Aminopyridine derivatives and their use as selective ALK-2 inhibitors

Abstract

To provide a compound as an ALK-2 inhibitor, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof.SOLUTION: The invention relates to a compound of formula (I) in free form or in pharmaceutically acceptable salt form (I), to pharmaceutical compositions comprising the compound, and to the use of the compound in the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.SELECTED DRAWING: None

Description

[Technical Field]

[0001] ALK-2, also known as activin A receptor type I (ACVR1) or serine / threonine protein kinase receptor R1 (SKR1), is a protein kinase encoded by the ACVR1 gene in humans.

[0002] ALK-2 is a widely expressed type I BMP receptor. It consists of an extracellular ligand-binding domain and a regulated intracellular serine / threonine kinase domain, both of which are required for signal transduction. [Background technology]

[0003] Bone morphogenetic proteins (BMPs) are multifunctional growth factors that are members of the transforming growth factor β (TGFβ) superfamily. BMP signaling plays a role in the development of the heart, nerves, and cartilage, as well as in postnatal bone formation. BMPs induce ectopic endochondral ossification and play a crucial role in skeletal and joint morphogenesis (Urist, Science 110:893-899 (1965); Olsen et al, Annu. Rev. Cell Dev. Biol. 16:191-220 (2000); Kronenberg, Nature 423:332-336 (2003); Thomas et al, Nat. Genet. 12:315-317 (1996); Thomas et al, Nat. Genet. 17:58-64 (1997); Polinkowsky et al, Nat. Genet. 17:18-19 (1997); Storm et al., Nature 368:639-643 (1994); and Wozney, Prog. Growth Factor Res. 1:267-280 (1989)).

[0004] BMP signaling is regulated at many levels, including through extracellular antagonists such as noggin (Massague, Nat. Rev. MoI. Cell. Biol. 1:169-178 (2000)). It has been suggested that untimely or unwanted activation of signaling pathways essential for normal development may promote disease processes such as spondyloarthritis. The effect of BMP signaling on the onset and progression of arthritis induced by noggin gene transfer has also been described (Lories et al, J. Clin. Invest., 115, 1571-1579 (2005)). The physiological roles of BMP and BMP receptor signaling in normal bone formation, including skeletal and limb development, have been studied and outlined in Zhao, Genetics 35:43-56 (2003).

[0005] Experiments using BMP antagonists demonstrate that the regulation of BMP signaling proteins is central to bone formation in vivo (Devlin et al., Endocrinology 144:1972-1978 (2003) and Wu et al., J. Clin. Invest., 112:924 (2003)).

[0006] Fibrodysplasia ossificans progressive (FOP) is a rare, physically debilitating genetic disorder characterized by congenital malformations of the great toe and progressive, ectopic endochondral ossification with a predictable anatomical pattern. Ectopic expression of BMP4 has been found in FOP patients (Gannon et al., Hum. Pathol. 28:339-343 (1997) and Xu et al, Clin. Genet. 58:291-298 (2000)). Patients with FOP have been shown to have activating mutations in ALK-2 (Shore et al., Nat. Genet., 38(5):525-7 (2006)).

[0007] It has been established that excessive BMP signaling can lead to some of the aforementioned pathological conditions. International Publication Nos. 2008033408 and 2009114180 describe inhibitors of the BMP signaling pathway. [Overview of the project] [Problems that the invention aims to solve]

[0008] However, there is still a need to find alternative ways in which BMP signaling can be regulated.

[0009] Such needs can be met by designing selective ALK-2 inhibitors.

[0010] Specific ALK-2 antibodies are described, for example, in International Publication No. 1994011502 and International Publication No. 2008030611. Bone morphogenetic proteins that bind to ALK-2 are described in International Publication No. 2012023113 and International Publication No. 2012077031.

[0011] International Publication No. 2007123896 describes a method for treating lesions associated with ectopic ossification by administering siRNA specific to the nucleic acid encoding ALK-2.

[0012] International Publication No. 2014160203 and International Publication No. 2014138088 describe BMP pathway inhibitors. International Publication No. 2015152183 describes ALK-2 inhibitors for the treatment of FOP. ALK-2 inhibitors are also described in International Publication No. 2014151871. [Means for solving the problem]

[0013] There is a continuing need to develop new ALK-2 inhibitors, which are excellent drug candidates. Such candidates would find use, among other things, in the treatment of fibrodysplasia ossificans progressive (FOP) or non-hereditary ectopic ossification (HO).

[0014] The present invention provides compounds that are ALK-2 inhibitors, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. The present invention further provides a method for treating, preventing, or improving fibrodysplasia ossificans progressive (FOP) or non-hereditary ectopic ossification (HO), comprising the step of administering an effective amount of an ALK-2 inhibitor to a subject in need thereof.

[0015] Various embodiments of the present invention are described herein.

[0016] In certain embodiments of this specification, formula (I) in free form or in pharmaceutically acceptable salt form, [ka] The compound is provided.

[0017] In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or its sub-formulas (Ia), (II), (IIa), (IIb) as defined herein, in free form or in pharmaceutically acceptable salt form, and one or more pharmaceutically acceptable carriers.

[0018] In a further embodiment, the present invention relates to a method for inhibiting ALK-2 receptor activity in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I) or its sub-formulas (Ia), (II), (IIa), (IIb) as defined herein, in free form or in pharmaceutically acceptable salt form.

[0019] In yet another aspect, the present invention relates to a method for treating a disorder or disease selected from ectopic ossification or progressive fibrodysplasia ossificans, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or its sub-formulas (Ia), (II), (IIa), (IIb) as defined herein, in free form or in pharmaceutically acceptable salt form to a target.

[0020] The compounds of the present invention exhibit desirable pharmacokinetic properties, are non-toxic, and have few side effects. In particular, the compounds of the present invention are selective inhibitors of ALK-2 more than other receptors. Furthermore, the ideal drug candidate is stable, non-hygroscopic, and readily formulateable. [Brief explanation of the drawing]

[0021] [Figure 1] This shows μCT quantification of ectopic bone formed in the right hind limb of mice 6 weeks after FOP-induced flare-up using adenovirus / CTX, demonstrating the effect of 6 weeks of compound A treatment on HO formation. Mean ± SEM. *: p<0.05, **: p<0.01, ***: p<0.01. Compared with vehicle treatment; one-way ANOVA with Dunnett's post-hoc test. [Figure 2] This shows μCT quantification of ectopic bone formed in the right hind limb of mice 8 weeks after FOP-induced flare-up using adenovirus / CTX, demonstrating the effect of 6 weeks of compound A treatment on HO formation. Mean ± SEM. *: p<0.05, **: p<0.01, ***: p<0.01. Comparison with vehicle treatment; t-test. [Figure 3] The X-ray powder diffraction pattern of crystalline free-form modified HA crystals of compound A is shown. [Figure 4] The differential scanning diagram of the crystalline free morphology-modified HA crystal of compound A is shown. [Figure 5] The thermogravimetric analysis diagram of crystalline free morphology modified HA of compound A is shown. [Figure 6] The Fourier transform infrared diagram of the crystalline free morphology modified HA of compound A is shown. [Figure 7]The X-ray powder diffraction pattern of compound A with crystalline free morphology modification A is shown. [Figure 8] The differential scanning diagram of crystalline free morphology modification A of compound A is shown. [Figure 9] The thermogravimetric analysis diagram of the crystalline free form modification A of compound A is shown. [Figure 10] The Fourier transform infrared diagram of the crystalline free morphology modification A of compound A is shown. [Figure 11] The X-ray powder diffraction pattern of crystalline fumarate-modified HA of compound A is shown. [Figure 12] The differential scanning diagram of crystalline fumarate-modified HA of compound A is shown. [Figure 13] The thermogravimetric analysis diagram of crystalline fumarate-modified compound A, HA, is shown. [Figure 14] The Fourier transform infrared diagram of crystalline fumarate-modified HA of compound A is shown. [Figure 15] The dynamic gas sorption diagram of crystalline fumarate-modified HA of compound A at 25°C is shown, under 50%-0%-90% relative humidity (RH). [Figure 16] A dynamic gas sorption diagram of crystalline fumarate-modified HA of compound A at 40°C, method 50%-0%-90% RH. [Figure 17] The X-ray powder diffraction pattern of the crystalline phosphate of compound A is shown. [Figure 18] The X-ray powder diffraction pattern of the crystalline free form anhydrous (Example 89C) is shown. [Figure 19] The X-ray powder diffraction pattern of the crystalline free form trihydrate (Example 89D) is shown. [Modes for carrying out the invention]

[0022] In particular, the present invention relates to formula (I) in a free form or an acceptable salt form, [ka] (In the formula, L is a bond, (CH2) n -CH(CH3)-, -O-(CH2) n -, -C(O)-, -C(O)-NH-(CH2) n -and; n is 1, 2, or 3; R1 is a C3-C7 cycloalkyl group optionally substituted once or twice or more with a substituent independently selected from hydroxyl, halogen, or C1-C3 alkyl groups; or a cross-linked C5-C1 alkyl group optionally substituted once or twice or more with a substituent independently selected from hydroxyl, hydroxyC1-C3 alkyl groups. 10 Selected from cycloalkyl groups; R2 and R3 are independently selected from H, halogens, and C1-C3 alkyl groups; R4 is an N-containing heterocyclic non-aromatic ring comprising one or more additional heteroatoms optionally selected from N, O, or S, which are optionally substituted one or more times at R7; R7 is C1-C3 alkyl, hydroxy C1-C3 alkyl, halo C1-C3 alkyl, C1-C3 alkoxy C1-C3 alkyl, halo C1-C3 alkoxy C1-C3 alkyl, C2-C4 alkynyl, cyano C1-C3 alkyl, (CH2) m -Selected independently from R8; m is 0, 1, 2, or 3; R8 is a 4, 5, or 6-membered saturated or unsaturated non-aromatic heterocycle comprising one or more heteroatoms selected from N, O, or S that are optionally substituted once or twice or more with substituents independently selected from oxo, SO2C1~C3 alkyl, or haloC1~C3 alkyl, or C3-C6 cycloalkyl groups that are optionally substituted once or more times with a halo. (Selected from) Regarding the compounds.

[0023] Unless otherwise specified, the term "compounds of the present invention" or "compounds of the invention" refers to compounds of formula (I), (Ia), (II), (IIa), (IIb), and salts thereof, as well as all stereoisomers (such as diastereoisomers and enantiomers), rotational isomers, tautomers, and isotope-labeled compounds (such as deuterium substitution), and inherently formed moieties. [[ID=II]]

[0024] As used herein, the term "C1-C3 alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having 1 to 3 carbon atoms, not containing unsaturation, and attached to the remainder of the molecule by a single bond. Examples of C1-C3 alkyl include methyl, ethyl, n-propyl, and 1-methylethyl (isopropyl).

[0025] As used herein, the term "hydroxy C1-C3 alkyl" refers to a free radical of the formula -R a -OH, where R a is C1-C3 alkyl as defined above.

[0026] As used herein, the term "C3-C7 cycloalkyl" refers to a saturated monocyclic hydrocarbon group having 3 to 7 carbon atoms. Examples of C3-C7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0027] As used herein, the term "C1-C3 alkoxy" refers to a free radical of the formula -OR a where R a is a C1-C3 alkyl free radical as generally defined above. Examples of C1-C3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, and hexyloxy.

[0028] In the use of this specification, the term "C1-C3 alkoxy C1-C3 alkyl" refers to the formula, -R b -OR a It refers to the free group, and in the formula, R a R is a C1-C3 alkyl free group as defined above, b These are C1-C3 alkyl free radicals as defined above. The oxygen atom may be bonded to any carbon atom of either alkyl free radical. Examples of C1-C3 alkoxyC1-C3 alkyls include methoxymethyl, methoxyethyl, and ethoxyethyl.

[0029] "Halogen" or "halo" refers to bromo, chloro, fluoro, or iodine.

[0030] In the use of this specification, the terms "halogen C1-C3 alkyl" or "halo C1-C3 alkyl" refer to a C1-C3 alkyl free radical as defined above, substituted with one or more halo free radicals as defined above. Examples of halogen C1-C3 alkyls include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, and 1-bromomethyl-2-bromoethyl.

[0031] In the use of this specification, the term "halo-C1-C3 alkoxy-C1-C3 alkyl" refers to the formula, -R b -OR a It refers to the free group, and in the formula, R a R is a C1-C3 alkyl free group as defined above, b These are halo-C1-C3 alkyl free radicals as defined above.

[0032] In the use of this specification, the term “N-containing heterocyclic non-aromatic ring comprising one or more additional heteroatoms optionally selected from N, O, or S” with respect to R4 means a saturated or unsaturated non-aromatic ring or ring system that is a 4, 5, 6, or 7-membered monoring containing one, two, or three heteroatoms selected from O, S, and N, wherein at least one heteroatom is N, and it is a bicyclic system of a 6, 7, 8, 9, 10, 11, or 12-membered ring containing one, two, three, four, or five heteroatoms selected from O, S, and N, wherein at least one heteroatom is N, or it is a tricyclic system of a 10, 11, 12, 13, 14, or 15-membered ring containing one, two, three, four, five, six, or seven heteroatoms selected from O, S, and N, wherein at least one heteroatom is N, and N and S can also be optionally oxidized to various oxidation states. The N-containing heterocyclic non-aromatic ring may be attached via heteroatoms or carbon atoms. N-containing heterocyclic aromatic rings may include fused or bridging rings and spiro rings. In preferred embodiments, "N-containing heterocyclic aromatic rings comprising one or more additional heteroatoms optionally selected from N, O, or S" are N-containing 5-membered saturated monorings, N-containing 6-membered saturated monorings or dirings, and N-containing 7-membered saturated spiro rings. Examples of N-containing heterocyclic aromatic rings include morpholine, piperazine, piperidine, imidazolidine, imidazoline, pyrroline, pyrrolidine, thiomorpholine, and 3-azabicyclo[3.1.0]hexane.

[0033] In the use herein, the term "N-containing five-membered heterocyclic non-aromatic ring comprising one or more additional heteroatoms optionally selected from N, O, or S" with respect to R4 includes, for example, pyrrolidine, 2,3-dihydropyrrole, oxazolidine, and imidazolidine. In preferred embodiments, it refers to pyrrolidine. The ring is attached to the rest of the molecule via the ring carbon atoms.

[0034] In the use herein, the term "N-containing six-membered heterocyclic non-aromatic monocyclic or dicyclic ring comprising one or more additional heteroatoms optionally selected from N, O, or S" with respect to R4 includes, as examples, morpholine, thiomorpholine, piperidine, piperazine, and 3-azabicyclo[3.1.0]hexane. In preferred embodiments, it refers to 3-azabicyclo[3.1.0]hexane. The ring is attached to the rest of the molecule via the ring carbon atoms.

[0035] In the use of this specification, with respect to embodiments in which R5 and R6 together with the N atom to which they are attached to form a ring, the term "a five-membered ring comprising one additional heteroatom optionally selected from N, O, or S" includes, for example, pyrrolidine, 2,3-dihydropyrrole, oxazolidine, and imidazolidine. In preferred embodiments, it refers to pyrrolidine.

[0036] In the use of this specification, with respect to embodiments in which R5 and R6 together with the N atom to which they are attached to form a ring, the term "six-membered ring comprising one additional heteroatom optionally selected from N, O, or S" includes, for example, piperidinyl, morpholinyl, and piperazinyl.

[0037] In the use of this specification, with respect to embodiments in which R5 and R6 together with the N atom to which they are attached to form a ring, the term “seven-membered spiro ring comprising one additional heteroatom optionally selected from N, O or S” includes, for example, 2-azaspiro[3.3]heptane and 2-oxa-6-azaspiro[3.3]heptane.

[0038] In the usage of this specification, "Cross-linked C5~C 10 The term "cycloalkyl" refers to a saturated bicyclic or tricyclic system comprising at least one crosslink. 10 Examples of cycloalkyls include, for example, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, and tricyclo-[3.3.1.1 3,7Deccan is one example.

[0039] In the use of this specification, the term "C2-C4 alkynyl" refers to a linear group consisting only of carbon and hydrogen atoms, having 2-4 carbon atoms and containing at least one triple bond, which are attached to the rest of the molecule by single bonds. Examples of C2-C4 alkynyls include, for example, ethynyl, prop-1-inyl, and buty-1-inyl.

[0040] In the use of this specification, the term "cyano C1-C3 alkyl" refers to the formula, -R a -Refers to the free group of CN, in the formula, R a These are C1-C3 alkyl groups as defined above.

[0041] In the use of this specification, the term “a 4, 5, or 6-membered saturated or unsaturated non-aromatic heterocycle comprising one or more heteroatoms selected from N, O, or S” includes, as examples, tetrahydropyran, morpholine, piperidine, and oxetane. In preferred embodiments, it is tetrahydropyran.

[0042] In the use of this specification, the term "ALK-2" refers to activin A receptor, type I (ACVRI); SKR1; ACVR1A; activin receptor type I; activin receptor-like kinase 2; serine / threonine protein kinase receptor R1; TGF-B superfamily receptor type I; ACTRI; TSRI; activin A receptor, type II-like kinase 2; activin receptor type-1; hydroxyalkyl protein kinase; ACTR-I; TSR-I.

[0043] Various embodiments of the present invention are described herein. It will be recognized that further embodiments of the present invention may be provided by combining the features specified in each embodiment with other specific features.

[0044] Embodiment 1. Formula (I) in free form or pharmaceutically acceptable salt form, [ka] (In the formula, L is a bond, (CH2) n -CH(CH3)-, -O-(CH2) n -, -C(O)-, -C(O)-NH-(CH2) n -and; n is 1, 2, or 3; R1 is a C3-C7 cycloalkyl group optionally substituted once or twice or more with a substituent independently selected from hydroxyl, halogen, or C1-C3 alkyl groups; or a cross-linked C5-C1 alkyl group optionally substituted once or twice or more with a substituent independently selected from hydroxyl, hydroxyC1-C3 alkyl groups. 10 Selected from cycloalkyl groups; R2 and R3 are independently selected from H, halogens, and C1-C3 alkyl groups; R4 is an N-containing heterocyclic non-aromatic ring comprising one or more additional heteroatoms optionally selected from N, O, or S, which are optionally substituted one or more times at R7; R7 is C1-C3 alkyl, hydroxy C1-C3 alkyl, halo C1-C3 alkyl, C1-C3 alkoxy C1-C3 alkyl, halo C1-C3 alkoxy C1-C3 alkyl, C2-C4 alkynyl, cyano C1-C3 alkyl, (CH2) m -Selected independently from R8; m is 0, 1, 2, or 3; R8 is a 4, 5, or 6-membered saturated or unsaturated non-aromatic heterocycle comprising one or more heteroatoms selected from N, O, or S that are optionally substituted once or twice or more with substituents independently selected from oxo, SO2C1~C3 alkyl, or haloC1~C3 alkyl, or C3-C6 cycloalkyl groups that are optionally substituted once or more times with a halo. (Selected from) A compound of [this].

[0045] Embodiment 2. Formula (Ia) described in Embodiment 1, in free form or in pharmaceutically acceptable salt form, [ka] A compound of [this].

[0046] Embodiment 3. The compound according to either Embodiment 1 or 2 in free form or in pharmaceutically acceptable salt form, wherein R4 is NR5R6, and R5 and R6, together with the N atom to which they are attached, comprise one additional heteroatom optionally selected from N, O, or S, and R7 optionally substituted once or twice or more to form a five-membered ring.

[0047] Embodiment 4. The compound according to either Embodiment 1 or 2 in free form or in pharmaceutically acceptable salt form, wherein R4 is NR5R6, and R5 and R6, together with the N atom to which they are attached, comprise one additional heteroatom optionally selected from N, O, or S, and R7 optionally substituted once or twice or more, forming a six-membered ring.

[0048] Embodiment 5. The compound according to either Embodiment 1 or 2 in free form or in pharmaceutically acceptable salt form, wherein R4 is NR5R6, and R5 and R6 together with the N atom to which they are attached comprises one additional heteroatom optionally selected from N, O, or S, and R7 optionally substituted once or twice or more, to form a 7-membered spiro ring.

[0049] Embodiment 6. The compound according to either Embodiment 1 or 2 in a free or pharmaceutically acceptable salt form, wherein R4 is an N-containing five-membered heterocyclic non-aromatic ring comprising one or more additional heteroatoms optionally selected from N, O, or S, the ring being optionally substituted once or twice or more with R7; and the ring being attached to the rest of the molecule via the ring carbon atoms.

[0050] Embodiment 7. The compound according to either Embodiment 1 or 2 in a free form or a pharmaceutically acceptable salt form, wherein R4 is an N-containing 6-membered heterocyclic non-aromatic monocyclic or dicyclic ring comprising one or more additional heteroatoms optionally selected from N, O, or S, wherein the ring is optionally substituted once or twice or more with R7; and the ring is attached to the rest of the molecule via the ring carbon atoms.

[0051] Embodiment 8. Formula (II) as described in any of Embodiments 1, 2, or 7, in free form or in pharmaceutically acceptable salt form, [ka] (In the formula, R7 is C1-C3 alkyl, hydroxy C1-C3 alkyl, halo C1-C3 alkyl, C1-C3 alkoxy C1-C3 alkyl, halo C1-C3 alkoxy C1-C3 alkyl, C2-C4 alkynyl, cyano C1-C3 alkyl, (CH2) m -Selected independently from R8; m is 0, 1, 2, or 3. A compound of [this].

[0052] Embodiment 9. Formula (IIa) as described in Embodiment 8, in free form or in pharmaceutically acceptable salt form, [ka] A compound of [this].

[0053] Embodiment 10. Formula (IIb) as described in Embodiment 8, in free form or in pharmaceutically acceptable salt form, [ka] A compound of [this].

[0054] Embodiment 11. R7 is (CH2) m -R8; R8 is a six-membered heterocycle comprising one or more heteroatoms selected from N, O, or S that are optionally substituted once or twice or more with substituents independently selected from oxo, SO2C1-C3 alkyl, and haloC1-C3 alkyl; m is 0, 1, 2, or 3. The compound according to any of the preceding embodiments, either in free form or in pharmaceutically acceptable salt form.

[0055] Embodiment 12. The compound according to Embodiment 11 in a free form or a pharmaceutically acceptable salt form, wherein R8 is an unsubstituted tetrahydropyran and m is 0.

[0056] Embodiment 13. The compound according to Embodiment 11 in free form or pharmaceutically acceptable salt form, wherein R8 is an unsubstituted morpholine and m is 2 or 3.

[0057] Embodiment 14. A compound according to any of the preceding embodiments, in free form or in pharmaceutically acceptable salt form, wherein R1 is a cyclohexyl that is optionally substituted once or twice or more with substituents independently selected from hydroxyl, halogen, and C1-C3 alkyl groups.

[0058] Embodiment 15.R1 is, [ka] The compound described in any of the preceding embodiments, either in free form or in pharmaceutically acceptable salt form.

[0059] Embodiment 16.R1 is, [ka] The compound described in any of the preceding embodiments, either in free form or in pharmaceutically acceptable salt form.

[0060] Embodiment 17. The compound according to any of Embodiments 1 to 13, in free form or in pharmaceutically acceptable salt form, wherein R1 is bicyclo[2.2.2]octanyl, which is once substituted with a hydroxyl group.

[0061] Embodiment 18.R1 is, [ka] The compound according to Embodiment 17, in its free form or in its pharmaceutically acceptable salt form.

[0062] Embodiment 19. The compound according to any embodiment of Embodiments 1 to 13, in free form or in pharmaceutically acceptable salt form, wherein R1 is bicyclo[1.1.1]pentanyl substituted with hydroxymethyl.

[0063] Embodiment 20.R1 is, [ka] The compound according to Embodiment 19, which is in a free form or a pharmaceutically acceptable salt form.

[0064] Embodiment 21.2-Amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-(-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(3-morpholinopropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-(-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(2-fluoro-4-(4-isopropylpiperazine-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-(-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(1-isopropylpyrrolidine-3-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxy-4-methylcyclohexyl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-(-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(pyrrolidine-3-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(3-fluoro-4-hydroxycyclohexyl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(2-azaspiro[3,3]heptan-2-ylmethyl)phenyl)-2-amino-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxy-4-methylcyclohexyl)-5-(4-(-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-(-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(2-fluoro-4-(piperazine-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-((2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; 2-amino-N-(4-hydroxycyclohexyl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-(-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-amino-5-(4-(-3-(buty-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(oxetan-3-ylmethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(2-(2,2,2-trifluoroethoxy)ethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide; 2-amino-5-(4-(-3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide 2-amino-5-(3-fluoro-4-(2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-morpholinophenyl)nicotinamide; 2-amino-5-(4-(-3-(2,2-difluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(4-(-3-(2-cyanoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(3-morpholinopropoxy)phenyl)nicotinamide; 2-amino-N-(4-hydroxycyclohexyl)-5-(4-(3-(prop-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)-2-chlorophenyl)-2-amino-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(2-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-5-(4-(-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-amino-5-(4-(-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(piperidine-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxy-4-methylcyclohexyl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-((2-(4-methylpiperazine-1-yl)ethyl)carbamoyl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-(-3-hydroxyadamantan-1-yl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(morpholine-4-carbonyl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxy-4-methylcyclohexyl)-5-(4-((2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; 2-amino-5-(2,3-difluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl-4-d)-5-(4-(-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide; 2-amino-5-(2-chloro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-N-(3-(2-hydroxypropane-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-cyclohexyl-5-(3-(morpholine-4-carbonyl)phenyl)nicotinamide; 2-amino-5-(3-chloro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-(-4-hydroxy-1-methylcyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxy-4-methylcyclohexyl)-5-(2-methyl-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; and 2-amino-N-cyclohexyl-5-(3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenyl)nicotinamide A compound according to Embodiment 1, selected from the free form or a pharmaceutically acceptable salt form.

[0065] Embodiment 22.2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 5-(4-((S)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(3-morpholinopropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(2-fluoro-4-(4-isopropylpiperazine-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4r)-4-hydroxycyclohexyl)-5-(4-(1-isopropylpyrrolidine-3-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-((1r,4r)-4-hydroxycyclohexyl)-5-(4-(pyrrolidine-3-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1R,3S,4R)-3-Fluoro-4-Hydroxycyclohexyl)-5-(4-((1R,5S)-3-(Tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1s,4S)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(2-azaspiro[3,3]heptan-2-ylmethyl)phenyl)-2-amino-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(2-fluoro-4-(piperazine-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(buty-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(oxetane-3-ylmethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-(2,2,2-trifluoroethoxy)ethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(2,2-difluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(2-cyanoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(prop-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(prop-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)-2-chlorophenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(2-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(buty-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-((2-(4-methylpiperazine-1-yl)ethyl)carbamoyl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1R,3R)-3-hydroxyadamantan-1-yl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(oxetane-3-ylmethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1s,4R)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-Hydroxy-4-methylcyclohexyl)-5-(4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-Amino-5-(2,3-difluoro-4-(((R)-2-methylpyrrolidin-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide; 2-Amino-5-(4-((1S,5R)-3-(2,2-difluoropropyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl-4-d)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide; 2-Amino-N-((1s,4s)-4-hydroxycyclohexyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide; 2-Amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-Amino-5-(2-chloro-4-(((R)-2-methylpyrrolidin-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-5-(4-((1R,5S)-३-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide; 2-Amino-5-(3-chloro-4-(((R)-2-methylpyrrolidin-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxy-1-methylcyclohexyl)nicotinamide; and 2-Amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)-5-(2-methyl-4-(((R)-2-methylpyrrolidin-1-yl)methyl)phenyl)nicotinamide A compound according to embodiment 21, in free form or in pharmaceutically acceptable salt form, selected from the above.

[0066] Embodiment 23. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of the preceding embodiments, in free form or in pharmaceutically acceptable salt form, and one or more pharmaceutically acceptable carriers.

[0067] Embodiment 24. A combination comprising a therapeutically effective amount of a compound according to any of embodiments 1 to 22, in free form or in pharmaceutically acceptable salt form, and one or more therapeutically active agents.

[0068] Embodiment 第25条. A compound according to any of embodiments 1 to 22, in free form or in pharmaceutically acceptable salt form, for use as a medicament. [[ID=二十一世紀]]

[0069] Embodiment 26. A compound according to any of embodiments 1 to 22, in free form or in pharmaceutically acceptable salt form, for use in the treatment of a disorder or disease selected from heterotopic ossification or progressive fibrodysplasia ossificans.

[0070] Embodiment 27. In particular, (i) having the first two, first three, first four, first five, first six, first eight, especially the first ten, or especially all of the 2θ values ​​in the reflected XRPD shown in Table A below; or (ii) having a DSC diagram as shown in Figure 4; or (iii) having a TGA diagram as shown in Figure 5; or (iv) having an FT-IR diagram as shown in Figure 6; or having two or three, or especially all, of the above (i) to (iv); or especially having an XRPD diagram as shown in Figure 3, especially free morphologically modified H A The free form of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide.

[0071] Embodiment 28. In particular, (i) having the first two, first three, first four, first five, first six, first eight, especially the first ten, or especially all of the 2θ values ​​in the reflected XRPD shown in Table B below; or (ii) having a DSC diagram as shown in Figure 8; or (iii) having a TGA diagram as shown in Figure 9; or (iv) having an FT-IR diagram as shown in Figure 10; or having two or three, or especially all, of the above (i) to (iv); or especially having an XRPD diagram as shown in Figure 7, the free form of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide in the modified A form, free form.

[0072] Embodiment 29. In particular, having the XRPD diagram shown in Figure 18, 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide as a free anhydrous form.

[0073] Embodiment 30. In particular, having the XRPD diagram shown in Figure 19, 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide as a free form trihydrate.

[0074] Embodiment 31. In particular, (i) having the first two, first three, first four, first five, first six, first eight, especially the first ten, or especially all of the 2θ values ​​in the reflected XRPD shown in Table C below; or (ii) having a DSC diagram as shown in Figure 12; or (iii) having a TGA diagram as shown in Figure 13; or (iv) having an FT-IR diagram as shown in Figure 14; or (v) having a DVS diagram at 25°C as shown in Figure 15; or (vi) having a DVS diagram at 40°C as shown in Figure 16; or having two, three, four, or five, or especially all of (i) to (iv) above; or especially having an XRPD diagram as shown in Figure 11, especially fumarate-modified H A 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide in fumarate form, particularly having a 1:1 compound A to fumarate molar ratio.

[0075] Embodiment 32. In particular, 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide of amorphous fumarate variant 1, which exhibits a glass transition of approximately 143°C when analyzed by controlled DSC for 60 seconds at a heating rate of 1 K / min and an amplitude temperature of 1 K, and in particular has a 1:1 compound A to fumarate molar ratio.

[0076] Embodiment 33. In particular, 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide of amorphous fumarate variant 2, which exhibits a glass transition of approximately 78°C when analyzed by DSC at a heating rate of 10 K / min, and in particular has a 1:1 compound A to fumarate molar ratio.

[0077] Embodiment 34. In particular, (i) having the first two, first three, first four, first five, first six, first eight, in particular the first ten or in particular all of the reflective XRPD values ​​of the 2θ values ​​shown in Table D below; or in particular having an XRPD diagram such as that shown in Figure 17, in particular having a compound A to phosphate molar ratio of 1:1.5, in the phosphate form of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide.

[0078] Embodiment 35. A compound in any one of Embodiments 27 to 34 for use as a pharmaceutical agent.

[0079] Embodiment 36. A compound in any one of Embodiments 27 to 34 for use in the treatment of a disorder or disease selected from ectopic ossification or progressive fibrodysplasia ossificans.

[0080] Where a 2θ value (or any value in the table “Angle” below) is given in this disclosure, this means each value ± 0.2, i.e., the value itself.

[0081] When the term "modification" is used, it refers to amorphous forms or, in particular, crystalline polymorphs (i.e., forms of crystalline structure), and also includes pseudo-polymorphs such as free forms or salts, solvated compounds or, in particular, hydrates.

[0082] Depending on the selection of starting materials and procedures, compounds may exist in the form of pure optical isomers, or as isomeric mixtures such as racemates and diastereoisomeric mixtures, depending on the number of chiral carbon atoms. The present invention is intended to include all such possible isomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R) and (S) isomers may be prepared using chiral synthons or chiral reagents, or separated using conventional techniques. If the compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis configuration or a trans configuration. All tautomers are also intended to be included.

[0083] In the use of this specification, the terms “salt” or “salts” refer to acid-added or base-added salts of the compounds of the present invention. “Salt” specifically refers to “pharmaceutically acceptable salts.” “pharmaceutically acceptable salts” refer to salts that retain the biological efficacy and properties of the compounds of the present invention and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acidic salts in the presence of a basic aminopyridine moiety. Where “free form” is referred to, this refers to a form without additional acids and / or bases, i.e., the compound itself (however, if the compound contains basic and acidic groups, it may form internal salts).

[0084] Pharmaceutically acceptable acid addition salts can be formed by inorganic acids and organic acids.

[0085] Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0086] Examples of organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0087] In another aspect, the present invention provides a compound of formula (I) in the form of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / bromohydrate, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutaconate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylicate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate.

[0088] All formulas provided herein are intended to represent both the unlabeled and isotopically labeled forms of the compound. An isotopically labeled compound has the structure represented by the formula provided herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 Examples include hydrogen, carbon, nitrogen, oxygen, phosphorous acid, fluorine, and chlorine isotopes such as I. The present invention relates to various isotope-labeled compounds as defined herein, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 This includes compounds containing non-radioactive isotopes such as 13C. Such isotope-labeled compounds are used in metabolic studies, including drug or substrate tissue distribution assays. 14 (by C), reaction dynamics studies (for example) 2 H or 3 It is useful in detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), or in radiotherapy for patients. In particular, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples, using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent.

[0089] Furthermore, heavier isotopes, especially deuterium (i.e., 2Substitution with H or D may result in specific therapeutic benefits, such as greater metabolic stability, including an increased in vivo half-life, a reduced required dose, or an improved therapeutic index. In this context, deuterium is understood to be a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, may be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a particular isotope. When the substituent of the compound of the present invention is deuterium, such a compound has an isotopic enrichment factor of 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 incorporation), 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) for each designated deuterium atom.

[0090] Examples of pharmaceutically acceptable solvation compounds according to the present invention include D2O, d6-acetone, d6-DMSO, etc., in which the crystallization solvent may be isotope-substituted.

[0091] Compounds of the present invention, i.e., compounds of formula (I), which contain groups capable of acting as donors and / or acceptors for hydrogen bonding, may form cocrystals with suitable cocrystal-forming agents. These cocrystals may be prepared from compounds of formula (I) by known cocrystal-forming procedures. Such procedures include steps of grinding, heating, co-sublimating, eu-melting, or contacting compounds of formula (I) with a cocrystal-forming agent in solution under crystallization conditions, and separating the cocrystals thereby. Suitable cocrystal-forming agents are those described in International Publication No. 2004 / 078163. Accordingly, the present invention further provides cocrystals comprising compounds of formula (I).

[0092] In the usage herein, the term “pharmaceutically acceptable carrier” includes all solvents, dispersions, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption retarders, salts, preservatives, drug stabilizers, conjugates, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, etc., and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289–1329). Unless any conventional carrier is incompatible with the active ingredient, its use in a therapeutic or pharmaceutical composition is intended.

[0093] The term “therapeutic effective dose” of the compound of the present invention refers to an amount of the compound of the present invention that elicits a biological or medical response in a subject, such as, for example, a reduction or inhibition of enzyme or protein activity, or alleviation of symptoms, reduction of a condition, slowing or delaying disease progression, or prevention of disease. In one non-limiting embodiment, the term “therapeutic effective dose” refers to an amount of the compound of the present invention that, when administered to a subject, is effective in reducing, inhibiting, preventing and / or improving at least to some extent a condition, disorder or disease mediated by (i) ALK-2, or (ii) related to ALK-2 activity, or (iii) characterized by ALK-2 activity (normal or abnormal); or (2) reducing or inhibiting ALK-2 activity; or (3) reducing or inhibiting ALK-2 expression. In another non-limiting embodiment, the term “therapeutic effective dose” means an amount of the compound of the present invention that, when administered to cells or tissues or non-cellular biological materials or culture media, is effective to reduce or inhibit the activity of ALK-2 to at least some extent; or to reduce or inhibit the expression of ALK-2 to at least some extent.

[0094] In the usage of this specification, the term "subject" refers to a human being.

[0095] In the context of this specification, the terms “inhibit,” “inhibit,” or “inhibiting” refer to the reduction or suppression of a given medical condition, symptom, disorder, or disease; or a significant decrease in the baseline activity of a biological activity or process.

[0096] In the use of this specification, the terms “treat,” “treating,” or “treatment” of any disease or disorder mean, in one embodiment, improving the disease or disorder (i.e., slowing, suppressing, or reducing the onset of the disease or at least one clinical symptom of the disease). In another embodiment, “treat,” “treating,” or “treatment” means mitigating or improving at least one physical parameter, including one that may not be perceived by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” means modulating the disease or disorder either physically (e.g., stabilizing identifiable symptoms), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, “treat,” “treating,” or “treatment” means preventing or delaying the onset, onset, or progression of the disease or disorder.

[0097] In the use of this specification, if an object "needs" such treatment, it is considered to "need" treatment if it benefits from such treatment biologically, medically, or in terms of quality of life.

[0098] In the context of this specification, the terms “a,” “an,” “the,” and similar terms used in the context of the present invention (particularly in the context of the claims) are to be interpreted as covering both singular and plural forms, unless otherwise specified herein or unless otherwise clearly inconsistent with the context.

[0099] All methods described herein may be carried out in any suitable order, unless otherwise clearly stated herein and unless otherwise clearly contradicted by the context. All examples provided herein, or the use of exemplary language (e.g., "such as"), are intended solely to facilitate understanding of the invention and do not constitute a limitation of the scope of the invention unless claimed.

[0100] Any chiral atom (e.g., carbon) in the compounds of the present invention may exist in a racemic or enantiomerically enriched configuration, such as (R) configuration, (S) configuration, or (R,S) configuration. In certain embodiments, each chiral atom has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the (R) or (S) configuration. Substituents of atoms having an unsaturated double bond may, if possible, exist in cis-(Z) or trans-(E) configuration.

[0101] Therefore, in the use herein, the compounds of the present invention may be in one form of possible isomers, rotational isomers, atropisomers, tautomers, or mixtures thereof, for example, substantially pure geometric isomers (cis or trans), diastereomers, optical isomers (antagonistic), racemates, or mixtures thereof.

[0102] Any resulting mixture of isomers can be separated, for example, by chromatography and / or fractionation crystallization, into pure or substantially pure geometric or optical isomers, diastereomers, or racemates based on the physicochemical differences of their constituent components.

[0103] Any resulting racemic final product or intermediate can be separated into optical counterparts by known methods, such as separation of its diastereomer salts obtained with an optically active acid or base, and liberation of the optically active acidic or basic compound. Therefore, the compounds of the present invention may be decomposed into their optical counterparts using the basic moiety by fractional crystallization of salts formed with an optically active acid, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic products can also be separated by chiral chromatography, such as high-pressure liquid chromatography (HPLC) with a chiral adsorbent.

[0104] Furthermore, the compounds of the present invention, including their salts, may also be obtained in the form of their hydrates or may contain other solvents used for their crystallization. The compounds of the present invention may spontaneously or intentionally form solvated compounds with pharmaceutically acceptable solvents (including water); in particular, the present invention is therefore intended to encompass both solvated and non-solvated forms. The term "solvated compound" refers to a molecular complex of the compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, such as water and ethanol, which are known to be harmless to recipients. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0105] The compounds of the present invention, including their salts, hydrates, and solvated compounds, may spontaneously or intentionally form polymorphs.

[0106] Typically, the compound of formula (I) can be prepared according to the following scheme.

[0107] Scheme 1 [ka] Step 1: Compounds of formula (III) (wherein R2, R3, R4, and L are as defined herein with respect to the compound of formula (I)) can be prepared by coupling a compound of formula (IV) (wherein the B(OR)2 portion forms a boronic acid derivative) (for example, R is hydrogen or pinacol) with a compound of formula (V) (wherein R2, R3, R4, and L are as defined herein with respect to the compound of formula (I)) in the presence of a suitable catalyst, which is preferably a palladium-based catalyst such as dioxane or 2-methyl-2-butanol, a base such as potassium carbonate, for example, and preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Compounds of formulas IV, V, III, and II may be used in free form or in salt form.

[0108] Step 2: The compound of formula (II) (wherein R2, R3, R4, and L are as defined herein with respect to the compound of formula (I)) can be prepared by treating the compound of formula (III) (wherein R2, R3, R4, and L are as defined herein with respect to the compound of formula (I)) with a suitable base, such as lithium hydroxide or sodium hydroxide, in the presence of a suitable solvent, such as an alkanol, such as tetrahydrofuran or methanol. The addition of an acid, such as HCl, yields the corresponding salt of the compound of formula II, such as a hydrochloride salt.

[0109] Step 3: Compounds of formula (I) (wherein R1, R2, R3, R4, and L are as defined herein) can be prepared by coupling a compound of formula (II) (wherein R2, R3, R4, and L are as defined herein with respect to the compound of formula (I)) with a suitable amine having formula R1-NH2 (wherein R1 is as defined herein with respect to the compound of formula (I), such as trans-4-aminocyclohexanol, a suitable amide coupling reagent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate, or a base such as N-methylmorpholine or triethylamine, in the presence of a suitable solvent such as N,N-dimethylformamide or acetonitrile.

[0110] Compounds of formulas (IV) and (V) can be obtained as described in the following examples.

[0111] Scheme 2 [ka] Step 1: The compound of formula (VII) (wherein R1 is as defined herein with respect to the compound of formula (I)) can be obtained by treating the compound of formula (VIII) with a suitable amine of formula R1-NH2, such as trans-4-aminocyclohexanol, a suitable amide coupling reagent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate, and a base such as N-methylmorpholine, in the presence of a suitable solvent such as N,N-dimethylformamide.

[0112] Step 2: Compounds of formula (VI) (wherein R1 is as defined herein with respect to the compound of formula (I), and the B(OR)2 portion forms a boronic acid derivative) (for example, R is hydrogen or pinacol) can be obtained by coupling a compound of formula (VII) (wherein R1 is as defined herein with respect to the compound of formula (I)) with a boron compound, such as bis(pinacolato)diboron, in the presence of a suitable solvent, such as dioxane, a salt, such as potassium acetate, and a suitable catalyst, preferably a palladium-based catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0113] Step 3: Compounds of formula (I) (wherein R1, R2, R3, R4, and L are as defined herein) can be obtained by coupling a compound of formula (VI) (wherein R1 is as defined herein with respect to the compound of formula (I), and the B(OR)2 portion forms a boronic acid derivative) (for example, R is hydrogen or pinacol) with a compound of formula (V) (wherein R2, R3, R4, and L are as defined herein with respect to the compound of formula (I)) in the presence of a suitable catalyst, which is preferably a palladium-based catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0114] Scheme 3 [ka] Step 1: Compounds of formula (VIII) (wherein R2, R3, L, R4 are as defined herein with respect to the compounds of formula (I), and the B(OR)2 portion forms a boronic acid derivative) (for example, R is hydrogen or pinacol) can be obtained by coupling a compound of formula (V) (wherein R2, R3, L, R4 are as defined herein with respect to the compounds of formula (I)) with a boron compound, such as bis(pinacolato)diboron, in the presence of a suitable catalyst, such as a suitable solvent, such as dioxane, a salt, such as potassium acetate, and preferably a palladium-based catalyst, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), or alternatively, in a suitable solvent, such as tetrahydrofuran, and a strong base, such as a mixture of n-butyllithium or isopropylmagnesium chloride or both, and a boron compound, such as trimethylboronic acid.

[0115] Step 2: Compounds of formula (I) (wherein R1, R2, R3, R4, and L are as defined herein) can be obtained by coupling a compound of formula (VIII) (wherein R2, R3, L, and R4 are as defined herein with respect to the compound of formula (I), and the B(OR)2 portion forms a boronic acid derivative) (for example, R is hydrogen or pinacol) with a compound of formula (VII) (wherein R1 is as defined herein with respect to the compound of formula (I)) in the presence of a suitable catalyst, which is preferably a palladium-based catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).

[0116] Scheme 4 [ka] Step 1: The compound of formula (IX) (wherein R2 and R3 are as defined herein with respect to the compound of formula (I)) can be obtained by treating the compound of formula (X) (wherein R2 and R3 are as defined herein with respect to the compound of formula (I)) with N-methyliminodiacetic acid in the presence of a suitable solvent, such as DMF.

[0117] Step 2: Compounds of formula (VIII-1) (wherein R1, R2, R3, R4, and L are as defined herein) can be obtained by treating a compound of formula (IX) (wherein R2 and R3 are as defined herein with respect to the compound of formula (I)) with a suitable amine, a suitable reducing agent such as sodium triacetoxyborate, and an acid such as acetic acid, in the presence of a suitable solvent such as THF.

[0118] Step 3: Compounds of formula (I) (wherein R1, R2, R3, R4, and L are as defined herein) can be obtained by coupling a compound of formula (VIII-1) (wherein R2, R3, L, and R4 are as defined herein with respect to the compound of formula (I)) with a compound of formula (VII) (wherein R1 is as defined herein with respect to the compound of formula (I)) in the presence of a suitable catalyst, which is preferably a palladium-based catalyst such as (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride.

[0119] In a further embodiment, the present invention is a) The step of coupling a compound of formula (II) as defined herein with a compound of formula R1-NH2 as defined herein to obtain a compound of formula (I); b) The step of collecting the compound of formula (I) in the free form or pharmaceutically acceptable salt form obtained in this manner. The present invention relates to a method for preparing a compound of formula (I) in free form or in a pharmaceutically acceptable salt form, comprising the above.

[0120] In a further embodiment, the present invention is a) A step of coupling a compound of formula (VI) as defined herein with a compound of formula (V) as defined herein to obtain a compound of formula (I), b) The step of collecting the compound of formula (I) in the free form or pharmaceutically acceptable salt form obtained in this manner. The present invention relates to a method for preparing a compound of formula (I) in free form or in a pharmaceutically acceptable salt form, comprising the above.

[0121] In a further embodiment, the present invention is a) The step of coupling a compound of formula (VIII) or a compound of formula (VIII-1) as defined herein with a compound of formula (VII) as defined herein to obtain a compound of formula (I); b) The step of collecting the compound of formula (I) in the free form or pharmaceutically acceptable salt form obtained in this manner. The present invention relates to a method for preparing a compound of formula (I) in free form or in a pharmaceutically acceptable salt form, comprising the above.

[0122] The present invention further includes any variation of the method of the present invention, wherein an intermediate product available at any stage is used as a starting material to carry out the remaining steps; or the starting material is formed in situ under reaction conditions; or the reactants are used in the form of their salts or optically pure materials.

[0123] The compounds and intermediates of the present invention can also be converted to each other by methods commonly known to those skilled in the art.

[0124] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For the purposes of the present invention, unless otherwise specified, solvated compounds and hydrates are generally considered to be compositions. Preferably, the pharmaceutically acceptable carriers are sterile. The pharmaceutical composition may be formulated for specific routes of administration, such as oral, parenteral, rectal, or transdermal administration. Furthermore, the pharmaceutical composition of the present invention may be in solid form (but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (but not limited to solutions, suspensions, or emulsions). The pharmaceutical composition may be subjected to conventional pharmaceutical operations such as sterilization, and / or may contain conventional inert diluents, smoothing agents, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0125] Typically, a pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient in combination with one or more of the following: a) Diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) Lubricants such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; In tablets, c) Binders such as, for example, aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired d) Disintegrants such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavorings, and sweeteners.

[0126] The tablets may be coated with either a film coating or an enteric coating according to methods known in the art.

[0127] Compositions suitable for oral administration contain an effective amount of the compound of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions for oral use are prepared according to any method known in the art of the manufacture of pharmaceutical compositions, and in order to provide pharmaceutically elegant and palatable preparations, such compositions may contain one or more activators selected from the group consisting of sweeteners, flavorings, colorings, and preservatives. Tablets may contain the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and smoothing agents such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be provided as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0128] Compounds of formula (I), in free or pharmaceutically acceptable salt forms, exhibit beneficial pharmacological properties, such as ALK-2 modulating properties, as demonstrated in in vitro and in vivo studies provided in the following sections, and are therefore suitable for therapeutic use or, for example, for use as a research chemical as a tool compound.

[0129] The compounds of the present invention may be useful in the treatment of indications selected from ectopic ossification or progressive ossifying fibrodysplasia.

[0130] While we do not wish to be constrained by theory, the compounds of the present invention, which are selective ALK-2 inhibitors, are thought to reduce / inhibit BMP signaling and associated abnormal tissue repair.

[0131] Accordingly, in further embodiments, the present invention provides the use of compounds of formula (I) or its sub-chemical formulas (Ia), (II), (IIa), and (IIb) in free or pharmaceutically acceptable salt forms in therapeutic applications. In further embodiments, the therapeutic application is selected from diseases that may be treated by inhibition of the ALK-2 receptor. In another embodiment, the disease is selected from heterotopic ossification or fibrodysplasia ossificans progressive.

[0132] Accordingly, in further embodiments, the present invention provides compounds of formula (I) or its sub-formulas (Ia), (II), (IIa), and (IIb) in free or pharmaceutically acceptable salt forms for therapeutic use. In further embodiments, the therapeutic method is selected from diseases that may be treated by inhibition of the ALK-2 receptor. In another embodiment, the disease is selected from ectopic ossification or fibrodysplasia ossificans progressive.

[0133] In another embodiment, the present invention provides a method for treating a disease treated by inhibition of the ALK-2 receptor, comprising the step of administering a therapeutically acceptable amount of a compound of formula (I) or its sub-chemical formulas (Ia), (II), (IIa), (IIb) in free form or in pharmaceutically acceptable salt form. In a further embodiment, the disease is selected from ectopic ossification or fibrodysplasia ossificans progressively.

[0134] Accordingly, in further embodiments, the present invention provides the use of compounds of formula (I) or its sub-chemical formulas (Ia), (II), (IIa), and (IIb) in free or pharmaceutically acceptable salt forms for the manufacture of a drug. In further embodiments, the drug is for the treatment of a disease which may be treated by inhibition of the ALK-2 receptor. In another embodiment, the disease is selected from ectopic ossification or fibrodysplasia ossificans progressive.

[0135] One embodiment of the present invention provides 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide in its free form or a pharmaceutically acceptable salt thereof, particularly one of the modifications referred to herein, for use in the treatment of ectopic ossification or fibrodysplasia ossificans progressively.

[0136] In one embodiment, 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide is provided in its free form or a pharmaceutically acceptable salt thereof, particularly one of the modifications referred to herein, for use in the treatment of ectopic ossification or fibrodysplasia ossificans progressively.

[0137] In one embodiment, 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide is provided in its free form or a pharmaceutically acceptable salt thereof, particularly one of the modifications referred to herein, for use in the treatment of ectopic ossification or fibrodysplasia ossificans progressively.

[0138] The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperatures are given in Celsius. Unless otherwise specified, all evaporation is carried out under reduced pressure, typically about 15 mmHg to 100 mmHg (= 20 to 133 millibars). The structures of the final product, intermediates, and starting materials are confirmed by standard analytical methods, such as trace analysis, and by spectroscopic properties, such as MS, IR, and NMR. Abbreviations used are those commonly used in the art.

[0139] All starting materials, basic elements, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those skilled in the art, or by the methods described in the examples or similar methods. Furthermore, the compounds of the present invention can be produced by organic synthesis methods known to those skilled in the art, as shown in the following examples. [Examples]

[0140] Abbreviation δ chemical shift Acetic acid (ACOH) aq rr aq. Water-based APCI-MS atmospheric pressure chemical ionization mass spectrometry BH3DMS Boranedimethyl sulfide complex Saturated sodium chloride solution n-BuLi n-butyllithium DCM Dichloromethane DMAP 4-(dimethylamino)pyridine DMF (N,N-dimethylformamide) DIPEA Diisopropylethylamine DMSO (Dimethyl Sulfoxide) DSC (Differential Scanning Calorimetry) DVS Dynamic Steam Adsorption eq equivalent Et ethyl Et3N triethylamine HCl ethyl acetate EtOH Ethanol ESI-MS (Electron Spray Ionization Mass Spectroscopy) FIA-MS Flow Injection Mass Spectroscopy FT-IR Fourier Transform Infrared Spectroscopy h time HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate HPLC (High-Performance Liquid Chromatography) HRMS high-resolution mass spectrometry IPA Isopropanol Isopropyl acetate (IPAc) i-PrOH Isopropanol IT internal temperature K2CO3 potassium carbonate K3PO4 potassium phosphate KOAc Potassium Acetate L (liters) LC-MS Liquid Chromatography-Mass Spectrometry LiAlH4 Lithium Aluminum Hydrogenated (Lithium) LiOH (Lithium Hydroxide) M molar concentration MCC (Microcrystalline Cellulose) mg milligrams mM millimolar concentration MeOH methanol min mL (milliliter) MgSO4 Magnesium Sulfate MHz (megahertz) MTBE methyl tert-butyl ether N Normal Sodium sulfate (Na2SO4) NaHCO3 (sodium bicarbonate) NaHMDS (Sodium-Bis(Trimethylsilyl))amide NaOH (Sodium Hydroxide) NH4Cl (Ammonium Chloride) NH4OH Ammonium hydroxide NH4OAc (Ammonium acetate) NMR nuclear magnetic resonance PdCl2(dppf) or Pd(dppf)Cl2[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) PdCl2(PPh3)2-bis(triphenylphosphine)palladium(II) chloride PrepHPLC (Preparative High-Performance Liquid Chromatography) ppm parts per million RT or rt Room temperature (23±3℃) sat. saturation SFC Supercritical Fluid Chromatography SPE solid phase extraction TEA (Triethylamine) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TGA thermogravimetric analysis t R Duration of stay UPLC-MS Ultrafast Liquid Chromatography Mass Spectroscopy XPhos Pd (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride XRPD (X-ray Powder Diffraction)

[0141] Analysis method 1H-NMR Measurements were performed using Bruker Ultrashield® 400 (400 MHz), Bruker Ultrashield® 600 (600 MHz), 400 MHz DRX Bruker Cryo Probe (400 MHz), or 500 MHz DRX Bruker Cryo Probe (500 MHz) spectrometers, with or without trimethylsilane as an internal standard. Chemical shifts (δ values) were reported in ppm at low magnetic fields from tetramethylsilane, and spectral resolving patterns were singlet (s), doublet (d), triplet (t), quadruplet (q), multiplet, unresolved or more overlapping signals (m), and broadband signals (bs). The solvent is indicated in parentheses.

[0142] UPLC-MS Column: Waters Acquity HSS T3, C18, 1.8 μm, 2.1 × 50 mm, oven at 60°C. Flow rate: 1.0 mL / min. Gradient: 1.40 min at 5%~98% B, then 0.40 min at 98% B, 0.10 min at 98%~5% B, and 0.10 min at 5% B; A = water + 0.05% formic acid + 3.75 mM NH4OAc, B = acetonitrile + 0.04% formic acid. Detection: UV / VIS (DAD), ESI (±). Mass spectrometer range: 100~1200 Da.

[0143] For Examples 46, 56, 74, 81, 85, and 87: Column: Waters Acquity BEH, C18, 1.7 μm, 2.1 × 50 mm, oven at 50°C. Flow rate: 1.0 mL / min. Gradient: 2% to 98% B for 4.40 minutes, then 98% B for 0.75 minutes, then 98% to 2% B for 0.04 minutes; A = water + 0.1% formic acid, B = acetonitrile + 0.1% formic acid. Detection: UV / VIS (DAD), ESI (±). Mass spectrometer range: 100 to 1200 Da.

[0144] UPLC-HRMS: Waters Acquity SDS, C18, 1.7 μm, 2.1 × 50 mm, oven at 50°C. Gradient: 7.50 minutes at 5% to 98% B, then 0.40 minutes at 98% B, then 0.15 minutes at 98% to 5% B; A = water + 5 mM NH4OH, B = acetonitrile + 5 mM NH4OH. Detection: UV / VIS (DAD), ESI (±). Mass spectrometer range: 100 to 1200 Da.

[0145] HPLC-MS Column: Waters Symmetry C8, 3.5 μm, 2.1 × 50 mm, oven at 50°C; Flow rate: 1.0 mL / min. Gradient: 10% to 95% B for 2 minutes, then 95% B for 1 minute, 95% to 10% B for 0.5 minutes, 10% B for 0.50 minutes; A = water + 0.1% TFA, B = acetonitrile + 0.1% TFA. Detection: UV / VIS (DAD), APCI (+). Mass spectrometer range: 100 to 1200 Da.

[0146] Optical rotation measurement Optical rotation was measured using a Perkin Elmer PE241 series No. 5325 polarimeter operating at 589 nm, with chloroform as the solvent.

[0147] Purification method PrepHPLC Gilson GX-281, pump 331 / 332. Column: Waters Sunfire C18, 30 x 100 mm, 5 μm. Flow rate: 30 mL / min. Mobile phase: Water (containing 0.1% TFA) and acetonitrile (Method 1a) or: Column: X-Bridge C18, 30×50mm, 5μm. Flow rate: 75mL / min. Mobile phase: Water (containing 5 mM NH4OH) and acetonitrile (Method 1b)

[0148] Normal-phase flash chromatography Teledyne ISCO CombiFlash: Column: Redisep RF Silica Flash Mobile phase: Cyclohexane / SiO (Method 2a) or DCM / MeOH (Method 2b). Biotage Flash-Master II: Column: Prefilled with silica gel 60 (40-63 μm) from Merck. Mobile phase: DCM and MeOH (containing 7.3 mM NH4OH) (Method 2c).

[0149] Reverse-phase flash chromatography: Teledyne ISCO CombiFlash: Redisep Rf Gold C18 High Performance column, 15.5g, 50g, or 240g pre-packed column, 20-40μm, 100A Mobile phase: Water and acetonitrile (containing 7.3 mM NH4OH) (Method 3a) or water (containing 0.1% TFA) and acetonitrile (Method 3b).

[0150] Example 1: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] To a solution of 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide TFA salt (intermediate 1a, 80 mg, 0.158 mmol) in DCM (4 mL), 1-(methylsulfonyl)piperidine-4-one (30.8 mg, 0.174 mmol) and AcOH (0.018 mL, 0.316 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 45 °C for 30 minutes. Sodium triacetoxyborate (84 mg, 0.395 mmol) was added at room temperature, and the reaction mixture was stirred at 45 °C for 1 hour. Next, the reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and mixed with ethyl acetate. After phase separation, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (Method 2b) to obtain the title compound as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.31(d,1H),8.11(d,1H),7.59(d,2H),7.24(d,2H),7.12(s,2H),4.58(d,1H),3.80-3.63(m,1H),3.45-3.36(m,4H),3. 15(dd,1H),2.89-2.83(m,5H),2.65(dd,1H),2.35-2.29(m,1H),1.98-1.81(m,7H),1.57-1.18(m,8H),0.83-0.70(m,1H).(UPLC-MS)t R0.49 min;ESI-MS 554[M+H] + .

[0151] Intermediate 1a: 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide To a solution of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b, 940 mg, 1.55 mmol) in dioxane (10 mL), a 4 M solution of HCl in dioxane (1.55 mL, 6.20 mmol) was added at room temperature. The reaction mixture was stirred at 65 °C for 5 hours, then concentrated under reduced pressure to obtain the title compound as its hydrochloride salt. The title compound was further purified by prepHPLC (method 1a), and after evaporation of the solvent, the TFA salt was obtained. (UPLC-MS) R 0.45 min;ESI-MS 393[M+H] + .

[0152] Intermediate 1b: (1R,5S)-tert-butyl 1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 1c, 630 mg, 1.59 mmol) in DMF (10 mL), trans-4-aminocyclohexanol (290 mg, 1.91 mmol), HATU (909 mg, 2.39 mmol), and N-methylmorpholine (0.53 mL, 4.78 mmol) were added at room temperature. The reaction mixture was stirred for 2 hours, diluted with saturated aqueous solution of NaHCO3, and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by prepHPLC (Method 1a) to obtain the title compound as a colorless solid. (UPLC-MS) R 1.00 min;ESI-MS 493[M+H] + .

[0153] Intermediate 1c: 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid A solution of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1d, 1.00 g, 2.44 mmol) in THF (15 mL) was mixed with a 2 M aqueous solution of LiOH (3.66 mL, 7.33 mmol) at room temperature. The reaction mixture was stirred at 65 °C for 2 hours and then concentrated under reduced pressure. The crude product was purified by prepHPLC (Method 1a) to obtain the title compound. (UPLC-MS) R 0.92 minutes;ESI-MS 396[M+H] + .

[0154] Intermediate 1d: (1R,5S)-tert-butyl-1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate Racemic tert-butyl-1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1e, 13.5g, 33.0 mmol) was chiral-prepared into SFCs (Waters SFC200, Waters SFC200, CHIRALPAK AD-H5μm30). * Separation was performed by 250 mm, mobile phase CO2 / i-PrOH 70:30, flow rate 120 g / min; UV detection at 278 nm. After concentration under reduced pressure, the title compound was obtained as a grayish-white solid. Chiral analysis was performed using an SFC (CHIRALPAK AD-3 3 μm²). * 100mm, mobile phase CO2 / MeOH + 0.1%DEA 60:40, flow rate 1mL / min; UV detection at 274nm):t R 2.30 minutes, ee=98.6%, [α] D 20 = +90°.

[0155] Intermediate 1e: tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl 1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (prepared as described in International Publication No. 2007 / 022935) (3.34 g, 9.38 mmol) in dioxane (75 mL), methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (prepared as described in International Publication No. 2012 / 087938) (3.91 g, 14.1 mmol) was added. A 2 M aqueous solution of K2CO3 (9.38 mL, 18.8 mmol) and Pd(dppf)Cl2-DCM adduct (0.766 g, 0.938 mmol) was added under a nitrogen atmosphere, and the mixture was heated under a nitrogen atmosphere at 80°C for 18 hours. The reaction mixture was diluted with 150 mL of water and extracted three times with dimethyl acetate. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by normal-phase chromatography (Method 2b) to obtain the title compound as a grayish-white solid. (UPLC-MS) R 1.29 minutes;ESI-MS 410[M+H] + .

[0156] Example 2: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] To a solution of 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate TFA salt (intermediate 2a, 117 mg, 0.259 mmol) in DMF (3 mL), trans-4-aminocyclohexanol hydrochloride (39.3 mg, 0.259 mmol), HATU (148 mg, 0.389 mmol), and N-methylmorpholine (0.085 mL, 0.778 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then diluted with saturated aqueous solution of NaHCO3 and mixed with ethyl acetate. After phase separation, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by prepHPLC (method 1a) to obtain the title compound as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.11(d,1H),7.58(d,2H),7.23(d,2H),7.12(s,2H),4.58(d,1H),3.82-3.66(m,1H),3.48-3.3 4(m,3H),3.07(d,1H),2.64-2.55(m,2H),1.96-1.77(m,5H),1.50-1.19(m,5H),1.04(dd,6H),0.75(dd,1H).(UPLC-MS)t R 0.50 min; ESI-MS 435[M+H] + .

[0157] Intermediate 2a: 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate TFA salt A solution of methyl 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 2b, 660 mg, 1.22 mmol) in THF (10 mL) was mixed with a 2 M aqueous solution of LiOH (1.22 mL, 2.44 mmol) at room temperature. The reaction mixture was stirred at 65 °C for 2 hours and then concentrated under reduced pressure. The crude product was purified by prepHPLC (Method 1a) to obtain the title compound as the TFA salt. (UPLC-MS) R0.37 min;ESI-MS 338[M+H] + .

[0158] Intermediate 2b: Methyl 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate To a solution of methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (prepared as described in International Publication No. 2012 / 087938) (462 mg, 1.663 mmol) in acetonitrile (7 mL), (1R,5S)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane (intermediate 2c, 466 mg, 1.66 mmol), 2 M aqueous K2CO3 (1.66 mL, 3.33 mmol), and PdCl2(dppf)-DCM adduct (67.9 mg, 0.083 mmol) were added at room temperature. The reaction mixture was sealed and irradiated in a microwave reactor at 120 °C for 10 minutes, then cooled, filtered on Celite, diluted in saturated aqueous NaHCO3, and mixed with ELISA. After phase separation, the aqueous layer was extracted again with ELISA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was used without further purification. (UPLC-MS)t R 0.62 min;ESI-MS 352[M+H] + .

[0159] Intermediate 2c: (1R,5S)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane To a solution of (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (prepared as described in International Publication No. 2007 / 022935) (525 mg, 2.21 mmol) in acetonitrile (10 mL), 2-iodopropane (0.420 mL, 2.65 mmol) and K2CO3 (609 mg, 4.41 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 65 °C for 3 hours, then diluted with ethyl acetate and mixed with a saturated aqueous solution of NaHCO3. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound as a grayish-white solid. (UPLC-MS)t R 0.72 min; ESI-MS 280 / 282[M+H] + .

[0160] Example 3: 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] To a solution of (6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)boronic acid (intermediate 3a, 300 mg, 0.645 mmol) in dioxane (5 mL), (R)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (intermediate 3b, 420 mg, 0.774 mmol), PdCl2 (dppf) (23.6 mg, 0.032 mmol), and 2N aqueous NaOH (0.645 mL, 1.29 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 2 hours and then diluted with HCl and water. After two extractions with HCl, the organic layer was washed with saturated aqueous solution of NaHCO3 and brine, respectively, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in MeOH and passed through a silica-thiol cartridge (loaded with 500 mg; pre-prepared with MeOH) to remove palladium. The filtrate was concentrated under reduced pressure. The residue was purified by normal-phase chromatography (Method 2b) to obtain the title compound as a brownish solid. 1H NMR(400MHz,DMSO-d6)δ 8.37(d,1H),8.27(d,1H),8.09-8.14(m,1H),7.57(bs,2H),7.33(bs,2H),7.12(bs,2H),4.54-4.58(m,1H),4.51-4.66(m,3H),3.55-3.81(m, (UPLC-MS)t R 0.45 min; ESI-MS 437[M+H] + .

[0161] Intermediate 3a: (6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)boronic acid. To a solution of 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (intermediate 3c, 1.00 g, 2.67 mmol) in dioxane (25 mL), bis(pinacolate)diboron (0.815 g, 3.21 mmol), PdCl2 (dppf) (0.098 g, 0.134 mmol), and KOAc (0.525 g, 5.35 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 18 hours, cooled, filtered through a Celite pad, and concentrated under reduced pressure to obtain the title compound as a crude brownish solid (the pinacolate ester was hydrolyzed under reaction conditions), which was used without further purification. (UPLC-MS)t R 0.32 min; ESI-MS 280[M+H] + .

[0162] Intermediate 3b: (R)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane. To a solution of (R)-1-(4-bromophenyl)ethanamine (0.216 mL, 1.499 mmol) in DMF (7 mL), DIPEA (0.524 mL, 3.00 mmol) and 3,3-bis(bromomethyl)oxetane (439 mg, 1.80 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 5 hours, cooled, and diluted with water and ethyl acetate. After phase separation, the aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound as a yellow oil, which was used without further purification. (UPLC-MS)t R 0.52 min; ESI-MS 282 / 284[M+H] + .

[0163] Intermediate 3c: 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide. To a solution of 2-amino-5-bromonicotinic acid (2.00 g, 9.22 mmol) in DMF (30 mL), trans-4-aminocyclohexanol (1.68 g, 11.1 mmol), HATU (7.01 g, 18.4 mmol), and N-methylmorpholine (4.05 mL, 36.9 mmol) were added at room temperature. After stirring for 2 hours, the reaction mixture was diluted with SiO2 and saturated aqueous solutions of NaHCO3. The aqueous phase was extracted twice with SiO2. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (Method 2a) to obtain the title compound as a yellow solid. (UPLC-MS) R 0.62 min;ESI-MS 314 / 316[M+H] + .

[0164] Example 4: 5-(4-((S)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 5-(4-((R)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 3), except that (S)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (Intermediate 4a) was used instead of (R)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (Intermediate 3b). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, 1H), 8.27 (d, 1H), 8.09 - 8.14 (m, 1H), 7.57 (bs, 2H), 7.33 (bs, 2H), 7.12 (bs, 2H), 4.54 - 4.58 (m, 1H), 4.51 - 4.66 (m, 3H), 3.55 - 3.81 (m, 1H), 3.35 - 3.54 (m, 2H), 3.20 - 3.24 (m, 1H), 3.20 - 3.27 (m, 2H), 3.15 (bs, 1H), 1.78 - 1.91 (m, 4H), 1.14 - 1.41 (m, 5H), 1.11 (bs, 3H). (UPLC-MS) t R 0.45 minutes; ESI-MS 437 [M+H] + .

[0165] Intermediate 4a: (S)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane The title compound was prepared in a similar manner to (R)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (Intermediate 3b), except that (S)-1-(4-bromophenyl)ethanamine was used instead of (R)-1-(4-bromophenyl)ethanamine. (UPLC-MS) t R 0.55 minutes; ESI-MS 282 / 284 [M+H] + .

[0166] Example 5: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(3-morpholinopropyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide [ka] To a solution of 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide TFA salt (intermediate 5a, 70 mg, 0.138 mmol) in acetonitrile (3 mL), K2CO3 (47.7 mg, 0.345 mmol) and 4-(3-bromopropyl)morpholine (47.9 mg, 0.166 mmol) were added at room temperature. The reaction mixture was stirred at 65 °C for 2 hours. The reaction mixture was then diluted with a saturated aqueous solution of NaHCO3 and mixed with ethyl acetate. After phase separation, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by prepHPLC (method 1a) to obtain the title compound as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.11(d,1H),7.58(d,2H),7.22(d,2H),7.12(s,2H),4.58(d,1H),3.82-3.67(m,1H),3.61-3.50(m,4) (UPLC-MS)t R 0.40 min;ESI-MS 520[M+H] + .

[0167] Intermediate 5a: 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide To a solution of (1S,5R)-tert-butyl 1-(4-(6-amino-5-(((1r,4S)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 5b, 1.18 g, 1.95 mmol) in dioxane (10 mL), a 4 M solution of HCl in dioxane (1.95 mL, 7.78 mmol) was added at room temperature. The reaction mixture was stirred at 65 °C for 5 hours, then concentrated under reduced pressure to obtain the title compound as its hydrochloride salt. The product was further purified by prepHPLC (Method 1a), and after evaporation of the solvent, the title compound was obtained as the TFA salt. (UPLC-MS) R 0.45 min;ESI-MS 393[M+H] + .

[0168] Intermediate 5b: (1S,5R)-tert-butyl 1-(4-(6-amino-5-(((1r,4S)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate The title compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 5c) was used instead of (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b). (UPLC-MS)t R 1.00 min;ESI-MS 493[M+H] + .

[0169] Intermediate 5c: 2-amino-5-(4-((1S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinic acid (Intermediate 1c), except that (1S,5R)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 5d) was used instead of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 1d). (UPLC-MS) t R 0.92 minutes; ESI-MS 396 [M+H] + .

[0170] Intermediate 5d: (1S,5R)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate Racemic tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridin-3-yl)phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (Intermediate 1e, 13.5 g, 33.0 mmol) was separated by chiral preparative SFC (CHIRALPAK AD-H 5 μm 30 * 250 mm, mobile phase CO2 / i-PrOH 70:30, flow rate 120 g / min; UV detection at 278 nm). After concentration under reduced pressure, the title compound was obtained as an off-white solid. HPLC for chiral analysis (CHIRALPAK AD-3 3 μm 2 * 100 mm, mobile phase CO2 / MeOH + 0.1% DEA 60:40, flow rate 1 mL / min; UV detection at 274 nm): t R 2.90 minutes, ee = 98.7%, [α] D 20 = -87°.

[0171] Example 6: 2-Amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] To a solution of 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide TFA salt (intermediate 1a, 70 mg, 0.138 mmol) in acetonitrile (3 mL), K2CO3 (38.2 mg, 0.276 mmol) and 1,3-difluoropropane-2-yltrifluoromethanesulfonate (intermediate 6a) (37.8 mg, 0.166 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then diluted with saturated aqueous solution of NaHCO3 and mixed with butyl. After phase separation, the aqueous layer was extracted again with butyl. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by prepHPLC (method 1a) to obtain the title compound. 1H NMR(400MHz,DMSO-d6)δ 8.41(d,1H),8.37(d,1H),8.18(s,1H),7.62(s,2H),7.35(d,1H),7.25(m,3H),4.64( d,3H),3.74(m,4H),2.89(d,4H),1.87(t,5H),1.34(m,6H),0.82(s,1H).(UPLC-MS)t R 0.68 min;ESI-MS 471[M+H] + .

[0172] Intermediate 6a: 1,3-difluoropropane-2-yltrifluoromethanesulfonate To a solution of 1,3-difluoropropan-2-ol (300 mg, 3.12 mmol) in DCM (8 mL), DMAP (26.7 mg, 0.219 mmol) and TEA (0.522 mL, 3.75 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was cooled to 0°C, and trifluoromethanesulfonic anhydride (0.630 mL, 3.75 mmol) was added. After stirring at 0°C for 60 minutes and at room temperature for 3 hours, the reaction mixture was diluted with DCM. The organic layer was washed twice with aqueous citric acid solution and twice with saturated aqueous NaHCO3 solution, dried over MgSO4, and concentrated at 500 mgbar. The labeled compound was obtained as crude oil and used without further purification.

[0173] Example 7: 2-Amino-N-(4-Hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 7a) instead of 2-amino-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 7a) and trans-4- The compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride was used instead of aminocyclohexanol. The crude product was purified first by prepHPLC (method 1a) and then by reverse-phase flash chromatography (method 3a) to obtain the title compound as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 8.34(d,1H),7.98(d,1H),7.79(s,1H),7.57(d,2H),7.21(d,2H),6.92(s,2H),4.32(s,1H),3.45(t,2H),3.41-3.29(m,2H),3.27(s, (UPLC-MS)t R 0.52 min;ESI-MS 477[M+H] + .

[0174] Intermediate 7a: 2-amino-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 2c), except that methyl 2-amino-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 7b) was used instead of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1d). (UPLC-MS)t R 0.32 min; ESI-MS 354[M+H] + .

[0175] Intermediate 7b: Methyl 2-amino-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate To a solution of methyl 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-aminonicotinate hydrochloride (intermediate 7c, 210 mg, 0.607 mmol) in acetonitrile (6 mL), K2CO3 (168 mg, 0.729 mmol) and 1-bromo-2-methoxyethane (0.068 mL, 0.729 mmol) were added at room temperature. The reaction mixture was stirred at 65 °C for 3 hours. The reaction mixture was then diluted with a saturated aqueous solution of NaHCO3 and mixed with ethyl acetate. After phase separation, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound, which was used without further purification. (UPLC-MS)t R 0.62 min; ESI-MS 368[M+H] + .

[0176] Intermediate 7c: Methyl 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-aminonicotinate hydrochloride A solution of (1S,5R)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 5d, 500 mg, 1.22 mmol) in dioxane (7 mL) was mixed with a 4 M solution of HCl in dioxane (1.22 mL, 4.88 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 3 hours, then concentrated under reduced pressure to obtain the title compound as its hydrochloride salt. (UPLC-MS)t R 0.58 min; ESI-MS 310[M+H] + .

[0177] Example 8: 2-Amino-5-(2-Fluoro-4-(4-Isopropylpiperazine-1-yl)phenyl)-N-((1r,4r)-4-Hydroxycyclohexyl)Nicotinamide [ka] To a solution of 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (intermediate 3c, 230 mg, 0.731 mmol) in dioxane (4 mL), 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (intermediate 8a, 463 mg, 0.731 mmol), 2N aqueous K2CO3 (0.73 mL, 1.46 mmol), and PdCl2(dppf)-DCM adduct (29.9 mg, 0.037 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80°C for 60 minutes and then diluted with ELISA and aqueous NaHCO3. After phase separation, the aqueous layer was extracted with ELISA. The organic layer was washed with saturated aqueous solution of NaHCO3 and brine, respectively, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by prepHPLC (Method 1a) to obtain the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.24-8.16 (m,2H), 7.95 (d,1H), 7.39 (t,1H), 7.06 (s,2H), 6.86 (d,2H), 4.54 (d,1H), 3.69 (m,1H), 3.41-3.33 (m,2H), 3.15 (s,3H), 2.66 (q,3H), 1.82 (m,4H), 1.42-0.88 (m,10H). (UPLC-MS) t R 0.48 min; ESI-MS 456[M+H] + .

[0178] Intermediate 8a: 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine To a solution of 1-(4-bromo-3-fluorophenyl)-4-isopropylpiperazine (intermediate 8b, 212 mg, 0.662 mmol) in dioxane (8 mL), bis(pinacorato)diboron (202 mg, 0.794 mmol), KOAc (130 mg, 1.323 mmol), and PdCl2(dppf)-DCM adduct (27 mg, 0.033 mmol) were added under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at 90°C for 2 hours, then filtered through a Celite pad and concentrated under reduced pressure to obtain the title compound, which was used without further purification. (UPLC-MS)t R 0.79 min;ESI-MS 349[M+H] + .

[0179] Intermediate 8b: 1-(4-bromo-3-fluorophenyl)-4-isopropylpiperazine To a solution of 1-(4-bromo-3-fluorophenyl)piperazine (intermediate 8c, 215 mg, 0.797 mmol) in acetonitrile (7 mL), 2-iodopropane (0.095 mL, 0.956 mmol) and K2CO3 (220 mg, 1.593 mmol) were added at room temperature. The reaction mixture was stirred at 65 °C for 4 hours and then diluted with siRNA and aqueous NaHCO3. After phase separation, the aqueous layer was extracted with siRNA. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound as a colorless oil, which was used without further purification. (UPLC-MS)t R 0.66 min;ESI-MS 302[M+H] + .

[0180] Intermediate 8c: 1-(4-bromo-3-fluorophenyl)piperazine To a solution of tert-butyl 4-(4-bromo-3-fluorophenyl)piperazine-1-carboxylate (300 mg, 0.835 mmol) in dioxane (8 mL), 4N HCl (0.84 mL, 3.34 mmol) in dioxane was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours and then diluted with HCl and aqueous NaHCO3. After phase separation, the aqueous layer was extracted with HCl. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound, which was used without further purification. (UPLC-MS) R 0.60 min; ESI-MS 260[M+H] + .

[0181] Example 9: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 2), except that 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 2) was used instead of 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Intermediate 9a). 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.11(d,1H),7.58(d,2H),7.23(d,2H),7.12(s,2H),4.58(d,1H),3.82-3.66(m,1H),3.48-3.3 4(m,3H),3.07(d,1H),2.64-2.55(m,2H),1.96-1.77(m,5H),1.50-1.19(m,5H),1.04(dd,6H),0.75(dd,1H).(UPLC-MS)t R 0.50 min; ESI-MS 435[M+H] + .

[0182] Intermediate 9a: 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate TFA salt The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate TFA salt (intermediate 2a), except that methyl 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 9b) was used instead of methyl 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 2a). (UPLC-MS)t R 0.37 min;ESI-MS 338[M+H] +.

[0183] Intermediate 9b: Methyl 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate The title compound was prepared in a similar manner to methyl 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 2b), except that (1S,5R)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane (intermediate 9c) was used instead of (1R,5S)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane (intermediate 2b). (UPLC-MS)t R 0.62 min;ESI-MS 352[M+H] + .

[0184] Intermediate 9c:(1S,5R)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane The title compound was prepared in a similar manner to (1R,5S)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane (intermediate 2c), except that (1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (prepared in the same manner as described in International Publication No. 2007 / 022935) was used instead of (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane. (UPLC-MS)t R 0.70 min; ESI-MS 280 / 282[M+H] + .

[0185] Example 10: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 4-(2-bromoethyl)morpholine was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a), and the reaction mixture was stirred at 65°C for 1 hour. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.11(d,1H),7.59(d,2H),7.22(d,2H),7.12(s,2H),4.59(d,1H),3.84-3.67(m,1H),3.63-3.51(m,4H) ,3.46-3.39(m,2H),3.09(d,1H),2.71-2.57(m,3H),2.42(s,6H),1.95-1.75(m,5H),1.53-1.15(m,5H),0.77(d,1H).(UPLC-MS) R 0.49 min;ESI-MS 506[M+H] + .

[0186] Example 11: 2-amino-5-(4-((1S,5R)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 1-bromo-2-fluoroethane was used instead of 4-(3-bromopropyl)morpholine, and the reaction mixture was stirred at 60°C for 5 hours. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.11(d,1H),7.59(d,2H),7.22(d,2H),7.13(s,2H),4.59(d,2H),4.50(s,1H) ,3.73(d,1H),3.41(d,3H),2.83-2.78(m,3H),1.85(t,5H),1.47-1.16(m,6H),0.78(s,1H).(UPLC-MS)t R 0.47 min;ESI-MS 439[M+H] + .

[0187] Example 12: 2-Amino-N-((1r,4r)-4-Hydroxycyclohexyl)-5-(4-(1-Isopropylpyrrolidine-3-yl)phenyl)Nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(2-fluoro-4-(4-isopropylpiperazine-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (Example 8), except that 1-isopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine (intermediate 12a) was used instead of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (intermediate 8a). 1H NMR(400MHz,DMSO-d6)δ 8.36(d,1H),8.26(d,1H),8.09(d,1H),7.62-7.51(m,2H),7.37-7.28(m,2H),7.09(s,2H),4.55(d,1H),3.70(dq,1H),3.44 -3.34(m,2H),3.03(d,1H),2.75(s,2H),2.29-2.06(m,2H),1.87-1.68(m,5H),1.42-1.17(m,5H),1.06(t,6H).(UPLC-MS)t R 0.48 min; ESI-MS 423[M+H] + .

[0188] Intermediate 12a: 1-Isopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine The title compound was prepared in a similar manner to 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (intermediate 8a), except that 3-(4-bromophenyl)-1-isopropylpyrrolidine (intermediate 12b) was used instead of 1-(4-bromo-3-fluorophenyl)-4-isopropylpiperazine (intermediate 8b). (UPLC-MS)t R 0.79 min;ESI-MS 316[M+H] + .

[0189] Intermediate 12b: 3-(4-bromophenyl)-1-isopropylpyrrolidine The title compound was prepared in a similar manner to 1-(4-bromo-3-fluorophenyl)-4-isopropylpiperazine (intermediate 8b), except that 3-(4-bromophenyl)pyrrolidine hydrochloride was used instead of 1-(4-bromo-3-fluorophenyl)piperazine (intermediate 8c). (UPLC-MS)t R 0.62 min;ESI-MS 269[M+H] + .

[0190] Example 13: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 4-(2-bromoethyl)morpholine was used instead of 4-(3-bromopropyl)morpholine. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.11(d,1H),7.59(d,2H),7.22(d,2H),7.12(s,2H),4.59(d,1H),3.84-3.67(m,1H),3.63-3.51(m,4H) ,3.46-3.39(m,2H),3.09(d,1H),2.71-2.57(m,3H),2.42(s,6H),1.95-1.75(m,5H),1.53-1.15(m,5H),0.77(d,1H).(UPLC-MS) R 0.49 min;ESI-MS 506[M+H] + .

[0191] Example 14: 2-Amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a), The preparation was similar to that of (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that trans-4-amino-1-methylcyclohexanol was used instead of trans-4-aminocyclohexanol. The crude product was purified by prepHPLC (method 1a) to obtain the title compound as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 8.53(d,1H),8.46(d,1H),8.35(s,1H),7.72(d,2H),7.71(bs,2H),7.41(d,2H),4.06(dd,1H),3.98(dd,2H),3.85-3.43(m,5H), 3.27(t,2H),2.26(dd,1H),1.99(d,2H),1.83-1.76(m,4H),1.68-1.56(m,3H),1.51-1.45(m,5H),1.21-1.13(m,5H).(UPLC-MS)t R 0.51 min;ESI-MS 491[M+H] + .

[0192] Intermediate 14a: 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (TFA salt) To a solution of methyl 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 14b, 1.30 g, 2.97 mmol) in anhydrous THF (16 mL), a 2 M aqueous solution of LiOH (4.46 mL, 8.92 mmol) was added at room temperature. The reaction mixture was stirred at 65 °C for 140 minutes and then concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (method 3b). The pure fraction was concentrated and lyophilized to obtain the title compound as a grayish-white TFA salt. (UPLC-MS) R 0.40 min;ESI-MS 380[M+H] + .

[0193] Intermediate 14b: Methyl 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate To a solution of methyl 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-aminonicotinate hydrochloride (intermediate 14c, 1.18 g, 3.28 mmol) in DCM (16 mL), dihydro-2H-pyran-4(3H)-one (0.33 mL, 3.60 mmol) and AcOH (0.38 mL, 6.55 mmol) were added at room temperature. The reaction mixture was stirred at 45°C for 30 minutes. Sodium triacetoxyborate (1.74 g, 8.19 mmol) was added at room temperature, and the reaction mixture was stirred at 45°C for 1 hour. The reaction mixture was then diluted with a saturated solution of NaHCO3 and mixed with ELISA. After phase separation, the aqueous layer was extracted again with ELISA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound, which was used without further purification. (UPLC-MS)t R 0.67 minutes;ESI-MS 394[M+H]+.

[0194] Intermediate 14c: Methyl 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-aminonicotinate hydrochloride A solution of (1R,5S)-tert-butyl-1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1d, 1.50 g, 3.66 mmol) in dioxane (25 mL) was mixed with a 4 M solution of HCl in dioxane (3.66 mL, 14.7 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 3 hours, then concentrated under reduced pressure to obtain the title compound as its hydrochloride salt. (UPLC-MS)t R 0.58 min; ESI-MS 310[M+H] + .

[0195] Example 15: 2-Amino-N-(4-Hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 15a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 15a) and trans-4 The compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride was used instead of aminocyclohexanol. The crude product was purified first by prepHPLC (method 1a) and then by reverse-phase flash chromatography (method 3a) to obtain the title compound as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 8.34(d,1H),7.98(d,1H),7.79(s,1H),7.56(d,2H),7.21(d,2H),6.92(s,2H),4.31(s,1H),3.58-3.56(m,4H),3.09(d,1H),2.64 -2.62(m,2H),2.59-2.41(m,9H),2.07-2.04(m,6H),1.82-1.79(m,1H),1.65-1.61(m,6H),1.31(t,1H),0.75(dd,1H).(UPLC-MS)t R 0.53 min;ESI-MS 532[M+H] + .

[0196] Intermediate 15a: 2-amino-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 2c), except that methyl 2-amino-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 15b) was used instead of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1d). (UPLC-MS)t R 0.39 min;ESI-MS 409[M+H] + .

[0197] Intermediate 15b: Methyl 2-amino-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate The title compound was prepared in a similar manner to methyl 2-amino-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 7b), except that methyl 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-aminonicotinate (intermediate 7c) was used instead of methyl 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 7b), and 4-(2-bromoethyl)morpholine was used instead of 1-bromo-2-methoxyethane. (UPLC-MS)t R 0.62 min; ESI-MS 423[M+H] + .

[0198] Example 16: 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 2), except that 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 9a) was used instead of 2-amino-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 2), except that (3-aminobicyclo[1.1.1]pentan-1-yl)methanol (intermediate 16a) was used instead of trans-4-aminocyclohexanol hydrochloride. 1H NMR(400MHz,DMSO-d6)δ 9.05(s,1H),8.41(d,1H),8.18(d,1H),7.61(d,2H),7.48(dd,1H),7.33-7.17(m,4H),4.55(t,1H),3.51(d,3H) ),3.31(s,2H),3.08(s,2H),2.07-1.99(m,1H),1.41-1.22(m,3H),1.17-0.98(m,9H),0.79(d,1H).(UPLC-MS)t R 0.54 min;ESI-MS 433[M+H] + .

[0199] Intermediate 16a: (3-aminobicyclo[1.1.1]pentan-1-yl)methanol To a solution of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate HCl (218 mg, 1.23 mmol) in THF (7 mL), LiAlH4 (140 mg, 3.68 mmol) was added in fractional amounts at 0°C. The reaction mixture was stirred at room temperature for 2 hours, quenched with a mixture of THF and water at 0°C, then filtered through a Celite pad and concentrated under reduced pressure to obtain the title compound as a yellow oil, which was used without further purification. FIA-MS114[M+H] + .

[0200] Example 17: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 3,3,3-trifluoropropyltrifluoromethanesulfonate was used instead of 4-(3-bromopropyl)morpholine, and the reaction mixture was stirred at room temperature for 60 minutes. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.31(d,1H),8.12(d,1H),7.60(d,2H),7.23(d,2H),7.12(s,2H),4.59(d,1H),3.79-3.66(m, (UPLC-MS)t R 0.59 min;ESI-MS 489[M+H] + .

[0201] Example 18: 2-Amino-N-((1r,4r)-4-hydroxycyclohexyl)-5-(4-(pyrrolidine-3-yl)phenyl)nicotinamide [ka] To a solution of tert-butyl 3-(4-(6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)pyrrolidine-1-carboxylate (intermediate 18a, 120 mg, 0.140 mmol) in dioxane (3 mL), 4N HCl (0.210 mL, 0.839 mmol) in dioxane was added at room temperature under a nitrogen atmosphere, and the resulting mixture was stirred for 4 hours. After concentration under reduced pressure, the crude product was purified by reverse-phase chromatography (method 3a). The pure fraction was partitioned between a saturated aqueous solution of NaHCO3 and ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound as a mixture of diastereomers. 1H NMR(400MHz,DMSO-d6)δ 8.26(d,1H),8.09(d,1H),7.57(d,2H),7.35-7.29(m,2H),7.09(s,2H),4.55(d,1H),3.77-3.69(m,2H),3.22-3. 15(m,2H),3.12-2.91(m,2H),2.74-2.62(m,2H),2.24-2.07(m,1H),1.83(dd,4H),1.42-1.16(m,5H).(UPLC-MS)t R 0.42 min;ESI-MS 381[M+H] + .

[0202] Intermediate 18a: tert-butyl 3-(4-(6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)pyrrolidine-1-carboxylate The title compound was prepared in a similar manner to 2-amino-5-(2-fluoro-4-(4-isopropylpiperazine-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (Example 8), except that tert-butyl3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate (intermediate 18b) was used instead of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (intermediate 8a). (UPLC-MS)t R 0.95 min; ESI-MS 481[M+H] + .

[0203] Intermediate 18b: tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate The title compound was prepared in a similar manner to 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (intermediate 8a), except that tert-butyl 3-(4-bromo-3-fluorophenyl)-4-isopropylpiperazine (intermediate 18c) was used instead of 1-(4-bromo-3-fluorophenyl)-4-isopropylpiperazine (intermediate 8b). (UPLC-MS)t R 1.43 minutes; ESI-MS 374[M+H] + .

[0204] Intermediate 18c: tert-butyl 3-(4-bromophenyl)pyrrolidine-1-carboxylate To a solution of 3-(4-bromophenyl)pyrrolidine (200 mg, 0.885 mmol) in DCM (7 mL), di-tert-butyl dicarbonate (0.308 mL, 1.327 mmol) and TEA (0.247 mL, 1.769 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours. The reaction mixture was then diluted with a saturated aqueous solution of NaHCO3 and mixed with DCM. After phase separation, the aqueous layer was extracted again with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound as a colorless oil, which was used without further purification. (UPLC-MS) R 1.33 minutes; ESI-MS 270[M+H] + .

[0205] Example 19: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a manner similar to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 1), except that dihydro-2H-pyran-4(3H)-one was used instead of 1-(methylsulfonyl)piperidine-4-one. 1H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),8.31(d,1H),8.12(d,1H),7.62(dd,2H),7.25(s,2H),7.12(s,2H),4.59(d,1H),3.97-3.63 (m,4H),3.40(m,2H),3.31(m,2H),3.19-3.03(m,2H),1.99-1.65(m,8H),1.51-1.16(m,8H).(UPLC-MS)t R 0.48 min; ESI-MS 477[M+H] + .

[0206] Example 20: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 1-bromo-2-methoxyethane was used instead of 4-(3-bromopropyl)morpholine, and the reaction mixture was stirred at 60°C for 4 hours. 1H NMR(400MHz,DMSO-d6)δ 8.38(s,1H),8.11(s,1H),7.59(d,2H),7.22(d,2H),7.13(s,2H),4.60(d,1H),3.73(d,1H),3.54 -3.36(m,4H),3.27(s,3H),2.64(m,4H),1.87(m,6H),1.40-1.27(m,6H),0.76(s,1H).(UPLC-MS)t R 0.49 min;ESI-MS 451[M+H] + .

[0207] Example 21: 2-Amino-N-((1R,3S,4R)-3-Fluoro-4-Hydroxycyclohexyl)-5-(4-((1R,5S)-3-(Tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a), and trans-4-amino The preparation was similar to that of (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that (1R,2S,4R)-4-amino-2-fluorocyclohexanol hydrochloride (intermediate 21a) was used instead of nocyclohexanol. The crude product was purified by prepHPLC (method 1a) to obtain the title compound as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 9.60(bs,1H),8.42(s,1H),8.35(d,1H),8.12(s,1H),7.64(bs,2H),7.36(bs,2H),7.14(s,2H),4.94(t,1H),4.80(d,1H),4.16-3.82(m,4H) ),3.81-3.45(m,4H),3.30-3.25(m,4H),2.15(bs,1H),1.88-1.85(m,2H),1.65-1.59(m,5H),1.76-1.27(m,3H),1.18(bs,1H).(UPLC-MS)t R 0.48 min; ESI-MS 495[M+H] + .

[0208] Intermediate 21a: (1R,2S,4R)-4-amino-2-fluorocyclohexanol hydrochloride To a solution of benzyl ((1R,3S,4R)-3-fluoro-4-hydroxycyclohexyl)carbamate (intermediate 21b, 376 mg, 1.41 mmol) in EtOH (20 mL), palladium (80 mg, 0.075 mmol) on charcoal (10%) was added under a nitrogen atmosphere. The reaction vessel was purged three times with nitrogen, then twice with hydrogen. After stirring at room temperature for 17 hours, the reaction mixture was passed through a Celite pad, and the filtration cake was washed with EtOH to obtain a colorless solution. Hydrochloric acid (1.25 M in EtOH, 14 mL, 17.5 mmol) was slowly added, and the mixture was stirred at room temperature for 5 hours. Concentration under reduced pressure yielded the title compound as a grayish-white hygroscopic solid. FIA ESI-MS 134[M+H] + .

[0209] Intermediate 21b: Benzyl ((1R,3S,4R)-3-fluoro-4-hydroxycyclohexyl)carbamate To a solution of benzyl ((1R,3S)-3-fluoro-4-oxocyclohexyl)carbamate (intermediate 21c, 768 mg, 2.90 mmol) in MeOH (15 mL), NaBH4 (274 mg, 7.24 mmol) was added in fractional amounts at 0°C. After stirring at 0°C for 30 minutes, the reaction mixture was diluted with a saturated aqueous solution of NH4Cl and allowed to stand at room temperature. The solvent was removed under reduced pressure, and DCM and water were added. After phase separation, the aqueous layer was extracted three times with DCM. The combined organic layers were washed with brine, dried on anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a white solid. The crude product was purified by normal-phase chromatography (Method 2b) to obtain the title compound as a colorless solid. (UPLC-MS)t R 0.76 min;ESI-MS 268[M+H] + The absolute configuration shown was confirmed by X-ray crystallography.

[0210] Intermediate 21c: Benzyl((1R,3S)-3-fluoro-4-oxocyclohexyl)carbamate To a solution of benzyl ((1R,3S,4S)-3-fluoro-4-hydroxycyclohexyl)carbamate (intermediate 21d, 710 mg, 2.66 mmol) in DCM (26 mL), pyridinium chlorochromate (859 mg, 3.98 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours. Another portion of pyridinium chlorochromate (573 mg, 2.66 mmol) was added, and the reaction mixture was stirred for a further 18 hours. After the addition of DCM and saturated aqueous NaHCO3 solution, both phases were separated, the aqueous layer was extracted twice with DCM, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography (Method 2b) to obtain the title compound as a colorless oil. (UPLC-MS)t R 0.82 min; ESI-MS 266[M+H] + .

[0211] Intermediate 21d: Benzyl ((1R,3S,4S)-3-fluoro-4-hydroxycyclohexyl)carbamate A vial was loaded with benzyl(1R,3R,6S)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate (intermediate 21e, 1.50 g, 6.07 mmol), and TEA hydrofluoric acid (4.94 mL, 30.3 mmol) was added. The vial was sealed and stirred at 100°C for 2 hours. After cooling, the reaction mixture was slowly poured into a (400 mL) K2CO3 (5.87 g, 42.5 mmol) solution in stirred water and extracted three times with DCM. The combined organic layers were washed with water and brine, dried on anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (Method 2b) to obtain a mixture of positional isomers, which were separated by preparative chiral HPLC (column: ChiralPak AD, 20 μm, 50 × 5 cm; flow rate: 90 mL / min; detection wavelength: 220 nm; mobile phase: n-heptane:EtOH in a 90:10 ratio until t=52 min, 85:15 until t=69 min, then 80:20). The title compound was isolated as a colorless oil and characterized by UPLC-MS (SQ13, column: Acquity HSS T3 1.8 μm, 2.1 × 50 mm, 60°C; eluent A: water + 0.05% formic acid + 3.75 mM NH4OAc; eluent B: acetonitrile + 0.04% formic acid; gradient: 5-98% B for 1.4 min; flow rate 1.0 mL / min; t R 0.81 min; ESI-MS 268[M+H] + ).

[0212] Intermediate 21e: (1R,3R,6S)-7-oxabicyclo[4.1.0]heptane-3-ylcarbamate The syn-benzyl(7-oxabicyclo[4.1.0]heptan-3-yl)carbamate (prepared as described by Gomez-Sanchez et al, Tetrahedron 2005, 61(5), 1207-1219) was separated by preparative chiral HPLC (column: ChiralPak AY, 10 μm, 25 × 5 cm; flow rate: 30 mL / min; detection wavelength: 214 nm; mobile phase: n-heptane:isopropanol 80:20). The title compound was isolated as a colorless oil and separated by chiral HPLC (ChiralPak AY-H, 5 μm, 15 × 0.46 cm; flow rate: 1 mL / min; detection wavelength: 214 nm; mobile phase: hexane:isopropanol 70:30; t R Characterization was performed using 2.24 min (99.2% ee) (UPLC-MS). R 0.90 min; ESI-MS 248[M+H] + .

[0213] Example 22: 2-Amino-N-((1s,4S)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a) instead of 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a) The compound was prepared in a manner similar to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that cis-4-aminocyclohexanol was used instead of trans-4-aminocyclohexanol. The crude product was purified by prepHPLC (method 1a) to obtain the title compound as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 9.50(bs,1H),8.41-8.33(m,2H),8.17(d,1H),7.62(bs,2H),7.26(bs,2H),7.14(s,1H),4.42(d,1H),4.05-3.79(m,5H), 3.34-3.24(m,4H),3.11(bs,1H),2.70-2.50(m,1H),1.83-1.71(m,7H),1.62-1.47(m,7H),1.35-1.29(m,1H).(UPLC-MS)t R 0.52 min;ESI-MS 477[M+H] + .

[0214] Example 23: 5-(4-(2-azaspiro[3,3]heptan-2-ylmethyl)phenyl)-2-amino-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(2-fluoro-4-(4-isopropylpiperazine-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (Example 8), except that 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2-azaspiro[3.3]heptane (intermediate 23a) was used instead of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (intermediate 8a). 1H NMR(400MHz,DMSO-d6)δ 8.40(d,1H),8.30(d,1H),8.14(d,1H),7.61(d,2H),7.33(d,2H),7.14(s,2H),4.58(d,1H),3.79-3.66(m, 1H),3.55(s,2H),3.41(dt,1H),3.14(s,3H),2.07(t,4H),1.94-1.72(m,6H),1.47-1.20(m,5H)(UPLC-MS)t R 0.51 min; ESI-MS 421 [M+H] + .

[0215] Intermediate 23a: 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2-azaspiro[3,3]heptane To a solution of 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.01 mmol) in acetonitrile (8 mL), 2-azaspiro[3.3]heptane (148 mg, 1.11 mmol) and cesium carbonate (428 mg, 1.31 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 60 minutes and then diluted with saturated aqueous solution of NaHCO3 and phenylalanine. After phase separation, the aqueous layer was extracted with phenylalanine, the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound, which was used without further purification (UPLC-MS). R 0.82 min; ESI-MS 314[M+H] + .

[0216] Example 24: 2-Amino-N-((1r,4R)-4-Hydroxy-4-methylcyclohexyl)-5-(4-((1R,5S)-3-Isopropyl-3-Azabicyclo[3.1.0]Hexane-1-yl)phenyl)Nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 2), except that trans-4-aminocyclohexanol was used instead of trans-4-aminocyclohexanol hydrochloride. 1H NMR(400MHz,DMSO-d6)δ 8.43(d,1H),8.34(d,1H),8.16(d,1H),7.68(d,2H),7.39(d,2H),4.06(dd,1H),3.86-3.41(m,9H), 2.26(dt,1H),1.78(d,2H),1.68-1.55(m,2H),1.47(t,4H),1.33(dd,6H),1.18(s,4H).(UPLC-MS)t R 0.53 min;ESI-MS 449[M+H] + .

[0217] Example 25: 2-Amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 1), except that 4,4-difluorocyclohexanone was used instead of 1-(methylsulfonyl)piperidine-4-one. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.32(d,1H),8.11(d,1H),7.59(d,2H),7.23(d,2H),7.13(s,2H),4.59(d,1H),3.73(d,1H),3.39(d,2H),3.09 (d,1H),2.68-2.55(m,2H),2.37(d,2H),2.00(s,2H),1.84(d,8H),1.64(d,2H),1.46-1.16(m,5H),0.78(s,1H).(UPLC-MS)t R 0.56 min;ESI-MS 511[M+H] + .

[0218] Example 26: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] To a solution of 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide TFA salt (intermediate 5a, 70 mg, 0.138 mmol) in DCM (4 mL), oxetane-3-one (12.0 mg, 0.166 mmol) and AcOH (0.012 mL, 0.207 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 45 °C for 30 minutes. Sodium triacetoxyborate (58.6 mg, 0.276 mmol) was added at room temperature, and the reaction mixture was stirred at 45 °C for 3 hours. Next, the reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and mixed with ethyl acetate. After phase separation, the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified first by prepHPLC (Method 1a) and then by reverse-phase flash chromatography (Method 3a) to obtain the title compound as a colorless solid. (UPLC-MS) R 0.48 min;ESI-MS 449[M+H] + .

[0219] Example 27: 2-Amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a manner similar to 2-amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 26), except that 4,4-difluorocyclohexanone was used instead of oxetan-3-one. After purification, the title compound was obtained as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 9.50(bs,1H),8.38(d,1H),8.32(d,1H),8.11(d,1H),7.59(d,2H),7.23(d,2H),7.13(s,2H),4.59(d,1H),4.12(bs,1H),3.73(d,1H) ),3.39(d,2H),3.09(d,1H),2.68-2.55(m,2H),2.37(d,2H),2.00(s,2H),1.84(d,8H),1.64(d,2H),1.46-1.16(m,5H).(UPLC-MS)t R 0.56 min;ESI-MS 511[M+H] + .

[0220] Example 28: 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 28a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 28a), and trans-4- The preparation was similar to that of (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that (3-aminobicyclo[1.1.1]pentan-1-yl)methanol (intermediate 16a) was used instead of aminocyclohexanol. The crude product was first purified by prepHPLC (method 1a) and then by reverse-phase flash chromatography (method 3a) to obtain the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6)δ 9.35(bs,1H),9.06(s,1H),8.44(s,1H),8.19(s,1H),7.68(d,2H),7.37(d, 2H),7.26(bs,2H),4.57(t,1H),4.12(d,1H),3.97(bs,1H),3.80-3.56(m,2H ),3.51(d,2H),3.35-3.20(m,6H),2.29-2.23(m,1H),2.11-2.05(m,1H),1. 99(bs,1H),1.97(s,6H),1.67-1.61(m,1H),1.19-1.14(bs,1H).(UPLC-MS)t R 0.50 min;ESI-MS 475[M+H] + .

[0221] Intermediate 28a: 2-amino-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 2c), except that methyl 2-amino-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 28b) was used instead of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1d). (UPLC-MS)t R 0.37 min;ESI-MS 380[M+H] + .

[0222] Intermediate 28b: Methyl 2-amino-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate The title compound was prepared in a similar manner to methyl 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 14b), except that methyl 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-aminonicotinate (intermediate 14b) was used instead of methyl 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 14b). (UPLC-MS)t R 0.62 min; ESI-MS 394[M+H] + .

[0223] Example 29: 2-Amino-5-(2-Fluoro-4-(piperazin-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4r)-4-hydroxycyclohexyl)-5-(4-(pyrrolidine-3-yl)phenyl)nicotinamide (Example 18), except that tert-butyl4-(4-(6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)-3-fluorophenyl)piperazine-1-carboxylate (intermediate 29a) was used instead of 3-(4-(6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)pyrrolidine-1-carboxylate (intermediate 18a). 1H NMR(400MHz,DMSO-d6)δ 8.29-8.16(m,2H),7.95(d,1H),7.38(t,1H),7.06(s,2H),6.88-6.75(m,2H),4.54(d,1H),3.69(m,1 H),3.42-3.32(m,2H),3.17(dd,4H),2.92(dt,4H),1.88-1.73(m,4H),1.43-1.15(m,4H).(UPLC-MS)t R 0.42 min; ESI-MS 414[M+H] + .

[0224] Intermediate 29a: tert-butyl 4-(4-(6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)-3-fluorophenyl)piperazine-1-carboxylate The title compound was prepared in a similar manner to 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (Example 8), except that tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 29b) was used instead of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (Example 8). The reaction mixture was stirred at 80°C for 60 minutes and purified by normal-phase chromatography (Method 2b) to obtain the title compound as a brownish solid. (UPLC-MS) R 0.96 min;ESI-MS 514[M+H] + .

[0225] Intermediate 29b: tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate The title compound was prepared in a similar manner to tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 8a), except that tert-butyl 4-(4-bromo-3-fluorophenyl)piperazine (intermediate 8b) was used instead. (UPLC-MS)t R 1.38 minutes; ESI-MS 407[M+H] + .

[0226] Example 30: 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a), and trans-4- The preparation was similar to that of (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that (3-aminobicyclo[1.1.1]pentan-1-yl)methanol (intermediate 16a) was used instead of aminocyclohexanol. The crude product was first purified by prepHPLC (method 1a) and then by reverse-phase flash chromatography (method 3a) to obtain the title compound as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 9.05(s,1H),8.41(d,1H),8.18(d,1H),7.61(d,2H),7.24-7.22(m,4H),4.55(t,1H),3.87-3.84(m,2H),3.51(d,2H),3.48- 3.25(m,2H),3.10(bs,1H),2.56-2.47(m,4H),1.97(s,6H),1.96-1.74(m,3H),1.39-0.30(m,3H),0.77(bs,1H).(UPLC-MS)t R 0.51 min; ESI-MS 475[M+H] + .

[0227] Example 31: 2-Amino-N-((1r,4R)-4-Hydroxycyclohexyl)-5-(4-(((R)-2-Methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(2-fluoro-4-(4-isopropylpiperazine-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (Example 8), except that (R)-(4-((2-methylpyrrolidine-1-yl)methyl)phenyl)boronic acid (intermediate 31a) was used instead of 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (intermediate 8a). Purification was carried out by normal-phase chromatography (Method 2b) to obtain the title compound as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 8.75(d,1H),8.65(d,1H),8.48(d,1H),7.81(dd,2H),7.63(d,2H),4.52(dd,1H),4.18(dd,1H),3.69(ddt,1H),3.5 1-3.31(m,2H),3.25-3.04(m,3H),2.19(ddt,1H),1.82(td,6H),1.64-1.52(m,1H),1.39-1.15(m,7H).(UPLC-MS)t R 0.44 min;ESI-MS 409[M+H] + .

[0228] Intermediate 31a: (R)-(4-((2-methylpyrrolidine-1-yl)methyl)phenyl)boronic acid To a solution of (4-(bromomethyl)phenyl)boronic acid (125 mg, 0.582 mmol) in acetonitrile (4 mL), K2CO3 (161 mg, 1.164 mmol) and (R)-2-methylpyrrolidine (54.5 mg, 0.640 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 60 minutes and then filtered through a Celite pad. The filtrate was concentrated under reduced pressure to obtain the title compound as a grayish-white solid, which was used without further purification. (UPLC-MS)t R 0.33 min; ESI-MS 220[M+H] + .

[0229] Example 32: 2-Amino-N-((1r,4S)-4-Hydroxy-4-methylcyclohexyl)-5-(4-((1S,5R)-3-Isopropyl-3-Azabicyclo[3.1.0]Hexane-1-yl)phenyl)Nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 2), except that 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate TFA salt (intermediate 9a) was used instead of 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 2), except that trans-4-amino-1-methylcyclohexanol was used instead of trans-4-aminocyclohexanol hydrochloride. 1H NMR(400MHz,DMSO-d6)δ 8.43(d,1H),8.34(d,1H),8.16(d,1H),7.68(d,2H),7.39(d,2H),4.06(dd,1H),3.86-3.41(m,9H), 2.26(dt,1H),1.78(d,2H),1.68-1.55(m,2H),1.47(t,4H),1.33(dd,6H),1.18(s,4H).(UPLC-MS)t R 0.50 min;ESI-MS 449[M+H] + .

[0230] Example 33: 2-Amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 26), except that dihydro-2H-pyran-4(3H)-one was used instead of oxetan-3-one. 1H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),8.31(d,1H),8.12(d,1H),7.62(dd,2H),7.25(s,2H),7.12(s,2H),4.59(d,1H),3.97-3.63 (m,4H),3.40(m,2H),3.31(m,2H),3.19-3.03(m,2H),1.99-1.65(m,8H),1.51-1.16(m,8H).(UPLC-MS)t R 0.47 min;ESI-MS 477[M+H] + .

[0231] Example 34: 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (also referred to herein as Compound A) [ka] To a solution of 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate TFA salt (intermediate 14a, 4.10 g, 8.14 mmol) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (2.17 g, 12.2 mmol) in anhydrous DMF (60 mL), N-methylmorpholine (2.24 mL, 20.4 mmol) and HATU (4.64 g, 12.2 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours, then diluted with saturated aqueous solution of NaHCO3 and extracted three times with SiO2. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (method 3b). The pure fraction was treated with saturated aqueous NaHCO3 solution and extracted three times with RINKAN. The combined organic extract was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound as a grayish-white solid. The absolute configuration shown was confirmed by X-ray crystallography of the title compound in complex with the ALK-2 kinase domain. 1H NMR (400 MHz, DMSO-d6) δ 8.34(d,1H),7.98(d,1H),7.79(s,1H),7.57(d,2H),7.23(d,2H),6.92(s,2H),4.31(s,1H),3.91-3.78(m,2H),3.40(bs,1H),3.33-3.24(m,2H),3.11(d,1H),2.57 (bs,1H),2.50-2.34(m,1H),2.34(bs,1H),2.12-1.94(m,6H),1.90-1.72(m,3H), 1.71-1.51(m,6H),1.51-1.34(m,2H),1.31(t,1H),0.82-0.68(m,1H).(UPLC-MS)t R 0.54 min;ESI-MS 503[M+H] + Chiral HPLC (ChiralPakId, 5 μm, flow rate: 1 mL / min; detection wavelength: 270 nm; mobile phase: 60:40 heptane:isopropanol (+0.1% diethylamine)); R 18.7 minutes; 92.3% ee.

[0232] Alternative Example 34A: Et3N (681.2g, 6.732mol) and HATU (767.9g, 2.019mol) were added at room temperature to a solution of 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (1kg, 1.683mol) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (343.9g, 1.935mol) in DMF (3500mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was heated to IT=45°C and 5200g of 5% NH3·H2O solution was added. After stirring for about 30 minutes, another 5% NH3·H2O solution (1800g) was added. The mixture was heated at IT=45°C for 2 hours. The mixture was cooled to IT=22°C. It was filtered, and the wet cake was washed with H2O (1500 mL x 3). The wet cake was dried under vacuum at 45°C for 24 hours. The crude product was dissolved in acetone (3000 mL), then filtered to remove some undissolved solids. The filtrate was heated to IT=50°C. H2O (2000 mL) was added. The mixture was stirred at IT=50°C for 30 minutes until a white precipitate formed. H2O (4000 mL) was slowly added. The mixture was stirred at IT=50°C for 2 hours. The mixture was cooled to IT=22°C for 2 hours, filtered, and the wet cake was washed with acetone:H2O=1:2 (v / v, 1000 mL x 2). The moist cake was dried under vacuum at 45°C for 24 hours to obtain a total of 760 g of white solid (yield 89%, 99.4% ee). 1H NMR(DMSO-d6)δ: 8.32(d,J=2.3 Hz,1H),7.97(d,J=2.3 Hz,1H),7.77(s,1H),7.54(d,J=8.3 Hz,2H),7.20(d,J=8.4 Hz,2H),6.90(s,2H),4.31(s,1H),3.82(m,2H),3.29(m,2H),3.07(d,J=8.5 Hz,1H),2.54(d,J=8.3 Hz,1H),2.44(dd,J=8.5,3.5 Hz,1H),2.37(m,1H),2.31(td,J=10.2,5.0 Hz,1H),2.04(m,6H),1.80(dt,J=7.9,3.8 Hz,1H),1.71(d,J=12.3 Hz,1H),1.65(d,J=11.5 Hz,1H),1.62(m,6H),1.38(m,1H),1.34(m,1H),1.29(t,J=3.9 Hz,1H),0.73(dd,J=7.9,3.6 Hz,1H). 13 C NMR(DMSO-d6)δ: 167.80,157.69,148.28,141.27,134.91,134.79,126.40,125.66,123.53,111.01,6 6.22,65.59,59.10,55.46,52.04,33.72,31.92,31.77,30.59,29.61,24.14,17.20. MS(ESI-TOF): 503.3018[M+H]+.

[0233] The starting material (hydrochloride salt) was obtained as follows: Methyl 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid dihydrochloride (10 g, 19.5 mmol, 1.0 equivalent) was suspended in MeOH (31.7 g). Next, a solution of NaOH (2.9 g, 72.2 mmol, 3.7 equivalents) in H2O (10 g) was added. The reaction mixture was heated to 45 ± 5 °C and stirred for more than 3 hours to obtain a suspension. In a separate flask containing acetone (200 g), 14.8 g (97.6 mmol, 5 equivalents) of 5-6 N HCl in i-PrOH was added. The solution was heated to 47 ± 3 °C. Next, the above MeOH suspension was added dropwise to the mixture and stirred at 47 ± 3 °C for 3 hours. The mixture was cooled to 23 ± 3 °C and stirred for 3 hours. After filtration, the wet cake was washed with acetone (40 g). The wet cake was dried under vacuum at 55 °C for 8 hours. 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (12.3 g, 99.3% HPLC purity, 62.1% assay yield) was obtained as a grayish-white solid. 1 H NMR(DMSO-d6)δ: 11.53(br s,1H),8.64(br s,1H),8.54(br s,1H),7.72-8.42(m,2H),7.64(br d,J=7.9 Hz,2H),7.38(br d,J=7.8 Hz,2H),3.85-4.04(m,3H),3.40-3.73(m,4H),3.15-3.33(m,2H),2.18(br d,J=3.9 Hz,1H),1.95-2.12(m,4H),1.88(br d,J=10.0 Hz,1H),1.05(br t,J=6.4 Hz,1H). 13 C NMR(DMSO-d6)δ: 167.2,155.8,144.3,142.0,139.6,133.8,127.7,126.3,124.1,110.0,65.8,62.5,55.7,53.2,29.9,28.8,28.7,23.5,16.6. MS(ESI-TOF):380.1974[M+H]+.

[0234] The starting material, 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate dihydrochloride, was obtained as follows: A 500 mL round-bottom flask was loaded with 1R,5S)-1-(4-bromophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-3-ium chloride (20 g, 1 equivalent), EA (200 mL), and 25% K2CO3 (62 g). The mixture was stirred for 30 minutes until all solids were dissolved. After phase separation, the organic layer was concentrated. 2-methyl-2-butanol (48 g, 60 mL) was added. The organic layer was concentrated again. 2-methyl-2-butanol (144 g, 180 mL) was added. The mixture was transferred to a 500 mL Redlay. K2CO3 (18.8 g, 2.5 equivalents) and methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (16.8 g, 1.04 equivalents; see intermediate 1e) were added. The mixture was degassed three times with N2. The mixture was heated at IT=50±5°C for no more than 1 hour. Pd(dppf)Cl2 (1.2 g, 0.03 equivalents) was added. The mixture was heated at IT=70±3°C and stirred for 2 hours. After cooling to 22°C, H2O (120 g) and EA (180 g) were added and stirred for 30 minutes. MCC (6 g) was added and the mixture was filtered through the MCC. The cake was washed with EA (54 g). After phase separation, the organic layer was washed with 5% NaCl (124 g). Next, Quadrasil MP (heavy metal scavenger from Johnson Matthey, 6g) was added to the organic layer. The mixture was heated at IT=55°C for 8 hours, filtered through MCC, and washed with EA (54g). Quadrasil MP (2g) was added to the organic layer. The mixture was heated at IT=55°C for 6 hours, filtered through CMC, and washed with EA (54g). The organic layer was concentrated. Acetone (158g, 200mL) was added. After stirring at IT=22±3°C for 30 minutes, the mixture was heated to IT=40±3°C. 15.5% HCl (38.4g) was added dropwise at IT<50°C. The mixture was stirred at IT=45±3°C for 1 hour. The mixture was cooled to 22±3°C. The mixture was stirred at 22±3°C for 1 hour and filtered. The cake was washed with acetone (32g x 2). The wet cake was dried under vacuum at 50°C for at least 8 hours. Starting material was obtained, and 22.5 g of white solid (97.1% HPLC purity, 5.2% water content, 87% assay yield) was obtained. 1H NMR(DMSO-d6)δ: 11.43(br d,J=5.7 Hz,1H),8.62-8.80(m,2H),7.85-8.58(m,2H),7.67(d,J=8.3 Hz,2H),7.39(d,J=8.4 Hz,2H),3.85-4.06(m,6H),3.60-3.69(m,2H),3.50-3.59(m,1H),3.44(br d,J=7.7 Hz,1H),3.14-3.31(m,2H),2.21(dt,J=8.4,4.2 Hz,1H),1.94-2.12(m,4H),1.76-1.93(m,1H),1.07(br t, J = 7.1 Hz, 1 H). 13 C NMR(DMSO-d6)δ: 165.0,154.0,143.5,142.0,140.1,132.8,127.7,126.5,124.2,110.7,65.8,62.5,55.6,53.3,53.3,29.9,28.9,28.8,23.6,16.8. MS(ESI-TOF):394.2071[M+H]+.

[0235] The starting material, 1R,5S)-1-(4-bromophenyl)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-3-ium chloride, was obtained as follows: (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-ium chloride (30 g, 1 equivalent), dihydro-2H-pyran-4(3H)-one (13.13 g, 1.2 equivalents), and THF (300 mL) were loaded into a 1 L Redlay. The mixture was stirred at IT=22±5°C for 1 hour. NaBH(OAc)3 (30.1 g, 1.3 equivalents) was added in small amounts while maintaining IT<30°C. The mixture was stirred at IT=22±5°C for 2 hours. 6.2% HCl (93 g, 90 ml, 1.5 equivalents) was added while maintaining IT<30°C and pH<2. The mixture was stirred for 10 minutes. 25% K2CO3 (259 g, 210 mL) was added to adjust the pH to 8-9. IPAc (300 mL) was added. The mixture was stirred for 10 minutes. After phase separation, H2O (150 g) was added to the organic layer. The mixture was stirred for 10 minutes. After phase separation, the organic layer was concentrated under vacuum (50-100 mg / L, 50°C water bath). IPA (120 g, 150 mL) was added. The organic layer was concentrated under vacuum (50-100 mg / L, 50°C water bath). IPA (144 g, 180 mL) was added. The mixture was filtered through CMC. The cake was washed with IPA (24 g x 2). H2O (5 g) was added to the organic layer. 31% HCl (19.3 g) was added dropwise at IT < 35°C. The mixture was stirred at IT = 22 ± 5°C for 2 hours and filtered. The cake was washed with IPA (48 g x 2). The wet cake was dried under vacuum at 50°C for at least 6 hours. The desired product (31.4 g, 98% HPLC purity, 78% yield) was obtained as a white solid. 1 H NMR (DMSO-d6 and D2O) δ: 7.46(br d,J=8.4 Hz,2H),7.15(br d,J=8.4 Hz,2H),3.90(br d,J=7.8 Hz,3H),3.62(br s,1H),3.51(br s,2H),3.16-3.38(m,3H),2.05-2.21(m,1H),1.93(br s,2H),1.49-1.71(m,2H),1.05-1.30(m,1H). 13C NMR(DMSO-d6)δ: 138.3,131.9,129.2,120.4,65.5,62.3,56.2,53.9,29.1,28.9,24.8,23.0. MS (ESI-TOF): 322.0761 [M+H]+

[0236] The complete method for producing alternative example 34A is shown in the reaction scheme 34A below: [ka]

[0237] The first compound A1 in this scheme can be obtained as follows: Steps 1-2: Synthesis of 1c and 1d Scheme 34A1 [ka]

[0238] Reaction procedure (see also Xu, Feng et al., Org. Lett. Vol 8, No. 17, 2006, pp. 3885-3888): NaHMDS (2.0 M in THF, 19.2 L, 38.4 mol, 2.5 equivalents) was added dropwise over 5 hours under N2 at -15 to 20°C to solutions of 1a (3.00 kg, 15.3 mol, 1.0 equivalent, e.g., available from Sigma-Aldrich) and 1b (1.80 kg, 19.47 mmol, 1.27 equivalents; e.g., available from Sigma-Aldrich) in THF (30 L). The reaction mixture was stirred at -15°C for a further 3 hours, then gradually warmed to room temperature and stirred for 16 hours. HPLC showed that 4-bromophenylacetonitrile was completely consumed.

[0239] BF3·Et2O (4.74 kg, 15.3 mol, 1.0 equivalent) was slowly added at 20-40°C. After the addition, BH3·DMS (19.2 L, 38.4 mol, 2.5 equivalents) was slowly added at 20-40°C. After the addition, the mixture was stirred at 50-55°C for 16 hours. HPLC showed that the intermediate was completely consumed.

[0240] The mixture was cooled to -5 to 0°C, and AcOH (4.5 kg, 74.4 mol, 4.86 equivalents) was slowly added. After the addition, 3N HCl (36 kg) was slowly added. The mixture was stirred for 1 hour, and most of the THF was removed under vacuum at 40 to 45°C. Next, the residue was extracted with MTBE (3 × 10 L). The MTBE phase was washed with 3N HCl (4 × 5 L). The combined aqueous layer was cooled to 0°C. Next, the aqueous layer was neutralized with 30% NaOH to pH > 10, extracted with IPAc (3 × 15 kg), washed with brine (5 L), and evaporated under vacuum to obtain crude compound 1d (3.71 kg), which was used directly in the subsequent steps.

[0241] Steps 3-4: Synthesis of 1e and 1f Scheme 34A2 [ka]

[0242] Reaction procedure: IPAc (12 L) was cooled to 0°C, and SOCl2 (5.46 kg, 45.9 mol, 1.5 equivalents) was added while maintaining the temperature at 0-4°C. After the addition, a solution of crude compound 1d (7.46 kg, two batches combined from 1a, 6 kg) from IPAc (24 L) was slowly added. After the addition, the mixture was stirred at 0°C for 1 hour, then heated to RT and stirred for 4 hours. HPLC showed that the intermediate was completely consumed.

[0243] The mixture was cooled to -5 to 0°C, quenched with water (30 L), and then slowly added a 30% NaOH aqueous solution to adjust the pH to 8.5 to 9. The mixture was stirred overnight at 0 to 5°C. HPLC showed that the intermediate was completely consumed.

[0244] A 30% aqueous NaOH solution was slowly added to adjust the pH to 11-12 at 0-10°C, and the mixture was stirred at room temperature for 30 minutes. Phase separation was performed, the aqueous layer was extracted with IPAc (10 kg), the combined organic phase was washed with brine (5 L), dried over Na2SO4, and filtered. The filtrate was then cooled to 0-5°C. 4M HCl\IPA (8.0 kg, 151 mol) was slowly added at 0-5°C. After the addition, the reaction mixture was stirred at 0-5°C for 4 hours. The mixture was filtered, the solid was collected, washed with MTBE (6 L), and vacuum-dried to obtain compound 1f (3.10 kg, assay 98%, yield 37%).

[0245] Alternative Example 34B: The starting material A5 in Scheme 34A may be obtained by alternative means as follows (reaction scheme 34B), and then used as shown in the alternative example 34A above: [ka]

[0246] In detail, the procedure is as follows: [ka] In a 100 ml three-necked flask, a solution of (1R,5S)-1-(4-bromophenyl)-3-tetrahydropyran-4-yl-3-azabicyclo[3.1.0]hexane (5.00 g, 15.52 mmol, 1.00 equivalent) in anhydrous THF (50.00 mL) was cooled to -78°C under N2. n-BuLi (2.5 M in hexane, 7.45 mL, 1.20 equivalent) was added dropwise at -78°C, and the mixture was stirred at -78°C for 1 hour. A solution of trimethylborate (4.84 g, 46.56 mmol, 5.26 mL, 3.00 equivalent) in anhydrous THF (10.00 mL) was added dropwise at -78°C. After the addition, the reaction mixture was allowed to warm to 25°C and stirred at 25°C for 16 hours. After the starting material was completely consumed, monitoring by LC-MS was continued, and 74.23% of the target compound was observed. The reaction mixture was cooled to 0°C under an ice bath and quenched with saturated NH4Cl solution (50 mL). The pH of the mixture was adjusted to 12-13 with NaOH solution (1 M), and extracted with HCl (30 mL x 3). The aqueous layer was concentrated under reduced pressure to obtain the residue (18 g). The residue was purified by preparative HPLC (TFA conditions) to obtain [4-[(1R,5S)-3-tetrahydropyran-4-yl-3-azabicyclo[3.1.0]hexane-1-yl]phenyl]boronic acid (4.60 g, 11.47 mmol, 73.88% yield, TFA salt) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ: 7.72(d,2H),7.24(d,2H),4.13(d,1H),4.06-4.03(m,2H),3.86(d,1H),3.70-3.67(m,2H),3. 45-3.32(m,3H),2.26-2.23(m,1H),2.11-2.05(m,2H),1.81-1.77(m,2H),1.34-1.20(m,2H). ESI-MS 288[M+H] + .

[0247] [ka] A mixture of dioxane (5.00 mL) and H2O (1.00 mL) containing [4-[(1R,5S)-3-tetrahydropyran-4-yl-3-azabicyclo[3.1.0]hexane-1-yl]phenyl]boronic acid (500.00 mg, 1.25 mmol, 1.00 equivalent, TFA salt), methyl 2-amino-5-bromopyridine-3-carboxylate (433.22 mg, 1.88 mmol, 1.50 equivalents), Pd(dppf)Cl2 (91.46 mg, 0.125 mmol, 0.10 equivalents), and K2CO3 (518.29 mg, 3.75 mmol, 3.00 equivalents) was heated to 100°C under N2 and stirred at 100°C for 16 hours. The reaction mixture was cooled to 30°C and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions) to obtain methyl 2-amino-5-[4-[(1R,5S)-3-tetrahydropyran-4-yl-3-azabicyclo[3.1.0]hexane-1-yl]phenyl]pyridine-3-carboxylate (100.00 mg, 20.02% yield, 98.47% HPLC purity) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ: 8.49(d,1H),8.35(d,1H),7.46(d,2H),7.24(d,2H),4.01-3.98(m,2H),3.94(s,3H),3.47-3.41(m,3H),3.19(d,1H),2.65 (d,1H),2.50-2.55(m,1H),2.45-2.35(m,1H),1.81-1.76(m,3H),1.64-1.46(m,2H),1.45-1.40(m,1H),0.86-0.83(m,1H). ESI-MS 394[M+H] + .

[0248] Example 35: 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 35a) instead ofR,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 35a), and The compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride was used instead of su-4-aminocyclohexanol. The crude product was purified by prepHPLC (method 1a) to obtain the title compound as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 9.05(bs,1H),8.42(d,1H),8.22(s,1H),8.02(s,1H),7.69(d,2H),7.50(bs,2H),7.39(d,2H),4.83(bs,1H),4.08(dd,1H),3.80-3. 25(m,6H),2.31-2.09(m,4H),2.09-1.99(m,6H),1.98-1.71(m,4H),1.70-1.56(m,6H),1.42-1.40(m,1H),1.10(t,1H).(UPLC-MS)t R 0.62 min;ESI-MS 537[M+H] + .

[0249] Intermediate 35a: 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 2c), except that methyl 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 35b) was used instead of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1d). (UPLC-MS)t R 0.46 min;ESI-MS 414[M+H] + .

[0250] Intermediate 35b: Methyl 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate The title compound was prepared in a similar manner to methyl 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 14b), except that methyl 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-aminonicotinate (intermediate 14b) was used instead of methyl 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 14b), and 4,4-difluorocyclohexanone was used instead of dihydro-2H-pyran-4(3H)-one. (UPLC-MS)t R 0.73 min;ESI-MS 428[M+H] + .

[0251] Example 36: 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 2), except that (3-aminobicyclo[1.1.1]pentan-1-yl)methanol (intermediate 16a) was used instead of trans-4-aminocyclohexanol hydrochloride. 1H NMR(400MHz,DMSO-d6)δ 9.05(s,1H),8.41(d,1H),8.18(d,1H),7.61(d,2H),7.48(dd,1H),7.33-7.17(m,4H),4.55(t,1H),3.51(d,3H) ),3.31(s,2H),3.08(s,2H),2.07-1.99(m,1H),1.41-1.22(m,3H),1.17-0.98(m,9H),0.79(d,1H).(UPLC-MS)t R 0.54 min;ESI-MS 433[M+H] + .

[0252] Example 37: 2-Amino-5-(4-((1S,5R)-3-(Buty-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 1-bromobuti-2-yin was used instead of 4-(3-bromopropyl)morpholine, and the reaction mixture was stirred at room temperature for 30 minutes. 1H NMR(400MHz,DMSO-d6)δ 8.38(s,1H),8.31(d,1H),8.12(d,1H),7.59(d,2H),7.21(s,2H),7.13(s,2H),4.60(d1H),3.72(s,1H), 3.39(s,3H),3.21(s,1H),2.98-2.58(m,3H),1.84(dd,8H),1.49-1.17(m,5H),0.78(s,1H).(UPLC-MS)t R 0.54 min;ESI-MS 445[M+H] + .

[0253] Example 38: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(oxetane-3-ylmethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 3-(iodomethyl)oxetane was used instead of 4-(3-bromopropyl)morpholine, and the reaction mixture was stirred at 60°C for 60 minutes. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.30(d,1H),8.11(d,1H),7.59(d,2H),7.22(d,2H),7.12(s,2H),4.73-4.61(m,2H),4.58(d,1H),4.29(s,2H),3.84-3.67 (m,1H),3.52-3.38(m,2H),3.27-3.12(m,2H),2.94(d,1H),2.80(s,2H),1.95-1.76(m,5H),1.54-1.14(m,6H),0.76(s,1H).(UPLC-MS)t R 0.49 min;ESI-MS 463[M+H] + .

[0254] Example 39: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 1), except that 1-(2,2,2-trifluoroethyl)piperidine-4-one was used instead of 1-(methylsulfonyl)piperidine-4-one. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.11(d,1H),7.58(d,2H),7.23(d,2H),7.12 (s,2H),4.55(bs,1H),3.80-3.62(m,1H),3.20-3.04(m,3H),2.88(d,2 (UPLC-MS)t R 0.62 min;ESI-MS 558[M+H] + .

[0255] Example 40: 2-Amino-N-(4-Hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound is 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide HCl salt (intermediate) instead of 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1- The reaction mixture was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 40a) was used and 4-(2-bromoethyl)morpholine was used instead of 4-(3-bromopropyl)morpholine, and the reaction mixture was stirred at 60°C for 3 hours. 1H NMR(400MHz,DMSO-d6)δ 8.34(d,1H),7.98(d,1H),7.79(s,1H),7.57(d,2H),7.21(d,2H),6.92(s,2H),4.32(s,1H),3.65-3.49(m,4H),3.08(d,1H),2. 61(t,2H),2.59-2.39(m,9H),2.15-1.98(m,6H),1.85-1.73(m,1H),1.70-1.54(m,6H),1.31(t,1H),0.75(dd,1H).(UPLC-MS)t R 0.52 min;ESI-MS 532[M+H] + .

[0256] Intermediate 40a: 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide The title compound is (1S,5R)-tert-butyl 1-(4-(6-amino-5-(((1r,4S)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 5b) instead of (1S,5R)-tert-butyl 1-(4-(6-amino-5-((4-hydroxybicyclo[2.2.2]octa The compound was prepared in a similar manner to 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (intermediate 5a), except that 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (intermediate 5a) was used. One fraction of the title compound was obtained as the hydrochloride salt after evaporation of dioxane; the other fraction was obtained as the TFA salt after further purification by prepHPLC (Method 1a). (UPLC-MS) R 0.48 min;ESI-MS 419[M+H] + .

[0257] Intermediate 40b: (1S,5R)-tert-butyl 1-(4-(6-amino-5-((4-hydroxybicyclo[2.2.2]octan-1-yl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate The title compound uses 2-amino-5-(4-((1S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 5c) instead of 2-amino-5-(4-((1S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 5c) and trans It was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride was used instead of -4-aminocyclohexanol. (UPLC-MS)t R 1.05 minutes;ESI-MS 519[M+H] + .

[0258] Example 41: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-(2,2,2-trifluoroethoxy)ethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 2-(2,2,2-trifluoroethoxy)ethyltrifluoromethanesulfonate (intermediate 41a) was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a). After purification, the title compound was obtained as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 9.15(bs,1H),8.40(s,1H),8.31(d,1H),8.12(d,1H),7.63(d,2H),7.23(s,2H),7.13(s,2H),4.59(d,1H),4 .11(s,2H),3.80-3.63(m,3H),3.40(m,4H),2.75-2.60(m,3H),1.86(m,5H),1.51-1.15(m,6H).(UPLC-MS)t R 0.60 min;ESI-MS 519[M+H] + .

[0259] Intermediate 41a: 2-(2,2,2-trifluoroethoxy)ethyltrifluoromethanesulfonate The title compound was prepared in a similar manner to 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a), except that 2-(2,2,2-trifluoroethoxy)ethanol was used instead of 1,3-difluoropropan-2-ol. The crude oil obtained was used without further purification.

[0260] Example 42: 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound is 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (intermediate 1a) instead of 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide HCl salt ( The compound was prepared in a manner similar to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 1), except that intermediate 40a) was used and dihydro-2H-pyran-4(3H)-one was used instead of 1-(methylsulfonyl)piperidine-4-one. After purification, the title compound was obtained as the TFA salt. 1H NMR (400 MHz, DMSO-d6)δ 9.62(bs,1H),8.38(d,1H),7.98(d,1H),7.81(s,1H),7.65(d,2H),7.37(d,2 H),6.95(s,2H),4.33(s,1H),4.06-3.97(m,3H),3.75-3.43(m,4H),3.29-3.2 6(m,2H),2.28-2.19(m,1H),2.07-2.03(m,6H),2.03-1.96(m,2H),1.75-1.63 (m,1H),1.63-1.61(m,6H),1.63-1.61(m,1H),1.25-1.17(m,1H).(UPLC-MS)t R 0.52 min;ESI-MS 503[M+H] + .

[0261] Example 43: 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide [ka] To a solution of 2-amino-5-bromo-N-cyclohexylnicotinamide (intermediate 43a, 50 mg, 0.168 mmol) in 2 ml of DMF / EtOH / water (2:1:1), 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine (60.9 mg, 0.168 mmol), K2CO3 (69.5 mg, 0.503 mmol), and PdCl2(PPh3)2 (11.8 mg, 0.017 mmol) were added. The reaction mixture was stirred at 80°C for 15 minutes, then cooled and diluted with 5 ml of ethyl acetate, and filtered over a Na2SO4 pad. After concentration under reduced pressure, the crude product was purified by prepHPLC (Method 1a) to obtain the title compound as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 8.34(d,1H),8.33(d,1H),8.09(d,1H),7.59(d,2H),7.06(s,2H),7.01(d,2H),4.03(t,2H),3.75(s,1H),2.50-2 .22(m,6H),1.95-1.65(m,6H),1.62(d,1H),1.52-1.48(m,4H),1.46-1.34(m,6H),1.32-1.15(m,1H).(HPLC-MS)t R 1.46 minutes; APCI-MS 437.3[M+H] + .

[0262] Intermediate 43a: 2-amino-5-bromo-N-cyclohexylnicotinamide The title compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 2-amino-5-bromonicotinic acid was used instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), and cyclohexaneamine was used instead of trans-4-aminocyclohexanol. The crude product was used without further purification. (HPLC-MS)R 0.98 min;ESI-MS 208 / 300[M+H] + .

[0263] Example 44: 2-amino-5-(4-((1R,5S)-3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a manner similar to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 1), except that dihydro-2H-thiopyran-4(3H)-one 1,1-dioxide was used instead of 1-(methylsulfonyl)piperidine-4-one. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.31(d,1H),8.12(d,1H),7.59(d,2H),7.24(d,2H),7.12(s,2H),4.58(d,1H),3.82-3.65(m,1H),3.48-3.35(m, (UPLC-MS)t R 0.48 min; ESI-MS 525[M+H] + .

[0264] Example 45: 2-amino-N-cyclohexyl-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that (4-methylpiperazine-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine was used instead. 1H NMR(400MHz,DMSO-d6)δ 8.46(d,1H),8.37(s,1H),8.21(d,1H),7.76(d,2H),7.47(d,2H),7.22(s,2H),3.82-3.55(m,1H),3.35(t,4H),2.31-2.22(t, (HPLC-MS)t R 1.29 minutes; APCI-MS 422[M+H] + .

[0265] Example 46: 2-amino-5-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide [ka] Microwave vials were loaded with 2-amino-5-bromo-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)nicotinamide (intermediate 59b, 33 mg, 0.10 mmol), (R)-2-(3-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazavolocan-4,8-dione (intermediate 46a, 38.3 mg, 0.11 mmol), and XPhosPd (7.39 mg, 0.01 mmol). Dioxane (1 mL) was added, followed by a 3N aqueous solution of K3PO4 (0.10 ml, 0.30 mmol). The reaction mixture was purged with a nitrogen stream for 5 minutes and then irradiated in a microwave reactor at 120°C for 30 minutes. After cooling, the reaction mixture was concentrated under reduced pressure and purified by prepHPLC (Method 1b) to obtain the title compound. UPLC-HRMSt R 3.21 minutes; ESI 441.26 [M+H] + .

[0266] Intermediate 46a: (R)-2-(3-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione A solution of 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 46b, 112 mg, 0.40 mmol), (R)-(2)-methylpyrrolidine (37.5 mg, 0.44 mmol), and acetic acid (2.4 mg, 0.040 mmol) in THF (2 mL) was shaken at room temperature for 2 hours, and sodium triacetoxyborate (110 mg, 0.52 mmol) was added. The resulting reaction mixture was shaken for 18 hours, then filtered through an SPE carbonate cartridge, followed by washing with THF. The filtrate and washings were concentrated under reduced pressure to obtain the title compound, which was used without further purification. ESI-MS 349[M+H] + .

[0267] Intermediate 46b: 2-Fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde A solution of (3-fluoro-4-formylphenyl)boronic acid (67 mg, 0.40 mmol) and N-methyliminodiacetic acid (65 mg, 0.44 mmol) in DMF (2 mL) was stirred at 90°C for 18 hours. The reaction mixture was cooled and filtered through an SPE carbonate cartridge, followed by three washes with acetonitrile. The filtrate and washings were concentrated under reduced pressure to obtain the title compound, which was used without further purification. ESI-MS 558[2M+H] + .

[0268] Example 47: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 3,3,3-trifluoropropyltrifluoromethanesulfonate was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a). 1H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),8.31(d,1H),8.12(d,1H),7.60(d,2H),7.23(d,2H),7.13(s,2H),4.59(d,1H),3.74(m,1H) ,3.40(m,3H),3.09(m,1H),2.72-2.64(m,4H),1.86(m,5H),1.49-1.14(m,6H),0.78(s,1H).(UPLC-MS)t R 0.60 min;ESI-MS 489[M+H] + .

[0269] Example 48: 2-amino-5-(4-((1R,5S)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 1-bromo-2-fluoroethane was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a). The reaction mixture was stirred at 60°C for 3 hours. After purification, the title compound was obtained as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 9.95(bs,1H),8.41(s,1H),8.32(d,1H),8.13(d,1H),7.70-7.57(m,2H),7.36(bs,2H),7.16(s,2H),4.80-4.62(m,2H),4. 59(d,1H),4.08(bs,1H),3.77-3.52(m,4H),3.51-3.35(m,3H),2.24(bs,1H),1.87(t,4H),1.59-1.13(m,6H).(UPLC-MS)t R 0.46 min;ESI-MS 439[M+H] + .

[0270] Example 49: 2-amino-N-cyclohexyl-5-(4-morpholinophenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine was used instead. 1H NMR(400MHz,DMSO-d6)δ 8.35(d,1H),8.34(s,1H),8.08(d,1H),7.55(d,2H),7.03(d,2H),7.03(s,2H),3.85-3.65(m,1H),3.77(t,4H),3. 14(t,4H),1.90-1.80(m,2H),1.80-1.70(m,2H),1.80(dd,1H),1.38-1.20(m,4H),1.19-1.05(m,1H).(HPLC-MS)t R 1.60 minutes; APCI-MS 381[M+H] + .

[0271] Example 50: 2-Amino-5-(4-((1R,5S)-3-(2,2-difluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 2,2-difluoropropyltrifluoromethanesulfonate was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a), and the reaction mixture was stirred at room temperature for 60 minutes. 1H NMR(400MHz,DMSO-d6)δ 8.39(s,1H),8.33(s,1H),8.14(s,1H),7.59(d,2H),7.32-7.11(m,4H),4.58(bs,1H),3.74(bs,1H),3. 11(bs,1H),3.00-2.66(m,5H),1.86(bs,5H),1.63(t,3H),1.48-1.18(m,6H),0.81(bs,1H).(UPLC-MS)t R 0.81 min;ESI-MS 471[M+H] + .

[0272] Example 51: 2-amino-5-(4-((1S,5R)-3-(2-cyanoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 3-bromopropanenitrile was used instead of 4-(3-bromopropyl)morpholine, and the reaction mixture was stirred at 60°C for 24 hours. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.30(d,1H),8.12(d,1H),7.60(d,2H),7.23(d,2H),7.12(s,2H),4.59(d,1H),3.73(d,1H),3. 18(d,1H),3.09(d,1H),2.81-2.62(m,6H),1.99-1.78(m,5H),1.48-1.18(m,6H),0.80(dd,1H).(UPLC-MS)t R 0.50 min;ESI-MS 446[M+H] + .

[0273] Example 52: 2-amino-N-cyclohexyl-5-(4-(3-morpholinopropoxy)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)morpholine was used instead of 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine. 1H NMR(400MHz,DMSO-d6)δ 8.35(d,1H),8.34(s,1H),8.10(d,1H),7.59(d,2H),7.06(s,2H),7.01(d,2H),4.04(t,2H),3.82-3.68(m,1H),3.58(t,4H) ,2.50-2.22(m,6H),1.90-1.78(m,4H),1.78-1.69(m,2H),1.63(dd,1H),1.38-1.20(m,4H),1.19-1.05(m,1H).(HPLC-MS)t R 1. 40 minutes; APCI-MS 439[M+H] + .

[0274] Example 53: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(prop-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a manner similar to 2-amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(3-morpholinopropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 5), except that 3-bromoprop-1-in was used instead of 4-(3-bromopropyl)morpholine. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.12(d,1H),7.59(d,2H),7.21(d,2H),7.13(s,2H),4.59(d,1H),3.73(d,1H),3.52-3.38(m,2H),3. 21(d,1H),2.93(d,1H),2.83(d,1H),2.72(d,1H),2.40(s,3H),1.95-1.75(m,4H),1.44-1.19(m,5H),0.80(dd,1H).(UPLC-MS)t R 0.49 min;ESI-MS 431[M+H] + .

[0275] Example 54: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(prop-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 3-bromoprop-1-yin was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a). 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.31(d,1H),8.12(d,1H),7.59(d,2H),7.21(d,2H),7.12(s,2H),4.59(d,1H),3.76-3.70(m,1H),3.46(s,2H),3.45-3. 37(m,1H),3.22(d,1H),2.83(d,1H),2.72(d,1H),2.71-2.69(m,2H),1.92-1.77(m,5H),1.51-1.17(m,5H),0.80(dd,1H).(UPLC-MS)t R 0.52 min;ESI-MS 431[M+H] + .

[0276] Example 55: 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)-2-chlorophenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 5-(4-((R)-1-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 3), except that (R)-6-(1-(4-bromo-3-chlorophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (intermediate 55a) was used instead of (R)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 3). 1H NMR(400 MHz,DMSO-d6)δ 8.17(m,2H),8.00(s,1H),7.42-7.44(m,2H),7.40(m,1H),7.34(bs,2H),4.62(s,3H),4.55 -4.57(m,1H),3.72(m,1H),3.35-3.54(m,4H),3.20-3.24(m,2H),3.15(bs,1H),1.78-1.88(m,4H),1.20-1.41(m,4H),1.11(bs,3H).(UPLC-MS)t R 0.47 min;ESI-MS 471 / 473[M+H] + .

[0277] Intermediate 55a: (R)-6-(1-(4-bromo-3-chlorophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane The title compound was prepared in a similar manner to (R)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (intermediate 3b), except that (R)-1-(4-bromophenyl)ethaneamine was used instead of (R)-1-(4-bromophenyl)ethaneamine. (UPLC-MS)t R 0.63 min;ESI-MS 316 / 318[M+H] + .

[0278] Example 56: 2-Amino-5-(2-Fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46), except that (R)-2-(2-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 56a) was used instead of (R)-2-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46). UPLC-HRMSt R 3.22 minutes; ESI 441.26 [M+H] + .

[0279] Intermediate 56a: (R)-2-(2-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione The title compound was prepared in a similar manner to (R)-2-(3-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 46a), except that 3-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 56b) was used instead of 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 46a). ESI-MS 349[M+H] + .

[0280] Intermediate 56b: 3-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde The title compound was prepared in a similar manner to 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 46b), except that (2-fluoro-4-formylphenyl)boronic acid was used instead of (3-fluoro-4-formylphenyl)boronic acid. ESI-MS 576[2M+H2O+H] + .

[0281] Example 57: 2-amino-5-(4-((1R,5S)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide [ka] The title compound is 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide HCl salt (intermediate 34) instead of 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide HCl salt (intermediate 34) The compound was prepared in a manner similar to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that a) was used and 1-bromo-2-fluoroethane was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a). After purification, the title compound was obtained as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 10.00(bs,1H),8.38(d,1H),8.04(d,1H),7.85(s,1H),7.77(d,2H),7.35(d,2H),7.08(s,2H),4.83(td,2H),4.74(bs,1H),4.08(bs (UPLC-MS)t R 0.53 min; ESI-MS 465[M+H] + .

[0282] Example 58: 2-Amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxy-4-methylcyclohexyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 35a) instead ofR,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 35a), The compound was prepared in a manner similar to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that trans-4-amino-1-methylcyclohexanol was used instead of lance-4-aminocyclohexanol. The crude product was purified by prepHPLC (method 1a) and passed through an ion exchange cartridge (PL-HCO3) for desalting to obtain the title compound. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.29(d,1H),8.10(d,1H),7.59(d,2H),7.25(d,2H),7.10(s,2H),4.33(s,1H),3.81(bs,1H),3.39(d,2H),2.62-2.56(m, (UPLC-MS)t R 0.61 min; ESI-MS 525[M+H] + .

[0283] Example 59: 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 5-(4-((R)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 3), except that (6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)boronic acid (intermediate 59a) was used instead of (6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)boronic acid (intermediate 59a). 1H NMR(400MHz,DMSO-d6)δ 8.38(s,1H),8.25(bs,1H),8.11(d,1H)7.71-7.54(m,2H),7.49-7.28(m,2H),7.12(bs,2H),4.61(bs,4H),4.31(s,1H),3.89-3.68(m,2H) ),3.31(s,15H),3.27-2.99(m,2H),1.86-1.69(m,2H),1.66-1.52(m,2H),1.51-1.35(m,5H),1.16(s,1H),1.30-0.95(m,2H).(UPLC-MS)t R 0.47 min;ESI-MS 451[M+H] + .

[0284] Intermediate 59a: (6-amino-5-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)carbamoyl)pyridine-3-yl)boronic acid The title compound was prepared in a similar manner to (6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)boronic acid (intermediate 3a), except that 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (intermediate 59b) was used instead of 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (intermediate 3c). (UPLC-MS)t R 0.33 min;ESI-MS 394[M+H] + .

[0285] Intermediate 59b: 2-amino-5-bromo-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)nicotinamide The title compound was prepared in a similar manner to 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (intermediate 3c), except that trans-4-amino-1-methylcyclohexanol was used instead of trans-4-aminocyclohexanol. (UPLC-MS)t R 0.68 min;ESI-MS 328 / 330[M+H] + .

[0286] Example 60: 2-Amino-5-(4-((1R,5S)-3-(Buty-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 1-bromobuti-2-yin was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a). 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.31(d,1H),8.12(d,1H),7.59(d,2H),7.21(d,2H),7.12(s,2H),4.58(d,1H),3.77-3.71(m,1H),3.43- 3.37(m,3H),3.22(d,1H),2.92(d,1H),2.80(d,1H),1.93-1.78(m,8H),1.44-1.19(m,6H),0.79(dd,1H).(UPLC-MS)t R 0.54 min;ESI-MS 445[M+H] + .

[0287] Example 61: 2-amino-N-cyclohexyl-5-(4-(piperidine-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that 4-(piperidine-1-yl)phenylboronic acid was used instead of 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine. 1H NMR(400MHz,DMSO-d6)δ 8.33(d,1H),8.33(s,1H),8.08(d,1H),7.51(d,2H),7.01(s,2H),7.00(d,2H),3.82-3.68(m,1H),3.17(t,4H) ),1.90-1.78(m,2H),1.78-1.69(m,2H),1.68-1.49(m,7H),1.38-1.20(m,4H),1.19-1.05(m,1H).(HPLC-MS)t R 1. 40 minutes; APCI-MS 379[M+H] + .

[0288] Example 62: 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 28a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 28a) instead of 2-amino-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 28a), instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 28a). The compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that trans-4-amino-1-methylcyclohexanol was used instead of trans-4-aminocyclohexanol. The crude product was purified first by prepHPLC (method 1a) and then by reverse-phase flash chromatography (method 3a) to obtain the title compound as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 8.92(d,1H),8.46(s,1H),8.22(s,1H),7.61(d,2H),7.25(d,2H),7.18(s,2H),4.15-4.09(m,1H),3.88-3.82(m,2H), 3.42-3.36(m,3H),3.10(bs,1H),2.65-2.34(m,12H),1.85-1.75(m,3H),1.45-1.31(m,6H),0.77(bs,1H).(UPLC-MS)t R 0.49 min;ESI-MS 491[M+H] + .

[0289] Example 63: 2-Amino-N-(4-Hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound is 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide instead of 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide (intermediate 1a). It was prepared in a similar manner to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 1), except that the HCl salt (intermediate 40a) was used and oxetane-3-one was used instead of 1-(methylsulfonyl)piperidine-4-one. 1H NMR(400MHz,DMSO-d6)δ 8.34(d,1H),7.98(d,1H),7.80(s,1H),7.57(d,2H),7.22(d,2H),6.92( s,2H),4.61-4.56(m,2H),4.52-4.48(m,2H),4.32(s,1H),3.80-3.74(m, 1H),3.03(d,1H),2.57-2.51(m,3H),2.14-1.98(m,6H),1.88-1.85(m,1 H),1.71-1.55(m,6H),1.45-1.35(m,1H),0.83-0.80(m,1H).(UPLC-MS)t R 0.51 min; ESI-MS 475[M+H] + .

[0290] Example 64: 2-Amino-N-(4-Hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound is 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide instead of 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide (intermediate 1a). It was prepared in a manner similar to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 1), except that the HCl salt (intermediate 34a) was used and oxetane-3-one was used instead of 1-(methylsulfonyl)piperidine-4-one. 1H NMR(400MHz,DMSO-d6)δ 8.34(d,1H),7.98(d,1H),7.80(s,1H),7.57(d,2H),7.22(d,2H),6.92( s,2H),4.61-4.56(m,2H),4.52-4.48(m,2H),4.31(s,1H),3.81-3.76(m, 1H),3.03(d,1H),2.57-2.51(m,3H),2.07-2.03(m,6H),1.88-1.85(m,1 H),1.65-1.61(m,6H),1.45-1.35(m,1H),0.83-0.80(m,1H).(UPLC-MS)t R 0.55 min; ESI-MS 475[M+H] + .

[0291] Example 65: 2-amino-N-cyclohexyl-5-(4-((2-(4-methylpiperazine-1-yl)ethyl)carbamoyl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 4-(6-amino-5-(cyclohexylcarbamoyl)pyridine-3-yl)benzoic acid (intermediate 65a) was used instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-3-yl)phenyl)nicotinic acid (intermediate 1c), and 2-(4-methylpiperazine-1-yl)ethaneamine was used instead of trans-4-aminocyclohexanol. The crude product was purified by normal-phase chromatography (Method 2c) to obtain the title compound as a grayish-white solid. ¹H NMR (400 MHz, DMSO-d6)δ 8.50(d,1H),8.42(t,1H),8.37(d,1H),8.23(d,1H),7.91(d,2H),7.80(d,2 H),7.25(s,2H),3.82-3.65(m,1H),3.40(q,2H),3.32-3.13(m,3H),2.99-2 .83(m,1H),2.43-2.31(m,6H),2.17(s,3H),1.90-1.80(m,2H),1.80-1.70( m,2H),1.70-1.55(m,1H),1.40-1.25(m,4H),1.20-1.10(m,1H).(HPLC-MS)t R 1.28 minutes; APCI-MS 465[M+H] + .

[0292] Intermediate 65a: 4-(6-amino-5-(cyclohexylcarbamoyl)pyridine-3-yl)benzoic acid The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. The crude product was ground with 2-propanol to obtain a brownish solid, which was purified by prepHPLC (Method 1a). The pure fraction was collected and concentrated under reduced pressure, then basicized with Na2CO3, causing the title compound to precipitate as a colorless solid. This was filtered and dried under reduced pressure. (HPLC-MS) R 1.52 minutes; ESI-MS 340[M+H] + .

[0293] Example 66: 2-Amino-5-(4-((1S,5R)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 1,3-difluoropropan-2-yl (intermediate 6a) was used instead of 4-(3-bromopropyl)morpholine. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.31(d,1H),8.12(d,1H),7.59(d,2H),7.24(d,2H),7.12(s,2H),4.68(t,2H),4.57(dd,3H),3.81-3.65(m,1H) ,3.46-3.35(m,2H),3.08(d,1H),2.93(d,1H),2.83(dd,1H),2.05-1.76(m,5H),1.53-1.16(m,6H),0.78(dd,1H).(UPLC-MS)t R 0.68 min;ESI-MS 471[M+H] + .

[0294] Example 67: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 2,2,2-trifluoroethyltrifluoromethanesulfonate was used instead of 4-(3-bromopropyl)morpholine. 1H NMR(400MHz,DMSO-d6)δ 8.46-8.31(m,2H),8.18(bs,1H),7.59(d,2H),7.29(bs,1H),7.23(d,2H),3.83-3.54(m,1H),3.51-3.24(m,5H),3.11(d,1H),2 .92(d,1H),2.86(m,1H),1.92-1.77(m,5H),1.29-1.21(m,1H),1.42-1.18(m,4H),1.14(bs,1H),0.85-0.79(m,1H).(UPLC-MS)t R 1.04 minutes;ESI-MS 475[M+H] + .

[0295] Example 68: 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,3R)-3-hydroxyadamantan-1-yl)nicotinamide [ka] The title compound was prepared in a similar manner to 5-(4-((R)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 3), except that (6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)boronic acid (intermediate 68a) was used instead of (6-amino-5-(((1r,3r)-3-hydroxyadamantan-1-yl)carbamoyl)pyridine-3-yl)boronic acid (intermediate 68a). 1H NMR(400MHz,DMSO-d6)δ 8.65(bs,1H),8.49(s,1H),8.35(s,1H),7.87(d,2H),7.59(d,2H),4.73(dd,2H),4.65-4.54(m,4H),4.45-4.39(m,1H),4. 16-4.10(m,1H),3.98(s,1H),3.90(bs,1H),2.21(s,2H),2.04-1.94(m,6H),1.60(bs,2H),1.49-1.43(m,3H).(UPLC-MS)t R 0.56 min;ESI-MS 489[M+H] + .

[0296] Intermediate 68a: 6-amino-5-(((1r,3r)-3-hydroxyadamantan-1-yl)carbamoyl)pyridine-3-yl)boronic acid The title compound was prepared in a similar manner to (6-amino-5-(((1r,4r)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)boronic acid (intermediate 3a), except that 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (intermediate 68b) was used instead of 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (intermediate 3c). (UPLC-MS)t R 0.47 min;ESI-MS 332[M+H] + .

[0297] Intermediate 68b: 2-amino-5-bromo-N-((1r,3r)-3-hydroxyadamantan-1-yl)nicotinamide The title compound was prepared in a similar manner to 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide intermediate 3c), except that 3-amino-1-adamantanol was used instead of trans-4-aminocyclohexanol. (UPLC-MS)t R 0.82 minutes; ESI-MS 366 / 368[M+H] + .

[0298] Example 69: 2-amino-N-cyclohexyl-5-(4-(morpholine-4-carbonyl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that 4-(morpholine-4-carbonyl)phenylboronic acid was used instead of 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine. 1H NMR(400 MHz,DMSO-d6)δ 8.47(d,1H),8.42(s,1H),8.30(d,1H),7.78(d,2H),7.51(d,2H),7.49(s,2H),3.85-3.70(m,1H),3.70 -3.50(m,8H),1.90-1.80(m,2H),1.80-1.70(m,2H),1.70-1.55(m,1H),1.35-1.29(m,4H),1.28-1.05(m,1H).(HPLC-MS)t R 1.51 minutes; APCI-MS 409[M+H] + .

[0299] Example 70: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(oxetan-3-ylmethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that oxetane-3-ylmethyltrifluoromethanesulfonate (intermediate 70a) was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a). The reaction mixture was stirred at 60°C for 3 hours. ¹H NMR (400 MHz, DMSO-d6)δ 8.38(d,1H),8.30(d,1H),8.11(d,1H),7.58(d,2H),7.21(d,2H),7.12(s,2 H),4.66(dt,2H),4.58(d,1H),4.28(t,2H),3.90-3.66(m,1H),3.43-3.35( m,1H),3.25(dd,1H),3.19-3.09(m,1H),2.97(d,1H),2.79(d,2H),2.62-2. 51(m,2H),1.98-1.75(m,5H),1.48-1.13(m,5H),0.75(dd,1H).(UPLC-MS)t R 0.46 min;ESI-MS 463[M+H] + .

[0300] Intermediate 70a: Oxetane-3-ylmethyltrifluoromethanesulfonate The title compound was prepared in a similar manner to 1,3-difluoropropane-2-yltrifluoromethanesulfonate (intermediate 6a), except that oxetane-3-ylmethanol was used instead of 1,3-difluoropropane-2-ol. It was obtained as a crude oil and used without further purification.

[0301] Example 71: 2-Amino-N-((1s,4R)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-((6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 71a) was used instead of 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 71a), and cis-4-aminocyclohexanol hydrochloride was used instead of trans-4-aminocyclohexanol. The crude product was purified by prepHPLC (Method 1a) to obtain the title compound as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.49-8.34 (m,2H), 8.17 (s,1H), 7.67 (s,2H), 7.36 (s,2H), 7.16 (s,2H), 4.43 (d,1H), 3.81 (s,2H), 3.81-3.59 (m,4H), 1.88-1.62 (m,5H), 1.61-1.44 (m,5H), 1.35 (s,6H), 1.16 (s,2H). (UPLC-MS) t R 0.52 min; ESI-MS 435[M+H] + .

[0302] Intermediate 71a: 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 1c), except that methyl 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 71b) was used instead of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1d). (UPLC-MS)t R 0.40 min;ESI-MS 338[M+H] + .

[0303] Intermediate 71b: Methyl 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate The title compound was prepared in a similar manner to methyl 2-amino-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 7b), except that 2-iodopropane was used instead of 1-bromo-2-methoxyethane. (UPLC-MS)t R 0.65 min;ESI-MS 352[M+H] + .

[0304] Example 72: 2-Amino-N-((1r,4R)-4-Hydroxy-4-methylcyclohexyl)-5-(4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide [ka] To a solution of (4-(bromomethyl)phenyl)boronic acid (73.1 mg, 0.340 mmol) in acetonitrile (2 mL), (R)-2-methylpyrrolidine (29.0 mg, 0.340 mmol) and K2CO3 (78 mg, 0.567 mmol) were added at room temperature under a nitrogen atmosphere, and the resulting white suspension was stirred at 60°C for 2 hours. Water (1 mL) was added at room temperature, followed by the addition of 2-amino-5-bromo-N-((1r,4r)-4-hydroxy-4-methylcyclohexyl)nicotinamide (intermediate 59b, 150 mg, 0.283 mmol) in acetonitrile (2 mL). Next, PdCl2 (dppf) (10.37 mg, 0.014 mmol) was added, and the reaction mixture was stirred at 90°C for 60 minutes. After filtration through a Celite pad and concentration under reduced pressure, the crude product was diluted with saturated aqueous solution of NaHCO3 and SiO2. After phase separation, the aqueous layer was extracted with SiO2, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified first by prepHPLC (Method 1a) and then by normal-phase flash chromatography (Method 2b) to obtain the title compound as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 9.75(d,1H),8.52(t,1H),8.41(d,1H),8.27(d,1H),7.85(d,2H),7.66( d,2H),7.38(bs,2H),4.67-4.53(m,1H),4.25(dd,1H),3.85(s,1H),3.58 -3.49(m,1H),3.37-3.18(m,3H),2.29(m,1H),2.06-1.88(m,2H),1.83(s ,2H),1.65(dd,2H),1.51(d,4H),1.39(dd,3H),1.22(d,3H).(UPLC-MS)t R 0.47 min;ESI-MS 423[M+H] + .

[0305] Example 73: 2-amino-5-(4-((1S,5R)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide [ka] The title compound is 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide HCl salt (intermediate) instead of 5-(4-((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1- The reaction mixture was prepared in a manner similar to that of 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that the compound 40a) was used and 1-bromo-2-fluoroethane was used instead of 4-(3-bromopropyl)morpholine, and the reaction mixture was stirred at 60°C for 3 hours. 1H NMR(400MHz,DMSO-d6)δ 8.35(d,1H),7.98(d,1H),7.79(s,1H),7.57(d,2H),7.22(d,2H),6.92 (s,2H),4.55(td,2H),4.31(s,1H),3.38(d,1H),3.10(d,1H),2.84(t, (UPLC-MS)t R 0.51 min;ESI-MS 465[M+H] + .

[0306] Example 74: 2-Amino-5-(2,3-difluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46), except that (R)-2-(2,3-difluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 74a) was used instead of (R)-2-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46). (UPLC-MS)t R 0.76 min;ESI-MS 459[M+H] + .

[0307] Intermediate 74a: (R)-2-(2,3-difluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione The title compound was prepared in a similar manner to (R)-2-(3-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-2-dione (intermediate 46a), except that 2,3-difluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 74b) was used instead of 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 46a). ESI-MS 367[M+H] + .

[0308] Intermediate 74b: 2,3-difluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde The title compound was prepared in a similar manner to 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 46b), except that (2,3-difluoro-4-formylphenyl)boronic acid was used instead of (3-fluoro-4-formylphenyl)boronic acid. ESI-MS 595[2M+H] + .

[0309] Example 75: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 1-bromo-2-methoxyethane was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a). The reaction mixture was stirred at 60°C for 3 hours. After purification, the title compound was obtained as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 9.70(bs,1H),8.41(s,1H),8.31(d,1H),8.12(d,1H),7.66-7.60(m,2H),7.30(bs,2H),7.14(s,2H),4.5 9(d,1H),3.81-3.38(m,8H),3.31(s,3H),2.75-2.25(m,4H),1.86(t,4H),1.50-1.21(m,6H).(UPLC-MS)t R 0.48 min;ESI-MS 451[M+H] + .

[0310] Example 76: 2-Amino-5-(4-((1S,5R)-3-(2,2-difluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 5), except that 2,2-difluoropropyltrifluoromethanesulfonate was used instead of 4-(3-bromopropyl)morpholine. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.33(d,1H),8.14(d,1H),7.60(d,2H),7.32-7.09(m,4H),4.59(bs,1H),3.74(bs,1H),3.11 (d,1H),2.98-2.63(m,5H),1.89-1.83(m,5H),1.63(t,3H),1.42-1.25(m,6H),0.81(bs,1H).(UPLC-MS)t R 0.82 min;ESI-MS 471[M+H] + .

[0311] Example 77: 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide (Example 6), except that 2,2,2-trifluoroethyltrifluoromethanesulfonate was used instead of 1,3-difluoropropan-2-yltrifluoromethanesulfonate (intermediate 6a), and the reaction mixture was stirred at 60°C for 1 hour. 1H NMR(400MHz,DMSO-d6)δ 8.39(d,1H),8.32(d,1H),8.13(d,1H),7.60(d,2H),7.24(d,2H),7.16(s,2H),4.58(s,1H),3.73(dt,1H),3.41( m,4H),3.13(d,1H),2.93(d,1H),2.84(dd,1H),1.92-1.77(m,5H),1.51-1.15(m,5H),0.84(dd,1H).(UPLC-MS)t R 1.03 minutes;ESI-MS 475[M+H] + .

[0312] Example 78: 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl-4-d)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 71a) instead of 2-amino-5-(4-((1S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 71a) and trans-4-aminocyclo The preparation was similar to that of (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that trans-4-aminocyclohexane-1-d-1-ol hydrochloride (intermediate 78a) was used instead of hexanol. The crude product was first purified by prepHPLC (method 1a) and then by reverse-phase flash chromatography (method 3a) to obtain the title compound as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ 8.38(d,1H),8.31(d,1H),8.11(d,1H),7.58(d,2H),7.22(d,2H),7.12(s,2H),4.56(s,1H),3.73(dt,1H),3.37(s,1H) ,3.06(d,1H),2.57(d,1H),2.49-2.41(m,2H),1.93-1.73(m,5H),1.31(m,5H),1.04(dd,6H),0.74(dd,1H).(UPLC-MS)t R 0.50 min;ESI-MS 436[M+H] + .

[0313] Intermediate 78a: Trans-4-aminocyclohexane-1-d-1-ol hydrochloride Deuterated aminocyclohexyl starting materials can be prepared using methods similar to those known in the art (e.g., Quirante, J. et al, J. Org. Chem. 67(7):2323-2328 (2002)). For example, tert-butylbenzyl(4-oxocyclohexyl)-carbamate can be reduced with NaBD4 to obtain deuterated tert-butylbenzyl((1r,4r)-4-hydroxycyclohexyl)carbamate, which can then be incorporated by the synthetic methods described herein after deprotection of the tert-butyloxycarbonyl and benzyl protecting groups.

[0314] Example 79: 2-amino-N-((1s,4s)-4-hydroxycyclohexyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide TFA salt [ka] The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that 2-amino-5-bromo-N-cyclohexylnicotinamide (intermediate 43a) was replaced with 2-amino-5-bromo-N-cyclohexylnicotinamide (intermediate 79a), and (4-methylpiperazine-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone was used instead of 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine. The reaction was carried out in a microwave reactor (irradiation time 15 minutes at 80°C). The title compound was obtained as a TFA salt. 1H NMR(400MHz,DMSO-d6)δ 10.01(s,2H),8.56(d,1H),8.51(d,1H),8.43(d,1H),7.85(d,2H),7.57(d,2H),3.86-3.55(m,3H),3.55-3.20 (m,4H),3.40-3.15(m,3H),2.85(s,3H),1.85-1.70(m,2H),1.70-1.65(m,2H),1.65-1.40(m,4H).(HPLC-MS)t R 0.35 min; ESI-MS 438[M+H] + .

[0315] Intermediate 79a: 2-amino-5-bromo-N-((1s,4s)-4-hydroxycyclohexyl)nicotinamide The title compound was prepared in a similar manner to 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide (intermediate 3c), except that cis-4-aminocyclohexanol was used instead of trans-4-aminocyclohexanol. (UPLC-MS)t R 0.53 min;ESI-MS 314 / 316[M+H] + .

[0316] Example 80: 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide [ka] The title compound is 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide HCl instead of 5-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1- (intermediate 1a). It was prepared in a manner similar to 2-amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide (Example 1), except that (intermediate 34a) was used and 4,4-difluorocyclohexanone was used instead of 1-(methylsulfonyl)piperidine-4-one. 1H NMR(400MHz,DMSO-d6)δ 8.32(d,1H),7.95(d,1H),7.76(s,1H),7.55(d,2H),7.21(d,2H),6.88(s,2H),4.28(s,1H),3.36(s,1H),3.07(s,1H),2.55 (s,1H),2.45(s,1H),2.32(d,1H),2.30-1.95(m,8H),1.77(d,5H),1.70-1.32(m,8H),1.27(t,1H),0.75(s,1H).(UPLC-MS)t R 0.63 min;ESI-MS 537[M+H] + .

[0317] Example 81: 2-amino-5-(2-chloro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide TFA salt [ka] The title compound was prepared in a similar manner to 2-amino-5-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46), except that (R)-2-(2-chloro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 81a) was used instead of (R)-2-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46). UPLC-HRMSt R 3.45 minutes 457.24 / 459.24 [M+H] + .

[0318] Intermediate 81a: (R)-2-(2-chloro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione The title compound was prepared in a similar manner to (R)-2-(3-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 46a), except that 3-chloro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 81b) was used instead of 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 46a). ESI-MS 365 / 367[M+H] + .

[0319] Intermediate 81b: 3-Chloro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde The title compound was prepared in a similar manner to 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 46b), except that (2-chloro-4-formylphenyl)boronic acid was used instead of (3-fluoro-4-formylphenyl)boronic acid. ESI-MS 313 / 315[M+H2O+H] + .

[0320] Example 82: 2-Amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 82a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 82a) instead of 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 82a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 82a), The preparation was similar to that of (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that trans-4-amino-1-methylcyclohexanol was used instead of lance-4-aminocyclohexanol. The crude product was purified by prepHPLC (method 1a) to obtain the title compound, which was obtained as the TFA salt. 1H NMR(400MHz,DMSO-d6)δ 8.37(s,1H),8.26(d,1H),8.09(d,1H),7.57(d,2H),7.23(d,2H),7.08(s,2H),4.33(s,1H),3.81(bs,1H),3.39(d,2H),2.62-2.56( (UPLC-MS)t R 0.61 min; ESI-MS 525[M+H] + .

[0321] Intermediate 82a: 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid The title compound was prepared in a similar manner to 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 2c), except that methyl 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 82b) was used instead of (1R,5S)-tert-butyl 1-(4-(6-amino-5-(methoxycarbonyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1d). (UPLC-MS)t R 0.46 min;ESI-MS 414[M+H] + .

[0322] Intermediate 82b: Methyl 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate The title compound was prepared in a similar manner to methyl 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinate (intermediate 14b), except that 4,4-difluorocyclohexanone was used instead of dihydro-2H-pyran-4(3H)-one. (UPLC-MS)t R 0.72 min; ESI-MS 428[M+H] + .

[0323] Example 83: 2-Amino-N-(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide [ka] The title compound uses 2-amino-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a) instead of 2-amino-5-(4-((1R,5S)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinic acid (intermediate 14a), and trans-4-aminocycline The compound was prepared in a similar manner to (1R,5S)-tert-butyl1-(4-(6-amino-5-(((1r,4R)-4-hydroxycyclohexyl)carbamoyl)pyridine-3-yl)phenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate 1b), except that 2-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-ol hydrochloride (intermediate 83a) was used instead of lohexanol. The crude product was purified by prepHPLC (method 1a) to obtain the title compound. 1H NMR(400MHz,DMSO-d6)δ 8.98(s,1H),8.37(s,1H),8.15(s,1H),7.57(d,2H),7.20(d,2H),7.18(s,2H),4.15(s,1H),3.85-3.79(m,2H),3.38(bs,1H) ,3.08(bs,1H),2.55-2.25(m,5H),1.90(s,6H),1.89-1.71(m,3H),1.39-1.22(m,3H),1.06(s,6H),0.75(bs,1H).(UPLC-MS)t R 0.59 min;ESI-MS 503[M+H] + .

[0324] Intermediate 83a: 2-(3-aminobicyclo[1.1.1]pentan-1-yl)propan-2-ol hydrochloride Tert-butyl(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (intermediate 83b, 298 mg, 1.235 mmol) was stirred in HCl saturated ethanol solution (3.8 mL) at room temperature for 29 hours. The reaction mixture was concentrated under reduced pressure to obtain the labeled compound as crude hydrochloride, which was used without further purification. ¹H-NMR (400 MHz, DMSO-d6) δ 8.51 (s, 3H), 1.78 (s, 6H), 1.03 (s, 6H).

[0325] Intermediate 83b: tert-butyl(3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (679 mg, 2.81 mmol) in anhydrous THF, 3M magnesium methylbromide in THF (4.13 mL, 12.4 mmol) was added dropwise under an argon atmosphere at -78°C. The reaction mixture was allowed to stand to room temperature, stirred for 4 hours, and then slowly diluted with 2 mL of MeOH under temperature control. The mixture was concentrated under reduced pressure, and the crude product was purified by normal-phase chromatography (Method 2a) to obtain the title compound. (UPLC-MS) R 0.22 min;ESI-MS 142[M+H] + This shows the loss of BOC groups under ionization conditions.

[0326] Example 84: 2-amino-N-cyclohexyl-5-(3-(morpholine-4-carbonyl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that 3-(morpholine-4-carbonyl)phenylboronic acid was used instead of 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine. 1H NMR(400MHz,DMSO-d6)δ 8.45(s,1H),8.38(d,1H),8.18(s,1H),7.78(d,1H),7.71(s,1H),7.52(t,1H),7.34(d,1H),7.20(s,2H),3.85-3.70(m,1H),3.70 -3.50(m,8H),1.90-1.80(m,2H),1.80-1.70(m,2H),1.70-1.55(m,1H),1.35-1.29(m,4H),1.28-1.05(m,1H).(HPLC-MS)t R 1.52 minutes; APCI-MS 409[M+H] + .

[0327] Example 85: 2-amino-5-(3-chloro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46), except that (R)-2-(3-chloro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 85a) was used instead of (R)-2-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46). (UPLC-MS)t R0.79 min;ESI-MS 457 / 459[M+H] + .

[0328] Intermediate 85a: (R)-2-(3-chloro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione The title compound was prepared in a similar manner to (R)-2-(3-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-2-dione (intermediate 46a), except that 2-chloro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 85b) was used instead of 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 46a). ESI-MS 365 / 367[M+H] + .

[0329] Intermediate 85b: 2-Chloro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde The title compound was prepared in a similar manner to 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 46b), except that (3-chloro-4-formylphenyl)boronic acid was used instead of (3-fluoro-4-formylphenyl)boronic acid. ESI-MS 591[2M+H] + .

[0330] Example 86: 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxy-1-methylcyclohexyl)nicotinamide [ka] To a solution of 2-amino-5-bromo-N-((1r,4r)-4-hydroxy-1-methylcyclohexyl)nicotinamide (intermediate 86a, 100 mg, 0.152 mmol) in dioxane (3 mL), (R)-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (intermediate 86b, 100 mg, 0.152 mmol), PdCl2 (dppf) (5.57 mg, 7.62 μmol), and 2N aqueous NaOH (0.152 mL, 0.305 mmol) were added under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at 80°C for 2 hours and then diluted with ethyl acetate and water. After two extractions with SiO2, the combined organic layers were washed with saturated aqueous solution of NaHCO3 and brine, respectively. After drying on MgSO4, filtration, and concentration under reduced pressure, the crude product was purified by normal-phase chromatography (Method 2b) to obtain the title compound. 1H NMR(400MHz,DMSO-d6)δ 8.37(s,1H),8.05(bs,1H),7.70(s,1H),7.62(bs,2H),7.38(bs,2H),6.92(bs,2H),4.62(s,4H),4.47(s,1H),3.4 8-3.42(m,1H),3.40-3.35(m,4H),3.27-3.20(m,2H),3.15(bs,1H),1.60(m,2H),1.65-1.16(m,13H).(UPLC-MS)t R 0.52 min;ESI-MS 451[M+H] + .

[0331] Intermediate 86a: 2-amino-5-bromo-N-((1r,4r)-4-hydroxy-1-methylcyclohexyl)nicotinamide. The title compound was prepared in a similar manner to 2-amino-5-bromo-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide intermediate 3c), except that trans-4-amino-4-methylcyclohexanol was used instead of trans-4-aminocyclohexanol. (UPLC-MS)t R 0.70 min;ESI-MS 328 / 330[M+H] + .

[0332] Intermediate 86b: (R)-6-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane The title compound was prepared in a similar manner to 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-isopropylpiperazine (intermediate 8a), except that (R)-6-(1-(4-bromophenyl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (intermediate 3b) was used instead of 1-(4-bromo-3-fluorophenyl)-4-isopropylpiperazine (intermediate 8b). (UPLC-MS)t R 0.70 min;ESI-MS 330[M+H] + .

[0333] Example 87: 2-Amino-N-((1r,4R)-4-Hydroxy-4-methylcyclohexyl)-5-(2-Methyl-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-5-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46), except that (R)-6-methyl-2-(2-methyl-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 87a) was used instead of (R)-2-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide (Example 46). (UPLC-MS)t R 0.65 min; ESI-MS 437[M+H] + .

[0334] Intermediate 87a: (R)-6-methyl-2-(2-methyl-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-1,3,6,2-dioxazabolocan-4,8-dione The title compound was prepared in a similar manner to (R)-2-(3-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-6-methyl-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 46a), except that 3-methyl-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 87b) was used instead of 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-4,8-dione (intermediate 46a). ESI-MS 345[M+H] + .

[0335] Intermediate 87b: 3-methyl-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde The title compound was prepared in a similar manner to 2-fluoro-4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazabolocan-2-yl)benzaldehyde (intermediate 46b), except that (4-formyl-2-methylphenyl)boronic acid was used instead of (3-fluoro-4-formylphenyl)boronic acid. ESI-MS 568[2M+H2O+H] + .

[0336] Example 88: 2-amino-N-cyclohexyl-5-(3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenyl)nicotinamide [ka] The title compound was prepared in a similar manner to 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide (Example 43), except that 3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenylboronic acid was used instead of 1-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine. 1H NMR(400MHz,DMSO-d6)δ 8.44(s,1H),8.38(d,1H),8.17(s,1H),7.77(d,1H),7.68(s,1H),7.51 (t,1H),7.31(d,1H),7.19(s,2H),4.44(t,1H),3.85-3.70(m,1H),3.70 -3.58(m,2H),3.58-3.48(m,2H),3.48-3.35(m,2H),2.50-2.32(m,6H),1.90-1.80(m,2H) ,1.80-1.70(m,2H),1.70-1.55(m,1H),1.35-1.29(m,4H),1.28-1.05(m,1H).(HPLC-MS)t R 1.31 minutes; APCI-MS 452[M+H] + .

[0337] Example 89: Salts, amorphous forms, and crystalline polymorphs and polymorphs of the compound from Example 34: A) Free form modified H A800 g of the free form of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide was dissolved in 3 liters of acetone. The resulting solution was stirred at 50°C and 2 liters of water were gradually added. The mixture was stirred at 50°C for 30 minutes, and then 4 liters of water were gradually added. The mixture was stirred at 50°C for 2 hours and cooled to 22°C over 2 hours. The solid was separated by suction filtration, washed twice with 1 liter of 1:2 acetone:water, and dried at 45°C for 24 hours without vacuum. Approximately 660g of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide free form modified H A It was obtained as a white solid. Free morphologically modified H A It is a monohydrate.

[0338] Figure 3 shows free morphological modification H A The XRPD diagram is shown below.

[0339] Table A below details the corresponding peaks and their 2θ values ​​("angles") along with their relative intensities (all 2θ values ​​are ±0.2):

[0340] [Table 1]

[0341] Figure 4 shows free morphological modification H A The diagram shows the differential scanning calorimetry (DSC) of an empty pan. The first endothermic peak in the DSC diagram is free morphologically modified H₂ A This corresponds to dehydration. The second endothermic peak corresponds to the melting of the anhydrous form resulting from dehydration.

[0342] Figure 5 shows free morphologically modified H AThe thermogravimetric analysis (TGA) diagram is shown.

[0343] The TGA results show that free morphological modification H A This indicates that it contains approximately 3.5% by weight of water, which is equivalent to about one water molecule.

[0344] Figure 6 shows free morphological modification H A This is the FT-IR diagram. The peaks observed are as follows: wavenumber (cm -1 Units: 3481(w), 3328(m), 2931(m), 2886(w), 2863(w), 2787(w), 1632(s), 1617(m), 1584(w), 1524(s), 1459(s), 1242(m), 1090(m), 885(m), 769(m). (s=strong, m=medium, w=weak)

[0345] B) Free form modification A: 0.5g of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide free form modification H A It was added to 3.5 ml of acetone. The mixture was stirred at 40°C for 1 hour and then cooled to 22°C. The solid was filtered and dried at 40°C for 12 hours. Approximately 0.4 g of free-form morphologically modified A was obtained as a white solid.

[0346] Figure 7 shows the XRPD diagram of free morphological modification A.

[0347] Table B below details the corresponding peaks and their 2θ values ​​("angles") along with their relative intensities (all 2θ values ​​are ±0.2):

[0348] [Table 2]

[0349] Figure 8 shows the differential scanning calorimetry (DSC) diagram of the empty pan with free morphological modification A.

[0350] Figure 9 shows the thermogravimetric analysis (TGA) diagram of free morphological modification A. The TGA results suggest that free morphological modification A is an anhydrous substance.

[0351] Figure 10 is the FT-IR diagram of free morphological modification A. The peaks observed are as follows: wavenumber (cm -1 Units: 3480(w), 3436(w), 3401(w), 3301(m), 2944(w), 2864(w), 2805(w), 1644(s), 1615(m), 1583(w), 1520(s), 1459(m), 1247(m), 1098(m), 883(m), 801(m). (s=strong, m=medium, w=weak)

[0352] C) Free form anhydrous: 100 mg 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide Free form modified H A The sample was exposed to an N2 atmosphere at 25°C for 6 hours. The resulting solid was characterized by XRPD under N2 protection. The solid is the free anhydrous form of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide.

[0353] Figure 18 shows the anhydrous form of XRPD diagum.

[0354] D) Free form trihydrate: 100 mg 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide Free form modified H AThe solid was exposed overnight at 25°C to 80% relative humidity. The solid was characterized by XRPD at 25°C to 80% relative humidity. The solid is the free form trihydrate of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide.

[0355] Figure 19 shows the XRPD diagram of the trihydrate morphology.

[0356] E) Fumarate-modified H A 3.03 g of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide in its free form was added to 30 ml of acetone:water (80:20, v / v). The mixture was stirred at 50°C for 0.5 hours to obtain a clear solution. To the solution, 708.4 mg of fumaric acid solution in 15 ml of acetone:water (80:20, v / v) was slowly added. The resulting suspension was gradually cooled to 25°C and stirred for 12 hours. The solid was separated by suction filtration, washed once with 10 ml of acetone, and exposed overnight to ambient conditions (approximately 25°C, 50% RH). 3.3g of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide fumarate modified H A The result was obtained as a white solid. Fumarate-modified H A It is a dihydrate.

[0357] Figure 11 shows fumarate-modified H A The XRPD diagram is shown below.

[0358] Table C below details the corresponding peaks and their 2θ values ​​("angles") along with their relative intensities (all 2θ values ​​are ±0.2):

[0359] [Table 3]

[0360] Figure 12 shows fumarate-modified H A The DSC diagram is shown. The broad endothermic peak before 150°C is due to fumarate-modified H A It is designed to combat dehydration.

[0361] Figure 13 shows fumarate-modified H A The thermogravimetric analysis (TGA) diagram is shown. The TGA results show fumarate-modified H A This indicates that it contains approximately 5.9% by weight of water, which corresponds to about 2 water molecules.

[0362] Figure 14 shows fumarate-modified H A This is the FT-IR diagram. The peaks observed are as follows: wavenumber (cm -1 Units: 3241(m), 2951(w), 2867(w), 1669(m), 1538(m), 1456(w), 1355(m), 1249(m), 1087(w), 979(w), 885(w), 797(w). (s=strong, m=medium, w=weak)

[0363] Figure 15 shows fumarate-modified H A The DVS diagram at 25°C is shown. From this, fumarate-modified H A However, it can be estimated that it is physically stable at 25°C and at least 0% to 90% RH.

[0364] Figure 16 shows fumarate-modified H A The DVS diagram at 40°C is shown. From this, fumarate-modified H A However, it can be estimated that it is physically stable at 40°C and at least 10% to 90% RH.

[0365] Fumarate-modified H AHowever, it should be noted that it is more stable over a wider humidity range than the free morphological polymorph (data not provided).

[0366] F) Amorphous form of fumarate (variant 1): 500 mg of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide fumarate modified H A The compound was added to 10 ml of ethanol at 25°C to form a clear solution. Next, 3 ml of heptane was added to the solution. A white solid precipitated. The solid was separated by suction filtration and dried overnight under vacuum at 40°C. 380 mg of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide in amorphous fumarate form was obtained as a white solid. The amorphous form showed a glass transition of approximately 143°C when analyzed by controlled DSC over 60 seconds at a heating rate of 2 K / min and an amplitude temperature of 1 K.

[0367] G) Amorphous form of fumarate (variant 2): 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide fumarate modified H A The sample was heated to 150°C at 10K / min and then cooled to -20°C at 20K / min by DSC. The resulting substance is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide fumarate in amorphous form, which is a white solid and exhibits a glass transition at approximately 78°C when analyzed by DSC at a heating rate of 10K / min.

[0368] H) 3.01 g of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide phosphate was added to 30 mL of acetone:water (75:25, v / v). The resulting mixture was stirred at 50°C for 0.5 hours to obtain a clear solution. 695.2 mg of the solution in 10 mL of acetone:water (95:5, v / v) was slowly added to the solution. The resulting suspension was gradually cooled to 25°C and stirred for 24 hours. 1.5 mL of water was added to the suspension. The mixture was stirred at 50°C for 12 hours and then slowly cooled to 25°C. The solid was separated by suction filtration, washed once with 10 mL of acetone:water (90:10, v / v), and exposed overnight to ambient conditions (approximately 25°C, 50% RH). 2.7 g of 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide phosphate was obtained as a white solid.

[0369] Figure 17 shows the XRPD diagram for phosphates.

[0370] Table D below details the corresponding peaks and their 2θ values ​​("angles") along with their relative intensities (all 2θ values ​​are ±0.2):

[0371] [Table 4]

[0372] I) Fumarate-modified H A (F) The above) free form modified H in several aqueous buffers A It exhibits better solubility than

[0373] [Table 5]

[0374] [Table 6]

[0375] [Table 7]

[0376] [Table 8]

[0377] [Table 9]

[0378] J) Lactates, tartrates, and malates of compound A can be obtained by a method similar to that described above.

[0379] K) Various solvates can be obtained from salts and many salt forms of compound A described above (details not shown).

[0380] In the examples mentioned above, the XRPD, TGA, DSC, FT-IR, and DVS data were obtained using the following method:

[0381] a) TGA method Equipment:TA Discovery,TA Discovery,New Castle,DE,USA Temperature range: 30~300℃ Scanning speed: 10°C / min Nitrogen flow rate: 20 mL / min Sample mass: approximately 2-10 mg

[0382] b) DSC method Equipment: TA discovery Temperature range: 30-250 or 300°C Scanning speed: 10°C / min Nitrogen flow rate: 50 mL / min Sample mass: approximately 2 mg

[0383] c) XRPD method: All XRPD diagrams were obtained in reflection mode.

[0384] (i) XRPD method 1 (Figures 3, 11, 17) Equipment: Bruker D8 Advance (Bruker, Bruchsal, Germany)) Detector: LYNXEYE (1D mode), Opening angle: 1.996° Irradiation: CuKα (0.15406nm) Monochromator: Nickel filter X-ray generator power: 40kV, 40mA Step size: Resolution 0.041 degrees Scanning range: 2° to 45° (2θ value) Scanning time: 36 minutes Primary slit: Fixed illumination, sample size 5mm; Secondary slit: 5mm; Axis solar angle 2.5°

[0385] (ii) XRPD method 2 (Figure 7) Equipment:Bruker D8 Advance Detector: LYNXEYE (1D mode), Opening angle: 1.996° Irradiation: CuKα (0.15406nm) Monochromator: Nickel filter X-ray generator power: 40kV, 40mA Step size: Resolution 0.041 degrees Scanning range: 2° to 45° (2θ value) Scanning time: 330 seconds Primary slit: Fixed lighting, sample size 5mm, Secondary slit: 5mm, Axis solar 2.5

[0386] XRPD method 3 (Figures 18, 19) Equipment: Bruker D8 Advance XRPD with Cryo-RH chamber (Bruker, Bruchsal, Germany) Detector: VANTEC-1 (1D detector) Irradiation: CuKα (0.15406nm) Monochromator: Nickel filter X-ray generator power: 40kV, 40mA Step size, resolution 0.0165 degrees Scanning range: 2° to 45° (2θ value) Scanning time: 17 minutes Slits; branch slit: V12, splash prevention slit: 10.0 mm, detection slit: 17.43 mm, Primary solar slit: 2.5°, Secondary solar slit: 2.5°

[0387] d) DVS Equipment: Advantage (Surface Measurement Systems, London, UK) Sample mass: approximately 10 mg Temperature: 25℃ dm / dt:0.002% / min

[0388] e) FT-IR Thermo Fisher Nicolet 6700 with Attenuated Total Internal Reflection (ATR), Thermo Fisher Scientific, Waltham, MA, USA

[0389] Biochemical assays (Examples 90 and 91) In all biochemical assays, human recombinant proteins were expressed and purified in baculovirus-transferred insect cells. The construct comprises the GS domain and kinase domain of wild-type ALK2 (aa172-499), ALK2FOP mutant (aa172-499R206H), ALK3 (aa198-525), ALK5 (aa162-503), and ALK6 (aa168-495).

[0390] Example 90: In vitro enzyme inhibition using a biochemical autophosphorylation assay (luminescence-based ADPGlo kinase activity assay) - "ADPGlo assay" A kinase selectivity panel was established to measure autophosphorylation of wild-type ALK2 (aa172-499) and ALK3 (aa198-525) using the ADP-Glo® kinase assay (Promega, V9101).

[0391] The assay was performed in a 384-well low-volume microtiter assay plate with a final reaction volume of 6 μl. Dose-response curves were prepared by incubating each 10 nM kinase at 32°C for 60 minutes in 50 mM Hepes pH 7.5, 0.02% Tween 20, 0.02% BSA, 1 mM DTT, 10 μm Na3VO4, 10 mM ss-glycerol phosphate, 1 mM MgCl2, 12 mM MnCl2, and 15 μm ATP, either in or out of the presence of DMSO-diluted compounds. The amount of ADP produced is a measure of kinase activity and is quantified using the ADP-Glo® kinase assay (Promega) according to the manufacturer's instructions. ADP is converted to ATP by adding 3 μl of ADP-Glo® reagent and incubating at 32°C for 60 minutes. Subsequently, 6 μl of luciferase assay reagent (kinase detection buffer + kinase detection substrate (Promega)) was added and incubated at 32°C for 60 minutes to convert ATP into a bioluminescent signal. For luminescence measurement, a PHERAstar® Multilabel Reader (optical module for luminescence measurement in the wavelength range of 230 nm to 750 nm) was used with a measurement interval of 0.1 seconds. The luminescence signal was positively correlated with kinase activity.

[0392] The specific activity is shown in the table below.

[0393] [Table 10]

[0394] [Table 11]

[0395] [Table 12]

[0396] Example 91: In vitro enzyme inhibition using a biochemical peptide phosphorylation assay - "Caliper assay" A kinase selectivity panel was established to measure the phosphorylation of substrate peptides for wild-type ALK2 (aa172-499), ALK2FOP mutant (aa172-499R206H), ALK1 (aa166-493), ALK5 (aa162-503), and ALK6 (aa168-495). The techniques used in the described assays are based on the separation and quantification of substrates and products in an electric field. During the kinase reaction, the peptide substrate is phosphorylated by the kinase. The movement of phosphate residues also leads to the introduction of two additional negative charges, and consequently, a change in the net charge of the phosphopeptide compared to the unphosphorylated peptide. Due to this difference in charge, phosphorylated and unphosphorylated peptides move at different rates in an electric field.

[0397] In the applied method, this separation occurs within a chip containing a complex capillary system that analyzes 12 samples simultaneously ("12-sipper chip," Caliper Technologies Corp., Mountain View, USA). To enable the detection and quantification of peptides in the capillary system, the peptides are fluorescently labeled (fluorescein). This label allows the peptides to be quantified by fluorescence intensity through the instrument's laser and detection system (LC3000, Caliper Life Sciences).

[0398] The assay was performed in a 384-well low-volume microtiter assay plate with a final reaction volume of 9 μl. Dose-response curves were prepared by incubating each 10 nM kinase with a 2 μm fluorescently labeled substrate peptide 5-Fluo-Ahx-KKYQAEEN-T-YDEYENKK-amid (10 mM stock solution in DMSO) in 50 mM Hepes pH 7.5, 0.02% Tween 20, 0.02% BSA, 1 mM MDTT, 10 μm Na3VO4, 10 mM ss-glycerol phosphate, 1 mM MgCl2, 12 mM MnCl2 (ALK1 and ALK6 7 mM), and 15 μm ATP, in or without the DMSO-diluted compound, at 30°C for 60 minutes.

[0399] The kinase reaction was stopped by adding 15 μl of STOP buffer (100 mM HEPES pH 7.5, 5% DMSO, 0.1% caliper coating reagent, 10 mM EDTA, and 0.015% Brij35).

[0400] The plates from which the kinase reaction was stopped were transferred to a Caliper LC3000 workstation (Caliper Technologies Corp., Mountain View USA) for reading. The relative amount r of the phosphorylated peptide was calculated using the substrate peak height s and the product peak p: r = p / (p + s). The specific activity is shown in the table below.

[0401] [Table 13]

[0402] [Table 14]

[0403] [Table 15]

[0404] [Table 16]

[0405] Example 92: BMP signaling reporter gene assay A human hepatocellular carcinoma cell line (HuH7) was stably transfected using a reporter plasmid consisting of a BMP response element (BRE) derived from the Id1 promoter fused to a luciferase reporter gene, and then generated by lentiviral transduction.

[0406] Cells were maintained at 37°C and 5% CO2 in DMEM (GIBCO #41965 high-glucose L-glutamine), 10% FCS (Amimed #2-01F10-I), 1% Pen / Strp (Amimed #4-01F00), and 5 ug / ml Blastidicin (InvivoGen #ant-bl-1). The assay was performed on a 384-well flat-bottom polystyrene microtiter plate (cell culture treatment) with a sterile lid. Sixteen hours prior to the assay, cells were starved by changing the medium in a medium without blastisin and FCS. Prior to the assay, cells were detached from the stock flask using trypsin / EDTA and counted. Cell suspensions were prepared in the same medium, without blastisin and FCS. Serial dilutions of each compound in DMSO (final DMSO concentration 0.5%) were added to each well of a plate already containing these dilutions, 2 × 10¹⁶ in a total volume of 40 ul. 4 Cells were added. The cells and compound were incubated at 37°C and 5% CO2 for 1 hour before stimulating with recombinant BMP6 (R&D Systems #507-BP / CF) at a final concentration of 100 ng / ml in 5 μl / well. The assay plate was incubated at 37°C and 5% CO2 for a further 5 hours before measuring luciferase levels.

[0407] The amount of expressed luciferase was quantified using the Steady-Glo® luciferase assay system (Promega #E2520). 5 μl of Steady-Glo® reagent was added to each well, and the plate was mixed by vigorously shaking before measuring luminescence at 1 second / well using a PHERAstar® Multilabel Reader (optical module for luminescence measurement in the wavelength range of 230 nm to 750 nm).

[0408] Further specific activities of the compounds of the present invention are shown in the table below.

[0409] [Table 17]

[0410] [Table 18]

[0411] Example 93: In vivo efficacy in a pediatric FOP (fibrodysplasia ossificans progressive) mouse model Ubiquitous heterozygous expression of FOP, which causes the BMP type I receptor Alk2 R206H mutant in mice, leads to perinatal lethality (Chakkalakal et al., 2012).

[0412] To study the postnatal role of Alk2(R206H) in juvenile organisms as a preclinical mouse model for FOP, inducible Alk2(R206H) mutant mice (Prof.D.Goldhamer, UConn, ASBMR abstract, 2013) are needed, which have a floxed arrest cassette with an insertion upstream of the mutant exon that makes the expression of the mutant allele Cre-recombinase-dependent. These mice were crossed with Rosa26-CreERt2 mice to enable temporally and spatially defined heterozygous expression of Alk2(R206H).

[0413] Here, ubiquitous inducible Alk2(R206H) heterozygous mice were used in conjunction with tamoxifen (tam)-inducible CreER-loxP technology. Successful induction of Alk2(R206H) expression was achieved following tamoxifen administration to 1-week-old male and female Alk2(R206H);Rosa26-CreERt2 mice.

[0414] FOP flare-up is induced through deep muscle injury by local intramuscular injection of cardiotoxin (CTX) and simultaneous intramuscular injection of adenovirus, which induces Alk2(R206H)-dependent local FOP flare-up. CTX induces injury in skeletal muscle by inhibiting Ca / Mg-ATPase in the plasma membrane and inducing calcium release from the sarcoplasmic reticulum.

[0415] The body weight of 1-week-old male and female Alk2(R206H);Rosa26-CreERt2 mice was measured at the start of the experiment and daily thereafter. All pup mice were subcutaneously treated with 20 mg / kg of tamoxifen (tamoxifen-free base (Sigma T5648), dissolved at 8 mg / ml in 10% anhydrous ethanol + 90% sunflower oil (Sigma S5007)) once daily for 10 days, starting at 1 week of age.

[0416] On the third day after tamoxifen injection, all pup mice were given a single intramuscular injection of 100 μl of adenovirus + cardiotoxin (CTX) into the gastrocnemius muscle of the right hind limb, taking care to avoid injecting into any blood vessels and to prevent the needle from touching the bone, thereby inducing localized muscle injury. To achieve this objective, 90 μl of adenovirus (Ad-GFP-2A-iCre, catalog number 1772, Vector Biolabs; titer: 1 × 10⁻¹⁴) was administered. 10PFU (plaque-forming units) / mL was mixed with 10 μl of 100 μm cardiotoxin stock solution (prepared using sterile saline from cardiotoxin, catalog no. L8102, Latoxan or cardiotoxin, catalog no. C9759, Sigma). Animals were anesthetized by low-dose isoflurane inhalation, the right hind limb was shaved, and the skin was disinfected with betaseptic before slow, careful intramuscular injection using an insulin syringe.

[0417] Alk2(R206H) heterozygous mice were given therapeutic oral treatment twice daily, starting 3 days after muscle injury, and administered compound A (compound from Example 34 = 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide) or the corresponding vehicle at doses of 2, 5, 10, and 25 mg / kg for 6 weeks. In all mice, ectopic ossification was evaluated every two weeks by whole-body and hindlimb radiography (Faxitron) and in vivo microcomputed tomography (μCT) imaging, starting 2 weeks after Ad / CTX application.

[0418] During autopsy, the right hind limb was collected for in vitro microCT imaging to determine the entire extent of the HO. The entire right hind limb with attached muscles was dissected as quickly as possible and transferred to 70% ethanol at 4°C. After 24 hours, the sample was transferred to fresh 70% ethanol for high-resolution microCT imaging using a Scanco Medical μCT40 device (voxel size: 16 μm, integration time: 250 ms, medium resolution, 55 E (kVp), 145 μA, mode: cone-beam continuous rotation, threshold 275, Gaussian filter: sigma 0.7, support 1). The total bone mass (mm3) of the ectopic bone in the hind limb was determined. The results are shown in Figure 1. The figure shows that compound A (compound from Example 34) suppresses bone mass in the in vitro right hind limb.

[0419] To investigate the effect of compound A (compound from Example 34) on the progression of ectopic ossification after process initiation, Alk2(R206H) heterozygous mice were similarly injected with 100 μl adenovirus + cardiotoxin (CTX) and allowed to develop ectopic bone for 2.5 weeks. Once HO formation was confirmed after 2 weeks, offspring mice were randomized based on the presence of HO, genetic background, and sex. Treatment was initiated 2.5 weeks after injury with compound A via vehicle or 10 mg / kg twice daily and continued for 6 weeks. In all mice, ectopic ossification was evaluated every two weeks by whole-body and hindlimb radiography (Faxitron) and in vivo microcomputed tomography (μCT) images, starting 2 weeks after Ad / CTX application.

[0420] During autopsy, the right hind limb was collected for in vitro microCT imaging to determine the entire extent of the occlusion (HO). The entire right hind limb with attached muscles was dissected as quickly as possible and transferred to 70% ethanol at 4°C. After 24 hours, the sample was transferred to fresh 70% ethanol for high-resolution microCT imaging using a Scanco Medical μCT40 device (voxel size: 16 μm, integration time: 250 ms, medium resolution, 55 E (kVp), 145 μA, mode: cone-beam continuous rotation, threshold 275, Gaussian filter: sigma 0.7, support 1). Total bone volume of ectopic bone in the hind limb (mm 3 The results were determined. The results are shown in Figure 2. The results indicate that compound A (compound from Example 34) prevents the progression of bone mass in the right hind limb in vitro.

[0421] The results shown in Figures 1 and 2 demonstrate that when the compound of the present invention (compound A) is administered early after muscle injury, it suppresses ectopic ossification, and when administered after ectopic ossification has already begun, it prevents further progression of ectopic ossification in ALK2(R206H) offspring mice.

[0422] Example 94: Achilles midpoint tendon transection-induced ectopic ossification in rats To test whether the compound of the present invention can prevent trauma-induced heterotopic ossification (HO) of soft tissue, the therapeutic efficacy in a rat model of unilateral Achilles midpoint tendon transection can be used (Rooney et al., Matrix 12:274-281, 1992). To achieve this objective, the left Achilles tendon of 8-week-old female Wistar rats (body weight 190-265g) is completely incised using a sterile scalpel (blade number 11) under isoflurane inhalation anesthesia, and analgesic treatment is performed by subcutaneously applying 0.03 mg / kg of buprenorphine every 10-12 hours for 48 hours. Prophylactic oral treatment with the compound of the present invention (10 mg / kg q.d.) or a vehicle (carboxymethylcellulose sodium:water:Tween 80, 0.5:99:0.5) is administered for 10 weeks starting from the day of surgery (n=11-12 rats per group). Rats were housed individually for 3-4 days post-surgery, then housed in groups of two per cage at 25°C in a 12-hour:12-hour light-dark cycle, fed a standard rodent diet (3890, Provimi Kliba SA) with an energy content of 15.8 MJ / kg, 18.2% protein, and 3.0% fat, with ad libitum access to food and water. Treatment efficacy was longitudinally evaluated at 4 and 10 weeks post-surgery by taking X-rays of the surgically treated distal lower limb (Faxitron LX-60 system). Ectopic bone mass was quantified in vivo at 6 and 9 weeks post-surgery by microcomputed tomography (micro-CT) under isoflurane inhalation anesthesia (vivaCT40 device, Scanco Medical AG; 17.5 μm resolution). This application also includes the following aspects: [Aspect 1] Formula (I) in free form or pharmaceutically acceptable salt form, [ka] (In the formula, L is bonded, (CH 2 ) n , -CH(CH 3 )-,-O-(CH 2 ) n -, -C(O)-, -C(O)-NH-(CH 2) n -and; n is 1, 2, or 3; R 1 is hydroxyl, halogen, C 1 ~C 3 C is optionally substituted once or twice or more with substituents independently selected from alkyl groups. 3 ~C 7 Cycloalkyl; hydroxyl, hydroxy C 1 ~C 3 Crosslinked C molecules optionally substituted once or twice or more with substituents independently selected from alkyl groups. 5 ~C 10 Selected from cycloalkyl groups; R 2 and R 3 H, halogen, C 1 ~C 3 Selected independently of alkyl; R 4 R 7 An N-containing heterocyclic non-aromatic ring comprising one or more additional heteroatoms optionally selected from N, O, or S, which are optionally substituted one or more times; R 7 C 1 ~C 3 Alkyl, hydroxy C 1 ~C 3 Alkyl, Halo C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl, Halo C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl, C 2 ~C 4 Alkinyl, Cyano C 1 ~C 3 Alkyl, (CH 2 ) m -R 8 Selected independently of; m is 0, 1, 2, or 3; R 8 Oxo, SO 2 C 1 ~C 3 Alkyl, Halo C 1 ~C 3 A 4, 5, or 6-membered saturated or unsaturated non-aromatic heterocycle comprising one or more heteroatoms selected from N, O, or S, which are optionally substituted one or more times with substituents independently selected from the alkyl, or C is optionally replaced once or more times with a halo. 3 ~C 6 Cycloalkyl (Selected from) A compound of [this]. [Aspect 2] A compound of formula (I) as described in embodiment 1, in free form or in pharmaceutically acceptable salt form, In the formula, R 4 However, NR 5 R 6 ;R 7 A 5-membered heterocyclic non-aromatic ring containing an N-containing ring, which is optionally substituted one or more times and attached to the rest of the molecule via the ring carbon atom, and optionally contains one or more additional heteroatoms selected from N, O, or S, or R 7 Selected from an N-containing 6-membered heterocyclic non-aromatic monocyclic or dicyclic, comprising one or more additional heteroatoms selected from N, O, or S, which are optionally substituted one or more times and attached to the rest of the molecule via carbon atoms, R 5 and R 6 However, together with the N atoms to which they are attached, R 7 A five-membered ring comprising one additional heteroatom selected from N, O, or S, which is optionally substituted one or more times in an optional manner; R 7 A six-membered ring comprising one additional heteroatom selected from N, O, or S, which is optionally substituted one or more times in an optional manner; R 7 A 7-membered ring comprising one additional heteroatom selected from N, O, or S, which is optionally substituted one or more times in an optional manner. A compound that forms a structure. [Aspect 3] R 2 and R 3 However, it is hydrogen; L is a combination; R 4 However, it is an N-containing 6-membered heterocyclic non-aromatic biring comprising one or more additional heteroatoms optionally selected from N, O, or S, wherein the ring is R 7 The ring is optionally substituted once or more times, and the ring is attached to the rest of the molecule via the ring carbon atoms; R 7 However, (CH 2 ) m -R 8 and; m is 0, 1, 2, or 3; R 8 However, oxo, SO 2 C 1 ~C 3 Alkyl, Halo C 1 ~C 3 A six-membered saturated or unsaturated non-aromatic heterocycle comprising one or more heteroatoms selected from N, O, or S, which are optionally substituted one or more times with substituents independently selected from the alkyl group. A compound of formula (I) as described in embodiment 1 or 2, in free form or in pharmaceutically acceptable salt form. [Aspect 4] R 1 A compound of formula (I) in the free form or pharmaceutically acceptable salt form according to any one of embodiments 1 to 3, wherein the compound is a cyclohexyl that is substituted once with a hydroxyl group. [Aspect 5] R 1 A compound of formula (I) in the free form or pharmaceutically acceptable salt form according to any one of embodiments 1 to 3, wherein the compound is bicyclo[2.2.2]octanyl substituted with hydroxyl. [Aspect 6] R 1 A compound of formula (I) in the free form or pharmaceutically acceptable salt form according to any one of embodiments 1 to 3, wherein the compound is bicyclo[1.1.1]pentanyl substituted with hydroxymethyl. [Aspect 7] 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-(-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(3-morpholinopropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-(-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(2-fluoro-4-(4-isopropylpiperazine-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-(-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(1-isopropylpyrrolidine-3-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxy-4-methylcyclohexyl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-(-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(pyrrolidine-3-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(3-fluoro-4-hydroxycyclohexyl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(2-azaspiro[3,3]heptan-2-ylmethyl)phenyl)-2-amino-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxy-4-methylcyclohexyl)-5-(4-(-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-(-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(2-fluoro-4-(piperazine-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-((2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; 2-amino-N-(4-hydroxycyclohexyl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-(-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-amino-5-(4-(-3-(buty-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(oxetan-3-ylmethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(2-(2,2,2-trifluoroethoxy)ethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(3-(piperidine-1-yl)propoxy)phenyl)nicotinamide; 2-amino-5-(4-(-3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide; 2-amino-5-(3-fluoro-4-(2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-morpholinophenyl)nicotinamide; 2-amino-5-(4-(-3-(2,2-difluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(4-(-3-(2-cyanoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(3-morpholinopropoxy)phenyl)nicotinamide; 2-amino-N-(4-hydroxycyclohexyl)-5-(4-(3-(prop-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)-2-chlorophenyl)-2-amino-N-(-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(2-fluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-5-(4-(-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-amino-5-(4-(-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(piperidine-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxy-4-methylcyclohexyl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-((2-(4-methylpiperazine-1-yl)ethyl)carbamoyl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-(-3-hydroxyadamantan-1-yl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-(morpholine-4-carbonyl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxy-4-methylcyclohexyl)-5-(4-((2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; 2-amino-5-(2,3-difluoro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl-4-d)-5-(4-(-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(-4-hydroxycyclohexyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide; 2-amino-5-(2-chloro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-N-(3-(2-hydroxypropane-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(4-(-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-cyclohexyl-5-(3-(morpholine-4-carbonyl)phenyl)nicotinamide; 2-amino-5-(3-chloro-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)-N-(-4-hydroxy-4-methylcyclohexyl)nicotinamide; 5-(4-(-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-(-4-hydroxy-1-methylcyclohexyl)nicotinamide; 2-amino-N-(-4-hydroxy-4-methylcyclohexyl)-5-(2-methyl-4-((2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; and 2-amino-N-cyclohexyl-5-(3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)phenyl)nicotinamide A compound according to embodiment 1, selected from the free form or a pharmaceutically acceptable salt form. [Aspect 8] 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(methylsulfonyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 5-(4-((S)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(3-morpholinopropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(2-fluoro-4-(4-isopropylpiperazine-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4r)-4-hydroxycyclohexyl)-5-(4-(1-isopropylpyrrolidine-3-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-((1r,4r)-4-hydroxycyclohexyl)-5-(4-(pyrrolidine-3-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1R,3S,4R)-3-Fluoro-4-Hydroxycyclohexyl)-5-(4-((1R,5S)-3-(Tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1s,4S)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-(2-azaspiro[3,3]heptan-2-ylmethyl)phenyl)-2-amino-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(2-fluoro-4-(piperazine-1-yl)phenyl)-N-((1r,4r)-4-hydroxycyclohexyl)nicotinamide; 2-amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(buty-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(oxetane-3-ylmethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(1-(2,2,2-trifluoroethyl)piperidine-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(2-morpholinoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-(2,2,2-trifluoroethoxy)ethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(3-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(3,3,3-trifluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(2,2-difluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(2-cyanoethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(prop-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(prop-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)-2-chlorophenyl)-2-amino-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-amino-5-(2-fluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(buty-2-in-1-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxy-4-methylcyclohexyl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-cyclohexyl-5-(4-((2-(4-methylpiperazine-1-yl)ethyl)carbamoyl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(1,3-difluoropropan-2-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1R,3R)-3-hydroxyadamantan-1-yl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(oxetane-3-ylmethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1s,4R)-4-hydroxycyclohexyl)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4R)-4-Hydroxy-4-methylcyclohexyl)-5-(4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-amino-5-(2,3-difluoro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(4-((1S,5R)-3-(2,2-difluoropropyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4S)-4-hydroxycyclohexyl)nicotinamide; 2-Amino-N-((1r,4R)-4-hydroxycyclohexyl)-5-(4-((1R,5S)-3-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-Amino-N-((1r,4S)-4-hydroxycyclohexyl-4-d)-5-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-N-((1s,4s)-4-hydroxycyclohexyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)nicotinamide; 2-amino-5-(2-chloro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-amino-5-(4-((1R,5S)-3-(4,4-difluorocyclohexyl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 2-Amino-N-(3-(2-hydroxypropane-2-yl)bicyclo[1.1.1]pentan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide; 2-amino-5-(3-chloro-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)-N-((1r,4R)-4-hydroxy-4-methylcyclohexyl)nicotinamide; 5-(4-((R)-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)phenyl)-2-amino-N-((1r,4R)-4-hydroxy-1-methylcyclohexyl)nicotinamide; and 2-Amino-N-((1r,4R)-4-Hydroxy-4-methylcyclohexyl)-5-(2-methyl-4-(((R)-2-methylpyrrolidine-1-yl)methyl)phenyl)nicotinamide A compound according to embodiment 1, selected from the free form or a pharmaceutically acceptable salt form. [Aspect 9] amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide in free form, fumarate form, or phosphate form, particularly as free form modified HA or A. [Aspect 10] amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide, in fumarate form or phosphate form, particularly as fumarate-modified HA. [Aspect 11] A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof described in any one of embodiments 1 to 10, and one or more pharmaceutically acceptable carriers. [Aspect 12] A method for inhibiting ALK-2 receptor activity in a subject, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of embodiments 1 to 10 to the subject. [Aspect 13] A method for treating a disorder or disease selected from ectopic ossification or progressive fibrodysplasia ossificans, comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of embodiments 1 to 10 to the subject. [Aspect 14] A compound according to any one of embodiments 1 to 10 for use as a pharmaceutical agent, or a pharmaceutically acceptable salt thereof. [Aspect 15] A compound according to any one of embodiments 1 to 10 or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder or disease selected from ectopic ossification or progressive fibrodysplasia ossificans. [Aspect 16] Use of any one of the compounds described in Embodiments 1 to 10 or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating a disorder or disease selected from ectopic ossification or progressive fibrodysplasia ossificans.

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, R １ is C which is unsubstituted or substituted one or more times with substituents independently selected from hydroxyl, halogen, and C １ to C ３ alkyl; or is bridged C which is unsubstituted or substituted one or more times with substituents independently selected from hydroxyl and hydroxy C ３ to C ７ alkyl; or is bridged C １ to C ３ alkyl; or is bridged C which is unsubstituted or substituted one or more times with substituents independently selected from hydroxyl and hydroxy C ５ to C １０ alkyl; and L is a bond, (CH ２ ) ｎ , -CH(CH ３ )-,-O-(CH ２ ) ｎ -, -C(O)- or -C(O)-NH-(CH ２ ) ｎ - and; n is 1, 2, or 3; R ２ and R ３ H, halogen and C １ ~C ３ Selected independently of alkyl; R ４ This is an N-containing heterocyclic non-aromatic ring comprising one or more additional heteroatoms selected from N, O, and S, where R ７ The N-containing heterocyclic non-aromatic ring is substituted once or twice or more, or is unsubstituted; R ７ C １ ~C ３ Alkyl, hydroxy C １ ~C ３ Alkyl, Halo C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy C １ ~C ３ Alkyl, Halo C １ ~C ３ Alkoxy C １ ~C ３ Alkyl, C ２ ~C ４ Alkinyl, Cyano C １ ~C ３ Alkyl and (CH ２ ) ｍ -R ８ Selected independently of; m is 0, 1, 2, or 3; R ８ teeth, A 4-membered, 5-membered, or 6-membered saturated or unsaturated non-aromatic heterocycle comprising one or more heteroatoms selected from N, O, and S, wherein the heteroatoms are oxo, SO ２ C １ ~C ３ Alkyl and Halo C １ ~C ３ The four-membered, five-membered, or six-membered saturated or unsaturated non-aromatic heterocycles that are substituted once or twice or more with substituents independently selected from the alkyl group, and, C that has been replaced once or twice or more by a halo, or has not been replaced. ３ ~C ６ Cycloalkyl (Selected from) A method for preparing a compound, or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer, or hydrate thereof, a) Equation (II): 【Chemistry 2】 Compound and formula: R １ -NH ２ The steps of coupling the compound with the compound of formula (I) to obtain the compound of formula (I); and b) A step of collecting the compound of formula (I), or its pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers, or hydrates. The method, including the method described above.

2. Furthermore, equation (III): 【Transformation 3】 The method according to claim 1, comprising preparing a compound of formula (II) by treating a compound with a base.

3. The method according to claim 2, wherein the base is lithium hydroxide or sodium hydroxide.

4. Furthermore, equation (IV): 【Chemistry 4】 (In the formula, each R is either independently a hydrogen atom or together forms pinacol.) Compound and formula (V): 【Transformation 5】 The method according to claim 2 or 3, comprising preparing a compound of formula (III) by coupling it with a compound of .

5. Equation (I): 【Transformation 6】 (In the formula, R １ These are hydroxyl, halogen and C １ ~C ３ A C molecule that is substituted once or twice or more with substituents independently selected from the alkyl group, or is unsubstituted. ３ ~C ７ Cycloalkyl; or hydroxyl and hydroxy C １ ~C ３ Crosslinked C molecules that are substituted once or twice or more with substituents independently selected from alkyl groups, or are unsubstituted. ５ ~C １０ It is cycloalkyl; L is a bond, (CH ２ ) ｎ , -CH(CH ３ )-,-O-(CH ２ ) ｎ -, -C(O)- or -C(O)-NH-(CH ２ ) ｎ - and; n is 1, 2, or 3; R ２ and R ３ H, halogen and C １ ~C ３ Selected independently of alkyl; R ４ This is an N-containing heterocyclic non-aromatic ring comprising one or more additional heteroatoms selected from N, O, and S, where R ７ The N-containing heterocyclic non-aromatic ring is substituted once or twice or more, or is unsubstituted; R ７ is independently selected from C １ to C ３ alkyl, hydroxy C １ to C ３ alkyl, halo C １ to C ３ alkyl, C １ to C ３ alkoxy C １ to C ３ alkyl, halo C １ to C ３ alkoxy C １ to C ３ alkyl, C ２ to C ４ alkynyl, cyano C １ to C ３ alkyl and (CH ２ ) ｍ -R ８ and is independently selected therefrom; m is 0, 1, 2, or 3; R ８ teeth, A 4-membered, 5-membered, or 6-membered saturated or unsaturated non-aromatic heterocycle comprising one or more heteroatoms selected from N, O, and S, wherein the heteroatoms are oxo, SO ２ C １ ~C ３ Alkyl and Halo C １ ~C ３ The four-membered, five-membered, or six-membered saturated or unsaturated non-aromatic heterocycles that are substituted once or twice or more with substituents independently selected from the alkyl group, and, C that has been replaced once or twice or more by a halo, or has not been replaced. ３ ~C ６ Cycloalkyl (Selected from) A method for preparing a compound, or a pharmaceutically acceptable salt, stereoisomer, rotational isomer, tautomer, or hydrate thereof, a) Equation (VI): 【Transformation 7】 (In the formula, each R is either independently a hydrogen atom or together forms a pinacol.) Compound and formula (V): 【Transformation 8】 The steps of coupling a compound with a compound of formula (I) to form a compound of formula (I); and b) A step of collecting the compound of formula (I), or its pharmaceutically acceptable salts, stereoisomers, rotational isomers, tautomers, or hydrates. The method, including the method described above.

6. Furthermore, equation (VII): 【Chemistry 9】 Compounds and B(OR) ２ The method according to claim 5, comprising preparing a compound of formula (VI) by reacting with .

7. The method according to any one of claims 1 to 6, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or hydrate thereof, is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or hydrate thereof.

8. The method according to any one of claims 1 to 6, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or hydrate is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or hydrate.

9. The method according to any one of claims 1 to 6, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, stereoisomer, rotational isomer, tautomer, or hydrate is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)nicotinamide fumarate.

Images