,2,2-trifluoroethan-1-one as a yellow solid (9.0 mg, 38.9%). 1 H NMR (400 MHz, CDCl3) δ: 8.00 (s, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.22 (t, 1H), 6.76 (s, 1H), 4.91 (br, 1H), 4.76 (t, 2H), 4.60 (br, 1H), 3.55 (d, 1H), 3.47 (d, 1H), 2.14-1.91 (m, 4H).

[0303] Example 87. 2,2,2-trifluoro-1-(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)ethan-1-one [ka] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 6, 25 mg, 0.072 mmol) in DMF (2 mL) was added DIPEA (46.7 mg, 0.361 mmol) and 2,2,2-trifluoroacetic anhydride (22.8 mg, 0.108 mmol) and the mixture was stirred at 30° C. for 1 h. The mixture was purified by preparative HPLC-6 (gradient 38-63%) to give 2,2,2-trifluoro-1-(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)ethan-1-one as a yellow solid (18.1 mg, 61.8%). LCMS m / z = 406.0 [M+H] + ;1H NMR (500 MHz, MeOH-d4) δ: 7.93 (s, 1H), 7.88-7.85 (m, 2H), 7.82 (s, 1H), 7.14 (s, 1H), 4.86-4.71 (m, 4H), 3.94 (s, 3H), 3.56-3.51 (m, 2H), 2.16-1.93 (m, 4H).

[0304] Example 88. ((1S,2R)-2-Fluorocyclopropyl)(3-(6-(2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] A mixture of ((1S,2R)-2-fluorocyclopropyl)(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 12, 20.0 mg, 0.045 mmol), 4-bromo-2-methoxy-pyridine (17.08 mg, 0.091 mmol), Pd(amphos)Cl (3.22 mg, 0.0045 mmol), and KF (3.0 M, 0.045 mL) was dissolved in dioxane (0.227 mL) and the reaction was purged with N for 5 minutes and then heated at 80 °C overnight. The cooled mixture was diluted with EtOAc, washed with NH4Cl, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by HPLC to give ((1S,2R)-2-fluorocyclopropyl)(3-(6-(2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (11.0 mg, 57.5% yield); LCMS m / z = 422.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 8.39 (d, 1H), 8.13 (d, 1H), 7.90 (dd, 1H), 7.46 (d, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 5.95 (dd, 1H), 4.77-4.96 (m, 2H), 4.63 (br s, 1H), 3.90-3.98 (m, 2H), 3.88 (s, 3H), 3.15-3.25 (m, 1H), 3.08 (br dd, 1H), 2.58-2.64 (m, 1H), 1.97-2.09 (m, 2H), 1.84-1.97 (m, 2H), 1.34-1.51 (m, 1H), 1.14-1.26 (m, 1H).

[0305] Examples 89 to 134. Using a method similar to that described in Example 88, the appropriate boronate-1: ((1S,2R)-2-fluorocyclopropyl)(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 12) or boronate-2: ((1S,2R)- The title compounds were prepared from either (2-fluorocyclopropyl)(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]octan-8-yl)methanone (Preparation 41) and the appropriate halide and purified by mass-directed preparative HPLC-1 (gradient 0-100%, optimized for each sample). [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7] [Table 16-8] [Table 16-9] [Table 16-10] [Table 16-11] [Table 16-12] [Table 16-13] [Table 16-14] [Table 16-15] [Table 16-16] [Table 16-17] [Table 16-18] [Table 16-19] [Table 16-20] [Table 16-21] [Table 16-22] [Table 16-23]

[0306] Examples 135 and 136. (3-(6-((R)-2,2-difluorocyclopropyl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone and (3-(6-((S)-2,2-difluorocyclopropyl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] *Arbitrarily assigned stereochemistry To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(2,2-difluorocyclopropyl)pyrrolo[1,2-b]pyridazine (Preparation 43, 58.0 mg, 0.191 mmol), (1S,2R)-2-fluorocyclopropanecarboxylic acid (29.8 mg, 0.286 mmol), and TEA (96.4 mg, 0.953 mmol) in DMF (0.95 mL) was added T3P® (50 wt% in EtOAc, 242 mg, 0.381 mmol), and the reaction was stirred at room temperature for 60 minutes. The reaction mixture was diluted with 1:1 EtOAc / heptane and washed successively with 0.5 N NaOH, water, saturated aqueous NH4Cl, and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chiral SFC (CHIRALPAK AD-H 30×250 mm, 5 μm; 30% MeOH in CO) to give:

[0307] Peak 1, Example 135: (3-(6-((R)-2,2-difluorocyclopropyl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (11.6 mg, 15.6%)

[0308] Peak 2, Example 136: (3-(6-((S)-2,2-difluorocyclopropyl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (11.40 mg, 15.3%).

[0309] Example 137. ((1S,2R)-2-Fluorocyclopropyl)(3-(6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] A mixture of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(6-methoxypyridazin-4-yl)pyrrolo[1,2-b]pyridazine hydrochloride (Preparation 48, 62.3 mg, 0.167 mmol), (1S,2R)-2-fluorocyclopropanecarboxylic acid (19.1 mg, 0.184 mmol), T3P® (50 wt% in EtOAc, 213 mg, 0.334 mmol), TEA (84.5 mg, 0.835 mmol), EtOAc (1.0 mL), and DMF (0.3 mL) was combined and heated to 60 °C for 1 h. The cooled reaction was diluted with saturated aqueous NH4Cl, water, and EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (twice), and the combined organic layers were concentrated in vacuo. The crude material was purified by preparative HPLC-1. LCMS m / z = 423.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ: 9.45 (d, 1H), 8.56 (d, 1H), 8.00-7.86 (m, 1H), 7.66 (d, 1H), 7.42 (s, 1H), 5.97 (dd, 1H), 4.97-4.74 (m, 2H), 4.68-4.57 (m, 1H), 4.06 (s, 3H), 4.00-3.87 (m, 2H), 3.25-3.01 (m, 2H), 2.68-2.58 (m, 1H), 2.11 - 2.00 (m, 2H), 1.98-1.80 (m, 2H), 1.50-1.33 (m, 1H), 1.28-1.13 (m, 1H)

[0310] Example 138. (3-(6-(6-(dimethylamino)pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] Following the procedure described in Example 137, 5-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrrolo[1,2-b]pyridazin-6-yl)-N,N-dimethylpyridazin-3-amine hydrochloride (Preparation 49) and (1S,2R)-2-fluorocyclopropanecarboxylic acid gave (3-(6-(6-(dimethylamino)pyridazin-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone as a solid. 1H NMR (500 MHz, DMSO-d6) δ: 9.06 (d, 1H), 8.53 (d, 1H), 7.92 (d, 1H), 7.44 - 7.22 (m, 2H), 5.97 (dd, 1H), 4.98-4.75 (m, 2H), 4.70-4.59 (m, 1H), 4.03-3.87 (m, 2H), 3.27-3.05 (m, 8H), 2.71-2.57 (m, 1H), 2.12 - 2.00 (m, 2H), 1.98-1.81 (m, 2H), 1.53 - 1.33 (m, 1H), 1.30 - 1.10 (m, 1H).

[0311] Example 139. (3-(5-fluoro-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] Following the procedure described in Example 137, 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 147) and (1S,2R)-2-fluorocyclopropanecarboxylic acid gave (3-(5-fluoro-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone as a solid. LCMS m / z = 440.3 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ: 11.89 (br s, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 7.23 (t, 1H), 7.13 (s, 1H), 6.96 (d, 1H), 4.99-4.83 (m, 2H), 4.54-4.53 (m, 1H), 4.03 (s, 3H), 3.89-3.85 (m, 1H), 3.73-3.59 (m, 3H), 2.25-1.97 (m, 5H), 1.50-1.45 (m, 2H).

[0312] Example 140. Cyclopropyl(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] A mixture of (3-(6-bromo-3-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 52, 12.0 mg, 0.031 mmol), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (11.17 mg, 0.046 mmol), Pd(amphos)Cl (2.16 mg, 0.003 mmol), and KF (3.0 M, 30.51 uL) was dissolved in dioxane (305.1 uL) and the reaction was purged with N for 5 minutes, then heated to 100 °C overnight. The cooled reaction was diluted with EtOAc and filtered through Celite®. The filtrate was washed with NH4Cl, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative HPLC-1 to give cyclopropyl(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-fluoropyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (2.5 mg, 19%). LCMS m / z = 431.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 8.69 (s, 1H), 8.24 (s, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.83 (t, 1H), 6.96 (d, 1H), 4.72 (br d, 1H), 4.60 (br d, 1H), 3.68 (br dd, 2H), 1.96-2.12 (m, 5H), 1.79-1.91 (m, 1H), 0.69-0.85 (m, 5H).

[0313] Example 141. (3-(7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] Part A. To a solution of tert-butyl 3-(7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 2, 20 mg, 0.047 mmol) in DCM (2 mL) was added HCl / dioxane (2 mL), and the mixture was stirred for 30 minutes at 20° C. The mixture was evaporated to dryness in vacuo to provide 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine hydrochloride (15 mg, 98%), which was used directly in Part B.

[0314] Part B. To a mixture of 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine hydrochloride (15 mg, 0.046 mmol) and (1S,2R)-2-fluorocyclopropane-1-carboxylic acid (4.77 mg, 0.046 mmol) in DMF (3 mL) was added T3P® (50 wt% in EtOAc, 72.9 mg, 0.229 mmol) and TEA (13.9 mg, 0.137 mmol). The mixture was evaporated to dryness and purified by preparative HPLC-5 (gradient 27-57%) to give (3-(7-fluoro-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone as a white solid (4.4 mg, 23.2%). LCMS m / z = 414.3 [M+H] + ; 1H NMR (500 MHz, CDCl3) δ: 8.01-8.04 (m, 1H), 7.80-7.83 (m, 2H), 7.78 (s, 1H), 4.77-4.95 (m, 2H), 4.52-4.61 (m, 2H), 4.29-4.31 (m, 1H), 3.97 (s, 3H), 3.56-3.64 (m, 2H), 2.31-2.34 (m, 1H), 2.14-2.20 (m, 3H), 1.90-2.01 (m, 1H), 1.43-1.48 (m, 2H).

[0315] Example 142. (3-(7-fluoro-2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] Following a procedure similar to that described in Example 141, except that the compound was purified by preparative HPLC-4 (gradient 45-75%), tert-butyl 3-(7-fluoro-2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Preparation 197) and (1S,2R)-2-fluorocyclopropane-1-carboxylic acid gave (3-(7-fluoro-2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone, 4.0 mg, 26.8% yield, as a white solid. LCMS m / z = 441.2 [M+H] + ; 1H NMR (500 MHz, CDCl3) δ: 8.21 (d, 1H), 8.13 (s, 1H), 8.10-8.07 (m, 1H), 7.35 (d, 1H), 7.28 (s, 1H), 4.96-4.79 (m, 2H), 4.74-4.71 (m, 1H), 4.69-4.55 (m, 1H), 4.34-4.30 (m, 1H), 4.00 (s, 3H), 3.63-3.58 (m, 2H), 2.40-2.33 (m, 1H), 2.22-2.13 (m, 3H), 2.01-1.98 (m, 1H), 1.50-1.44 (m, 2H).

[0316] Example 143. Cyclopropyl(3-(6-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of cyclopropyl(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 13, 50 mg, 0.083 mmol) in DMSO (2 mL) was added 4-iodo-1-methyl-1H-imidazole (25.8 mg, 0.124 mmol), KCO (22.9 mg, 0.165 mmol), and Pd(dppf)Cl (6.1 mg, 0.0083 mmol) under N and the mixture was stirred at 90 °C for 3 h. The mixture was filtered and the filtrate was purified by preparative HPLC-3 (gradient 23-53%) to give cyclopropyl(3-(6-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a brown solid (8.0 mg, 25.6%). LCMS m / z = 378.0 [M+H] + ; 1H NMR (500 MHz, MeOH-d4) δ: 7.89 (d, 1H), 7.81 (s, 1H), 7.63 (s, 1H), 7.38 (s, 1H), 7.16 (d, 1H), 4.84-4.66 (m, 4H), 3.76 (s, 3H), 3.53-3.43 (m, 2H), 2.05-1.84 (m, 5H), 0.98-0.86 (m, 4H).

[0317] Examples 144-145. Using a method similar to that described in Example 143, the title compound was prepared from cyclopropyl(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 13) and the appropriate halide. [Table 17]

[0318] Example 146. Cyclopropyl(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)methanone [ka] A suspension of (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 8, 50 mg, 0.133 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (55.3 mg, 0.266 mmol), KCO (55.1 mg, 0.399 mmol), and Pd(dppf)Cl.DCM (10.9 mg, 0.0133 mmol) in dioxane (0.9 mL) and HO (0.44 mL) was purged with N for 15 min and then warmed to 70 °C. The reaction mixture was diluted with EtOAc and filtered through Celite®. The combined organics were washed with NH4Cl, dried (MgSO4), and evaporated to dryness in vacuo. The residue was purified by preparative HPLC-1 to give cyclopropyl(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)methanone (40 mg, 79.8%). LCMS m / z = 378.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 8.02 (s, 1H), 7.99 (d, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.19 (d, 1H), 4.79 (br d, 1H), 4.66 (br s, 3H), 4.54 (br d, 1H), 3.85 (s, 3H), 1.92-2.08 (m, 2H), 1.75-1.90 (m, 2H), 1.66-1.75 (m, 1H), 0.70-0.86 (m, 5H).

[0319] Examples 147 to 155. The title compound was prepared from (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 8) and the appropriate boronate using a method similar to that described in Example 146. Unless otherwise specified in the table, purification method preparative HPLC-1 was used. [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5]

[0320] Examples 156 and 157. Cyclopropyl(3-(6-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone and cyclopropyl(3-(6-(1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] *Arbitrarily assigned stereochemistry Chiral SFC (CHIRALPAK IA 30 x 250 mm, 5 μm; 45% MeOH / DCM (1:1) + 0.1% DEA in CO2) gave the title compound from Example 152.

[0321] Peak 1, Example 156; cyclopropyl(3-(6-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (9 mg, 15.6%). LCMS m / z = 434.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 8.15 (s, 1H), 8.02 (d, 1H), 7.86 (d, 2H), 7.22 (d, 1H), 4.99-5.06 (m, 1H), 4.76-4.83 (m, 1H), 4.67 (br s, 3H), 4.55 (br d, 1H), 3.96-4.03 (m, 2H), 3.90-3.95 (m, 1H), 3.83 (dt, 1H), 2.37-2.45 (m, 1H), 2.23-2.32 (m, 1H), 1.97-2.06 (m, 2H), 1.77-1.88 (m, 2H), 1.65-1.77 (m, 1H), 0.69-0.86 (m, 5H).

[0322] Peak 2, Example 157; cyclopropyl(3-(6-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (10 mg, 17.3%). LCMS m / z = 434.1 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ: 8.15 (s, 1H), 8.02 (d, 1H), 7.86 (d, 2H), 7.22 (d, 1H), 4.99-5.06 (m, 1H), 4.76-4.83 (m, 1H), 4.67 (br s, 3H), 4.55 (br d, 1H), 3.96-4.03 (m, 2H), 3.90-3.95 (m, 1H), 3.83 (dt, 1H), 2.37-2.45 (m, 1H), 2.23-2.32 (m, 1H), 1.97-2.06 (m, 2H), 1.77-1.88 (m, 2H), 1.65-1.77 (m, 1H), 0.69-0.86 (m, 5H).

[0323] Example 158. Cyclopropyl(3-(6-(3-methylisoxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 8, 28.0 mg, 0.133 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (50 mg, 0.133 mmol) in DMSO (6 mL) was added Pd(dppf)Cl.DCM (11 mg, 0.0133 mmol) and KCO (37.0 mg, 0.266 mmol) and the mixture was stirred at 110 °C under microwave irradiation for 2 h. The reaction mixture was purified by preparative HPLC (gradient 30-60%) to give cyclopropyl(3-(6-(3-methylisoxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a brown solid (8.9 mg, 17.5%). LCMS m / z = 379.1 [M+H]+ ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.04 (s, 1H), 7.88-7.86 (m, 1H), 7.28 (d, 1H), 6.53 (s, 1H), 4.81-4.65 (m, 4H), 3.51-3.46 (m, 2H), 2.30 (s, 3H), 2.03-1.80 (m, 5H), 0.95-0.82 (m, 4H).

[0324] Example 159. ((1S,2R)-2-Fluorocyclopropyl)(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] A mixture of (3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 40, 1.12 g, 2.85 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (889.5 mg, 4.28 mmol), Pd(amphos)Cl (201.66 mg, 0.285 mmol), and KF (3.0 M, 2.85 mL) was dissolved in dioxane (5.70 mL) and the reaction was purged with N for 5 minutes, then heated at 80 °C overnight. The cooled mixture was adsorbed onto silica gel and purified by column chromatography (0–80% EtOAc:heptane) to give ((1S,2R)-2-fluorocyclopropyl)(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (330.0 mg, 29.4% yield). LCMS m / z = 395.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ: 8.05 (s, 1H), 7.92 (d, 1H), 7.83 (dd, 1H), 7.81 (s, 1H), 6.83 (br s, 1H), 5.93 (dd, 1H), 4.74-4.98 (m, 2H), 4.63 (br s, 1H), 3.80-3.91 (m, 5H), 3.00-3.20 (m, 2H), 2.59-2.67 (m, 1H), 1.99-2.09 (m, 2H), 1.83-1.99 (m, 2H), 1.36-1.49 (m, 1H), 1.15-1.26 (m, 1H).

[0325] Examples 160-174. The title compounds were prepared from the appropriate bromide (bromide-1, bromide-2, bromide-3, or bromide-4) and the appropriate boronate using a method similar to that described in Example 159. Bromide-1: (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 8); Bromide-2: (3-(6-bromo-5-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 14); Bromide-3: (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 11), bromide-4: (3-(6-bromopyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 40) [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5] [Table 19-6] [Table 19-7] [Table 19-8]

[0326] Example 175. ((1S,2R)-2-Fluorocyclopropyl)(3-(6-(tetrahydrofuran-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Pd / C (8.63 mg, 0.0081 mmol, 10% purity) was added at room temperature to a solution of (3-(6-(2,5-dihydrofuran-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 53, 31 mg, 0.081 mmol) in EtOAc / IPA (3:1) (0.81 mL). The mixture was stirred at room temperature under an atmosphere of H (balloon) for 13 hours. The suspension was filtered through Celite® and the filter cake was thoroughly washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by SiO (0–100% EtOAc / heptane) to give ((1S,2R)-2-fluorocyclopropyl)(3-(6-(tetrahydrofuran-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (16 mg, 51.3%).

[0327] Examples 176 to 185. [ka] The title compound was prepared using the one-step library protocol described below. A vial was charged with (3-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Preparation 8, 1.0 equiv.) and the appropriate boronic acid (1.3 equiv.). Under an inert atmosphere, dioxane (0.4 mL) was added, followed by a solution of XPhos Pd G3* (5% mol.) and an aqueous solution of Na2CO3 (2.5 equiv., 0.15 mL). The reaction mixture was sealed and heated with stirring at 100 °C for 15 h. The reaction mixture was cooled, the pH adjusted to approximately 7 by the addition of TFA, and evaporated to dryness in vacuo. The residue was dissolved in DMSO (1 mL), treated with metal scavenger SiliaMetS DMT (50 mg), and filtered. The filtrate was purified by preparative HPLC-7 (gradient optimized for each compound) to give the title compounds. *The Pd(dppf)Cl2 indicated in the table was used. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5]

[0328] Example 186. Cyclopropyl(3-(6-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of (3-(6-(2H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone hydrochloride (Preparation 18, 75 mg, 0.187 mmol) in MeCN (5 mL) was added MeI (39.8 mg, 0.281 mmol) and KCO (77.6 mg, 0.561 mmol) and the mixture was stirred at 85 °C for 2 h. The reaction was quenched with HO (1 mL) and the solid was removed by filtration. The filtrate was purified by preparative HPLC-3 (gradient 23-53%) to give cyclopropyl(3-(6-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow solid (13.9 mg, 19.6%). LCMS m / z = 379.0 [M+H] + ; 1 H NMR (500 MHz, MeOH-d4) δ: 8.18 (s, 1H), 7.99 (d, 1H), 7.85 (s, 1H), 7.26 (d, 1H), 4.81-4.69 (m, 4H), 4.15 (s, 3H), 3.54-3.45 (m, 2H), 2.14-1.84 (m, 5H), 0.99-0.86 (m, 4H).

[0329] Example 187. 4-(8-(cyclopropylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine [ka] To a solution of 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 7, 30.0 mg, 0.087 mmol) in DMF (2.0 mL) was added DIPEA (33.6 mg, 0.260 mmol) and the solution was cooled to 0° C. Cyclopropanesulfonyl chloride (18.3 mg, 0.130 mmol) was added and the reaction mixture was stirred at 30° C. for 3 h. The reaction was evaporated to dryness and the residue was purified by preparative HPLC-3 (gradient 24-54%) to give 4-(8-(cyclopropylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (11.0 mg, 30.66% yield). LCMS m / z = 414.0 [M+H] + 1 H NMR (400MHz, MeOH-d4) δ: 7.90 (s, 1H), 7.82-7.78 (m, 3H), 7.08 (s, 1H), 4.76-4.72 (m, 2H), 4.404.39 (m, 2H), 3.92 (s, 3H), 3.51 (d, 2H), 2.60-2.58 (m, 1H), 2.14-2.12 (m, 2H), 1.88-1.85 (m, 2H), 1.15-1.07 (m, 4H).

[0330] Example 188. 4-(8-(cyclopropylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine [ka] 4-(8-(cyclopropylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine was prepared from 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazine hydrochloride (Preparation 6) and cyclopropanesulfonyl chloride according to the procedure described in Example 187. LCMS m / z = 450.1 [M+H] + ; 1 HNMR (400MHz, MeOH-d4) δ: 8.38 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.49 (t, 1H), 7.19 (s, 1H), 4.75 (d, 2H), 4.41-4.39 (m, 2H), 3.54-3.50 (m, 2H), 2.60-2.59 (m, 1H), 2.13-2.11 (m, 2H), 1.88-1.85 (m, 2H), 1.15-1.06 (m, 4H).

[0331] Example 189. 4-(8-(cyclopropylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine [ka] 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 33, 40 mg, 0.116 mmol) in DMF (2 mL) was added cyclopropanesulfonyl chloride (81.5 mg, 0.58 mmol) and TEA (35.2 mg, 0.348 mmol) and the mixture was stirred at 25° C. for 1 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC-4 (gradient 29-59%) to give 4-(8-(cyclopropylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine as a white solid (24.6 mg, 51.4%). LCMS m / z = 413.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 7.80 (d, 1H), 7.71-7.74 (m, 2H), 7.58 (s, 1H), 6.49 (s, 1H), 5.78 (d, 1H), 4.36-4.38 (m, 2H), 3.95 (s, 3H), 3.78-3.82 (m, 2H), 3.26-3.30 (m, 2H), 2.35-2.39 (m, 1H), 2.08-2.19 (m, 4H), 1.22-1.25 (m, 2H), 1.03-1.07 (m, 2H).

[0332] Examples 190-196. Using a method similar to that described in Example 189, the title compound was prepared from cyclopropanesulfonyl chloride, the appropriate amine, and an aprotic base. [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4]

[0333] Examples 197 and 198. 4-(8-(((S)-2,2-difluorocyclopropyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine and 4-(8-(((R)-2,2-difluorocyclopropyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine [ka] *Arbitrarily assigned stereochemistry 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 33, 100 mg, 0.290 mmol) in DMF (2 mL) was added 2,2-difluorocyclopropane-1-sulfonyl chloride (76.8 mg, 0.435 mmol) and DIPEA (112 mg, 0.870 mmol) and the reaction was stirred at 25° C. for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC-4 (gradient 20-40%) to give 4-(8-((2,2-difluorocyclopropyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine as a white solid (42.0 mg, 34.8% yield). Chiral SFC (Daicel CHIRALCEL OJ-H 250 × 30 mm, 5 μm; 45% (EtOH + 0.1% NHOH in CO) gave the title compound.

[0334] Peak 1, Example 197, 4-(8-(((S)-2,2-difluorocyclopropyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine as a white solid (15.8 mg, 45%). LCMS m / z = 449.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.80 (d, 1H), 7.77-7.71 (m, 2H), 7.58 (s, 1H), 6.47 (d, 1H), 5.79 (d, 1H), 4.45-4.42 (m, 2H), 3.95 (s, 3H), 3.84-3.80 (m, 2H), 3.30-3.25 (m, 2H), 3.08-3.03 (m, 1H), 2.30-2.28 (m, 1H), 2.15-2.10 (m, 4H), 2.08-2.04 (m, 1H).

[0335] Peak 2, Example 198, 4-(8-(((R)-2,2-difluorocyclopropyl)sulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine as a white solid (15.2 mg, 43%). LCMS m / z = 449.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 7.80 (d, 1H), 7.75-7.71 (m, 2H), 7.58 (s, 1H), 6.48 (s, 1H), 5.79 (d, 1H), 4.45-4.42 (m, 2H), 3.95 (s, 3H), 3.84-3.80 (m, 2H), 3.30-3.25 (m, 2H), 3.08-3.04 (m, 1H), 2.31-2.28 (m, 1H), 2.15-2.10 (m, 4H), 2.08-2.04 (m, 1H).

[0336] Example 199. Cyclopropyl(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)methanone [ka] 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 74, 74.0 mg, 0.214 mmol) in DMF (4 mL) was added DIPEA (69.1 mg, 0.535 mmol) and cyclopropanecarbonyl chloride (22.4 mg, 0.214 mmol) and the reaction was stirred at 25° C. for 30 min. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC-4 (gradient 15-45%) to give cyclopropyl(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)methanone as a white solid (22.4 mg, 27% yield). LCMS m / z = 378.2 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.22 (s, 1H), 8.07 (s, 1H), 7.90 (d, 1H), 6.52 (d, 1H), 4.81-4.77 (m, 3H), 4.63-4.60 (m, 1H), 3.99 (s, 3H), 3.27-3.26 (m, 1H), 3.20-3.17 (m, 1H), 2.15-2.00 (m, 5H), 0.98-0.85 (m, 4H).

[0337] Example 200. ((1S,2R)-2-Fluorocyclopropyl)(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)methanone [ka] 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 74, 30.0 mg, 0.097 mmol) and (1S,2R)-2-fluorocyclopropanecarboxylic acid (12.1 mg, 0.116 mmol) in EtOAc (2 mL) was added TEA (29.4 mg, 0.291 mmol) followed by T3P® (50 wt% in EtOAc, 30.8 mg, 0.097 mmol) and the reaction was stirred at 25° C. for 10 min. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC-4 (gradient 19-46%) to give ((1S,2R)-2-fluorocyclopropyl)(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)methanone as a white solid (18.0 mg, 46.9%). LCMS m / z = 396.2 [M+H] + ; 1 H NMR (500 MHz, MeOH-d4) δ: 8.22 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 6.52 (s, 1H), 4.80-4.66 (m, 5H), 3.98 (s, 3H), 3.27-3.14 (m, 2H), 2.54-2.52 (m, 1H), 2.17-2.12 (m, 2H), 2.05-2.02 (m, 2H), 1.35-1.33 (m, 1H), 1.30-1.27 (m, 1H).

[0338] Example 201. ((S)-2,2-Difluorocyclopropyl)(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)methanone [ka] Following a procedure similar to that described in Example 200, (S)-2,2-difluorocyclopropanecarboxylic acid and 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 74) gave ((S)-2,2-difluorocyclopropyl)(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)methanone as a white solid (10 mg, 27.9%). LCMS m / z = 414.2 [M+H] + . 1 H NMR (400 MHz, MeOH-d4) δ: 8.23 ​​(s, 1H), 8.07 (s, 1H), 7.90 (d, 1H), 6.52 (d, 1H), 4.80-4.60 (m, 3H), 3.99 (s, 3H), 3.22-3.00 (m, 3H), 2.15-1.99 (m, 7H).

[0339] Examples 202-213. Following a procedure similar to that described in Example 200, the compounds in the following table were prepared from the appropriate imidazo[4,5-b]pyridine (SM) and (1S,2R)-2-fluorocyclopropanecarboxylic acid. [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 22-5] [Table 22-6] [Table 22-7] [Table 22-8] [Table 22-9]

[0340] Example 214. Cyclopropyl(3-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of cyclopropyl(3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 92, 70.0 mg, 0.244 mmol) in DMF (3 mL) was added TsOH (4.2 mg, 0.024 mmol) and 1-(difluoromethyl)-1H-pyrazole-4-carbaldehyde (42.7 mg, 0.292 mmol) and the reaction was stirred at 20° C. for 16 h. The mixture was purified by preparative HPLC-3 (gradient 22-52%) to give cyclopropyl(3-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as an off-white solid (57.1 mg, 56.7%). LCMS m / z = 414.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 13.17 (s, 1H), 8.79 (s, 1H), 8.36 (s, 1H), 7.94 (t, 1H), 7.93 (d, 1H), 6.46 (d, 1H), 4.81-4.52 (m, 4H), 3.19-3.06 (m, 2H), 2.06-1.83 (m, 5H), 0.82-0.71 (m, 4H).

[0341] Example 215. 2-(7-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopropane-1-carbonitrile [ka] Following a method similar to that described in Example 214, (3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 93) and 2-formylcyclopropane-1-carbonitrile gave 2-(7-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopropane-1-carbonitrile as a white solid (13.4 mg, 35.9%) (purified by preparative HPLC-3 (gradient 18-48%)); LCMS m / z = 381.2 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 7.87-7.85 (m, 1H), 6.48-6.44 (m, 1H), 4.76-4.52 (m, 5H), 3.26-3.16 (m, 2H), 2.81-2.78 (m, 1H), 2.50-2.45 (m, 1H), 2.20-1.93 (m, 5H), 1.79-1.68 (m, 2H), 1.40-1.35 (m, 1H), 1.31-1.27 (m, 1H).

[0342] Example 216. (3-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] To a solution of (3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 93, 15.0 mg, 0.049 mmol) in DMF (2 mL) was added TsOH (0.768 mg, 0.004 mmol) and 3-fluoro-1-methyl-1H-pyrazole-4-carbaldehyde (9.4 mg, 0.074 mmol) and the reaction was stirred at 80° C. for 2 h. The cooled mixture was concentrated in vacuo and the residue was purified by preparative HPLC-5 (gradient 21-51%) to give (3-(2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone as a white solid (4.3 mg, 21.2%). LCMS m / z = 414.3 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.06 (s, 1H), 7.91 (s, 1H), 6.52 (s, 1H), 4.80-4.64 (m, 3H), 3.86 (s, 3H), 3.35-3.29 (m, 2H), 3.25-3.14 (m, 2H), 2.54-2.53 (m, 1H), 2.14-2.13 (m, 2H), 2.01-1.98 (m, 2H), 1.37-1.33 (m, 1H), 1.32-1.29 (m, 1H).

[0343] Example 217. ((1S,2R)-2-Fluorocyclopropyl)(3-(2-(2-(methylamino)pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Part A: To a solution of (3-(2,3-diaminopyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 93, 50.0 mg, 0.164 mmol) in DMF (3 mL), TsOH (3.46 mg, 0.049 mmol) and tert-butyl N-(4-formylpyridin-2-yl)carbamate (46.4 mg, 0.197 mmol) were added and the reaction was stirred at 50° C. for 2 h. The mixture was concentrated in vacuo, and the crude was purified by preparative TLC (DCM / MeOH=10 / 1) to give tert-butyl (4-(7-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)(methyl)carbamate as a yellow oil (45.0 mg, crude). LCMS m / z=522.2 [M+H] + .

[0344] Part B: To a solution of tert-butyl (4-(7-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)(methyl)carbamate (45.0 mg, 0.086 mmol) in DCM (3.0 mL), HCl / EtOAc (4 M, 3.0 mL) was added and the reaction was stirred at 20° C. for 30 min. The mixture was concentrated in vacuo and the crude was purified by preparative HPLC-3 (gradient 20-50%) to give ((1S,2R)-2-fluorocyclopropyl)(3-(2-(2-(methylamino)pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow solid (9.1 mg, 25.0% yield). LCMS m / z = 422.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ: 8.19 (br s, 1H), 8.02 (br s, 1H), 7.23 (d, 1H), 7.05 (s, 1H), 6.33 (br s, 1H), 5.12-4.03 (m, 5H), 3.40-3.26 (m, 2H), 2.95 (s, 3H), 2.21-1.94 (m, 5H), 1.43-1.35 (m, 2H).

[0345] Example 218. ((1S,2R)-2-Fluorocyclopropyl)(3-(2-(4-methylmorpholin-2-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Part A: To a solution of tert-butyl 2-(7-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)morpholine-4-carboxylate (Preparation 94, 65.0 mg, 0.130 mmol) in EtOAc (3.0 mL), HCl / EtOAc (4 M, 6 mL) was added and the reaction was stirred at 25° C. for 4 h. The mixture was concentrated in vacuo, the pH was neutralized, and the mixture was purified by preparative HPLC-4 (gradient 15-45%) to give ((1S,2R)-2-fluorocyclopropyl)(3-(2-(morpholin-2-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow solid (32 mg, yield 61.5%).

[0346] Part B: To a solution of ((1S,2R)-2-fluorocyclopropyl)(3-(2-(morpholin-2-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (19.0 mg, 0.047 mmol) in MeOH (5 mL), formaldehyde (10.7 mg, 0.119 mmol) and NaBHCN (8.9 mg, 0.142 mmol) were added and the reaction was stirred at 60° C. for 4 h. The mixture was concentrated and purified by preparative HPLC-4 (gradient 14-44%) to give ((1S,2R)-2-fluorocyclopropyl)(3-(2-(4-methylmorpholin-2-yl)-3H-imidazo[4,5-b]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a white solid (9.7 mg, 49.3%). LCMS m / z = 415.3 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 7.93 (d, 1H), 6.52-6.49 (m, 1H), 4.82-4.72 (m, 5H), 4.60-4.59 (m, 1H), 4.09-4.05 (m, 1H), 3.89-3.85 (m, 1H), 3.27-3.15 (m, 3H), 2.82-2.78 (m, 1H), 2.39-2.33 (m, 6H), 2.13-1.96 (m, 4H), 1.35-1.29 (m, 2H).

[0347] Example 219. Cyclopropyl(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of cyclopropyl(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 100, 93.0 mg, 0.164 mmol) in MeOH (5 mL) was added KCO (67.9 mg, 0.492 mmol) and the reaction was stirred at 50 °C for 1 h. The reaction mixture was concentrated in vacuo and the crude was purified by preparative HPLC-5 (gradient 30-60%) to give cyclopropyl(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a white solid (25.8 mg, 38.1%). LCMS m / z = 414.2 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.43 (s, 1H), 8.16-8.14 (m, 2H), 7.53 (t, 1H), 6.93 (s, 1H), 4.81-4.54 (m, 4H), 3.43-3.37 (m, 2H), 2.11-1.93 (m, 5H), 0.97-0.85 (m, 4H).

[0348] Example 220. Cyclopropyl(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)methanone [ka] Following a procedure similar to that described in Example 219, cyclopropyl(3-(6-(1-methyl-1H-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 101) gave cyclopropyl(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)methanone as a white solid (43.3 mg, 65.4%). LCMS m / z = 378.2 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 8.30 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 6.49 (s, 1H), 4.89-4.88 (m, 1H), 4.73-4.69 (m, 1H), 4.63-4.60 (m, 1H), 4.46-4.42 (m, 1H), 3.99 (s, 3H), 3.56-3.41 (m, 2H), 2.09-1.76 (m, 5H), 1.25-1.04 (m, 2H), 0.84-0.80 (m, 2H).

[0349] Example 221. (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone [ka] To a solution of 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (Preparation 128, 45.0 mg, 0.118 mmol) in DMF (1 mL) was added TEA (45.7 mg, 0.451 mmol), and (1S,2R)-2-fluorocyclopropanecarboxylic acid (13.5 mg, 0.130 mmol), and T3P® (50 wt% in EtOAc, 1.0 mL) and the reaction was stirred at 20° C. for 30 min. The mixture was concentrated in vacuo and the crude was purified by preparative HPLC-5 (gradient 26-56%) to give (3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone as an off-white solid (17.2 mg, 33.8%). LCMS m / z = 432.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 12.20 (s, 1H), 8.62 (s, 1H), 8.32-8.30 (m, 1H), 8.17 (s, 1H), 7.90 (t, 1H), 7.08-7.06 (m, 1H), 4.98-4.58 (m, 2H), 4.50-4.44 (m, 3H), 3.31-3.23 (m, 2H), 2.65-2.61 (m, 1H), 2.08-1.71 (m, 4H), 1.44-1.22 (m, 2H).

[0350] Example 222. ((S)-2,2-Difluorocyclopropyl)(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Following a procedure similar to that described in Example 221 using preparative HPLC-4 (gradient 25-55%), 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (Preparation 128) and (S)-2,2-difluorocyclopropane-1-carboxylic acid gave ((S)-2,2-difluorocyclopropyl)(3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a yellow solid (21.7 mg, 41%). LCMS m / z = 450.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ: 12.19 (s, 1H), 8.63-8.61 (m, 1H), 8.32-8.29 (m, 1H), 8.17 (s, 1H), 7.91 (t, 1H), 7.10-7.06 (m, 1H), 4.73-4.51 (m, 4H), 3.40-3.37 (m, 1H), 3.20-3.16 (m, 2H), 2.09-1.82 (m, 6H).

[0351] Examples 223 to 235. Following a similar method as described in Example 222, the compounds in the following table were prepared from the appropriate pyrrolo[2,3-d]pyrimidine (SM) and (1S,2R)-2-fluorocyclopropanecarboxylic acid using the preparative HPLC method indicated in the table. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5] [Table 23-6] [Table 23-7]

[0352] Example 236. Cyclopropyl(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)methanone [ka] To a solution of cyclopropyl(3-(2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 177, 180 mg, 0.339 mmol) in MeOH (5 mL) was added NaOH (5 M, 0.4 mL) and the reaction was stirred at 50° C. for 18 h. The mixture was filtered and the filtrate was purified by preparative HPLC-3 (gradient 23-53%) to give cyclopropyl(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)methanone as an off-white solid (68.5 mg, 53.6%). LCMS m / z = 377.3 [M+H] + ; 1 H NMR (400MHz, MeOH-d4) δ: 8.00 (s, 1H), 7.90 (s, 1H), 7.85 (d, 1H), 6.66 (s, 1H), 6.43 (d, 1H), 4.80-4.77 (m, 2H), 3.99-3.87 (m, 5H), 3.25-3.12 (m, 2H), 2.14-1.97 (m, 5H), 0.96-0.82 (m, 4H).

[0353] Example 237. Cyclopropyl(3-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Following a procedure similar to that described in Example 236, cyclopropyl(3-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (Preparation 178) gave cyclopropyl(3-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (37.6 mg, 52.7%) as an off-white solid (37.6 mg, 52.7%). LCMS m / z = 413.1 [M+H] + ; 1 H NMR (500 MHz, MeOH-d4) δ: 8.50 (s, 1H), 8.22 (s, 1H), 7.93 (d, 1H), 7.56 (t, 1H), 6.90 (s, 1H), 6.49 (d, 1H), 4.84-4.82 (m, 2H), 4.05-3.94 (m, 2H), 3.32-3.20 (m, 2H), 2.19-2.00 (m, 5H), 1.00-0.87 (m, 4H).

[0354] Example 238. ((1S,2R)-2-Fluorocyclopropyl)(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)methanone [ka] 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 179, 76.0 mg, 0.164 mmol) and (1S,2R)-2-fluorocyclopropanecarboxylic acid (17.1 mg, 0.164 mmol) in EtOAc (3 mL) was added TEA (45.55 μL) and T3P® (50 wt % in EtOAc, 0.164 mmol, 1 mL) and the reaction was stirred at 18° C. for 10 min. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC-4 (gradient 21-51%) to give (1S,2R)-2-fluorocyclopropyl)(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)methanone as a white solid (26.3 mg, 40.6%). LCMS m / z = 395.2 [M+H] + ; 1 H NMR (400 MHz, MeOH-d4) δ: 8.00 (s, 1H), 7.90 (s, 1H), 7.86-7.85 (m, 1H), 6.66 (d, 1H), 6.45-6.42 (m, 1H), 4.77-4.74 (m, 3H), 3.99-3.89 (m, 5H), 3.24-3.13 (m, 2H), 2.51-2.49 (m, 1H), 2.17-2.01 (m, 4H), 1.33-1.27 (m, 2H).

[0355] Examples 239-247. Using a method similar to that described in Example 238, the following compounds were prepared from the appropriate pyrrolo[2,3-b]pyridines (1-6) and the appropriate carboxylic acids (RCOH). Pyrrolo[2,3-b]pyridine (1): 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 179), pyrrolo[2,3-b]pyridine (2): 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(5- Fluoro-1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 181), pyrrolo[2,3-b]pyridine (3): 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation Preparation 180), pyrrolo[2,3-b]pyridine (4): 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 182), pyrrolo[2,3-b]pyridine (5): 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 183), pyrrolo[2,3-b]pyridine (6): 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3-fluoro-2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 184) [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5]

[0356] Example 248. ((1S,2R)-2-Fluorocyclopropyl)(3-(2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] To a solution of 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazine hydrochloride (Preparation 198, 12.0 mg, 0.036 mmol) in DMF (2 mL) was added (1S,2R)-2-fluorocyclopropanecarboxylic acid (3.7 mg, 0.036 mmol), TEA (10.8 mg, 0.107 mmol), and T3P® (0.3 mL, 50% solution in EtOAc) and the mixture was stirred at 20° C. for 10 min. The mixture was purified by preparative HPLC-4 (gradient 37-67%) to give ((1S,2R)-2-fluorocyclopropyl)(3-(2-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a white solid (1.7 mg, 11.3%). LCMS m / z = 423.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ: 8.21 (d, 1H), 8.18 (s, 1H), 7.99-7.97 (m, 1H), 7.37 (d, 1H), 7.32 (s, 1H), 6.01-5.98 (m, 1H), 5.37-5.35 (m, 1H), 4.97-4.77 (m, 2H), 4.64-4.62 (m, 1H), 4.36-4.34 (m, 1H), 4.00 (s, 3H), 3.38-3.28 (m, 2H), 2.21-1.97 (m, 6H), 1.48-1.42 (m, 1H).

[0357] Example 249. ((1S,2R)-2-Fluorocyclopropyl)(3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Following a procedure similar to that described in Example 248, except that the HPLC column gradient was 27-57%, ((1S,2R)-2-fluorocyclopropyl)(3-(3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone was prepared from 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride (Preparation 189) and (1S,2R)-2-fluorocyclopropane-1-carboxylic acid as a white solid (28.5 mg, 45%). LCMS m / z = 409.3 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 10.09 (br s, 1H), 8.08-8.04 (m, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 6.65-6.62 (m, 1H), 4.94-4.80 (m, 2H), 4.55-4.53 (m, 1H), 4.02 (s, 3H), 3.53-3.50 (m, 1H), 3.36-3.32 (m, 1H), 3.15-3.09 (m, 2H), 2.65 (s, 3H), 2.38-2.35 (m, 1H), 2.25-2.22 (m, 3H), 2.17-2.14 (m, 1H), 1.46-1.40 (m, 2H)

[0358] Example 250. 4-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile [ka] Following a procedure similar to that described in Example 248, tert-butyl 3-(3-cyano-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 186) and (1S,2R)-2-fluorocyclopropane-1-carboxylic acid gave 4-(8-((1S,2R)-2-fluorocyclopropane-1-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile as a white solid (10 mg, 27.5%), which was purified using preparative HPLC-8 (gradient 16-47%). LCMS m / z = 420.2 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ: 8.25 (s, 1H), 8.16-8.13 (m, 1H), 8.06 (s, 1H), 6.65-6.62 (m, 1H), 4.92-4.85 (m, 2H), 4.61-4.59 (m, 1H), 4.06 (s, 3H), 3.99-3.94 (m, 1H), 3.61-3.57 (m, 1H), 3.24-3.15 (m, 2H), 2.37-2.35 (m, 1H), 2.30-2.28 (m, 1H), 2.20-2.00 (m, 3H), 1.49-1.41 (m, 2H).

[0359] Example 251. ((1S,2R)-2-Fluorocyclopropyl)(3-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] A mixture of (3-(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((1S,2R)-2-fluorocyclopropyl)methanone (Preparation 200, 50 mg, 0.127 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (39.58 mg, 0.190 mmol), Pd(amphos)Cl (8.98 mg, 0.0013 mmol), and KF (3.0 M, 0.127 mL) in dioxane (0.634 mL) was purged with N for 5 minutes and then heated at 80 °C overnight. The cooled mixture was adsorbed onto silica gel and purified by column chromatography (0-80% EtOAc:heptane) to give ((1S,2R)-2-fluorocyclopropyl)(3-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (16 mg, 31.9%). LCMS m / z=396.3 [M+H] + .

[0360] Example 252. ((1S,2R)-2-Fluorocyclopropyl)(3-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone [ka] Following a procedure similar to that described in Example 238, except that the mixture was purified by preparative HPLC-4 (gradient 25-55%), 8-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine hydrochloride (Preparation 199) and (1S,2R)-2-fluorocyclopropane-1-carboxylic acid gave ((1S,2R)-2-fluorocyclopropyl)(3-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone as a white solid (44.0 mg, 38.7%). LCMS m / z = 396.3 [M+H] + ; 1 H NMR (500 MHz, MeOH-d4) δ: 8.00 (s, 1H), 7.99 (s, 1H), 7.96 (d, 1H), 7.87 (s, 1H), 6.18 (t, 1H), 5.02-4.99 (m, 1H), 4.79-4.68 (m, 4H), 3.93 (s, 3H), 3.27-3.13 (m, 2H), 2.52-2.51 (m, 1H), 2.17-2.12 (m, 2H), 2.00-1.97 (m, 2H), 1.29-1.28 (m, 1H), 1.33-1.32 (m, 1H).

[0361] Biological assays Compounds of the present disclosure were evaluated for their ability to inhibit TYK2, JAK1, JAK2, and JAK3 activity. The inhibitory properties of the compounds of the present disclosure described herein can be demonstrated by testing them in any one of the following protocols.

[0362] The kinase activity of recombinantly produced catalytic kinase (also known as JH1) domains of human JAK1, JAK2, JAK3, and TYK2 was assessed in a plate-based assay using the ADP-Glo™ kinase assay platform. Specifically, 4 nM recombinant JAK1 kinase domain was used to phosphorylate 50 μM JAK3-342 (sequence ALVDGYFRLTT) peptide in the presence of 35 μM ATP. The catalytic activity of recombinant JAK2, JAK3, and TYK2 kinase domains (0.2, 0.3, and 2 nM, respectively) was assessed by measuring the phosphorylation state of JAK3-974 (50 μM; sequence LPLDKDYYVVR) peptide in the presence of ATP (15, 4, and 10 μM, respectively). The reaction was allowed to proceed for 100 min, and catalytic activity was quantified by first depleting unused ATP and converting hydrolyzed ADP to ATP to generate luminescence in a luciferase reaction, which is the basis of the ADP-Glo ​​platform. Compounds are tested at a top concentration of either 10 μM or 1 μM, with 11 3-fold dilutions. Data are normalized and percent activity versus log compound concentration is fitted with a four-parameter logistic model to generate curves and IC50 values. [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4] [Table 25-5] [Table 25-6] [Table 25-7]

Claims

1. A compound of formula (I'): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ is a bicyclic heteroaryl ring, 【Chemistry 2】 is a single bond or a double bond, X １ is N, NH, or CR １ and X ２ But N or CR ２ and X ３ But N or CR ３ and X ４ But N or CR ４ and X ５ is CR 5 ; X ６ is C or N, X 7 is C; Y is C(O) or S(O) ２ and R １ , R ２ , R ３ , and R ４ each independently, if present, is H, halo, —CN, —NR １ａ R １ｂ , -OR １ｃ , C １－４ Alkyl, and C １－４ haloalkyl; R ５ is C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 5-7 membered partially saturated heterocyclyl, 5 or 6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl, wherein the C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, 5-7 membered partially saturated heterocyclyl, 5 or 6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl are each optionally substituted with 1, 2, or 3 R 7 ; R ６ But H, C １－６ Alkyl, C ３－８ Cycloalkyl, C ６－１０ aryl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; R ６ The C represented by １－６ alkyl, the C ３－８ cycloalkyl, the C ６－１０ aryl, said 4- to 10-membered heterocycloalkyl, and said 5- to 10-membered heteroaryl each optionally comprise one or more R ８ is replaced by R 7 at each occurrence is independently halo, —CN, oxo (═O), —NR 1a R 1b , —OR 1c , —C(O)OR 1c , C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or 4- to 6-membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein the C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —NR 1a R 1b , —OR 1c , and 4- to 6-membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; R ８ is, for each occurrence independently, halo, -NR １ａ R １ｂ , -OR １ｃ , -CN,C １－６ Alkyl, C １－３ Hydroxyalkyl, —C(═O)OR １ｃ , and C １－６ haloalkyl; R １ａ and R １ｂ are each independently H or C １－４ is alkyl, R １ｃ But H, C １－４ Alkyl, or C １－４ is haloalkyl, The compound or a pharmaceutically acceptable salt thereof, wherein m is 0 or an integer of 1 to 6.

2. The compound is represented by formula (I): 【Transformation 3】 During the ceremony, X １ is N and X ２ But, CR ２ or X ２ is N and X １ But, CR １ 2. The compound of claim 1, wherein:

3. X １ But, CR １ and X ２ is N, or a pharmaceutically acceptable salt thereof.

4. R １ , R ２ , R ３ , and R ４ each independently, if present, is H, halo, —NH ２ , -OH, C １－４ Alkyl, or C １－４ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

5. The compound is represented by the following formula: 【Chemistry 4】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. Y is S(O) ２ 6. The compound according to any one of claims 1 to 5, wherein:

7. 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y is C(O).

8. R ３ If present, H, halo, C １－４ Alkyl, or C １－４ 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

9. R ３ 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or halo.

10. R ５ is a 5- or 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl, and said 5- or 6-membered monocyclic heteroaryl and said 8- to 10-membered bicyclic heteroaryl each optionally contain one, two, or three R ７ is replaced by R ７ may each occur independently as halo, -CN, -NR １ａ R １ｂ , -OR １ｃ , -C(O)OR １ｃ , C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, １－４ alkyl, the C １－４ haloalkyl, the C ３－６ cycloalkyl, and said 4- to 6-membered monocyclic heterocycloalkyl, each optionally selected from halo, C １－４ Alkyl, C １－４ Haloalkyl, —NR １ａ R １ｂ , -OR １ｃ and a 4- to 6-membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, or a pharmaceutically acceptable salt thereof.

11. R ５ is a 5- or 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, S, and N, and said 5- or 6-membered monocyclic heteroaryl optionally contains 1, 2, or 3 R ７ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, substituted with:

12. R ５ is a 5-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from O, S, and N, and said 5-membered monocyclic heteroaryl optionally contains 1, 2, or 3 R ７ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, substituted with:

13. The 5-membered monocyclic heteroaryl is pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, or pyrrole, each of which optionally contains one, two, or three R ７ 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, substituted with:

14. R ７ However, for each occurrence, independently, halo, C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, １－４ alkyl, the C ３－６ 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl and said 4- to 6-membered monocyclic heterocycloalkyl are each optionally substituted with one or two substituents independently selected from halo and 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O.

15. The compound is represented by the following formula: 【Transformation 5】 During the ceremony, R ９ａ But C １－４ Alkyl, C ３－６ cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, １－４ alkyl, the C ３－６ cycloalkyl, and said 4- to 6-membered monocyclic heterocycloalkyl, each optionally selected from halo, C １－４ Alkyl, C １－４ Haloalkyl, —NR １ａ R １ｂ , -OR １ｃ and 4-6 membered monocyclic heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O; R ９ｂ and R ９ｃ are each independently H, C １－４ Alkyl, or C １－４ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

16. R ９ａ が、-CH ３ 、-CH ２ CH ３ 、 【Transformation 6】 and R ９ｂ and R ９ｃ One of the groups is H, and the other is H, —CH ３ , -CHF ２ , or -CF ３ 16. The compound of claim 15, wherein:

17. R ６ But C １－４ Alkyl, C ３－６ Monocyclic cycloalkyl, C ５－８ a bicyclic cycloalkyl, a 4- to 6-membered monocyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, or a 5- to 8-membered bicyclic heterocycloalkyl containing one or two heteroatoms independently selected from N and O, １－４ alkyl, the C ３－６ monocyclic cycloalkyl, ５－８ The bicyclic cycloalkyl, the 4- to 6-membered monocyclic heterocycloalkyl, and the 5- to 8-membered bicyclic heterocycloalkyl are each optionally selected from halo, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－３ Hydroxyalkyl, —C(═O)OR １ｃ , and C １－４ substituted with 1 to 3 substituents independently selected from alkoxy; １ｃ is H or C １－３ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is alkyl.

18. R ６ But halo, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－３ Hydroxyalkyl, —C(═O)OR １ｃ , and C １－４ C optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy ３－６ is a monocyclic cycloalkyl, and R １ｃ is H or C １－３ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

19. R ６ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is selected from halo, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－３ Hydroxyalkyl, —C(═O)OR １ｃ , and C １－４ optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; １ｃ is H or C １－３ 20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

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

21. 20. The compound according to any one of claims 1 to 19, wherein m is 1, or a pharmaceutically acceptable salt thereof.

22. -(CH ２ ) ｍ -R ６ が、CH ３ 、-CH ２ CH ３ 、 【Transformation 7】 17. The compound according to any one of claims 1 to 16, wherein:

23. The compound is represented by the formula: 【Transformation 8】 or a pharmaceutically acceptable salt thereof, wherein: R ６ But halo, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－３ Hydroxyalkyl, —C(═O)OR １ｃ , and C １－４ C optionally substituted with 1 or 2 substituents independently selected from alkoxy ３－６ is a monocyclic cycloalkyl, and R １ｃ is H or C １－３ is alkyl, R ９ａ But C １－４ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

24. R ６ But, Halo, C １－４ Alkyl, and C １－４ C optionally substituted with 1 or 2 substituents independently selected from haloalkyl ３－６ is a monocyclic cycloalkyl; R ９ａ But C １－３ 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

25. R ６ But, Halo, C １－４ Alkyl, and C １－４ cyclopropyl optionally substituted with 1 or 2 substituents independently selected from haloalkyl; R ９ａ But C １－３ 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

26. A pharmaceutical composition comprising the compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

27. 27. A pharmaceutical composition for use in the treatment of a disease or disorder responsive to the inhibition of tyrosine kinase 2 (TYK2), comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

28. The disease or disorder is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathy, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, cerebral trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, 28. The pharmaceutical composition of claim 27, wherein the therapeutic effect is on glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, muscle pain, endotoxic 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 redness, eczema, psoriasis, atopic dermatitis, and sunburn.

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