Modulators of Myc family proto-oncogene proteins

Abstract

Disclosed herein are compounds and compositions that are effective in regulating Myc family proteins.Such compounds and compositions can be used in the treatment of proliferative diseases, such as cancer, or in the treatment of diseases in which the regulation of Myc family proteins is desired.Also disclosed herein are methods of using said compounds and compositions.

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 313,905, filed February 25, 2022, and PCT / US2022 / 017863, filed February 25, 2022, each of which is incorporated by reference in its entirety into this specification. [Background technology]

[0002] The MYC proto-oncogene family contains three members: c-MYC, MYCN, and MYCL. These oncogenes encode the oncoproteins c-Myc, N-Myc, and L-Myc, respectively, which belong to a family of "super-transcription factors" that control the transcription of over 15% of the genome. Recent studies in mouse models have demonstrated that even transient inactivation of Myc can result in tumor regression, suggesting that control of oncogenic Myc proteins could potentially lead to the development of cancer therapies. However, the development of drugs and therapies that directly target Myc proteins has faced two major challenges. First, Myc proteins lack a well-defined active site for small molecule binding, thus posing challenges to functionally modulating or inhibiting their activity. Second, Myc proteins are primarily located in the cell nucleus, and targeting nuclear Myc proteins with antibodies can be technically challenging. These challenges have led to the development of strategies for indirect control of Myc proteins.

[0003] For example, amplification and overexpression of N-Myc can lead to tumorigenesis. Excess N-Myc is associated with a variety of tumors, such as neuroblastoma. MYCN can also be activated in tumors through somatic mutations.

[0004]

[0004] C-Myc can also be constitutively expressed in various cancers, such as cervical cancer, colon cancer, breast cancer, lung cancer, and gastric cancer, and such constitutive expression can lead to increased expression of other genes associated with cell proliferation.

[0005] For example, amplification of the N-Myc gene in patients often leads to poor health outcomes. However, strategies for direct regulation of Myc proteins have not been developed because Myc proteins are not easily targeted. Summary of the Invention

[0006]

[0006] Thus, there remains a need for small molecule therapeutic modulators of Myc proteins for the treatment of various diseases, illnesses and disorders, such as cancer. overview

[0007] The present disclosure provides compounds and compositions that are useful as Myc protein modulators, and methods of using them. Additionally, the present disclosure contemplates the use of the compounds and compositions of the present disclosure as direct modulators of Myc proteins in the treatment of proliferative diseases, such as cancer, or diseases in which modulation of Myc family proteins is desirable.

[0007]

[0008] For example, the present disclosure provides a compound of formula I:

[0008] [ka]

[0009] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); Ring Z is a 4-10 membered N-linked heterocycle, wherein Z is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), oxo, C1-C4 alkoxy, and cyano; L 1 is a bond or a C1-C6 alkylene (one, two or three R 4 Optionally replaced by R 3 is H, C1-C6 alkyl, NR'R', S(O) 0~2 C1-C4 alkyl, SO2N(R N )2, N(R N )SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C4 alkoxy, and oxo; R 4 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R N is selected from the group consisting of H and C1-C3 alkyl, or two R N is R N together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocyclic ring; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 Cycloalkyl, spiro C5-C 10 The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl; R 5 is selected from the group consisting of H, halo, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens); or R 2 and R 5 is R 2 and R5 together with the carbon atom to which it is attached to form a 5- or 6-membered carbon ring; When ring Z is a 6-membered monocyclic heterocycle, L 1 is C1-C6 alkylene, or L 1 is a bond and R 3 is selected from C2-C6 alkyl, SO2C1-C4 alkyl, and NHR', where R' is selected from the group consisting of C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, where the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo.

[0010] Exemplary contemplated compounds are of formula VI:

[0011] [ka]

[0012] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, and C(CH2CH2); Ring Z is a 4-10 membered N-linked heterocycle, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; L 1 is a bond or C1-C6 alkylene (optionally substituted with 1, 2 or 3 halogens); R 3 is selected from the group consisting of H, C1-C6 alkyl, NR'R', and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 The cycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, C3-C7 cycloalkyl, and heterocyclyl; When ring Z is a 6-membered monocyclic heterocycle, L 1 is C1-C6 alkylene, or L 1 is a bond and R 3is selected from C1-C6 alkyl and NHR'.

[0013] Also contemplated herein are compounds represented by formula II:

[0014] [ka]

[0015] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); Ring A is a 5-6 membered heteroaryl optionally substituted with C1-C4 alkyl; Ring Z is selected from the group consisting of a 6-10 membered spiroheterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, oxo, C1-C4 alkoxy, and cyano; L 1 is a bond or a C1-C6 alkylene (one, two or three R 4 Optionally replaced by R 3 is H, C1-C6 alkyl, NR'R', S(O) 0~2 C1-C4 alkyl, SO2N(R N )2, N(R N)SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C4 alkoxy, and oxo; R 4 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R N is selected from the group consisting of H and C1-C3 alkyl, or two R N is R N together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocyclic ring; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 Cycloalkyl, spiro C5-C 10The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl; R 5 is selected from the group consisting of H, halo, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens); or R 2 and R 5 is R 2 and R 5 Together with the carbon atom to which it is attached, it forms a 5- or 6-membered carbocyclic ring.

[0016] Exemplary contemplated compounds are those represented by formula III:

[0017] [ka]

[0018] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); Ring Z is selected from the group consisting of a 6-10 membered spiroheterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, oxo, C1-C4 alkoxy, and cyano; L 1 is a bond or a C1-C6 alkylene (one, two or three R 4 Optionally replaced by R 3 is H, C1-C6 alkyl, NR'R', S(O) 0~2 C1-C4 alkyl, SO2N(R N )2, N(R N )SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C4 alkoxy, and oxo; R 4 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R His selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R N is selected from the group consisting of H and C1-C3 alkyl, or two R N is R N together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocyclic ring; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 Cycloalkyl, spiro C5-C 10 The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, C-C cycloalkyl, and heterocyclyl; R 5 is selected from the group consisting of H, halo, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens); or R 2 and R 5 is R 2 and R 5 Together with the carbon atom to which it is attached, it forms a 5- or 6-membered carbocyclic ring.

[0019] Other contemplated compounds of the present disclosure are compounds represented by formula IV:

[0020] [ka]

[0021] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); Ring Z is a 4-10 membered N-linked heterocycle, wherein Z is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), oxo, C1-C4 alkoxy, and cyano; L 1 is a bond or a C1-C6 alkylene (one, two or three R 4 Optionally replaced by R 3 is H, C1-C6 alkyl, NR'R', S(O) 0~2 C1-C4 alkyl, SO2N(R N )2, N(R N )SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C4 alkoxy, and oxo; R 4 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R N is selected from the group consisting of H and C1-C3 alkyl, or two R N is R N together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocyclic ring; R 1 is C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10 bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10 The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, methyl, C-C cycloalkyl, and heterocyclyl; R 5 is selected from the group consisting of H, halo, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens); or R 2 and R 5is R 2 and R 5 Together with the carbon atom to which it is attached, it forms a 5- or 6-membered carbocyclic ring.

[0022] Also contemplated herein are compounds represented by formula V:

[0023] [ka]

[0024] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W' is selected from the group consisting of N, CH, and CF; Y' is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); R L is H or C1-C6 alkyl; L 2 is a bond or a C1-C6 alkylene (one, two or three R 24 Optionally replaced by R 23 is NR'R'; R 24 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, which is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo, or two R' together with the nitrogen to which they are attached form a heterocyclyl, which may be optionally substituted with methyl, halo, cyano, oxo, or hydroxyl; R H ' is selected from the group consisting of H, C1-C3 alkyl, -C(O)-C1-C3 alkyl, and C(O)-O-C1-C3 alkyl; R 21 is C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10 bicycloalkyl, heterocyclyl, cyano, halo, heteroaryl, and H; wherein C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10 The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 22 is selected from the group consisting of H, F, —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, methyl, C3-C7 cycloalkyl, and heterocyclyl.

[0025] Pharmaceutical compositions comprising the compounds of the present disclosure, or pharmaceutically acceptable salts, stereoisomers, and / or N-oxides thereof, can be prepared as described herein, e.g., the pharmaceutical compositions of the present disclosure can include at least one or more pharmaceutically acceptable carriers, diluents, stabilizers, excipients, dispersing agents, suspending agents, and / or thickening agents. The present disclosure also provides methods for preparing the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, and / or N-oxides thereof.

[0026]

[0015] Methods for regulating the amount and activity of Myc family proteins (i.e., C-Myc, N-Myc, L-Myc, or human Myc) are also provided, for example, the activity of Myc family proteins can be regulated in cells by contacting the cells with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0027]

[0016] The present disclosure also provides methods of treating a Myc family protein-associated disease in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, including embodiments in any example, table, or figure. In some embodiments, the subject is a human subject, and the disease is a proliferative disease, such as cancer. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0029] It is understood that the definitions provided herein are not intended to be mutually exclusive, and thus some chemical moieties may fall within the definitions of more than one term.

[0030] The term "alkoxy," as used herein, refers to a straight or branched chain alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups are those described herein as C, C, C- ... 1~6 Alkoxy, and C 2~6 Including, but not limited to, alkoxy groups of 1 to 6 or 2 to 6 carbon atoms, referred to as alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0031] The term "alkyl," as used herein, refers to a saturated straight or branched chain hydrocarbon. Exemplary alkyl groups are those described herein as C 1~6 Alkyl, C 1~4 Alkyl, and C 1~3 These include, but are not limited to, straight or branched chain hydrocarbons of 1 to 6, 1 to 4, or 1 to 3 carbon atoms, referred to as alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[0032]

[0021] As used herein, the term "alkylene" refers to a diradical alkyl group. Examples include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), 2-methylpropylene (-CH2-CH(CH3)-CH2-), hexylene (-(CH2)6-), and the like.

[0033] The term "alkenyl," as used herein, refers to an unsaturated, straight- or branched-chain hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups are those described herein as C, ... 2~6 Alkenyl, and C 3~4 These include, but are not limited to, straight or branched chain groups of 2 to 6 or 3 to 4 carbon atoms, referred to as alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and the like.

[0034] The term "alkynyl," as used herein, refers to an unsaturated, straight- or branched-chain hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups are those described herein as C, C, C-C ... 2~6 Alkynyl, and C 3~6 These include, but are not limited to, straight or branched chain groups of 2 to 6, or 3 to 6 carbon atoms, referred to as alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

[0035] As used herein, the terms "alkenylene," "alkynylene," "arylene," "arylalkylene," and "alkylarylene" refer to the diradical alkenyl, alkynyl, aryl, arylalkyl, and alkylaryl groups, respectively.

[0036] As used herein, the term "azido" refers to the group --N.sub.3.

[0026] As used herein, the terms "carboxyl," "carboxy," or "carboxylate" refer to -CO2H or salts thereof.

[0037] As used herein, the term "carbamoyl" refers to the group NH2CO-. The terms "cycloalkyl" or "carbocyclic group" as used herein mean C3~10 Cycloalkyl, or C 4~6 Cycloalkyl refers to saturated or partially unsaturated hydrocarbon groups, e.g., 3 to 10, 3 to 6, or 4 to 6 carbons, having mono- or bicyclic ring structures, e.g., 4 to 9- or 4 to 6-membered saturated ring structures, which may contain bridged, fused, or spirocyclic rings. Exemplary cycloalkyl groups include, but are not limited to, adamantanyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclopropyl, and indanyl.

[0038] As used herein, the following groups are

[0039] [ka]

[0040] is used interchangeably and referred to as a cyclohexyl group. As used herein, the terms "cyano" and "carbonitrile" refer to the group --CN.

[0041] As used herein, the term "formyl" refers to a -C(O)H group. As used herein, the term "guanidino" refers to the group --NHC(.dbd.NH)NH.sub.2.

[0042] As used herein, the terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent. As used herein, the terms "hydroxy" and "hydroxyl" refer to an --OH group.

[0043] The term "heteroaryl" or "heteroaromatic group," as used herein, refers to a monocyclic aromatic 5- or 6-membered ring system containing one or more heteroatoms, such as nitrogen, oxygen, and sulfur, e.g., 1 to 3 heteroatoms. Where possible, the heteroaryl ring may be linked to adjacent radicals through a carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, or pyrimidine, and the like.

[0044] The term "heterocyclyl" or "heterocyclic group" is art-recognized and refers to a saturated or partially unsaturated, monocyclic or bicyclic ring structure, e.g., 4- to 9- or 4- to 6-membered saturated ring structure, including bridged, fused, or spiro rings, whose ring structures contain 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to adjacent radicals through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, or dihydrofuran, and the like.

[0045] As used herein, the term "nitro" refers to the group --NO.sub.2. As used herein, the term "oxo" refers to the (=O) or (O) group.

[0046] As used herein, the term "isomer" refers to compounds that contain the same number and kinds of atoms or components, but have different structural arrangements and connectivity of the atoms.

[0040] As used herein, the term "tautomer" refers to one of two or more structural isomers that readily convert from one isomeric form to another and that exist in equilibrium.

[0047] The compounds of the present disclosure contain one or more chiral centers and therefore may exist as stereoisomers. The term "stereoisomer," as used herein, consists of all enantiomers or diastereomers. These compounds may be represented by the symbols "(+)," "(-)," "R," or "S," depending on the configuration of substituents around the chiral center carbon atom, although those of skill in the art will recognize that a structure may implicitly represent one chiral center. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by "(±)" in the nomenclature, although those of skill in the art will recognize that a structure may implicitly represent one chiral center.

[0048]

[0042] The compounds of the present disclosure contain one or more double bonds and, therefore, can exist as geometric isomers resulting from the arrangement of substituents around the carbon-carbon double bond.

[0049] [ka]

[0050] indicates a bond that may be a single bond, double bond, or triple bond, as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Substituents around a carbon-carbon double bond may alternatively be designated as "cis" or "trans," with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond.

[0051] The compounds of the present disclosure contain carbocyclic or heterocyclic rings and therefore can exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents around a carbocyclic or heterocyclic ring can be designated as "cis" or "trans," with the term "cis" referring to substituents on the same side of the plane of the ring and the term "trans" referring to substituents on opposite sides of the plane of the ring. Mixtures of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring are designated "cis / trans."

[0052] Individual enantiomers and diastereomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the mixture of enantiomers to a chiral auxiliary, recrystallization or chromatographic separation of the resulting diastereomeric mixture, and liberation of the optically pure product from the auxiliary; (2) salt formation utilizing an optically active resolving agent; (3) direct separation of the mixture of optical enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods such as chiral-phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the generation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may also involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH:Weinheim, 2009.

[0053] The compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present disclosure is intended to encompass both solvated and unsolvated forms. In one embodiment, the compounds of the present disclosure are amorphous. In one embodiment, the compounds of the present disclosure are a single polymorph. In another embodiment, the compounds of the present disclosure are a mixture of polymorphs. In another embodiment, the compounds of the present disclosure are crystalline.

[0054]

[0046] The present disclosure also encompasses isotopically labeled compounds of the present disclosure, which are identical to those referred to herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure are, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 It includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as Cl. For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0055] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium (i.e., 2Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferable in some circumstances. Isotopically labeled compounds of the present disclosure may generally be prepared by procedures similar to those disclosed in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0056] As used herein, singular articles such as "a," "an," and "the," and similar referents in the context of describing an element, should be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. Reference to ranges of values ​​herein, unless otherwise indicated herein, includes the upper and lower boundaries of the range, and is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, each separate value being incorporated herein as if individually referred to herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein, unless otherwise specified, is intended merely to better elucidate the present embodiments and does not pose a limitation on the scope of the invention.

[0057] In some embodiments, when the term "about" is used before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless otherwise specified. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or inferred. When a percentage is provided with respect to the amount of an ingredient or material in a composition, the percentage should be understood to be a percentage by weight, unless otherwise specified or understood from the context.

[0058]

[0050] When molecular weights are provided and not absolute values, such as for polymers, the molecular weight should be understood to be an average molecular weight unless otherwise specified or understood from the context.

[0059]

[0051] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0060] As used herein, a dash ("-") that is not between two letters or symbols indicates the point of bond or attachment to a substituent. For example, -NH2 is attached through the nitrogen atom.

[0061]

[0053] As used herein, the terms "active agent," "drug," "pharmacologically active agent," and "active pharmaceutical ingredient" are used interchangeably and refer to a compound or composition that, when administered to a subject, produces a desired pharmacological or physiological effect through local or systemic action, or both.

[0062] As used herein, the term "prodrug" refers to a compound that is converted in vivo to provide a compound described herein or a pharmaceutically acceptable salt, hydrate, or solvate of a compound. Conversion can occur by various mechanisms (i.e., esterase, amidase, phosphatase, oxidative and / or reductive metabolism) and at various locations (i.e., within the intestinal lumen or upon passage to the intestine, blood, or liver).

[0063]

[0055] As used herein, the term "modulator" refers to a compound or composition that increases or decreases the level or function of a target, which may be, but is not limited to, a Myc family protein such as c-Myc, N-Myc, L-Myc, and human Myc.

[0064] As used herein, the term "degrader" refers to a compound or composition that reduces the amount or activity of a target. In some embodiments, the target may be a Myc family protein, including, but not limited to, c-Myc, N-Myc, L-Myc, and human Myc.

[0065] As used herein, the term "degrading" refers to a method or process of reducing the amount or activity of a target. In some embodiments, the target may be a Myc family protein, including, but not limited to, c-Myc, N-Myc, L-Myc, and human Myc.

[0066]

[0058] As used herein, the term "Myc family protein" refers to any one of the proteins c-Myc, N-Myc, or L-Myc described herein. In some embodiments, the Myc protein is a c-Myc protein. In some embodiments, the Myc protein is an N-Myc protein. In some embodiments, the Myc protein is an L-Myc protein. In some embodiments, the Myc protein is a human c-Myc protein. In some embodiments, the Myc protein is a human N-Myc protein. In some embodiments, the Myc protein is a human L-Myc protein. In some embodiments, the Myc family protein is a human Myc family protein.

[0067] As used herein, the terms "N-Myc" and "MycN" may be used interchangeably and refer to the protein "V-Myc myelocytomatosis viral-associated oncogene, neuroblastoma-derived," including wild-type and mutant forms of the protein. In some embodiments, MycN refers to the protein associated with one or more of the following database entries: Entrez Gene 4613, OMIM 164840, UniProt P04198, and RegSeqNP_005369.

[0068] As used herein, the term "c-Myc" refers to the protein "V-Myc myelocytomatosis viral oncogene," including wild-type and mutant forms of the protein. In some embodiments, c-Myc refers to a protein associated with one or more of the following database entries: Entrez Gene 4609, OMIM 190080, UniProt P01106, and RegSeq Np_002458.

[0069] As used herein, the term "L-Myc" refers to the protein "V-Myc myelocytomatosis viral oncogene homolog, lung cancer derived," including wild-type and mutant forms of the protein. In some embodiments, L-Myc refers to a protein associated with one or more of the following database entries: Entrez Gene 4610, OMIM 164850, UniProt P12524, and RegSeq NP_001028253.

[0070] The terms "individual," "host," "subject," and "patient" are used interchangeably herein and refer to animals including, but not limited to, humans and non-human primates, including apes and humans; rodents, including rats and mice; bovines; equines; ovines; felines; canines; and the like. "Mammal" means a member or members of any mammalian species, including, by way of example, canines, felines, equines, bovines, ovines, rodents, and the like, and primates, i.e., non-human primates, and humans. Non-human animal models, i.e., mammals, non-human primates, murines, lagomorphs, and the like, can be used in experimental investigations.

[0071] As used herein, the terms "treating," "treatment," and the like refer to obtaining a desired pharmacological and / or physiological effect, such as reducing tumor burden. The effect can be prophylactic, in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic, in terms of a partial or complete cure for the disease and / or side effects caused by the disease. "Treatment," as used herein, includes any treatment of disease in mammals, particularly humans: (a) preventing the onset of the disease or symptoms of the disease in a subject who may be predisposed to the disease but has not yet been diagnosed with the disease (i.e., including diseases that may be associated with or caused by a causative disease); (b) inhibiting the disease, i.e., arresting the onset of the disease; and (c) palliating the disease, i.e., causing regression of the disease (i.e., reduction in tumor burden). In some embodiments, certain methods described herein treat cancers associated with the signaling pathway of Myc family proteins, such as c-Myc, N-Myc, L-Myc, or human Myc.

[0072] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a subject. It is understood that such salts, together with the counterion, have acceptable mammalian safety for a given dosing regimen. Such salts may also be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, and may include organic and inorganic counterions. The neutral forms of the compounds described herein may be converted to the corresponding salt forms by contacting the compound with a base or acid and isolating the resulting salt.

[0073] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.

[0074] Other examples of salts include N + , NH4 + , and NW4 + (wherein W can be a C1-C8 alkyl group). For therapeutic use, salts of the compounds of the present disclosure will be pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0075] The compounds contained in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds include non-toxic acid addition salts, i.e., malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, superphosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, acid bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Acids that form salts containing pharmacologically acceptable anions are not limited to these.

[0076]

[0068] Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0077]

[0069] Compounds containing a basic or acidic moiety contained in the present compositions can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups; for example, one amino group and one carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or base salts.

[0078]

[0070] As used herein, the terms "determining," "measuring," "assessing," and "assaying" are used interchangeably and include both quantitative and qualitative determinations.

[0079] As used herein, the phrase "signal transduction pathway" refers to a series of interactions between cellular components, both intracellular and extracellular, that result in a change in one or more other components within an organism, which may then cause subsequent changes in additional components. Optionally, changes brought about by one signal transduction pathway can propagate to other signal transduction pathway components. Examples of cellular components include, but are not limited to, proteins, nucleic acids, peptides, lipids, and small molecules.

[0080] As used herein, the terms "effective amount" and "therapeutically effective amount" are used interchangeably and refer to the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to affect such treatment for the disease, condition, or disorder. An "effective amount" or "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated.

[0081] As used herein, the terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable diluent," "pharmaceutically acceptable carrier," and "pharmaceutically acceptable adjuvant" refer to excipients, diluents, carriers, and adjuvants that are useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients, diluents, carriers, and adjuvants that are acceptable for veterinary as well as human pharmaceutical use. As used in this specification and claims, the phrase "pharmaceutically acceptable excipients, diluents, carriers, and adjuvants" includes both one and more than one such excipient, diluent, carrier, and adjuvant.

[0082] As used herein, the term "pharmaceutical composition" is intended to encompass compositions suitable for administration to a subject, such as a mammal, particularly a human. Generally, a "pharmaceutical composition" is sterile and free of contaminants capable of eliciting an undesirable response in a subject (i.e., the compound(s) in the pharmaceutical composition are of pharmaceutical grade). Pharmaceutical compositions can be designed for administration to a subject or patient in need thereof via many different routes of administration, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, etc.

[0083] In general, a reference or depiction of a particular element, such as hydrogen or H, is intended to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Tritium, 14 C. 32 P and 35 Compounds containing radioisotopes such as S are therefore within the scope of the present technology. Procedures for incorporating such labels into compounds of the present technology will be readily apparent to those of skill in the art based on the disclosure herein.

[0084]

[0076] Unless a specific stereochemistry is specified, all chiral, diastereomeric, and racemic forms of a compound are intended. Accordingly, the compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms, as is clear from the depiction. Racemic mixtures of the (R)- and (S)-enantiomers, as well as mixtures of enantiomerically enriched stereoisomers containing the (R)- and (S)-enantiomers, can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, as well as the individual optical isomers, and all of these stereoisomers are within the scope of the present technology.

[0085] The compounds described herein may exist as solvates, particularly hydrates, and all such solvates and hydrates are contemplated unless otherwise specified. Hydrates may be formed during the preparation of the compounds or compositions containing the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may also exist as organic solvent solvates, including solvates of DMF, ethers, and alcohols, among others. The identification and preparation of any particular solvate is within the skill of one of ordinary skill in the art of synthetic organic chemistry or medicinal chemistry.

[0086]

[0078] As described herein, this document represents various embodiments of the present compounds, compositions, and methods. The various embodiments described are intended to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of the various embodiments provided herein may be of overlapping scope. The embodiments described herein are merely exemplary and are not intended to limit the scope of the present technology.

[0087] compound

[0079] The present disclosure relates generally to compounds that modulate (e.g., degrade) MycN and / or MycC and, therefore, may have significant anti-cancer properties. The disclosed compounds and pharmaceutical compositions thereof find use in a variety of applications in which modulation of Myc protein amount and activity is desirable, including use as potent anti-cancer agents.

[0088] Accordingly, provided herein, in part, is a compound of Formula I:

[0089] [ka]

[0090] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); Ring Z is a 4-10 membered N-linked heterocycle, wherein Z is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), oxo, C1-C4 alkoxy, and cyano; L 1 is a bond or a C1-C6 alkylene (one, two or three R 4 Optionally replaced by R 3 is H, C1-C6 alkyl, NR'R', S(O) 0~2 C1-C4 alkyl, SO2N(R N )2, N(R N )SO2—C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C4 alkoxy, and oxo. ; R 4 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R N is selected from the group consisting of H and C1-C3 alkyl, or two R N is R N together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocyclic ring; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 Cycloalkyl, spiro C5-C 10 The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl; R 5 is selected from the group consisting of H, halo, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens); or R 2 and R 5 is R 2 and R5 together with the carbon atom to which it is attached to form a 5- or 6-membered carbon ring; When ring Z is a 6-membered monocyclic heterocycle, L 1 is C1-C6 alkylene, or L 1 is a bond and R 3 is selected from C2-C6 alkyl, SO2C1-C4 alkyl, and NHR', where R' is selected from the group consisting of C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, where the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo.

[0091] For example, Formula I:

[0092] [ka]

[0093] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, and C(CH2CH2); Ring Z is a 4-10 membered N-linked heterocycle, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; L 1 is a bond or C1-C6 alkylene (optionally substituted with 1, 2 or 3 halogens); R 3 is selected from the group consisting of H, C1-C6 alkyl, NR'R', and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C1-C6 alkyl, C3-C7 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, C3-C7 cycloalkyl, and heterocyclyl; When ring Z is a 6-membered monocyclic heterocycle, L 1 is C1-C6 alkylene, or L 1 is a bond and R 3is selected from C1-C6 alkyl and NHR'; or :

[0094] In some embodiments, provided herein is a compound of Formula VI:

[0095] [ka]

[0096] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, and C(CH2CH2); Ring Z is a 4-10 membered N-linked heterocycle, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; L 1 is a bond or C1-C6 alkylene (optionally substituted with 1, 2 or 3 halogens); R 3 is selected from the group consisting of H, C1-C6 alkyl, NR'R', and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 The cycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, C3-C7 cycloalkyl, and heterocyclyl; When ring Z is a 6-membered monocyclic heterocycle, L 1 is C1-C6 alkylene, or L 1 is a bond and R 3 is selected from C1-C6 alkyl and NHR'.

[0097] In some embodiments, W is CH. In other embodiments, W is CF. In other embodiments, W is N. In some embodiments, R His selected from the group consisting of H, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl. In some embodiments, R H is H.

[0098] In some embodiments, for example, W is N and the compound has Formula Ia:

[0099] [ka]

[0100] or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof. In some embodiments, R 1 is a 5-6 membered heterocyclyl or C-C cycloalkyl. 1 is C3-C6 cycloalkyl. For example, R 1 may be cyclopropyl or cyclopentyl.

[0101] In some embodiments, ring Z is selected from the group consisting of a 4-6 membered monocyclic heterocycle, a 6-10 membered spiro heterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, and oxo.

[0102] In some embodiments, ring Z is selected from the group consisting of a 4-6 membered monocyclic heterocycle, a 6-10 membered spiro heterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo.

[0103] In some embodiments, ring Z is selected from the group consisting of a 6- to 10-membered spiroheterocycle, a 6- to 10-membered fused bicyclic heterocycle, and a 6- to 10-membered bridged cycloheteroalkyl, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, and oxo.

[0104] In some embodiments, ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged cycloheteroalkyl, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo.

[0105] In some embodiments, ring Z is

[0106] [ka]

[0107] is selected from the group consisting of: In some embodiments, ring Z is

[0108] [ka]

[0109] is selected from the group consisting of: In some embodiments, ring Z is

[0110] [ka]

[0111] is selected from the group consisting of: Exemplary compounds of the present disclosure have formula Ib:

[0112] [ka]

[0113] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. Other contemplated compounds provided herein are those of formula Ic:

[0114] [ka]

[0115] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein m is 0, 1, or 2. Other contemplated compounds provided herein are those of formula Id:

[0116] [ka]

[0117] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. Also provided herein in some embodiments are compounds represented by formula Ie:

[0118] [ka]

[0119] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. In some embodiments, L 1is C1-C6 alkylene. For example, L 1 may be methylene, ethylene, or propylene. In some embodiments, L 1 is methylene.

[0120] In some embodiments, L 1 is one or two R 4 For example, L 1 is one or two R 4 In some embodiments, L 1 is one R 4 In some embodiments, L is a C1-C4 alkylene substituted with 1 is two R 4 In some embodiments, R 4 is C1-C3 alkyl (optionally substituted with 1, 2 or 3 halogens). For example, R 4 may each be independently selected from the group consisting of methyl, ethyl, and propyl. 4 is R 4 Together with the carbon to which it is attached, it forms a C3-C4 carbocyclic ring. For example, two R 4 is R 4 together with the carbon to which it is attached to form a cyclopropyl.

[0121] In another embodiment, L 1 is a bond. In some embodiments, R 3 is H or C1-C6 alkyl. For example, R 3 may be H or methyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl.

[0122] In another embodiment, R 3is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl. 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens). For example, R 3 may be NH2, NH(CH3), or N(CH3)2.

[0123] In some embodiments, R 3 is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0124] In some embodiments, R 3 is NH'R', where R' is C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NH'R', where R' is C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0125] In another embodiment, R 3 is a 4-6 membered heterocyclyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. In some embodiments, R 3 is a 4-6 membered heterocyclyl containing at least one nitrogen, wherein the heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. In some embodiments, R 3is a 4-membered heterocyclyl containing at least one nitrogen, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo.

[0126] In some embodiments, R 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, C-C cycloalkyl, and 4-6 membered heterocyclyl. 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, and C-C cycloalkyl. 2 is selected from the group consisting of H, F, —O-methyl, and 4-membered heterocyclyl. 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, and —O-methyl. 2 is H or F. In some embodiments, R 2 is H.

[0127] In some embodiments, R 5 is H or methyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is H. In other embodiments, R 2 and R 5 is R 2 and R 5 together with the carbon atom to which it is attached form a five-membered carbocyclic ring.

[0128] Contemplated compounds include, for example:

[0129] [ka]

[0130]

change

[0131]

change

[0132]

change

[0133]

change

[0134]

change

[0135]

change

[0136]

change

[0137]

change

[0138]

change

[0139]

change

[0140]

change

[0141] [ka]

[0142] [ka]

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. Also contemplated herein are compounds represented by Formula II:

[0148] [ka]

[0149] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); Ring A is a 5-6 membered heteroaryl optionally substituted with C1-C4 alkyl; Ring Z is selected from the group consisting of a 6-10 membered spiroheterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, oxo, C1-C4 alkoxy, and cyano; L 1 is a bond or a C1-C6 alkylene (one, two or three R 4 Optionally replaced by R 3 is H, C1-C6 alkyl, NR'R', S(O) 0~2 C1-C4 alkyl, SO2N(R N )2, N(R N )SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C4 alkoxy, and oxo; R 4 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R N is selected from the group consisting of H and C1-C3 alkyl, or two R N is R N together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocyclic ring; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 Cycloalkyl, spiro C5-C 10 The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl; R 5 is selected from the group consisting of H, halo, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens); or R 2 and R 5 is R 2 and R5 Together with the carbon atom to which it is attached, it forms a 5- or 6-membered carbocyclic ring.

[0150] Exemplary contemplated compounds have the formula II-A:

[0151] [ka]

[0152] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, and C(CH2CH2); Ring A is a 5-6 membered heteroaryl; Ring Z is selected from the group consisting of a 6-10 membered spiroheterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, and oxo; L 1 is a bond or C1-C6 alkylene (optionally substituted with 1, 2 or 3 halogens); R 3 is selected from the group consisting of H, C1-C6 alkyl, NR'R', and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 The cycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, C3-C7 cycloalkyl, and heterocyclyl.

[0153]

[0111] In some embodiments, ring A is a 5-6 membered heteroaryl containing at least one nitrogen atom in the heteroaryl. For example, ring A can be pyridyl, pyrimidyl, pyrazinyl, triazinyl, pyrazolyl, imidazolyl, or triazolyl.

[0154] In some embodiments, W is CH. In other embodiments, W is CF. In other embodiments, W is N. In some embodiments, R His selected from the group consisting of H, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl. In some embodiments, R H is H.

[0155] In some embodiments, R 1 is a 5-6 membered heterocyclyl or C-C cycloalkyl. 1 is C3-C6 cycloalkyl. For example, R 1 may be cyclopropyl or cyclopentyl.

[0156] In some embodiments, ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged cycloheteroalkyl, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo.

[0157] In some embodiments, ring Z is:

[0158] [ka]

[0159] is selected from the group consisting of: In some embodiments, ring Z is:

[0160] [ka]

[0161] is selected from the group consisting of: In some embodiments, L 1 is C1-C6 alkylene. For example, L 1may be methylene, ethylene, or propylene. In some embodiments, L 1 is methylene.

[0162] In some embodiments, L 1 is one or two R 4 For example, L 1 is one or two R 4 In some embodiments, L 1 is one R 4 In some embodiments, L is a C1-C4 alkylene substituted with 1 is two R 4 In some embodiments, R 4 is C1-C3 alkyl (optionally substituted with 1, 2 or 3 halogens). For example, R 4 may each be independently selected from the group consisting of methyl, ethyl, and propyl. 4 is R 4 Together with the carbon to which it is attached, it forms a C3-C4 carbocyclic ring. For example, two R 4 is R 4 together with the carbon to which it is attached to form a cyclopropyl.

[0163] In another embodiment, L 1 is a bond. In some embodiments, R 3 is H or C1-C6 alkyl. For example, R 3 may be H or methyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl.

[0164] In another embodiment, R 3is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl. 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens). For example, R 3 may be NH2, NH(CH3), or N(CH3)2.

[0165] In some embodiments, R 3 is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0166] In some embodiments, R 3 is NH'R', where R' is C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NH'R', where R' is C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0167] In another embodiment, R 3 is a 4-6 membered heterocyclyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. In some embodiments, R 3 is a 4-6 membered heterocyclyl containing at least one nitrogen, wherein the heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. In some embodiments, R 3is a 4-membered heterocyclyl containing at least one nitrogen, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo.

[0168] In some embodiments, R 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, C-C cycloalkyl, and 4-6 membered heterocyclyl. 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, and C-C cycloalkyl. 2 is selected from the group consisting of H, F, —O-methyl, and 4-membered heterocyclyl. 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, and —O-methyl. 2 is H or F. In some embodiments, R 2 is H.

[0169] In some embodiments, R 5 is H or methyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is H. In other embodiments, R 2 and R 5 is R 2 and R 5 together with the carbon atom to which it is attached form a five-membered carbocyclic ring.

[0170] Contemplated compounds include, for example:

[0171] [ka]

[0172] [ka]

[0173] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. Also provided herein, in some embodiments, is a compound represented by Formula III:

[0174] [ka]

[0175] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); Ring Z is selected from the group consisting of a 6-10 membered spiroheterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, oxo, C1-C4 alkoxy, and cyano; L 1 is a bond or a C1-C6 alkylene (one, two or three R 4 Optionally replaced by R 3 is H, C1-C6 alkyl, NR'R', S(O) 0~2 C1-C4 alkyl, SO2N(R N )2, N(RN )SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C4 alkoxy, and oxo; R 4 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R N is selected from the group consisting of H and C1-C3 alkyl, or two R N is R N together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocyclic ring; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 Cycloalkyl, spiro C5-C 10The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, C-C cycloalkyl, and heterocyclyl; R 5 is selected from the group consisting of H, halo, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens); or R 2 and R 5 is R 2 and R 5 Together with the carbon atom to which it is attached, it forms a 5- or 6-membered carbocyclic ring.

[0176] Exemplary contemplated compounds have the formula III-A:

[0177] [ka]

[0178] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, and C(CH2CH2); Ring Z is selected from the group consisting of a 6-10 membered spiroheterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, and oxo; L 1 is a bond or C1-C6 alkylene (optionally substituted with 1, 2 or 3 halogens); R 3 is selected from the group consisting of H, C1-C6 alkyl, NR'R', and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R 1 is C3~C 10 Cycloalkyl, spiro C5-C 10 selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; 10 The cycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, C3-C7 cycloalkyl, and heterocyclyl.

[0179] In some embodiments, W is CH. In other embodiments, W is CF. In other embodiments, W is N. In some embodiments, R H is selected from the group consisting of H, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl. In some embodiments, R H is H.

[0180] In some embodiments, for example, W is N and the compound has formula IIIa:

[0181] [ka]

[0182] or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof. In some embodiments, R 1 is a 5-6 membered heterocyclyl or C-C cycloalkyl. 1 is C3-C6 cycloalkyl. For example, R 1 may be cyclopropyl or cyclopentyl.

[0183] In some embodiments, ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged cycloheteroalkyl, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo.

[0184] In some embodiments, ring Z is:

[0185] [ka]

[0186] is selected from the group consisting of: In some embodiments, ring Z is:

[0187] [ka]

[0188] is selected from the group consisting of: Exemplary contemplated compounds are of formula IIIb:

[0189] [ka]

[0190] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. In some embodiments, L 1 is C1-C6 alkylene. For example, L 1 may be methylene, ethylene, or propylene. In some embodiments, L 1 is methylene.

[0191] In some embodiments, L 1 is one or two R 4 For example, L 1 is one or two R 4 In some embodiments, L 1 is one R 4 In some embodiments, L is a C1-C4 alkylene substituted with 1 is two R 4 In some embodiments, R 4 is C1-C3 alkyl (optionally substituted with 1, 2 or 3 halogens). For example, R 4may each be independently selected from the group consisting of methyl, ethyl, and propyl. 4 is R 4 Together with the carbon to which it is attached, it forms a C3-C4 carbocyclic ring. For example, two R 4 is R 4 together with the carbon to which it is attached to form a cyclopropyl.

[0192] In another embodiment, L 1 is a bond. In some embodiments, R 3 is H or C1-C6 alkyl. For example, R 3 may be H or methyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl.

[0193] In some embodiments, R 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl. 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens). For example, R 3may be NH2, NH(CH3), or N(CH3)2.

[0194] In some embodiments, R 3 is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0195] In some embodiments, R 3 is NH'R', where R' is C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0196] In some embodiments, R3 is a 4-6 membered heterocyclyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. In some embodiments, R 3 is a 4-6 membered heterocyclyl containing at least one nitrogen, wherein the heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. In some embodiments, R 3 is a 4-membered heterocyclyl containing at least one nitrogen, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo.

[0197] In some embodiments, R 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, C-C cycloalkyl, and 4-6 membered heterocyclyl. 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, and C-C cycloalkyl. 2 is selected from the group consisting of H, F, —O-methyl, and 4-membered heterocyclyl. 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, and —O-methyl. 2 is H or F. In some embodiments, R 2 is H.

[0198] In some embodiments, R 5is H or methyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is H. In other embodiments, R 2 and R 5 is R 2 and R 5 together with the carbon atom to which it is attached form a five-membered carbocyclic ring.

[0199] Other contemplated compounds of the present disclosure are compounds represented by Formula IV:

[0200] [ka]

[0201] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); Ring Z is a 4-10 membered N-linked heterocycle, wherein Z is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), oxo, C1-C4 alkoxy, and cyano; L 1 is a bond or a C1-C6 alkylene (one, two or three R 4 Optionally replaced by R 3 is H, C1-C6 alkyl, NR'R', S(O) 0~2 C1-C4 alkyl, SO2N(R N )2, N(R N)SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C4 alkoxy, and oxo; R 4 are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R N is selected from the group consisting of H and C1-C3 alkyl, or two R N is R N together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocyclic ring; R 1 is C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10 bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, methyl, C-C cycloalkyl, and heterocyclyl; R 5 is selected from the group consisting of H, halo, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens); or R 2 and R 5 is R 2 and R 5 Together with the carbon atom to which it is attached, it forms a 5- or 6-membered carbocyclic ring.

[0202] Exemplary contemplated compounds have the formula IV-A:

[0203] [ka]

[0204] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, CH, and CF; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, and C(CH2CH2); Ring Z is a 4-10 membered N-linked heterocycle, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; L 1is a bond or C1-C6 alkylene (optionally substituted with 1, 2 or 3 halogens); R 3 is selected from the group consisting of H, C1-C6 alkyl, NR'R', and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo; R H is selected from the group consisting of H, C1-C3 alkyl, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl; R 1 is C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10 bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C1-C6 alkyl, C3-C 10 The cycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 2 is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, methyl, C3-C7 cycloalkyl, and heterocyclyl.

[0205] In some embodiments, W is CH. In other embodiments, W is CF. In other embodiments, W is N. In some embodiments, R H is selected from the group consisting of H, —C(O)—C1-C3 alkyl, and C(O)—O—C1-C3 alkyl. In some embodiments, R H is H.

[0206] In some embodiments, for example, W is N and the compound of formula IVa:

[0207] [ka]

[0208] or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof. In some embodiments, R 1 is a 5-6 membered heterocyclyl or C-C cycloalkyl. 1 is C3-C6 cycloalkyl. For example, R 1 may be cyclopropyl or cyclopentyl.

[0209] In some embodiments, ring Z is selected from the group consisting of a 4-6 membered monocyclic heterocycle, a 6-10 membered spiro heterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, and oxo.

[0210] In some embodiments, ring Z is selected from the group consisting of a 4-6 membered monocyclic heterocycle, a 6-10 membered spiro heterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo.

[0211] In some embodiments, ring Z is selected from the group consisting of a 6- to 10-membered spiroheterocycle, a 6- to 10-membered fused bicyclic heterocycle, and a 6- to 10-membered bridged cycloheteroalkyl, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), —C(O)OH, —C(O)—O—C1-C4 alkyl, and oxo.

[0212] In some embodiments, ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged cycloheteroalkyl, wherein Z is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo.

[0213] In some embodiments, ring Z is

[0214] [ka]

[0215] is selected from the group consisting of: In some embodiments, ring Z is

[0216] [ka]

[0217] is selected from the group consisting of: In some embodiments, ring Z is

[0218] [ka]

[0219] is selected from the group consisting of: Exemplary contemplated compounds disclosed herein are those of formula IVb:

[0220] [ka]

[0221] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. Also contemplated herein are compounds represented by formula IVc:

[0222] [ka]

[0223] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein m is 0, 1, or 2. Other exemplary contemplated compounds have the formula IVd:

[0224] [ka]

[0225] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. In some other embodiments, contemplated compounds have formula IVe:

[0226] [ka]

[0227] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. In some embodiments, L 1 is C1-C6 alkylene. For example, L 1 may be methylene, ethylene, or propylene. In some embodiments, L 1 is methylene.

[0228] In some embodiments, L 1 is one or two R 4 For example, L 1 is one or two R 4 In some embodiments, L 1 is one R 4 In some embodiments, L is a C1-C4 alkylene substituted with 1 is two R 4 In some embodiments, R 4 is C1-C3 alkyl (optionally substituted with 1, 2 or 3 halogens). For example, R 4 may each be independently selected from the group consisting of methyl, ethyl, and propyl. 4 is R 4 Together with the carbon to which it is attached, it forms a C3-C4 carbocyclic ring. For example, two R 4 is R 4 together with the carbon to which it is attached to form a cyclopropyl.

[0229] In another embodiment, L 1 is a bond. In some embodiments, R 3is H or C1-C6 alkyl. For example, R 3 may be H or methyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl.

[0230] In some embodiments, R 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl. 3 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens). For example, R 3 may be NH2, NH(CH3), or N(CH3)2.

[0231] In some embodiments, R 3is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0232] In some embodiments, R 3 is NH'R', where R' is C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 3 is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0233] In some embodiments, R 3is a 4-6 membered heterocyclyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. In some embodiments, R 3 is a 4-6 membered heterocyclyl containing at least one nitrogen, wherein the heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. In some embodiments, R 3 is a 4-membered heterocyclyl containing at least one nitrogen, wherein the heterocyclyl is optionally substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo.

[0234] In some embodiments, R 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, C-C cycloalkyl, and 4-6 membered heterocyclyl. 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, and C-C cycloalkyl. 2 is selected from the group consisting of H, F, —O-methyl, and 4-membered heterocyclyl. 2 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, and —O-methyl. 2 is H or F. In some embodiments, R 2 is H.

[0235] In some embodiments, R 5 is H or methyl. In some embodiments, R5 is methyl. In some embodiments, R 5 is H. In other embodiments, R 2 and R 5 is R 2 and R 5 together with the carbon atom to which it is attached form a five-membered carbocyclic ring.

[0236] Contemplated compounds include, for example:

[0237] [ka]

[0238] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. Also contemplated herein are compounds represented by formula V:

[0239] [ka]

[0240] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W' is selected from the group consisting of N, CH, and CF; Y' is selected from the group consisting of NH, N-CH3, O, S, CH2, CFH, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); R L is H or C1-C6 alkyl; L 2 is a bond or a C1-C6 alkylene (one, two or three R 24 Optionally replaced by R 23 is NR'R'; R 24are each independently selected from the group consisting of halogen and C1-C6 alkyl, or two R 4 is R 4 together with the carbon to which it is attached to form a C3-C5 carbocyclic ring; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, which is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo, or two R' together with the nitrogen to which they are attached form a heterocyclyl, which may be optionally substituted with methyl, halo, cyano, oxo, or hydroxyl; R H ' is selected from the group consisting of H, C1-C3 alkyl, -C(O)-C1-C3 alkyl, and C(O)-O-C1-C3 alkyl; R 21 is C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10 bicycloalkyl, heterocyclyl, cyano, halo, heteroaryl, and H; wherein C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C 10 The bicycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 22 is selected from the group consisting of H, F, —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, methyl, C3-C7 cycloalkyl, and heterocyclyl.

[0241] Exemplary contemplated compounds have the formula VA:

[0242] [ka]

[0243] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W' is selected from the group consisting of N, CH, and CF; Y' is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, and C(CH2CH2); R L is H or C1-C6 alkyl; L 2 is a bond or C1-C6 alkylene (optionally substituted with 1, 2 or 3 halogens); R 23 is NR'R'; R' at each occurrence is independently selected from the group consisting of H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, and heterocyclyl, which is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo, or two R' together with the nitrogen to which they are attached form a heterocyclyl, which may be optionally substituted with methyl, halo, cyano, oxo, or hydroxyl; R H ' is selected from the group consisting of H, C1-C3 alkyl, -C(O)-C1-C3 alkyl, and C(O)-O-C1-C3 alkyl; R 21 is C1-C6 alkyl, C3-C 10 Cycloalkyl, spiro C5-C10 bicycloalkyl, heterocyclyl, cyano, halo, heteroaryl, and H; wherein C1-C6 alkyl, C3-C 10 The cycloalkyl, heterocyclyl, or heteroaryl may be optionally substituted by 1, 2, or 3 substituents each independently selected from halo and C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens); R 22 is selected from the group consisting of H, F, —C(O)—O-methyl, —C(O)OH, —O-methyl, methyl, C3-C7 cycloalkyl, and heterocyclyl.

[0244] In some embodiments, W' is CH. In other embodiments, W' is CF. In other embodiments, W' is N. In some embodiments, R H In some embodiments, R ' is selected from the group consisting of H, -C(O)-C1-C3 alkyl, and C(O)-O-C1-C3 alkyl. H’ is H.

[0245] In some embodiments, for example, W' is N and the compound has formula Va:

[0246] [ka]

[0247] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. In some embodiments, R 21 is a 5-6 membered heterocyclyl or C-C cycloalkyl. 21 is C3-C6 cycloalkyl. For example, R 21 may be cyclopropyl or cyclopentyl.

[0248] In some embodiments, L 2 is C1-C6 alkylene. For example, L 2 may be methylene, ethylene, or propylene. In some embodiments, L 2 is propylene. In other embodiments, L 2 is a bond.

[0249] In some embodiments, R 23 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 23 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl. 23 is NR'R', where each R' is independently H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens). 23 is NH2, NH(CH3), or N(CH3)2.

[0250] In some embodiments, R 23is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2, or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 alkylene-SO2-C1-C4 alkyl, or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted with 1, 2, or 3 halogens), and oxo. 23 is NH'R', where R' is H, C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogens), C1-C6 alkylene-O-C1-C4 alkyl, or C1-C6 alkylene-SO2-C1-C4 alkyl.

[0251] In another embodiment, R 23 is NR'R, where two R's together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl. In some embodiments, R 22 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, methyl, —C(O)OH, —O-methyl, and C-C cycloalkyl. 22 is selected from the group consisting of H, F, CF, —C(O)—O-methyl, —C(O)OH, —O-methyl, and methyl. In some embodiments, R 22 is H, F, or methyl. In some embodiments, R 22 is H or F. In some embodiments, R 22 is H.

[0252] In some embodiments, R L is H. In other embodiments, R L is methyl. Contemplated compounds include, for example:

[0253] [ka]

[0254] or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof. The compounds described and disclosed herein may exist in salt form, which salt form of the compounds is a pharmaceutically acceptable salt, and / or the compounds described herein may exist in prodrug form. Any convenient prodrug form of the subject compounds may be prepared in accordance with the strategies and methods described, for example, by Rautio et al. ("Prodrugs: design and clinical applications," Nature Reviews Drug Discovery 7, pp. 255-270 (February 2008)). The compounds described herein may also exist in solvate form.

[0255] In some embodiments, the compounds, or prodrug forms thereof, are provided in the form of pharmaceutically acceptable salts. Compounds containing an amine function or a nitrogen-containing heteroaryl group may be basic in nature and may react with any number of inorganic and organic acids to form the corresponding pharmaceutically acceptable salts. Inorganic acids commonly used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as related inorganic acids. Organic acids commonly used to form such salts include para-toluenesulfonic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, fumaric acid, maleic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related organic acids. Such pharmaceutically acceptable salts include, therefore, sulfate, pyrosulfate, bisulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chloramphenicol ... These include benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, hippurate, gluconate, lactobionate, and related salts.

[0256]

[0192] It is understood that all modifications, such as salts, solvates, hydrates, prodrugs and stereoisomers, are intended to be encompassed by the present disclosure. Pharmaceutical Compositions and Formulations

[0193] The compounds, prodrugs, and compositions described herein can be useful as pharmaceutical compositions for administration to a subject in need thereof.

[0257]

[0194] Thus, provided are pharmaceutical compositions that can include at least a compound described herein, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and at least one pharmaceutically acceptable carrier, diluent, stabilizer, excipient, dispersant, suspending agent, or thickener. For example, a pharmaceutical composition of the present disclosure can include one or more of a compound described herein, a pharmaceutically acceptable salt thereof, or a prodrug thereof. Contemplated compositions can include a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or a prodrug thereof; for example, a pharmaceutical composition of the present disclosure can be formulated for parenteral administration to a subject in need thereof, for intravenous administration to a subject in need thereof, or for subcutaneous administration to a subject in need thereof.

[0258] Treatment method As noted above, embodiments of the present disclosure include the use of the compounds, prodrugs, and pharmaceutical compositions described herein to treat a Myc protein-associated proliferative disorder in a subject in need thereof. Such proliferative disorders include cancers selected from the group consisting of head and neck cancer, nervous system cancer, brain cancer, neuroblastoma, lung / mediastinal cancer, breast cancer, esophageal cancer, gastric cancer, liver cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer, colorectal cancer, gynecological cancer, genitourinary cancer, ovarian cancer, thyroid cancer, adrenal cancer, skin cancer, melanoma, osteosarcoma, soft tissue sarcoma, pediatric malignancies, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, leukemia, and metastasis from an unknown primary site.

[0259]

[0196] In some embodiments, the contemplated therapeutic method includes treating a Myc protein-associated cancer, for example, a cancer in which the Myc protein is selected from the group consisting of N-Myc protein, c-MYc protein, L-Myc protein, human N-Myc protein, human c-Myc protein, and human L-Myc protein.

[0260] For example, provided herein is a method of treating a cancer selected from the group consisting of neuroblastoma, small cell lung cancer, breast cancer, or hematopoietic cancer. In some embodiments, the disclosed methods for treating cancer further include a second therapy, wherein the second therapy is an anti-cancer therapy; for example, contemplated methods may further include administering an anti-cancer therapy, such as one or more agents selected from a DNA topoisomerase I or II inhibitor, a DNA damaging agent, an immunotherapeutic agent (e.g., an antibody, cytokine, immune checkpoint inhibitor, or cancer vaccine), an antimetabolite or thymidylate synthase (TS) inhibitor, a microtubule targeting agent, ionizing radiation, an inhibitor of a mitotic regulator or mitotic checkpoint regulator, an inhibitor of a DNA damage signaling factor, and an inhibitor of a DNA damage repair enzyme. For example, the additional anti-cancer therapy may be selected from the group consisting of immunotherapy (e.g., immuno-oncology therapy), radiation therapy, photodynamic therapy, gene-directed enzyme prodrug therapy (GDEPT), antibody-directed enzyme prodrug therapy (ADEPT), gene therapy, and a nutrient-controlled diet.

[0261]

[0199] The present disclosure also contemplates the use of the compounds, prodrugs, and pharmaceutical compositions described herein to modulate (in vitro or in a patient) the amount and activity of Myc proteins, which may be, for example, N-Myc proteins, c-MYc proteins, L-Myc proteins, human N-Myc proteins, human c-Myc proteins, and / or human L-Myc proteins.

[0262]

[0200] For example, the present disclosure provides a method for regulating the amount (e.g., concentration) and / or activity of Myc protein (e.g., degrading Myc protein or regulating the degradation rate of Myc protein), etc., which comprises contacting Myc protein with an effective amount of a compound described herein, including embodiments, or from any example, table, or figure, or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0263]

[0201] Contemplated methods include methods of modulating protein-protein interactions of Myc family proteins, or methods of reducing the amount of Myc protein and methods of reducing the activity level of Myc protein.

[0264]

[0202] The disclosed method for regulating the amount and activity of Myc protein may include co-administering a compound described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second agent, e.g., a therapeutic agent. [Example]

[0265]

[0203] The following are examples of specific embodiments for carrying out the present disclosure. The examples are provided for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to the numbers used (i.e., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0266] General Experiment

[0204] 1 H and 13C NMR spectra were recorded in CDCl3 (residual internal standard CHCl3 = δ 7.26), DMSO-d6 (residual internal standard CD3SOCD2H = δ 2.50), methanol-d4 (residual internal standard CD2HOD = δ 3.20), or acetone-d6 (residual internal standard CD3COCD2H = δ 2.05). Reported chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are given in hertz (Hz). Spin multiplicities are reported as follows: s = singlet, bs = broad singlet, bm = broad multiplet, d = doublet, t = triplet, q = quartet, p = pentaplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dt = doublet of triplets, td = triplet of doublets, tt = triplet of triplets, and m = multiplet.

[0267] UPLC-MS analysis was performed on a Waters Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, an Acquity I-Class Binary Solvent Manager, and an Acquity UPLC Column Manager. UV detection was performed using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), while mass detection was achieved using an Acquity QDa detector (mass scanning from 100 to 1250 Da; simultaneous positive and negative ion detection modes). Analytes were separated using a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 mm).

[0268] Samples were prepared by dissolving in 1 mL of 50% (v / v) MeCN in water (with or without sonication). The resulting solution was then filtered through a 0.2 mm syringe filter before analysis. All solvents, including formic acid and 36% ammonia solution, were purchased as HPLC grade. Conditions (acidic, 2 min): 0.1% v / v formic acid in water [eluent A]; 0.1% v / v formic acid in MeCN [eluent B]; flow rate 0.8 mL / min; injection volume 2 mL with 1.5 min equilibration time between samples. Conditions (acidic, 4 min): 0.1% v / v formic acid in water [eluent A]; 0.1% v / v formic acid in MeCN [eluent B]; flow rate 0.8 mL / min; injection volume 2 mL with 1.5 min equilibration time between samples. Conditions (basic 2 min): 0.1% ammonia in water [eluent A]; 0.1% ammonia in MeCN [eluent B]; flow rate 0.8 mL / min; injection volume 2 mL and 1.5 min equilibration time between samples. Conditions (basic 4 min): 0.1% ammonia in water [eluent A]; 0.1% ammonia in MeCN [eluent B]; flow rate 0.8 mL / min; injection volume 2 mL and 1.5 min equilibration time between samples.

[0269] General synthetic scheme

[0270] [ka]

[0271] In certain embodiments, a compound of Formula I is prepared according to Scheme 1. Intermediate A1 (e.g., as described herein) is reacted with amine B1 (e.g., an amine described herein) in the presence of a base (e.g., N,N-diisopropylethylamine) at elevated temperature to provide a compound of Formula I. In certain embodiments, amine B1 can contain a protecting group (e.g., tert-butyloxycarbonyl (Boc), benzyl carbamate (Cbz)). In certain embodiments, when amine B1 contains a protecting group (e.g., tert-butyloxycarbonyl (Boc), benzyl carbamate (Cbz)), the intermediate resulting from the reaction of amine B1 with intermediate A1 in the presence of a base can be further deprotected (e.g., in the presence of a reducing agent such as hydrogen (e.g., using Pd / C as a catalyst) or LiAlH4, or an acid such as TFA or HBr) to provide a compound of Formula I.

[0272] Synthesis of intermediates 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine

[0273] [ka]

[0274] A solution of 5-cyclopropyl-1H-pyrazol-3-amine (4.55 g, 36.9 mmol), 2,4-dichloropyrimidine (5.00 g, 33.6 mmol), and N,N-diisopropylethylamine (8.8 mL, 50 mmol) in DMSO (50 mL) was heated to 60° C. and stirred for 16 hours. The reaction mixture was then cooled to ambient temperature and then added to ice water (approximately 1 L). The precipitate was collected by filtration and then dried under reduced pressure to give the title compound as a solid (7.41 g, 31.4 mmol, 94%).

[0275]

[0209] 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.26 (s, 1H), 8.14 (s, 1H), 7.31 (s, 1H), 5.93 (s, 1H), 1.89 (tt, J = 8.7, 5.2 Hz, 1H), 1.01 - 0.88 (m, 2H), 0.68 (q, J = 3.5, 1.9 Hz, 2H).

[0210] UPLC-MS (basic method, 2 minutes): Rt: 0.87 minutes, m / z: 236.2 [M+H] + .

[0276] Synthesis of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine

[0277] [ka]

[0278] A solution of 2,4-dichloropyrimidine (450 mg, 3.0 mmol, 1.0 equiv) in anhydrous DMSO (10.0 mL) was treated sequentially with 5-cyclopentyl-1H-pyrazol-3-amine (502 mg, 3.2 mmol, 1.10 equiv) and N,N-diisopropylethylamine (0.79 mL, 4.5 mmol, 1.50 equiv), and the resulting solution was stirred at 60° C. for 20 h. The reaction mixture was cooled to ambient temperature and poured into ice water to give a suspension, which was stirred for 5 min. The mixture was filtered to give a solid, which was washed with water (50 mL) and then evaporated to constant weight in vacuo to give the desired compound as a solid (675 mg, 2.56 mmol, 85%). UPLC-MS (basic method, 2 min): rt 0.98 min, m / z = 263.3 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 10.31 (s, 1H), 8.16 (s, 1H), 3.02 (q, J = 8.3 Hz, 1H), 2.05 - 1.94 (m, 2H), 1.74 - 1.66 (m, 2H), 1.58 (ddt, J = 20.3, 15.7, 7.0 Hz, 4H).

[0279] Synthesis of tert-butyl 4-(methylsulfonyloxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0280] [ka]

[0281] Diisopropyl 3-hydroxyiminocyclobutane-1,1-dicarboxylate Diisopropyl 3-oxocyclobutane-1,1-dicarboxylate (50.00 g, 206 mmol) and hydroxylamine hydrochloride (28.68 g, 413 mmol) were dissolved in a mixture of ethanol (400 mL) and water (400 mL). Sodium carbonate (65.62 g, 619 mmol) was added, and the mixture was heated to reflux for 1 hour. The reaction was cooled to room temperature, and the volatiles were removed under reduced pressure. The resulting residue was suspended in water (150 mL), cooled to 5° C., and filtered. The resulting white solid was dried in a vacuum oven at 40° C. for 2 hours. The solid was then triturated in heptane (250 mL) and filtered to give the title compound as a solid (44.50 g, 173 mmol, 84%).

[0282]

[0213] 1 H NMR (400 MHz, chloroform-d) δ 8.20–7.99 (m, 1H), 5.13–4.99 (m, 2H), 3.45–3.34 (m, 4H), 1.27–1.19 (m, 12H).

[0214] UPLC MS-ELS (2 min, basic method, ELSD) rt=1.02 min, m / z=258.1[M+H + ].

[0283] Diisopropyl 3-(tert-butoxycarbonylamino)cyclobutane-1,1-dicarboxylate To a suspension of di-tert-butyl dicarbonate (22.56 g, 103 mmol) and nickel(II) chloride hexahydrate (6.14 g, 25.8 mmol) in 1-butanol (130 mL) was added a solution of diisopropyl 3-hydroxyiminocyclobutane-1,1-dicarboxylate (13.30 g, 51.7 mmol) in methanol (70 mL) followed by sodium borohydride (7.82 g, 207 mmol) in small portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 hours. Diethylenetriamine (13 mL, 119 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with water (130 mL) and i-PrOAc (260 mL). After stirring for 15 minutes, the organic layer was separated, and the aqueous layer was extracted with i-PrOAc (130 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound as an oil that solidified upon standing (16.20 g, 47.2 mmol, 91%).

[0284]

[0216] 1 H NMR (400 MHz, chloroform-d) δ 5.10 - 4.96 (m, 2H), 4.83 (d, J = 8.7 Hz, 1H), 2.88 (d, J = 13.4 Hz, 2H), 2.40 - 2.28 (m, 2H), 1.43 (d, J = 2.1 Hz, 1H), 1.41 (s, 9H), 1.29 - 1.14 (m, 12H).

[0285]

[0217] UPLC MS (2 minutes, basic method, ELSD) rt=1.24 minutes, m / z=342.2[MH] - . tert-Butyl N-[3,3-bis(hydroxymethyl)cyclobutyl]carbamate To diisopropyl 3-(tert-butoxycarbonylamino)cyclobutane-1,1-dicarboxylate (17.9 g, 52.1 mmol) in THF (270 mL) was added lithium borohydride (4.54 g, 208 mmol). The reaction mixture was warmed to 50° C., and methanol (54 mL) was added dropwise to the reaction mixture over 10 minutes. Once the effervescence had ceased, the reaction was heated to reflux for 1 hour. The reaction mixture was then cooled to room temperature, and 0.5 M aqueous citric acid (100 mL) was added. After stirring for 16 hours, the reaction mixture was transferred to a separatory funnel with water (300 mL) and EtOAc (400 mL). The aqueous layer was further extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na2SO4 and concentrated to dryness under reduced pressure. The crude material was purified by trituration in ether to give the title compound as a solid (11.0 g, 47.6 mmol, 91%).

[0286]

[0219] 1 H NMR (400 MHz, methanol-d4) δ 4.14–3.78 (m, 1H), 3.55 (s, 2H), 3.46 (s, 2H), 2.17–2.06 (m, 2H), 1.79–1.67 (m, 2H), 1.40 (s, 9H). [3-(tert-butoxycarbonylamino)-1-(methylsulfonyloxymethyl)cyclobutyl]methyl methanesulfonate In a round-bottom flask, tert-butyl N-[3,3-bis(hydroxymethyl)cyclobutyl]carbamate (10.70 g, 46.3 mmol) and triethylamine (26 mL, 185 mmol) were suspended in chloroform (100 mL). The reaction mixture was cooled to 0° C. Methanesulfonyl chloride (7.9 mL, 102 mmol) was then added dropwise, and the reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was transferred to a separatory funnel with water (200 mL) and DCM (300 mL). The layers were separated, and the aqueous layer was further extracted with DCM (2×200 mL). The combined organic extracts were washed with brine (200 mL), dried over NaSO, and then concentrated to dryness under reduced pressure. The residue was purified by normal phase flash column chromatography eluting with a gradient of 0 to 60% EtOAc in iso-hexane to afford the title compound as a solid (7.00 g, 18.1 mmol, 39%).

[0287]

[0221] 1 H NMR (400 MHz, chloroform-d) δ 4.77 (s, 1H), 4.25 (d, J = 0.7 Hz, 2H), 4.19 (d, J = 0.7 Hz, 2H), 3.08 - 3.00 (m, 6H), 2.41 - 2.31 (m, 2H), 2.05- 1.91 (m, 2H), 1.41 (s, 9H).

[0288] tert-Butyl 4-(methylsulfonyloxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a solution of [3-(tert-butoxycarbonylamino)-1-(methylsulfonyloxymethyl)cyclobutyl]methyl methanesulfonate (7.00 g, 18.1 mmol) in DCM (100 mL) was added methanesulfonic acid (3.6 mL, 54 mmol), and the reaction mixture was stirred at room temperature for 2 h. THF (30 mL) was added, and stirring was continued for an additional 2 h. The volatiles were then removed under reduced pressure to give a semi-solid residue. The residue was dissolved in toluene (50 mL) and N,N-diisopropylethylamine (14 mL, 81 mmol), then IPA (25 mL) was added, and the reaction was heated to reflux and stirred for 16 h. The reaction mixture was then cooled to room temperature, followed by the sequential addition of N,N-diisopropylethylamine (6.3 mL, 36.1 mmol) and di-tert-butyl dicarbonate (5.91 g, 27.1 mmol). After stirring at room temperature for 16 h, the reaction mixture was transferred to a separatory funnel with water (400 mL) and EtOAc (200 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (300 mL). The combined organics were washed with brine (400 mL), dried over Na2SO4, and concentrated under reduced pressure to give an oily residue. The crude material was purified by normal-phase column chromatography on silica gel eluting with a gradient of EtOAc in iso-hexane (50% to 100%; v / v) to give the title compound as a solid (2.50 g, 8.58 mmol, 48%).

[0289]

[0223] 1 H NMR (400 MHz, chloroform-d) δ 4.42–4.34 (m, 3H), 3.28 (s, 2H), 3.02 (s, 3H), 1.92–1.82 (m, 2H), 1.63–1.47 (m, 2H), 1.46 (s, 9H). [Example]

[0290] Example 1. Synthesis of Compound 1

[0291] [ka]

[0292] tert-Butyl (2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (400 mg, 1.69 mmol), tert-butyl N-(2-azaspiro[3.3]heptan-6-yl)carbamate hemioxalate (873 mg, 3.39 mmol), and N,N-diisopropylethylamine (0.888 mL, 5.10 mmol) in n-butanol (15 mL) was heated to 100° C. and stirred for 44 hours. The reaction mixture was then cooled to ambient temperature, and the volatiles were removed under reduced pressure. The crude residue was triturated with a 1:1 mixture of EtOAc and water to give the title compound as a solid (430 mg, 0.961 mmol, 57%).

[0293]

[0225] 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.33 (s, 1H), 6.18 (s, 1H), 4.04 (s, 2H), 3.93 (s, 2H), 3.85 (d, J = 7.7 Hz, 1H), 2.44 (t, J = 10.0 Hz, 3H), 2.10 (dd, J = 11.8, 8.6 Hz, 2H), 1.95 - 1.77 (m, 1H), 1.37 (s, 11H), 1.26 (t, J = 6.2 Hz, 4H), 0.97 - 0.88 (m, 2H), 0.67 (d, J = 5.3 Hz, 2H).

[0294]

[0226] UPLC-MS (basic method, 4 minutes): Rt: 1.01 minutes, m / z: 412.3 [M+H] + . 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-methyl-2-azaspiro[3.3]heptan-6-amine To a solution of tert-butyl (2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl)carbamate (150 mg, 0.365 mmol) in anhydrous THF (25 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.5 mL, 3.6 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was then cooled to 0° C. and then quenched with water (140 μL), followed by 15% w / v NaOH solution (140 μL), followed by water (420 μL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (10 mL). The eluate was then concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase acidic preparative HPLC using TFA as an additive, followed by reverse-phase basic preparative HPLC using ammonia as an additive, to give the title compound as a solid (27 mg, 79 μmol, 22%).

[0295]

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.44 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.29 (s, 1H), 6.13 (s, 1H), 3.96 (s, 2H), 3.86 (s, 2H), 3.10 - 2.83 (m, 1H), 2.36 (t, J = 9.5 Hz, 2H), 2.15 (s, 4H), 1.86 (m, 3H), 1.04 (d, J = 6.1 Hz, 1H), 0.90 (d, J = 8.2 Hz, 2H), 0.65 (d, J = 5.0 Hz, 2H).

[0296]

[0229] UPLC-MS (basic method, 4 minutes): Rt: 1.10 minutes, m / z: 326.3 [M+H] + . [Example]

[0297] Example 2. Synthesis of Compound 2

[0298] [ka]

[0299] tert-Butyl 6-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.27 mmol), tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (405 mg, 1.91 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.2 mmol) in NMP (3 mL) was heated to 120° C. in a sealed tube and stirred for 24 h. The reaction mixture was then cooled to ambient temperature and added dropwise to ice water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (405 mg, 0.984 mmol, 77%).

[0300]

[0231] 1H NMR (400 MHz, DMSO-d6, 90℃) δ 11.86 (s, 1H), 9.30 (s, 1H), 7.83 (d, J = 5.8 Hz, 1H), 6.40 - 6.04 (m, 2H), 3.86 - 3.75 (m, 4H), 3.61 (s, 2H), 3.50 (t, J = 6.7 Hz, 2H), 2.11 (t, J = 6.8 Hz, 2H), 1.91 - 1.81 (m, 1H), 1.39 (s, 9H), 0.95 - 0.86 (m, 2H), 0.74 - 0.59 (m, 2H).

[0301]

[0232] UPLC-MS (basic method, 2 minutes): Rt: 1.04 minutes, m / z: 412.4 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,6-diazaspiro[3.4]octan-6-yl)pyrimidin-4-amine To a solution of tert-butyl 6-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (100 mg, 0.243 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol) and the reaction mixture was stirred at ambient temperature for 1 h, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (62 mg, 0.20 mmol, 82%).

[0302]

[0234] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.34 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.35 - 6.02 (m, 2H), 4.02 (s, 1H), 3.57 (s, 2H), 3.49 - 3.34 (m, 6H), 2.08 (t, J = 6.8 Hz, 2H), 1.91 - 1.83 (m, 1H), 0.94 - 0.88 (m, 2H), 0.70 - 0.62 (m, 2H).

[0303]

[0235] 1 H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 5.8 Hz, 1H), 6.37 - 6.00 (m, 2H), 3.75 - 3.67 (m, 4H), 3.63 - 3.53 (m, 4H), 2.24 (t, J = 6.9 Hz, 2H), 1.95 - 1.85 (m, 1H), 1.01 - 0.92 (m, 2H), 0.77 - 0.68 (m, 2H).

[0304]

[0236] UPLC-MS (basic method, 4 minutes): Rt: 1.00 minutes, m / z: 312.3 [M+H] + . [Example]

[0305] Example 3. Synthesis of Compound 3

[0306] [ka]

[0307] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)pyrimidin-4-amine To a solution of tert-butyl 6-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (150 mg, 0.365 mmol) in anhydrous THF (20 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.5 mL, 3.6 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was then cooled to 0° C. and then quenched with water (150 μL), followed by 15% w / v sodium hydroxide solution (150 μL), followed by water (450 μL). The reaction mixture was allowed to warm to ambient temperature and stirred for 10 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for a further 10 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (64 mg, 0.20 mmol, 54%).

[0308]

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.32 (s, 1H), 7.82 (d, J = 5.6 Hz, 1H), 6.39 - 6.03 (m, 2H), 3.54 (s, 2H), 3.45 (t, J = 6.3 Hz, 2H), 3.12 (d, J = 6.7 Hz, 2H), 3.06 (d, J = 6.7 Hz, 2H), 2.22 (s, 3H), 2.05 (t, J = 6.9 Hz, 2H), 1.92 - 1.80 (m, 1H), 0.94 - 0.88 (m, 2H), 0.70 - 0.61 (m, 2H).

[0309]

[0239] 1H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 5.9 Hz, 1H), 6.36 - 5.96 (m, 2H), 3.65 (s, 2H), 3.57 (t, J = 7.1 Hz, 2H), 3.37 - 3.26 (m, 4H), 2.38 (s, 3H), 2.19 (t, J = 7.0 Hz, 2H), 1.96 - 1.85 (m, 1H), 1.01 - 0.94 (m, 2H), 0.77 - 0.69 (m, 2H).

[0310]

[0240] UPLC-MS (basic method, 4 minutes): Rt: 1.14 minutes, m / z: 326.3 [M+H] + . [Example]

[0311] Example 4. Synthesis of Compound 4

[0312] [ka]

[0313] tert-Butyl 6-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.27 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (465 mg, 1.91 mmol), and N,N-diisopropylethylamine (0.78 mL, 4.46 mmol) in NMP (5 mL) was heated to 100° C. and stirred for 16 hours. The reaction mixture was then cooled to ambient temperature and added dropwise to ice water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (300 mg, 0.611 mmol, 48%).

[0314]

[0242] 1 H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 6.0 Hz, 1H), 6.22 (s, 2H), 4.20 (s, 4H), 4.11 (s, 4H), 1.90 (m, 1H), 1.45 (s, 9H), 0.97 (d, J = 8.0 Hz, 2H), 0.82 - 0.69 (m, 2H).

[0315]

[0243] UPLC-MS (basic method, 2 minutes): Rt: 1.00 minutes, m / z: 398.4 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-amine To a solution of tert-butyl 6-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (149 mg, 0.375 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.6 mL, 3.8 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was then cooled to 0° C. and then quenched with water (150 μL), followed by 15% w / v sodium hydroxide solution (150 μL), followed by water (450 μL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for a further 15 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (16 mg, 21 μmol, 13%).

[0316]

[0245] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.43 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.32 (s, 1H), 6.14 (s, 1H), 4.00 (s, 4H), 3.25 (s, 4H), 2.17 (s, 3H), 1.98 - 1.64 (m, 1H), 1.05 - 0.80 (m, 2H), 0.75 - 0.56 (m, 2H).

[0246] UPLC-MS (basic method, 4 minutes): Rt: 1.08 minutes, m / z: 312.3 [M+H] + . [Example]

[0317] Example 5. Synthesis of Compound 5

[0318] [ka]

[0319] tert-Butyl ((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-yl)methyl)(methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (220 mg, 0.934 mmol), tert-butylmethyl(piperidin-4-ylmethyl)carbamate (533 mg, 2.33 mmol), and N,N-diisopropylethylamine (0.57 mL, 3.3 mmol) in n-butanol (10 mL) was heated to 100° C. and stirred for 24 hours. The reaction mixture was then concentrated to dryness under reduced pressure, then diluted with water (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with water (2×100 mL), then saturated aqueous brine solution (100 mL), then dried over NaSO, and then concentrated to dryness under reduced pressure. The residue was purified by automated flash column chromatography on silica gel eluting with a gradient of CH2Cl2 to 1:9 2M ammonia in MeOH:CH2Cl2 to give the title compound as an oil (250 mg, 0.497 mmol, 53%).

[0320]

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.33 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 6.23 (s, 1H), 6.07 (s, 1H), 3.06 (d, J = 7.1 Hz, 2H), 2.79 (d, J = 9.5 Hz, 5H), 1.85 (s, 2H), 1.57 (s, 2H), 1.38 (s, 9H), 1.05 (d, J = 12.2 Hz, 2H), 0.95 - 0.80 (m, 3H), 0.62 (d, J = 5.2 Hz, 2H).

[0321]

[0249] UPLC-MS (basic method, 2 minutes): Rt: 1.11 minutes, m / z: 428.4 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((dimethylamino)methyl)piperidin-1-yl)pyrimidin-4-amine To a solution of tert-butyl ((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-yl)methyl)(methyl)carbamate (110 mg, 0.257 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.1 mL, 2.6 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 2.5 h. The reaction mixture was then cooled to 0° C. and then quenched with water (100 μL), then 15% w / v sodium hydroxide solution (100 μL), followed by water (300 μL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for a further 15 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (125 mg, 0.399 mmol, 27%).

[0322]

[0251] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.33 (s, 1H), 7.85 (d, J = 5.6 Hz, 1H), 6.23 (s, 1H), 6.04 (s, 1H), 4.59 (d, J = 13.1 Hz, 2H), 2.93 - 2.67 (m, 2H), 2.11 (s, 6H), 2.05 (d, J = 6.8 Hz, 2H), 1.91 - 1.80 (m, 1H), 1.71 (d, J = 11.3 Hz, 3H), 1.08 - 0.96 (m, 2H), 0.94 - 0.86 (m, 2H), 0.69 - 0.58 (m, 2H).

[0323]

[0252] UPLC-MS (basic method, 4 minutes): Rt: 1.15 minutes, m / z: 342.1 [M+H] + . [Example]

[0324] Example 6. Synthesis of Compound 6

[0325] [ka]

[0326] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-amine To a solution of tert-butyl 6-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (120 mg, 0.302 mmol) in CHCl (3 mL) was added trifluoroacetic acid (3.0 mL, 39 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The reaction mixture was then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase acidic preparative HPLC using TFA as an additive, followed by reverse-phase basic preparative HPLC using ammonia as an additive, to give the title compound as a solid (36 mg, 0.12 mmol, 38%).

[0327]

[0254] 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.42 (s, 1H), 7.82 (d, J = 5.8 Hz, 1H), 6.31 (s, 1H), 6.14 (s, 1H), 4.02 (s, 4H), 3.59 (s, 4H), 2.02 - 1.66 (m, 1H), 0.91 (d, J = 7.9 Hz, 2H), 0.66 (d, J = 5.2 Hz, 2H).

[0328]

[0255] UPLC-MS (basic method, 4 minutes): Rt: 0.89 minutes, m / z: 298.3 [M+H] + . [Example]

[0329] Example 7. Synthesis of Compound 7

[0330] [ka]

[0331] tert-Butyl (R)-((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (600 mg, 2.55 mmol), (S)-tert-butyl(pyrrolidin-3-ylmethyl)carbamate (765 mg, 3.82 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.4 mmol) in NMP (6 mL) was heated to 120° C. in a sealed tube and stirred for 21 hours. The reaction mixture was then cooled to ambient temperature and added dropwise to ice water (250 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (810 mg, 2.02 mmol, 79%).

[0332]

[0257] 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.31 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.99 (s, 1H), 6.37 - 6.01 (m, 2H), 3.61 - 3.52 (m, 2H), 3.46 - 3.37 (m, 1H), 3.17 - 3.12 (m, 1H), 3.03 - 2.95 (m, 2H), 2.44 - 2.30 (m, 1H), 2.02 - 1.91 (m, 1H), 1.89 - 1.82 (m, 1H), 1.70 - 1.61 (m, 1H), 1.38 (s, 9H), 0.97 - 0.86 (m, 2H), 0.69 - 0.63 (m, 2H).

[0333]

[0258] UPLC-MS (basic method, 2 minutes): Rt: 1.00 minutes, m / z: 400.4 [M+H] + . (R)—N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-((methylamino)methyl)pyrrolidin-1-yl)pyrimidin-4-amine To a solution of tert-butyl (R)-((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate (600 mg, 1.50 mmol) in anhydrous THF (20 mL) at 0° C. was added dropwise a 2.4 M solution of lithium aluminum hydride in THF (6.3 mL, 15 mmol). The reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was then cooled to 0° C. and then quenched with water (0.65 mL), then 15% w / v sodium hydroxide solution (0.65 mL), followed by water (1.95 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 5 g) was added and the reaction mixture stirred for a further 15 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (125 mg, 0.399 mmol, 27%).

[0334]

[0260] 1H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 5.9 Hz, 1H), 6.21 - 6.03 (m, 2H), 3.77 (dd, J = 10.4, 7.7 Hz, 1H), 3.73 - 3.65 (m, 1H), 3.56 - 3.45 (m, 1H), 3.19 (t, J = 9.3 Hz, 1H), 2.72 - 2.59 (m, 2H), 2.51 (dq, J = 14.8, 7.3 Hz, 1H), 2.41 (s, 3H), 2.25 - 2.13 (m, 1H), 1.89 (tt, J = 8.4, 5.1 Hz, 1H), 1.74 (dq, J = 12.3, 8.5 Hz, 1H), 1.01 - 0.90 (m, 2H), 0.75 - 0.67 (m, 2H).

[0335]

[0261] UPLC-MS (basic method, 4 minutes): Rt: 1.08 minutes, m / z: 314.1 [M+H] + . [Example]

[0336] Example 8. Synthesis of Compound 8

[0337] [ka]

[0338] tert-Butyl (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)(methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.27 mmol), (S)-tert-butylmethyl(pyrrolidin-3-yl)carbamate (382 mg, 1.91 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.2 mmol) in NMP (3 mL) was heated to 120° C. in a sealed tube and stirred for 20 hours. The reaction mixture was then cooled to ambient temperature and added dropwise to ice water (250 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (389 mg, 0.945 mmol, 74%).

[0339]

[0263] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.36 (s, 1H), 7.84 (d, J = 5.8 Hz, 1H), 6.23 (s, 2H), 4.64 (s, 1H), 3.72 - 3.62 (m, 2H), 3.48 - 3.32 (m, 2H), 2.75 (s, 3H), 2.12 - 1.98 (m, 2H), 1.88 - 1.80 (m, 1H), 1.42 (s, 9H), 0.92 - 0.85 (m, 2H), 0.68 - 0.59 (m, 2H).

[0340]

[0264] UPLC-MS (basic method, 2 minutes): Rt: 1.05 minutes, m / z: 400.4 [M+H] + . (S)—N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine To a solution of tert-butyl (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (100 mg, 0.250 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol) and the reaction mixture was stirred at ambient temperature for 1 h, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase acidic preparative HPLC using TFA as an additive, followed by reverse-phase basic preparative HPLC using ammonia as an additive to give the title compound as a solid (37 mg, 0.12 mmol, 49%).

[0341]

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.32 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.40 - 6.00 (m, 2H), 3.66 - 3.49 (m, 2H), 3.48 - 3.39 (m, 1H), 3.25 (d, J = 4.7 Hz, 1H), 3.21 - 3.12 (m, 1H), 2.29 (d, J = 4.9 Hz, 3H), 2.02 (dq, J = 12.5, 6.5 Hz, 1H), 1.91 - 1.70 (m, 3H), 0.95 - 0.86 (m, 2H), 0.72 - 0.60 (m, 2H).

[0342]

[0267] 1H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 6.0 Hz, 1H), 6.36 - 6.00 (m, 2H), 3.79 (dd, J = 10.4, 5.6 Hz, 1H), 3.75 - 3.66 (m, 1H), 3.61 - 3.51 (m, 1H), 3.42 - 3.33 (m, 2H), 2.43 (s, 3H), 2.30 - 2.17 (m, 1H), 1.96 - 1.83 (m, 2H), 1.01 - 0.92 (m, 2H), 0.76 - 0.67 (m, 2H).

[0343]

[0268] UPLC-MS (basic method, 4 minutes): Rt: 1.02 minutes, m / z: 300.1 [M+H] + . [Example]

[0344] Example 9. Synthesis of Compound 9

[0345] [ka]

[0346] (S)—N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-4-amine To a solution of tert-butyl (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (150 mg, 0.375 mmol) in anhydrous THF (10 mL) at 0° C. was added dropwise a 2.4 M solution of lithium aluminum hydride in THF (1.6 mL, 3.8 mmol). The reaction mixture was heated to reflux and stirred for 6 h. The reaction mixture was then cooled to 0° C. and then quenched with water (150 μL), followed by 15% w / v sodium hydroxide solution (150 μL), followed by water (450 μL). The reaction mixture was allowed to warm to ambient temperature and stirred for 10 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for a further 10 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (64 mg, 0.20 mmol, 54%).

[0347]

[0270] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.37 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.21 (s, 2H), 3.77 (dd, J = 10.6, 7.1 Hz, 1H), 3.67 (t, J = 9.8 Hz, 1H), 3.45 - 3.34 (m, 1H), 3.14 (t, J = 9.5 Hz, 1H), 2.78 - 2.68 (m, 1H), 2.21 (s, 6H), 2.18 - 2.07 (m, 1H), 1.85 (tt, J = 8.4, 5.1 Hz, 1H), 1.81 - 1.70 (m, 1H), 0.96 - 0.83 (m, 2H), 0.70 - 0.59 (m, 2H).

[0348]

[0271] 1H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 5.7 Hz, 1H), 6.89 (s, 1H), 6.04 (s, 1H), 5.91 (s, 1H), 3.93 (dd, J = 10.4, 7.1 Hz, 1H), 3.82 (ddd, J = 10.9, 8.8, 2.0 Hz, 1H), 3.53 (td, J = 10.6, 6.9 Hz, 1H), 3.33 (t, J = 9.6 Hz, 1H), 2.84 - 2.72 (m, 1H), 2.32 (s, 6H), 2.27 - 2.16 (m, 1H), 1.97 - 1.80 (m, 2H), 0.99 - 0.88 (m, 2H), 0.77 - 0.68 (m, 2H).

[0349]

[0272] UPLC-MS (basic method, 4 minutes): Rt: 1.22 minutes, m / z: 314.3 [M+H] + . [Example]

[0350] Example 10. Synthesis of Compound 10

[0351] [ka]

[0352] tert-Butyl ((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (120 mg, 0.509 mmol), tert-butyl 4-piperidinylmethylcarbamate (273 mg, 1.27 mmol), and N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) in n-butanol (5 mL) was heated to 100° C. and stirred for 24 h. The reaction mixture was then concentrated to dryness under reduced pressure, the residue was dissolved in CHCl (30 mL), and the organic layer was washed with water (2×30 mL) followed by saturated aqueous brine solution (30 mL). The organic layer was then dried over NaSO and concentrated to dryness under reduced pressure. The residue was purified by automated flash column chromatography on silica gel eluting with a gradient of CH2Cl2 to 1:9 2M NH3:CH2Cl2 in MeOH to give the title compound as a solid (115 mg, 0.278 mmol, 54%).

[0353]

[0274] 1 H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 5.7 Hz, 1H), 6.14 (s, 2H), 4.63 (d, J = 13.2 Hz, 2H), 3.35 (s, 1H), 2.95 (d, J = 6.2 Hz, 2H), 2.87 (t, J = 12.9 Hz, 2H), 1.93 - 1.82 (m, 1H), 1.74 (d, J = 12.0 Hz, 2H), 1.44 (s, 9H), 1.24 - 1.07 (m, 2H), 0.97 (d, J = 8.2 Hz, 2H), 0.79 - 0.62 (m, 2H).

[0354]

[0275] UPLC-MS (basic method, 2 minutes): Rt: 1.04 minutes, m / z: 414.4 [M+H] + . 2-(4-(aminomethyl)piperidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl ((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamate (115 mg, 0.278 mmol) in CHCl (3 mL) was added trifluoroacetic acid (3.0 mL, 26 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, the cartridge was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to afford the title compound as a solid (66 mg, 0.21 mmol, 74%).

[0355]

[0277] 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.30 (s, 1H), 7.86 (d, J = 5.6 Hz, 1H), 6.23 (s, 1H), 6.05 (s, 1H), 4.62 (d, J = 13.0 Hz, 2H), 2.88 - 2.73 (m, 2H), 2.58 (d, J = 6.4 Hz, 1H), 1.92 - 1.82 (m, 2H), 1.81 - 1.56 (m, 3H), 1.18 - 0.99 (m, 2H), 0.96 - 0.86 (m, 2H), 0.68 - 0.47 (m, 2H).

[0278] UPLC-MS (basic method, 4 minutes): Rt: 1.04 minutes, m / z: 314.3 [M+H] + . [Example]

[0356] Example 11. Synthesis of Compound 11

[0357] [ka]

[0358] (R)-2-(3-(aminomethyl)pyrrolidin-1-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl (R)-((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)methyl)carbamate (100 mg, 0.250 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol) and the reaction mixture was stirred at ambient temperature for 1 h, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, and the cartridge was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase acidic preparative HPLC using TFA as an additive, followed by reverse-phase basic preparative HPLC using ammonia as an additive, to give the title compound as a solid (37 mg, 0.12 mmol, 49%).

[0359]

[0281] 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.31 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.44 - 5.95 (m, 2H), 3.66 - 3.50 (m, 2H), 3.46 - 3.36 (m, 1H), 3.21 - 3.10 (m, 1H), 2.59 (t, J = 6.1 Hz, 2H), 2.28 - 2.17 (m, 1H), 2.07 - 1.94 (m, 1H), 1.90 - 1.79 (m, 1H), 1.67 (q, J = 9.4Hz, 1H), 0.95 - 0.86 (m, 2H), 0.69 - 0.60 (m, 2H).

[0360]

[0282] 1H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 5.9 Hz, 1H), 6.11 (s, 2H), 3.80 - 3.64 (m, 2H), 3.52 (q, J = 8.7 Hz, 1H), 3.21 (t, J = 9.4 Hz, 1H), 2.82 - 2.67 (m, 2H), 2.41 (p, J = 7.1 Hz, 1H), 2.22 - 2.11 (m, 1H), 1.95 - 1.83 (m, 1H), 1.81 - 1.67 (m, 1H), 0.99 - 0.91 (m, 2H), 0.74 - 0.67 (m, 2H).

[0361]

[0283] UPLC-MS (basic method, 4 minutes): Rt: 1.03 minutes, m / z: 300.1 [M+H] + . [Example]

[0362] Example 12. Synthesis of Compound 12

[0363] [ka]

[0364] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((methylamino)methyl)piperidin-1-yl)pyrimidin-4-amine To a solution of tert-butyl ((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidin-4-yl)methyl)(methyl)carbamate (111 mg, 0.258 mmol) in CHCl (3 mL) was added trifluoroacetic acid (3.0 mL, 26 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, the cartridge was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to afford the title compound as a solid (78 mg, 0.24 mmol, 92%).

[0365]

[0285] 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.30 (s, 1H), 7.85 (d, J = 5.6 Hz, 1H), 6.22 (s, 1H), 6.04 (s, 1H), 4.60 (d, J = 12.9 Hz, 2H), 2.91 - 2.71 (m, 3H), 2.33 (d, J = 6.3 Hz, 2H), 2.26 (s, 3H), 1.93 - 1.77 (m, 1H), 1.76 - 1.54 (m, 3H), 1.10 - 0.98 (m, 2H), 0.95 - 0.87 (m, 2H), 0.69 - 0.55 (m, 2H).

[0366]

[0286] UPLC-MS (basic method, 4 minutes): Rt: 1.69 minutes, m / z: 328.3 [M+H] + . [Example]

[0367] Example 13. Synthesis of Compound 13

[0368] [ka]

[0369] tert-Butyl (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)(methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (670 mg, 2.84 mmol), tert-butyl N-[(3R)-pyrrolidin-3-ylmethyl]carbamate hydrochloride (1.01 g, 4.26 mmol), and N,N-diisopropylethylamine (1.7 mL, 10 mmol) in NMP (8 mL) was heated to 120° C. and stirred for 21 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of CH2Cl2 to 1:9 2M NH3:CH2Cl2 in MeOH to afford the title compound as an oil (800 mg, 1.92 mmol, 68%).

[0370]

[0288] 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.31 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.99 (d, J = 6.5 Hz, 1H), 6.20 (s, 2H), 4.15 - 4.00 (m, 2H), 3.67 - 3.49 (m, 2H), 2.99 (t, J = 6.6 Hz, 2H), 2.41 - 2.33 (m, 1H), 2.05 - 1.92 (m, 1H), 1.88 - 1.78 (m, 1H), 1.75 - 1.59 (m, 1H), 1.38 (s, 9H), 0.90 (d, J = 8.2 Hz, 2H), 0.72 - 0.60 (m, 2H).

[0371]

[0289] UPLC-MS (basic method, 2 minutes): Rt: 1.00 minutes, m / z: 400.4 [M+H] + . (S)—N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine To a solution of tert-butyl (S)-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (120 mg, 0.300 mmol) in CHCl (4 mL) was added trifluoroacetic acid (4.0 mL, 52 mmol) at 0° C. The reaction mixture was kept at 0° C. and stirred for 30 min, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, and the cartridge was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (30 mg, 94 μmol, 31%).

[0372]

[0291] 1 H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 5.9 Hz, 1H), 6.36 - 6.00 (m, 2H), 3.83 - 3.65 (m, 2H), 3.56 - 3.41 (m, 1H), 3.22 (t, J = 9.4 Hz, 1H), 2.80 (m, 2H), 2.50 - 2.35 (m, 1H), 2.19 (q, J = 5.8, 5.2 Hz, 1H), 1.98 - 1.83 (m, 1H), 1.80 - 1.65 (m, 1H), 0.96 (d, J = 8.1 Hz, 2H), 0.72 (d, J = 3.5, 2.0 Hz, 2H).

[0373]

[0292] UPLC-MS (basic method, 4 minutes): Rt: 1.04 minutes, m / z: 300.1 [M+H] + . [Example]

[0374] Example 14. Synthesis of Compound 14

[0375] [ka]

[0376] tert-Butyl 4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate A solution of 2-methyl-2-propanyl 4-{[(methylsulfonyl)oxy]methyl}-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.48 g, 5.08 mmol) in a 2.0 M solution of methylamine in MeOH (68 mL) was heated to 70 °C in a microwave reactor and stirred for 2 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was then diluted with 0.5 M aqueous NaOH (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over NaSO and then concentrated to dryness under reduced pressure to give the title compound as an oil (820 mg, 3.62 mmol, 71%).

[0377]

[0294] 1 H NMR (400 MHz, chloroform-d) δ 4.34 (s, 1H), 3.23 (s, 2H), 2.83 (s, 2H), 2.47 (s, 3H), 1.78–1.70 (m, 2H), 1.54–1.38 (m, 11H).

[0295] UPLC-MS (basic method, 2 minutes): Rt: 0.92 minutes, m / z=227.1 [M+H] + .

[0378] tert-Butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a solution of tert-butyl 4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (815 mg, 3.60 mmol) and triethylamine (753 μL, 5.40 mmol) in CHCl (10 mL) was added benzyl chloroformate (565 μL, 3.96 mmol), and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was then diluted with water (50 mL) and then extracted with CHCl (3×50 mL). The combined organic extracts were washed with saturated aqueous brine (50 mL) and then concentrated to dryness under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of 1:4 EtOAc:iso-hexane to 4:6 EtOAc:iso-hexane to give the title compound (1.16 g, 3.12 mmol, 87%) as an oil.

[0379]

[0297] 1 H NMR (400 MHz, chloroform-d) δ 7.39–7.28 (m, 5H), 5.14–5.08 (m, 2H), 4.29 (s, 1H), 3.57–3.49 (m, 2H), 3.29–3.11 (m, 2H), 2.99–2.93 (m, 3H), 1.78–1.66 (m, 2H), 1.46 (s, 11H).

[0380]

[0298] UPLC-MS (basic method, 2 minutes): Rt: 1.26 minutes, m / z=361.1[M+H] + . Benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate To a solution of tert-butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.15 g, 3.19 mmol) in CHCl (10 mL) was added trifluoroacetic acid (5.0 mL, 65 mmol) and the reaction mixture was stirred at room temperature for 30 min. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as an oil (760 mg, 2.92 mmol, 92%).

[0381]

[0300] 1 H NMR (400 MHz, chloroform-d) δ 7.39–7.29 (m, 5H), 5.15–5.08 (m, 2H), 3.60–3.51 (m, 2H), 2.99–2.93 (m, 3H), 2.84–2.72 (m, 2H), 1.65–1.55 (m, 2H), 1.36–1.23 (m, 2H).

[0382]

[0301] UPLC-MS (basic method, 2 minutes): Rt: 0.86 minutes, m / z=261.1[M+H] + . Benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (570 mg, 2.42 mmol), benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (756 mg, 2.90 mmol), and N,N-diisopropylethylamine (0.93 mL, 5.3 mmol) in NMP (6 mL) was heated to 120° C. in a sealed tube and stirred for 18 hours. The reaction mixture was cooled to ambient temperature and then added dropwise with stirring to ice water (200 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (970 mg, 2.11 mmol, 87%).

[0383]

[0303] UPLC-MS (basic method, 2 minutes): Rt: 1.07 minutes, m / z=460.4[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-amine To a solution of benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (220 mg, 0.479 mmol) in methanol (5 mL) under a stream of nitrogen was added a suspension of 10% w / w palladium on activated carbon (51 mg, 48 μmol) in water (0.1 mL). The reaction vessel was then placed under vacuum and back-filled with nitrogen three times. The reaction vessel was then placed under vacuum and then back-filled with hydrogen a total of three times. The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was then filtered through a pad of Celite and the filter cake was washed with EtOAc (10 mL). The eluent was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to afford the title compound as a solid (90 mg, 0.277 mmol, 58%).

[0384]

[0305] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.31 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.35 - 5.97 (m, 2H), 4.68 (s, 1H), 3.32 (s, 2H), 2.75 (s, 2H), 2.32 (s, 3H), 1.86 (tt, J = 8.5, 5.1 Hz, 1H), 1.82 - 1.76 (m, 2H), 1.42 - 1.31 (m, 2H), 0.95 - 0.86 (m, 2H), 0.69 - 0.62 (m, 2H).

[0385]

[0306] 1 H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 6.0 Hz, 1H), 6.27 - 5.92 (m, 1H), 4.78 (s, 1H), 3.44 (s, 2H), 2.89 (s, 2H), 2.44 (s, 3H), 1.97 - 1.84 (m, 3H), 1.58 - 1.47 (m, 1H), 1.02 - 0.92 (m, 2H), 0.77 - 0.68 (m, 2H).

[0386]

[0307] UPLC-MS (basic method, 2 minutes): Rt: 1.15 minutes, m / z=326.0[M+H] + . [Example]

[0387] Example 15. Synthesis of Compound 15

[0388] [ka]

[0389] 2-[rac-(3aR,6aS)-2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl rac-(3aS,6aR)-2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (200 mg, 0.486 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (2.0 mL, 4.9 mmol) was heated to reflux and stirred for 2 hours. The reaction mixture was then cooled to 0° C. and quenched with water (1.8 mL), followed by 15% w / v sodium hydroxide solution (1.8 mL), followed by water (5.2 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was passed through a pad of Celite, and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound (13 mg, 39 μmol, 8%) as a solid.

[0390]

[0309] 1 H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 1.2 Hz, 1H), 6.82 (s, 1H), 6.02 (s, 1H), 5.79 (s, 1H), 3.87 - 3.72 (m, 2H), 3.56 (dd, J = 11.2, 3.0 Hz, 2H), 2.97 (s, 2H), 2.71 (t, J = 7.7 Hz, 2H), 2.48 (d, J = 9.5 Hz, 2H), 2.33 (s, 3H), 1.91 - 1.81 (m, 1H), 0.95 (dd, J = 8.4, 2.2 Hz, 2H), 0.74 (dd, J = 5.0, 2.0 Hz, 2H).

[0391]

[0310] UPLC-MS (basic method, 4 minutes): Rt: 1.16 minutes, m / z: 326.3 [M+H] + . [Example]

[0392] Example 16. Synthesis of Compound 16

[0393] [ka]

[0394] tert-Butyl N-[[(3R)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]methyl]carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (367 mg, 1.56 mmol), tert-butyl N-[[(3S)-3-piperidyl]methyl]carbamate (501 mg, 2.34 mmol), and N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 16 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude material was purified by automated flash column chromatography eluting with a gradient of CH2Cl2 to 1:9 2M NH3:CH2Cl2 in MeOH to afford the title compound as a solid (471 mg, 1.12 mmol, 72%).

[0395]

[0312] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.28 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 6.89 - 6.72 (m, 1H), 6.33 - 5.97 (m, 2H), 4.62 - 4.23 (m, 2H), 2.86 (t, J = 6.6 Hz, 3H), 2.70 - 2.52 (m, 1H), 1.93 - 1.81 (m, 1H), 1.80 - 1.73 (m, 1H), 1.64 (s, 1H), 1.40 - 1.35 (m, 10H), 1.27 - 1.13 (m, 1H), 1.01 - 0.85 (m, 2H), 0.74 - 0.56 (m, 2H).

[0396]

[0313] UPLC-MS (basic method, 2 minutes): Rt: 1.07 minutes, m / z: 414.5 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(3R)-3-(methylaminomethyl)-1-piperidyl]pyrimidin-4-amine To a solution of tert-butyl N-[[(3R)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]methyl]carbamate (180 mg, 0.435 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.8 mL, 4.4 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was then cooled to 0° C. and then quenched with water (180 μL), followed by 15% w / v sodium hydroxide solution (180 μL), followed by water (540 μL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (13 mg, 39 μmol, 8%).

[0397]

[0315] 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.32 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.15 (s, 2H), 4.56 (d, J = 12.7 Hz, 1H), 4.44 (d, J = 13.3 Hz, 1H), 2.91 - 2.83 (m, 1H), 2.68 - 2.56 (m, 1H), 2.36 (d, J = 6.7 Hz, 2H), 2.26 (s, 3H), 1.89 - 1.75 (m, 2H), 1.69 - 1.51 (m, 2H), 1.37 (q, J = 12.0 Hz, 1H), 1.32 - 1.09 (m, 1H), 1.00 - 0.86 (m, 2H), 0.74 - 0.61 (m, 2H).

[0398]

[0316] UPLC-MS (basic method, 4 minutes): Rt: 1.26 minutes, m / z: 328.3 [M+H] + . [Example]

[0399] Example 17. Synthesis of Compound 17

[0400] [ka]

[0401] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl N-[(3R)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate (94 mg, 0.235 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.0 mL, 2.4 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 3 hours. The reaction mixture was then cooled to 0° C. and then quenched with water (180 μL), followed by 15% w / v sodium hydroxide solution (180 μL), followed by water (540 μL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (50 mg, 0.16 mmol, 67%).

[0402]

[0318] 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.34 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.22 (s, 2H), 3.76 (dd, J = 10.6, 7.1 Hz, 1H), 3.66 (t, J = 9.7 Hz, 1H), 3.36 (s, 1H), 3.13 (t, J = 9.5 Hz, 1H), 2.71 (dt, J = 15.9, 8.1 Hz, 1H), 2.20 (s, 6H), 2.14 - 2.10 (m, 1H), 1.91 - 1.82 (m, 1H), 1.78 - 1.71 (m, 1H), 0.94 - 0.86 (m, 2H), 0.66 - 0.56 (m, 2H).

[0403]

[0319] UPLC-MS (basic method, 4 minutes): Rt: 1.23 minutes, m / z: 314.3 [M+H] + . [Example]

[0404] Example 18. Synthesis of Compound 18

[0405] [ka]

[0406] tert-Butyl rac-(3aS,6aR)-2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (500 mg, 2.35 mmol), cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (370 mg, 1.57 mmol), and N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) in NMP (5 mL) was heated to 120° C. and stirred for 20 h. The reaction mixture was then cooled to ambient temperature and added dropwise to ice water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as an oil (607 mg, 1.28 mmol, 82%).

[0407]

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.35 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.21 (s, 2H), 3.68 (s, 2H), 3.31 (d, J = 7.0 Hz, 1H), 3.14 (s, 2H), 2.93 (s, 2H), 2.69 (s, 1H), 2.17 (t, J = 8.1 Hz, 1H), 1.95 - 1.82 (m, 2H), 1.38 (s, 9H), 0.97 - 0.86 (m, 2H), 0.68 - 0.62 (m, 2H).

[0408]

[0322] UPLC-MS (basic method, 2 minutes): Rt: 1.02 minutes, m / z: 412.4 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[rac-(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]pyrimidin-4-amine To a solution of tert-butyl rac-(3aS,6aR)-2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (200 mg, 0.48 mmol) in CHCl (4 mL) was added trifluoroacetic acid (4.0 mL, 52 mmol) at 0° C. The reaction mixture was kept at 0° C. and stirred for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (38 mg, 0.115 mmol, 24%).

[0409]

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.36 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.20 (s, 2H), 3.68 (dd, J = 11.1, 7.3 Hz, 2H), 3.52 (s, 1H), 3.15 (d, J = 11.4 Hz, 1H), 2.95 - 2.88 (m, 2H), 2.77 (s, 2H), 2.64 - 2.57 (m, 2H), 1.86 (td, J = 8.6, 4.4 Hz, 1H), 0.95 - 0.86 (m, 2H), 0.69 - 0.61 (m, 2H).

[0410]

[0325] 1H NMR (400 MHz, methanol-d4) δ 7.85 (d, J = 5.9 Hz, 1H), 6.16 (s, 2H), 3.75 (dd, J = 11.4, 7.1 Hz, 2H), 3.53 (d, J = 3.2 Hz, 1H), 3.50 (d, J = 3.2 Hz, 1H), 3.22 (dd, J = 11.5, 7.1 Hz, 2H), 3.01 (d, J = 3.8 Hz, 2H), 2.86 (d, J = 3.9 Hz, 1H), 2.83 (d, J = 4.0 Hz, 1H), 2.07 - 1.72 (m, 1H), 0.97 (d, J = 8.3 Hz, 2H), 0.88 - 0.53 (m, 2H).

[0411]

[0326] UPLC-MS (basic method, 4 minutes): Rt: 0.99 minutes, m / z: 312.3 [M+H] + . [Example]

[0412] Example 19. Synthesis of Compound 19

[0413] [ka]

[0414] tert-Butyl N-[(3R)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.849 mmol), (R)-tert-butylmethyl(pyrrolidin-3-yl)carbamate (255 mg, 1.27 mmol), and N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) in NMP (5 mL) was heated to 120° C. and stirred for 18 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of 1:4 EtOAc:iso-hexane to 4:6 EtOAc:iso-hexane to afford the title compound as an oil (219 mg, 0.450 mmol, 82%).

[0415]

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.35 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.24 (s, 2H), 4.64 (s, 1H), 3.66 (s, 2H), 3.41 (d, J = 9.8 Hz, 2H), 2.75 (s, 3H), 2.06 (d, J = 8.2 Hz, 2H),1.76 (s, 1H), 1.42 (s, 9H), 0.91 (m, 2H), 0.69 - 0.56 (m, 2H).

[0416]

[0329] UPLC-MS (basic method, 2 minutes): Rt: 0.93 minutes, m / z: 400.4 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl N-[(3R)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate (85 mg, 0.213 mmol) in CHCl (3 mL) was added trifluoroacetic acid (3.0 mL, 39 mmol), and the reaction mixture was stirred at ambient temperature for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase acidic preparative HPLC using TFA as an additive, followed by reverse-phase basic preparative HPLC using ammonia as an additive, to give the title compound as a solid (22 mg, 73 μmol, 35%).

[0417]

[0331] 1 H NMR (400 MHz, DMSO-d6, 90℃) δ 8.83 (s, 1H), 7.85 (d, J = 5.6 Hz, 1H), 6.21 (d, J = 5.7 Hz, 1H), 6.11 (s, 1H), 3.70 - 3.61 (m, 1H), 3.61 - 3.55 (m, 1H),3.52 - 3.44 (m, 1H), 3.33 - 3.21 (m, 2H), 2.35 (s, 3H), 2.12 - 1.99 (m, 1H), 1.90 - 1.82 (m, 1H), 1.78 - 1.70 (m, 1H), 0.96 - 0.83 (m, 2H), 0.70 - 0.61 (m, 2H).

[0418]

[0332] UPLC-MS (basic method, 4 minutes): Rt: 1.02 minutes, m / z: 300.1 [M+H] + . [Example]

[0419] Example 20. Synthesis of Compound 20

[0420] [ka]

[0421] tert-Butyl N-[3-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]amino]propyl]-N-methyl-carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.27 mmol), 3-(N-Boc-N-methylamino)propylamine (610 μL, 3.18 mmol), and N,N-diisopropylethylamine (0.78 mL, 4.5 mmol) in n-butanol (7 mL) was heated to 100° C. and stirred for 44 h. The reaction mixture was then cooled to ambient temperature and then concentrated to dryness under reduced pressure. The residue was suspended in water (20 mL) and extracted with CHCl (3×20 mL). The combined organic extracts were dried over NaSO and then concentrated to dryness under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of CH2Cl2 to 9:1 2M NH3 in MeOH:CH2Cl2 to afford the title compound as a solid (270 mg, 0.665 mmol, 51%).

[0422]

[0334] 1 H NMR (400 MHz, chloroform-d) δ 7.97 (dd, J = 13.1, 5.8 Hz, 1H), 6.24 (s, 1H), 5.87 (s, 1H), 3.51 - 3.39 (m, 3H), 3.10 (s, 1H), 2.87 (s, 3H), 1.88 (td, J = 8.7, 4.3 Hz, 2H), 1.53 - 1.41 (m, 10H), 0.95 (t, J = 6.8 Hz, 2H), 0.77 (d, J = 5.6 Hz, 2H).

[0423]

[0335] UPLC-MS (basic method, 2 minutes): Rt: 1.01 minutes, m / z: 388.4 [M+H] + . N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[3-(dimethylamino)propyl]pyrimidine-2,4-diamine To a solution of tert-butyl N-[3-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]amino]propyl]-N-methyl-carbamate (159 mg, 0.410 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.7 mL, 4.1 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was then cooled to 0° C. and then quenched with water (1.5 mL), followed by 15% w / v sodium hydroxide solution (1.5 mL), followed by water (4.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (25 mg, 80 μmol, 19%).

[0424]

[0337] 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.22 (s, 1H), 7.75 (s, 1H), 6.57 (s, 1H), 6.33 - 5.96 (m, 2H), 3.24 (q, J = 6.7 Hz, 2H), 2.24 (t, J = 7.1 Hz, 2H), 2.11 (s, 6H), 1.83 (s, 1H), 1.69 - 1.60 (m, 2H), 0.90 (s, 2H), 0.65 (s, 2H).

[0425]

[0338] UPLC-MS (basic method, 4 minutes): Rt: 1.11 minutes, m / z: 302.1 [M+H] + . [Example]

[0426] Example 21. Synthesis of Compound 21

[0427] [ka]

[0428] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(3S)-3-(methylaminomethyl)pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl N-[[(3S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate (495 mg, 1.24 mmol) in anhydrous THF (15 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (5.2 mL, 12 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was then cooled to 0° C. and then quenched with water (510 μL), followed by 15% w / v sodium hydroxide solution (510 μL), followed by water (1.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase acidic preparative HPLC using TFA as a modifier, followed by reverse-phase basic preparative HPLC using ammonia as a modifier, to give the title compound as a solid (91 mg, 0.29 mmol, 23%).

[0429]

[0340] 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.33 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.20 (s, 2H), 3.69 - 3.51 (m, 2H), 3.43 - 3.39 (m, 1H), 3.20 - 3.11 (m, 1H), 2.62 - 2.50 (m, 2H), 2.45 - 2.34 (m, 1H), 2.33 (s, 3H), 2.09 - 1.97 (m, 1H), 1.85 (tt, J = 8.4, 5.1 Hz, 1H), 1.65 (dd, J = 12.2, 8.0 Hz, 1H), 0.95 - 0.84 (m, 2H), 0.69 - 0.61 (m, 2H).

[0430]

[0341] UPLC-MS (basic method, 4 minutes): Rt: 1.04 minutes, m / z: 314.3 [M+H] + . [Example]

[0431] Example 22. Synthesis of Compound 22

[0432] [ka]

[0433] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-[(dimethylamino)methyl]-2-azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine To a solution of benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (149 mg, 0.324 mmol) in anhydrous THF (3 mL) at 0° C. was added dropwise a 2.4 M solution of lithium aluminum hydride in THF (1.4 mL, 3.3 mmol). The reaction mixture was heated to reflux and stirred for 1 hour. The reaction mixture was then cooled to 0° C. and then quenched with water (140 μL), followed by 15% w / v sodium hydroxide solution (140 μL), followed by water (450 μL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture stirred for a further 15 minutes. The reaction mixture was passed through a pad of Celite, and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, and the cartridge was then washed with methanol. The compound was then eluted with 2M NH3 in methanol. The eluate was concentrated under reduced pressure to give the title compound as a solid (73 mg, 0.21 mmol, 65%).

[0434]

[0343] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.30 (s, 1H), 7.83 (d, J = 5.6 Hz, 1H), 6.41 - 6.03 (m, 2H), 4.68 (s, 1H), 3.35 (s, 2H), 2.55 (s, 2H), 2.16 (s, 6H), 1.86 (td, J = 8.3, 4.2 Hz, 1H), 1.79 (d, J = 4.2 Hz, 2H), 1.44 (dd, J = 4.3, 1.8 Hz, 2H), 0.91 (d, J = 6.1 Hz, 2H), 0.70 - 0.61 (m, 2H).

[0435]

[0344] UPLC-MS (basic method, 4 minutes): Rt: 1.37 minutes, m / z: 340.1 [M+H] + . [Example]

[0436] Example 23. Synthesis of Compound 23

[0437] [ka]

[0438] tert-Butyl N-[[(3R)-1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (298 mg, 1.13 mmol), (S)-tert-butyl(pyrrolidin-3-ylmethyl)carbamate (357 mg, 1.78 mmol), and N,N-diisopropylethylamine (0.49 mL, 2.82 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 48 h. The reaction mixture was then cooled to ambient temperature and then added dropwise to ice water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound (576 mg, 1.01 mmol, 89%) as a foam.

[0439]

[0346] 1 H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 5.7 Hz, 1H), 6.91 (s, 1H), 6.09 (s, 2H), 4.71 (s, 1H), 3.83 - 3.67 (m, 2H), 3.56 (q, J = 8.1 Hz, 1H), 3.27 (t, J = 9.0 Hz, 2H), 3.21 - 2.99 (m, 3H), 2.58 - 2.46 (m, 1H), 2.17 - 2.07 (m, 2H), 1.84 - 1.64 (m, 6H), 1.45 (s, 9H).

[0440]

[0347] UPLC-MS (basic method, 2 minutes) rt=1.13 minutes, m / z=428.2[M+H]+ . 2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl N-[[(3R)-1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate (102 mg, 0.178 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol), and the reaction mixture was stirred at ambient temperature for 15 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (30 mg, 92 μmol, 52%).

[0441]

[0349] 1 H NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 7.0 Hz, 1H), 6.42 (s, 2H), 3.25 - 2.98 (m, 4H), 2.83 - 2.66 (m, 1H), 2.48 - 2.29 (m, 1H), 2.18 - 1.87 (m, 3H), 1.89 - 1.58 (m, 6H), 1.31 (d, J = 15.4 Hz, 3H).

[0442]

[0350] UPLC-MS (basic method, 4 minutes): rt=1.27 minutes, m / z=328.1[M+H] + . [Example]

[0443] Example 24. Synthesis of Compound 24

[0444] [ka]

[0445] tert-Butyl N-[[(3S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]methyl]carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.27 mmol), (R)-tert-butyl(piperidin-3-ylmethyl)carbamate (409 mg, 1.91 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.18 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 18 hours. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as an oil (414 mg, 0.80 mmol, 63%).

[0446]

[0352] 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.86 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 6.24 (d, J = 5.8 Hz, 1H), 6.09 (s, 1H), 3.64 - 3.53 (m, 2H), 3.50 - 3.40 (m, 3H), 3.30 - 3.20 (m, 2H), 2.01 - 1.80 (m, 6H), 1.43 (s, 9H), 0.94 - 0.86 (m, 2H), 0.71 - 0.60 (m, 2H).

[0447]

[0353] UPLC-MS (basic method, 2 minutes) rt: 1.07 minutes; m / z: 414.4 [M+H] + . 2-[(3S)-3-(aminomethyl)-1-piperidyl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl N-[[(3S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]methyl]carbamate (100 mg, 0.242 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol), and the reaction mixture was stirred at ambient temperature for 15 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC using ammonia as an additive to give the title compound as a solid (49 mg, 0.155 mmol, 64%).

[0448]

[0355] 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.32 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 6.36 - 5.94 (m, 2H), 4.57 - 4.32 (m, 2H), 2.96 - 2.80 (m, 1H), 2.66 (dd, J = 13.1, 9.5 Hz, 1H), 2.54 (s, 1H), 2.45 (d, J = 6.6 Hz, 2H), 1.96 - 1.73 (m, 2H), 1.63 (dt, J = 7.5, 3.4 Hz, 1H), 1.50 - 1.28 (m, 2H), 1.27 - 1.09 (m, 1H), 1.00 - 0.81 (m, 2H), 0.74 - 0.56 (m, 2H).

[0449]

[0356] UPLC-MS (basic method, 4 minutes): rt=1.10 minutes, m / z=314.1[M+H] + . [Example]

[0450] Example 25. Synthesis of Compound 25

[0451] [ka]

[0452] tert-Butyl 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,7-diazaspiro[3.4]octane-7-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (305 mg, 1.29 mmol), tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (431 mg, 2.03 mmol), and N,N-diisopropylethylamine (0.56 mL, 3.22 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 48 h. The reaction mixture was then cooled to ambient temperature and added dropwise to ice water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (797 mg, 1.86 mmol, 143%).

[0453]

[0358] 1 H NMR (400 MHz, chloroform-d) δ 7.97 (d, J = 5.9 Hz, 1H), 4.08 - 3.96 (m, 4H), 3.53 (d, J = 11.4 Hz, 2H), 2.11 (m, 2H), 1.86 (m, 1H), 1.46 (d, J = 5.7 Hz, 9H), 1.01 (d, J = 6.6 Hz, 2H), 0.95 (d, J = 7.2 Hz, 2H), 0.77 - 0.68 (m, 2H). The compound was contaminated with the amine starting material.

[0454]

[0359] UPLC-MS (basic method, 2 minutes) rt=1.06 minutes, m / z=412.2[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,7-diazaspiro[3.4]octan-2-yl)pyrimidin-4-amine To a solution of tert-butyl 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,7-diazaspiro[3.4]octane-7-carboxylate (105 mg, 0.246 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol), and the reaction mixture was stirred at ambient temperature for 15 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (7.6 mg, 0.024 mmol, 9.7%).

[0455]

[0361] 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.46 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 6.32 (s, 1H), 6.16 (s, 1H), 3.98 (d, J = 8.7 Hz, 2H), 3.91 (d, J = 8.5 Hz, 2H), 3.28 (s, 2H), 3.13 (t, J = 7.3 Hz, 2H), 2.14 (t, J = 7.3 Hz, 2H), 1.84 (tt, J = 8.4, 5.1 Hz, 1H), 0.95 - 0.81 (m, 2H), 0.70 - 0.62 (m, 2H).

[0456]

[0362] UPLC-MS (basic method, 4 minutes): rt=0.97 minutes, m / z=312.1[M+H] + . [Example]

[0457] Example 26. Synthesis of Compound 26

[0458] [ka]

[0459] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(7-methyl-2,7-diazaspiro[3.4]octan-2-yl)pyrimidin-4-amine To a solution of tert-butyl 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,7-diazaspiro[3.4]octane-7-carboxylate (160 mg, 0.37 mmol) in anhydrous THF (3.5 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.55 mL, 3.672 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 3 hours. The reaction mixture was then cooled to 0° C. and quenched with water (0.15 mL), followed by 10% w / v sodium hydroxide solution (0.15 mL), followed by water (0.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (30 mg, 0.092 mmol, 25%).

[0460]

[0364] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.40 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.34 (s, 1H), 6.17 (s, 1H), 3.88 (q, J = 8.4 Hz, 4H), 2.64 (s, 2H), 2.46 (t, J = 7.0 Hz, 2H), 2.23 (s, 3H), 2.04 (t, J = 7.0 Hz, 2H), 1.85 (td, J = 8.4, 4.3 Hz, 1H), 0.91 (d, J = 6.2 Hz, 2H), 0.69 - 0.61 (m, 2H).

[0461]

[0365] UPLC-MS (basic method, 4 minutes): rt=1.20 minutes, m / z=326.1[M+H] + . [Example]

[0462] Example 27. Synthesis of Compound 27

[0463] [ka]

[0464] tert-Butyl 3-[1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]azetidine-1-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (469 mg, 1.78 mmol), tert-butyl 3-(pyrrolidin-3-yl)azetidine-1-carboxylate (550 mg, 2.43 mmol), and N,N-diisopropylethylamine (0.77 mL, 4.4 mmol) in NMP (9 mL) was heated to 120° C. and stirred for 48 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude residue was purified by automated flash column chromatography on silica gel eluting with a gradient of CH2Cl2 to 1:9 2M NH3:CH2Cl2 in MeOH to afford the title compound as a foam (463 mg, 0.938 mmol, 53%).

[0465]

[0367] 1H NMR (400 MHz, chloroform-d) δ 7.98 (s, 1H), 6.09 (s, 2H), 4.03 (q, J = 7.8 Hz, 2H), 3.82 - 3.62 (m, 3H), 3.56 (dt, J = 10.9, 7.8 Hz, 1H), 3.17 (dd, J = 10.5, 6.7 Hz, 1H), 3.05 (dt, J = 14.9, 7.3 Hz, 1H), 2.53 (d, J = 3.2 Hz, 2H), 2.14 - 1.95 (m, 4H), 1.80 - 1.58 (m, 7H), 1.44 (s, 9H).

[0368] UPLC-MS (basic method, 2 minutes) rt=1.18 minutes, m / z=454.3[M+H] + .

[0466] N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-[3-(1-methylazetidin-3-yl)pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl 3-[1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]azetidine-1-carboxylate (134 mg, 0.37 mmol) in anhydrous THF (3 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.1 mL, 2.7 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 3 hours. The reaction mixture was then cooled to 0° C. and quenched with water (0.13 mL), followed by 10% w / v sodium hydroxide solution (0.13 mL), followed by water (0.4 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The residue was purified by reverse phase basic preparative HPLC to give the title compound as a solid (83 mg, 0.217 mmol, 80%).

[0467]

[0370] 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.34 (s, 1H), 7.82 (d, J = 5.5 Hz, 1H), 6.42 (s, 1H), 6.18 (s, 1H), 3.64 (s, 1H), 3.62 - 3.53 (m, 1H), 3.44 - 3.23 (m, 2H), 3.09 - 2.94 (m, 2H), 2.90 - 2.80 (m, 2H), 2.47 - 2.29 (m, 2H), 2.20 (s, 3H), 2.05 - 1.92 (m, 3H), 1.75 - 1.44 (m, 8H).

[0468]

[0371] UPLC-MS (basic method, 4 minutes): rt=1.40 minutes, m / z=368.1[M+H] + . [Example]

[0469] Example 28. Synthesis of Compound 28

[0470] [ka]

[0471] 2-[3-(azetidin-3-yl)pyrrolidin-1-yl]-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl 3-[1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]azetidine-1-carboxylate (142 mg, 0.288 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol), and the reaction mixture was stirred at ambient temperature for 15 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (14 mg, 37 μmol, 13%).

[0472]

[0373] 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.37 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.39 (s, 1H), 6.18 (s, 1H), 3.59 - 3.55 (m, 5H), 3.09 - 2.94 (m, 3H), 2.02 - 1.91 (m, 4H), 1.75 - 1.66 (m, 2H), 1.66 - 1.47 (m, 7H).

[0374] UPLC-MS (basic method, 4 minutes): rt=1.24 minutes, m / z=354.1[M+H] + . [Example]

[0473] Example 29. Synthesis of Compound 29

[0474] [ka]

[0475] 2-[(3R)-3-(aminomethyl)-1-piperidyl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl N-[[(3R)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]methyl]carbamate (171 mg, 0.41 mmol) in CHCl (4 mL) was added trifluoroacetic acid (4 mL, 52 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (53 mg, 0.167 mmol, 40%).

[0476]

[0376] 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.35 (s, 1H), 7.84 (d, J = 4.6 Hz, 1H), 6.13 (s, 2H), 4.52 (d, J = 12.3 Hz, 1H), 4.41 (d, J = 13.5 Hz, 1H), 2.97 - 2.77 (m, 2H), 2.70 - 2.55 (m, 1H), 2.44 (d, J = 6.6 Hz, 2H), 1.92 - 1.81 (m, 2H), 1.69 - 1.58 (m, 1H), 1.43 - 1.31 (m, 2H), 1.21 - 1.10 (m, 1H), 0.96 - 0.86 (m, 2H), 0.72 - 0.58 (m, 2H).

[0477]

[0377] UPLC-MS (basic method, 4 minutes): Rt: 1.16 minutes, m / z: 314.1 [M+H] + . [Example]

[0478] Example 30. Synthesis of Compound 31

[0479] [ka]

[0480] Benzyl N-[[2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methyl]-N-methyl-carbamate A solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (185 mg, 0.702 mmol), benzyl N-(2-azabicyclo[2.1.1]hexan-4-ylmethyl)-N-methyl-carbamate (320 mg, 1.10 mmol), and N,N-diisopropylethylamine (0.74 mL, 1.84 mmol) in NMP (7 mL) was heated to 120° C. and stirred for 48 hours. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (228 mg, 0.431 mmol, 61%).

[0481]

[0379] 1 H NMR (400 MHz, chloroform-d) δ 7.99 (d, J = 5.7 Hz, 1H), 7.41 - 7.28 (m, 5H), 7.08 (s, 1H), 6.17 (s, 1H), 6.10 - 6.01 (m, 1H), 5.12 (s, 2H), 4.81 (d, J = 15.9 Hz, 1H), 3.63 - 3.58 (m, 2H), 3.50 - 3.44 (m, 2H), 3.09 - 2.95 (m, 4H), 2.14 - 2.02 (m, 2H), 1.92 - 1.55 (m, 10H).

[0482]

[0380] UPLC-MS (basic method, 2 minutes) rt=1.19 minutes, m / z=488.2[M+H] + . N-(5-Cyclopentyl-1H-pyrazol-3-yl)-2-[4-(methylaminomethyl)-2-azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine To a solution of benzyl N-[[2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methyl]-N-methyl-carbamate (115 mg, 0.235 mmol) in MeOH (3 mL) was added 10% w / w palladium on carbon (30 mg, 0.28 mmol) under nitrogen. The atmosphere was replaced with hydrogen, and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered through a pad of Celite, washed with EtOAc (10 mL), and concentrated to dryness under reduced pressure. The crude residue was purified by automated flash column chromatography eluting with a gradient of 2 M NH in MeOH (0 to 20% v / v) in CHCl to give the title compound as a solid (50 mg, 0.140 mmol, 59%).

[0483]

[0382] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.33 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.28 (s, 2H), 4.69 (s, 1H), 3.36 (s, 2H), 3.02 (p, J = 7.9 Hz, 1H), 2.90 (s, 2H), 2.40 (s, 3H), 2.08 - 1.95 (m, 2H), 1.90 - 1.80 (m, 2H), 1.75 - 1.68 (m, 2H), 1.65 - 1.51 (m, 4H), 1.40 (dd, J = 4.3, 1.8 Hz, 2H).

[0484]

[0383] UPLC-MS (basic method, 4 minutes): rt=1.28 minutes, m / z=354.1[M+H] + . [Example]

[0485] Example 31. Synthesis of Compound 32

[0486] [ka]

[0487] tert-Butyl N-methyl-N-[[rac-(3S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (275 mg, 1.17 mmol), tert-butyl (S)-methyl(pyrrolidin-3-ylmethyl)carbamate (250 mg, 1.17 mmol), and N,N-diisopropylethylamine (0.51 mL, 2.93 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 48 h. The reaction mixture was then cooled to ambient temperature and then added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound (371 mg, 0.798 mmol, 68%) as a foam.

[0488]

[0385] 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 3.9 Hz, 1H), 6.02 (s, 1H), 5.88 (s, 1H), 3.83 - 3.64 (m, 2H), 3.64 - 3.48 (m, 1H), 3.48 - 3.09 (m, 3H), 2.90, (s, 3H), 2.68 - 2.51 (m, 1H), 2.07 (dt, J = 12.3, 6.4 Hz, 1H), 1.86 (tt, J = 8.5, 5.0 Hz, 1H), 1.81 - 1.65 (m, 1H), 1.43 (s, 9H), 0.98 - 0.88 (m, 2H), 0.77 - 0.68 (m, 2H).2H).

[0489]

[0386] UPLC-MS (basic method, 2 minutes) rt=1.06 minutes, m / z=414.3[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[rac-(3R)-3-[(dimethylamino)methyl]pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl N-methyl-N-[[rac-(3S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate (154 mg, 0.331 mmol) in anhydrous THF (3 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.34 mL, 3.22 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 3 hours. The reaction mixture was then cooled to 0° C. and then quenched with water (0.13 mL), followed by 10% w / v sodium hydroxide solution (0.13 mL), followed by water (0.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was filtered and washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (86 mg, 0.256 mmol, 77%).

[0490]

[0388] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.30 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.25 (s, 1H), 6.18 (s, 1H), 3.73 - 3.48 (m, 2H), 3.47 - 3.35 (m, 1H), 3.22 - 3.08 (m, 1H), 2.48 - 2.37 (m, 1H), 2.24 (d, J = 7.7 Hz, 2H), 2.17 (s, 6H), 2.09 - 1.94 (m, 1H), 1.84 (ddd, J = 13.2, 8.4, 5.0 Hz, 1H), 1.70 - 1.49 (m, 1H), 0.98 - 0.82 (m, 2H), 0.69 - 0.56 (m, 2H).

[0491]

[0389] UPLC-MS (basic method, 4 minutes): rt=1.33 minutes, m / z=328.1[M+H] + . [Example]

[0492] Example 32. Synthesis of Compound 33

[0493] [ka]

[0494] tert-Butyl N-methyl-N-[[rac-(3R)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (250 mg, 1.06 mmol), tert-butyl N-methyl-N-[[(3R)-pyrrolidin-3-yl]methyl]carbamate (250 mg, 1.17 mmol), and N,N-diisopropylethylamine (0.18 mL, 1.06 mmol) in NMP (5 mL) was heated to 120° C. and stirred for 24 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of CH2Cl2 to 1:9 2M NH3:CH2Cl2 in MeOH to afford the title compound as a solid (192 mg, 0.464 mmol, 44%).

[0495]

[0391] 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.37 (s, 1H), 7.79 (dd, J = 5.8, 3.6 Hz, 1H), 6.17 (s, 1H), 3.60 - 3.38 (m, 3H), 2.78 (s, 3H), 2.03 - 1.91 (m, 1H), 1.81 (tt, J = 8.4, 5.1 Hz, 1H), 1.68 - 1.57 (m, 1H), 1.40 - 1.27 (m, 9H), 1.22 - 1.12 (m, 1H), 0.92 - 0.83 (m, 2H), 0.60 (dt, J = 6.4, 3.2 Hz, 2H).

[0496]

[0392] UPLC-MS (basic method, 2 minutes) Rt=1.05 minutes, m / z=414.2[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[rac-(3S)-3-[(dimethylamino)methyl]pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl N-methyl-N-[[rac-(3R)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate (120 mg, 0.290 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.2 mL, 2.9 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 4.5 hours. The reaction mixture was then cooled to 0° C. and then quenched with water (1.0 mL), followed by 10% w / v sodium hydroxide solution (1.0 mL), followed by water (1.0 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 5 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 5 minutes. The reaction mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure to give the title compound as a solid (50 mg, 0.153 mmol, 53%).

[0497]

[0394] 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.29 (s, 1H), 7.82 (s, 1H), 6.38 - 6.08 (m, 2H), 3.69 - 3.52 (m, 2H), 3.38 (s, 1H), 3.20 - 3.11 (m, 1H), 2.46 - 2.38 (m, 1H), 2.24 (d, J = 6.9 Hz, 2H), 2.17 (s, 6H), 2.01 (s, 1H), 1.84 (s, 1H), 1.63 (s, 1H), 0.90 (d, J = 8.1 Hz, 2H), 0.64 (s, 2H).

[0498]

[0395] UPLC-MS (basic method, 4 minutes): Rt=1.35 minutes, m / z=328.1[M+H] + . [Example]

[0499] Example 33. Synthesis of Compound 35

[0500] [ka]

[0501] N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-[(3R)-3-(methylaminomethyl)pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl N-[[(3R)-1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate (150 mg, 0.263 mmol) in anhydrous THF (2.6 mL) was added dropwise a 2.4 M solution of lithium aluminum hydride in THF (1.1 mL, 2.6 mmol) at 0° C. The reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was then cooled to 0° C. and then quenched with water (0.11 mL), followed by 10% w / v sodium hydroxide solution (0.11 mL), followed by water (0.35 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was filtered and washed with EtOAc (10 mL). The eluate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (28 mg, 81 μmol, 32%).

[0502]

[0397] 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.32 (s, 1H), 7.82 (d, J = 5.6 Hz, 1H), 6.40 (s, 1H), 6.18 (s, 1H), 3.70 - 3.61 (m, 1H), 3.57 (ddd, J = 11.7, 8.1, 4.1 Hz, 1H), 3.39 (d, J = 9.0 Hz, 1H), 3.21 - 3.10 (m, 1H), 3.00 (p, J = 7.8 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.30 (s, 3H), 2.09 - 1.91 (m, 4H), 1.76 - 1.51 (m, 8H).

[0503]

[0398] UPLC-MS (basic method, 4 minutes): rt=1.34 minutes, m / z=342.1[M+H] + . [Example]

[0504] Example 34. Synthesis of Compound 37

[0505] [ka]

[0506] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(3S)-3-(methylaminomethyl)-1-piperidyl]pyrimidin-4-amine To a solution of tert-butyl N-[[(3S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]methyl]carbamate (150 mg, 0.363 mmol) in anhydrous THF (4 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.5 mL, 3.6 mmol) was added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. The reaction mixture was then heated to reflux and stirred for 3 hours. The reaction mixture was then cooled to 0° C. and quenched with water (0.15 mL), followed by 10% w / v sodium hydroxide solution (0.15 mL), followed by water (0.5 mL). The reaction mixture was warmed to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was filtered and washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound (43 mg, 0.130 mmol, 36%) as a solid.

[0507]

[0400] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.37 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.12 (s, 2H), 4.76 - 4.24 (m, 2H), 2.88 (t, J = 11.1 Hz, 1H), 2.63 (t, J = 11.6 Hz, 1H), 2.36 (d, J = 6.7 Hz, 2H), 2.27 (s, 3H), 1.90 - 1.77 (m, 2H), 1.68 - 1.52 (m, 2H), 1.43 - 1.30 (m, 1H), 1.16 (qd, J = 11.8, 3.9 Hz, 1H), 0.94 - 0.87 (m, 2H), 0.70 - 0.64 (m, 2H).

[0508]

[0401] UPLC-MS (basic method, 4 minutes): rt=1.30 minutes, m / z=328.1[M+H] + . [Example]

[0509] Example 35. Synthesis of Compound 38

[0510] [ka]

[0511] tert-Butyl 3-[1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]azetidine-1-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (348 mg, 1.48 mmol), tert-butyl 3-(pyrrolidin-3-yl)azetidine-1-carboxylate (501 mg, 2.22 mmol), and N,N-diisopropylethylamine (0.64 mL, 3.7 mmol) in NMP (5 mL) was heated to 120° C. and stirred for 24 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude residue was purified by automated flash column chromatography eluting with a gradient of CH2Cl2 to 1:9 2M NH3 in MeOH:CH2Cl2 to afford the title compound as an oil (365 mg, 0.849 mmol, 58%).

[0512]

[0403] 1 H NMR (400 MHz, DMSO-d6) δ 11.98 - 11.81 (m, 1H), 9.33 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.22 (s, 2H), 3.93 (s, 2H), 3.80 - 3.53 (m, 4H), 3.41 (d, J = 9.4 Hz, 1H), 3.04 (dd, J = 10.9, 6.9 Hz, 1H), 2.09 - 1.96 (m, 1H), 1.92 - 1.80 (m, 1H), 1.66 - 1.51 (m, 1H), 1.44 - 1.32 (m, 11H), 0.91 (dd, J = 8.1, 2.9 Hz, 2H), 0.63 (td, J = 6.0, 3.8 Hz, 2H).

[0513]

[0404] UPLC-MS (basic method, 2 minutes): Rt: 1.06 minutes, m / z: 426.5 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[3-(1-methylazetidin-3-yl)pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl 3-[1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]azetidine-1-carboxylate (360 mg, 0.85 mmol) in anhydrous THF (12 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (3.5 mL, 8.5 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 2 hours. The reaction mixture was then cooled to 0° C. and quenched with water (3.2 mL), followed by 15% w / v sodium hydroxide solution (3.2 mL), followed by water (9.6 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The eluate was concentrated to dryness under reduced pressure. 50 mg of the crude residue was loaded onto an SCX cartridge, then the cartridge was washed with methanol, then the compound was eluted with 2M NH3 in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (30 mg, 88 μmol, 10%).

[0514]

[0406] 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.34 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.20 (s, 2H), 3.67 - 3.53 (m, 2H), 3.49 - 3.41 (m, 2H), 3.41 - 3.35 (m, 1H), 3.14 - 2.96 (m, 3H), 2.47 - 2.42 (m, 2H), 2.34 (s,3H), 2.04 - 1.94 (m, 1H), 1.85 (tt, J = 8.4, 5.1 Hz, 1H), 1.59 - 1.49 (m, 1H), 0.96 - 0.81 (m, 2H), 0.67 - 0.54 (m, 2H).

[0515]

[0407] UPLC-MS (basic method, 4 minutes): Rt: 1.17 minutes, m / z: 340.1 [M+H] + . [Example]

[0516] Example 36. Synthesis of Compound 42

[0517] [ka]

[0518] (±)-tert-Butyl 7-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (700 mg, 2.97 mmol), (±)-tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (498 mg, 1.10 mmol), and N,N-diisopropylethylamine (1.3 mL, 7.4 mmol) in NMP (7 mL) was heated to 120° C. and stirred for 18 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (1.10 g, 2.59 mmol, 87%).

[0519]

[0409] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.29 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 6.92 - 6.82 (m, 1H), 6.24 (s, 1H), 6.09 (s, 1H), 4.53 - 4.37 (m, 2H), 2.94 - 2.80 (m, 3H), 2.66 - 2.55 (m, 1H), 1.88 (tt, J = 8.2, 5.2 Hz, 1H), 1.80 - 1.72 (m, 1H), 1.71 - 1.61 (m, 1H), 1.61 - 1.49 (m, 1H), 1.43 - 1.29 (m, 10H), 1.24 - 1.10 (m, 1H), 0.96 - 0.87 (m, 2H), 0.66 (dt, J = 6.6, 3.3 Hz, 2H).

[0520]

[0410] UPLC-MS (basic method, 2 minutes): Rt: 1.05 minutes, m / z: 426.5 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-amine To a solution of tert-butyl 7-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate (550 mg, 0.48 mmol) in CHCl (10 mL) was added trifluoroacetic acid (10 mL, 130 mmol) at ambient temperature, and the reaction was stirred for 30 minutes. The reaction mixture was then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (359 mg, 1.10 mmol, 85%).

[0521]

[0412] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.32 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.34 - 6.00 (m, 2H), 3.60 - 3.38 (m, 4H), 2.85 (t, J = 7.0 Hz, 2H), 2.67 (s, 2H), 1.96 - 1.78 (m, 3H), 1.67 (dt, J = 8.1, 3.8 Hz, 2H), 0.95 - 0.86 (m, 2H), 0.71 - 0.60 (m, 2H).

[0522]

[0413] 1 H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 5.9 Hz, 1H), 6.28 - 5.98 (m, 2H), 3.71 - 3.56 (m, 2H), 3.56 - 3.43 (m, 2H), 3.03 (t, J = 7.1 Hz, 2H), 2.92 - 2.79 (m, 2H), 2.01 (t, J = 7.0 Hz, 2H), 1.95 - 1.78 (m, 3H), 1.01 - 0.92 (m, 2H), 0.76 - 0.67 (m, 2H).

[0523]

[0414] UPLC-MS (basic method, 4 minutes): Rt: 1.10 minutes, m / z: 326.1 [M+H] + . [Example]

[0524] Example 37. Synthesis of Compound 41

[0525] [ka]

[0526] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-4-amine To a solution of tert-butyl 7-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate (550 mg, 0.741 mmol) in anhydrous THF (20 mL) was added dropwise a 2.4 M solution of lithium aluminum hydride in THF (5.4 mL, 13 mmol) at 0° C. The reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was then cooled to 0° C. and quenched with water (500 μL), followed by 15% w / v sodium hydroxide solution (500 μL), followed by water (1.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 2 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with CHCl (20 mL). The eluate was then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, and the cartridge was then washed with methanol. The compound was then eluted with 2M NH3 in methanol, and the eluate was concentrated to dryness under reduced pressure. 50 mg of the crude material was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (34 mg, 0.10 mmol, 8%).

[0527]

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.31 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.42 - 6.00 (m, 2H), 3.53 - 3.32 (m, 4H), 2.58 - 2.52 (m, 2H), 2.45 - 2.35 (m, 2H), 2.23 (s, 3H), 1.99 - 1.81 (m, 3H), 1.75 (t, J = 7.0 Hz, 2H), 0.95 - 0.83 (m, 2H), 0.69 - 0.60 (m, 2H).

[0528]

[0417] 1H NMR (400 MHz, methanol-d4) δ 7.80 (d, J = 5.9 Hz, 1H), 6.35 - 5.96 (m, 2H), 3.70 - 3.40 (m, 4H), 2.76 - 2.50 (m, 4H), 2.35 (s, 2H), 2.10 - 1.92 (m, 2H), 1.92 - 1.81 (m, 3H), 0.97 - 0.90 (m, 2H), 0.74 - 0.65 (m, 2H).

[0529]

[0418] UPLC-MS (basic method, 4 minutes): Rt: 1.20 minutes, m / z: 340.2 [M+H] + . [Example]

[0530] Example 38. Synthesis of Compound 43

[0531] [ka]

[0532] tert-Butyl 8-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,8-diazaspiro[3.5]nonane-2-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (360 mg, 1.53 mmol), tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate hemioxalate (497 mg, 1.83 mmol), and N,N-diisopropylethylamine (0.85 mL, 4.9 mmol) in NMP (5 mL) was heated to 120° C. and stirred for 24 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude residue was purified by automated flash column chromatography eluting with a gradient of CH2Cl2 to 1:9 2M NH3:CH2Cl2 in MeOH to give the title compound as a solid (120 mg, 68% pure by UPLC-MS, 0.192 mmol, 13%).

[0533]

[0420] 1 H NMR (400 MHz, methanol-d4) δ 7.81 (d, J = 6.0 Hz, 1H), 6.11 (s, 2H), 3.67 - 3.51 (m, 5H), 3.26 (s, 4H), 1.90 - 1.76 (m, 2H), 1.57 - 1.51 (m, 2H), 1.39 (s, 9H), 0.98 - 0.87 (m, 2H), 0.74 - 0.62 (m, 2H).

[0534]

[0421] UPLC-MS (basic method, 2 minutes): Rt: 1.11 minutes, m / z: 426.3 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]pyrimidin-4-amine To a solution of tert-butyl 8-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,8-diazaspiro[3.5]nonane-2-carboxylate (100 mg, 0.24 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.0 mL, 2.4 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched with water (900 μL), followed by 15% w / v sodium hydroxide solution (900 μL), followed by water (2.7 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite, and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC to afford the title compound as a solid (22 mg, 65 μmol, 28%).

[0535]

[0423] 1 H NMR (400 MHz, methanol-d4) δ 7.88 (d, J = 5.9 Hz, 1H), 6.20 (s, 1H), 6.06 (s, 1H), 3.90 (s, 2H), 3.75 - 3.61 (m, 2H), 3.43 (d, J = 8.8 Hz, 2H), 3.35 (s, 2H), 2.57 (s, 3H), 1.94 - 1.82 (m, 3H), 1.61 - 1.54 (m, 2H), 1.08 - 0.93 (m, 2H), 0.79 - 0.67 (m, 2H).

[0536]

[0424] UPLC-MS (basic method, 4 minutes): Rt: 1.36 minutes, m / z: 340.3 [M+H] + . [Example]

[0537] Example 39. Synthesis of Compound 50

[0538] [ka]

[0539] tert-Butyl rac-(3aS,6aS)-2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (415 mg, 1.76 mmol), (±)-tert-butyl (3aS,6aS)-octahydropyrrolo[3,4-c]pyrrole-2-carboxylate hemioxalate (498 mg, 1.10 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.1 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 48 h. An additional portion of N,N-diisopropylethylamine (1.1 mL, 6.1 mmol) was added, and the reaction was heated to 120° C. and stirred for an additional 24 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under vacuum to give the title compound as a solid (559 mg, 1.36 mmol, 77%).

[0540]

[0426] 1 H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 5.7 Hz, 1H), 6.94 (s, 1H), 6.07 (s, 1H), 5.85 (s, 1H), 4.00 - 3.88 (m, 2H), 3.74 (dd, J = 9.9, 5.9 Hz, 1H), 3.67 (dd, J = 9.7, 6.1 Hz, 1H), 3.32 - 3.16 (m, 2H), 3.09 (td, J = 10.2, 3.4 Hz, 2H), 2.38 - 2.21 (m, 2H), 1.87 (tt, J = 8.4, 5.1 Hz, 1H), 1.48 (s, 9H), 1.02 - 0.90 (m, 2H), 0.77 - 0.68 (m, 2H).

[0541]

[0427] UPLC-MS (basic method, 2 minutes): Rt: 1.04 minutes, m / z: 412.4 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]pyrimidin-4-amine

[0542] [ka]

[0543] To a solution of tert-butyl rac-(3aS,6aS)-2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (250 mg, 0.48 mmol) in CHCl (10 mL) was added trifluoroacetic acid (10 mL, 130 mmol) at ambient temperature and stirred for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (189 mg, 0.589 mmol, 97%).

[0544]

[0429] 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.34 (s, 1H), 7.83 (d, J = 5.6 Hz, 1H), 6.32 - 6.08 (m, 2H), 3.80 - 3.73 (m, 2H), 3.14 - 2.87 (m, 4H), 2.62 - 2.53 (m, 2H), 2.33 - 2.10 (m, 2H), 1.91 - 1.80 (m, 1H), 0.91 - 0.90 (m, 1H), 0.73 - 0.60 (m, 2H).

[0545]

[0430] 1 H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 6.0 Hz, 1H), 6.23 - 6.01 (m, 2H), 3.98 - 3.81 (m, 2H), 3.25 - 3.17 (m, 4H), 2.77 (t, J = 10.3 Hz, 2H), 2.47 - 2.30 (m, 2H), 1.95 - 1.83 (m, 1H), 1.01 - 0.88 (m, 2H), 0.75 - 0.67 (m, 2H).

[0546]

[0431] UPLC-MS (basic method, 4 minutes): Rt: 0.97 minutes, m / z: 312.0 [M+H] + . [Example]

[0547] Example 40. Synthesis of Compound 47

[0548] [ka]

[0549] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[rac-(3aR,6aR)-2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]pyrimidin-4-amine To a solution of tert-butyl rac-(3aS,6aS)-2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (305 mg, 0.741 mmol) in anhydrous THF (20 mL) was added dropwise a 2.4 M solution of lithium aluminum hydride in THF (3.1 mL, 7.4 mmol) at 0° C. The reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was then cooled to 0° C. and quenched with water (300 μL), followed by 15% w / v sodium hydroxide solution (300 μL), and then water (900 μL). The reaction mixture was warmed to ambient temperature and stirred for 15 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was passed through a pad of Celite, and the filter cake was washed with CHCl (20 mL) followed by ethanol (20 mL). The eluent was then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure to give the title compound as a solid (115 mg, 0.353 mmol, 48%).

[0550]

[0433] 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.29 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.43 - 6.01 (m, 2H), 3.79 - 3.69 (m, 2H), 3.15 - 2.97 (m, 2H), 2.83 - 2.74 (m, 2H), 2.60 - 2.52 (m, 2H), 2.44 (s, 3H), 2.32 - 2.18 (m, 2H), 1.86 (tt, J = 8.7, 5.0 Hz, 1H), 0.93 - 0.87 (m, 2H), 0.69 - 0.60 (m, 2H).

[0551]

[0434] 1H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 6.0 Hz, 1H), 6.32 - 6.04 (m, 2H), 3.93 - 3.75 (m, 2H), 3.22 - 3.09 (m, 2H), 2.98 (dd, J = 9.4, 5.7 Hz, 2H), 2.66 (t, J = 9.9 Hz, 2H), 2.56 (s, 3H), 2.47 - 2.35 (m, 2H), 1.89 (tt, J = 8.9, 5.1 Hz, 1H), 0.99 - 0.92 (m, 2H), 0.78 - 0.67 (m, 2H).

[0552]

[0435] UPLC-MS (basic method, 4 minutes): Rt: 1.17 minutes, m / z: 326.1 [M+H] + . [Example]

[0553] Example 41. Synthesis of Compound 66

[0554] [ka]

[0555] 2-(2-Azabicyclo[2.1.1]hexan-4-ylmethyl)isoindoline-1,3-dione trifluoroacetate To a solution of tert-butyl 4-[(1,3-dioxoisoindolin-2-yl)methyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (600 mg, 1.75 mmol) in CHCl (20 mL) was added trifluoroacetic acid (4 mL, 52.27 mmol) and the reaction was stirred at 0° C. for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure to give the title compound as a solid (590 mg, 1.66 mmol, 95%).

[0556]

[0437] 1H NMR (400 MHz, methanol-d4) δ 7.92 - 7.85 (m, 2H), 7.85 - 7.77 (m, 2H), 4.12 (td, J = 3.4, 2.0 Hz, 1H), 4.08 - 3.94 (m, 2H), 3.27 - 3.22 (m, 2H), 2.04 (d, J = 7.0 Hz, 2H), 1.65 - 1.50 (m, 2H).

[0557]

[0438] UPLC-MS (basic method, 2 minutes): Rt: 0.72 minutes, m / z=243.1 [M+H] + . 2-[[2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methyl]isoindoline-1,3-dione A solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.758 mmol), 2-(2-azabicyclo[2.1.1]hexan-4-ylmethyl)isoindoline-1,3-dione trifluoroacetate (220 mg, 0.910 mmol), and N,N-diisopropylethylamine (0.66 mL, 3.79 mmol) in NMP (5 mL) was heated to 120° C. and stirred for 96 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The residue was purified by normal phase column chromatography on silica gel eluting with a gradient of CH2Cl2 to 0.1% NEt3 in 9:1 CH2Cl2:MeOH to afford the title compound as a solid (112 mg, 0.239 mmol, 31%).

[0558]

[0440] 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.31 (s, 1H), 7.86 - 7.73 (m, 5H), 6.22 (s, 2H), 4.62 (t, J = 1.8 Hz, 1H), 3.90 (s, 2H), 2.95 (p, J = 8.0 Hz, 1H), 1.96 (d, J = 10.1 Hz, 2H), 1.83 - 1.75 (m, 2H), 1.70 (s, 2H), 1.57 (s, 4H), 1.38 (dd, J = 4.4, 1.8 Hz, 2H), 1.15 (t, J = 16.9 Hz, 2H).

[0559]

[0441] UPLC-MS (basic method, 2 minutes): Rt: 1.09 minutes, m / z=470.2 [M+H] + . 2-[4-(aminomethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of 2-[[2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methyl]isoindoline-1,3-dione (110 mg, 0.23 mmol) in EtOH (4 mL) was added hydrazine hydrate (34 μL, 0.35 mmol), and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was cooled to room temperature and then filtered through a pad of Celite. The filtrate was then concentrated to dryness under reduced pressure. The crude compound was loaded onto an SCX cartridge, and the cartridge was then washed with methanol. The compound was then eluted with 2 M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (58 mg, 0.17 mmol, 73%).

[0560]

[0443] 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.28 (s, 1H), 7.79 (d, J = 5.7 Hz, 1H), 6.22 (s, 2H), 4.68 - 4.61 (m, 1H), 2.97 (p, J = 8.0 Hz, 1H), 2.78 (s, 2H), 2.00 - 1.90 (m, 2H), 1.77 - 1.71 (m, 2H), 1.70 - 1.48 (m, 7H), 1.33 - 1.26 (m, 2H).

[0561]

[0444] 1 H NMR (400 MHz, methanol-d4) δ 7.84 - 7.75 (m, 1H), 6.33 - 6.05 (m, 2H), 4.77 - 4.74 (m, 1H), 3.37 (s, 2H), 3.10 - 3.00 (m, 1H), 2.95 (s, 2H), 2.12 - 1.97 (m, 2H), 1.93 - 1.83 (m, 2H), 1.80 - 1.57 (m, 6H), 1.51 - 1.40 (m, 2H).

[0562]

[0445] UPLC-MS (basic method, 4 minutes): Rt: 1.28 minutes, m / z=340.1 [M+H] + . [Example]

[0563] Example 42. Synthesis of Compound 102

[0564] [ka]

[0565] N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-[4-(methylaminomethyl)-2-azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine To a solution of benzyl N-[[2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methyl]-N-methyl-carbamate (104 mg, 0.213 mmol) in THF (3 mL) was added a 2.4 M solution of lithium aluminum hydride in THF (0.89 mL, 2.1 mmol) under nitrogen. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to 0° C. and then quenched with water (0.9 mL), followed by 10% w / v sodium hydroxide solution (0.9 mL), followed by water (0.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (62 mg, 0.166 mmol, 78%).

[0566]

[0447] 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.33 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.24 (s, 2H), 4.68 (t, J = 1.8 Hz, 1H), 3.37 (s, 2H), 3.02 (p, J = 7.9 Hz, 1H), 2.55 (s, 2H), 2.16 (s, 6H), 2.03 - 1.93 (m, 2H), 1.81 - 1.76 (m, 2H), 1.76 - 1.67 (m, 2H), 1.67 - 1.52 (m, 4H), 1.44 (dd, J = 4.3, 1.8 Hz, 2H).

[0567]

[0448] UPLC-MS (basic method, 4 minutes): rt=1.61 minutes, m / z=368.2[M+H] + . [Example]

[0568] Example 43. Synthesis of Compound 84

[0569] [ka]

[0570] tert-Butyl 6-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate A solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (557 mg, 2.11 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (507 mg, 2.08 mmol), and N,N-diisopropylethylamine (0.82 mL, 4.69 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 72 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude residue was purified by automated flash column chromatography on silica gel eluting with a gradient of CH2Cl2 to 1:9 2M NH3:CH2Cl2 in MeOH to afford the title compound as a solid (391 mg, 0.873 mmol, 84%).

[0571]

[0450] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 5.7 Hz, 1H), 6.29 (s, 1H), 6.12 (s, 1H), 4.25 (s, 4H), 4.11 (s, 4H), 3.71 - 3.60 (m, 2H), 3.11 - 3.01 (m, 1H), 2.15 - 2.04 (m, 2H), 1.86 - 1.53 (m, 4H), 1.45 (s, 9H).

[0572]

[0451] UPLC-MS (basic method, 2 minutes): Rt: 1.09 minutes, m / z: 426.2 [M+H] + . N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-amine To a solution of tert-butyl 6-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (153 mg, 0.359 mmol) in anhydrous THF (3 mL) was added a 2.4 M solution of lithium aluminum hydride in THF (1.5 mL, 3.6 mmol) under nitrogen. The reaction mixture was stirred at reflux for 1 h. The reaction mixture was then cooled to 0° C. and quenched with water (0.15 mL), followed by 10% w / v sodium hydroxide solution (0.15 mL), followed by water (0.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added, and the reaction mixture was stirred for an additional 15 min. The reaction mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The eluate was then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH3 in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (64 mg, 0.19 mmol, 53%).

[0573]

[0453] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.43 (s, 1H), 7.83 (d, J = 5.9 Hz, 1H), 6.28 (s, 2H), 4.00 (s, 4H), 3.26 (s, 4H), 3.05 - 2.93 (m, 1H), 2.18 (s, 3H), 1.98 (ddd, J = 11.2, 7.7, 4.8 Hz, 2H), 1.81 - 1.68 (m, 2H), 1.67 - 1.46 (m, 4H).

[0574]

[0454] UPLC-MS (basic method, 4 minutes): Rt: 1.40 minutes, m / z: 340.2 [M+H] + . [Example]

[0575] Example 44. Synthesis of Compound 51

[0576] [ka]

[0577] tert-Butyl (1R,5S)-3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.849 mmol), (1R,5S)-tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (202 mg, 1.02 mmol), and N,N-diisopropylethylamine (0.37 mL, 2.12 mmol) in NMP (2 mL) was heated to 120° C. and stirred for 18 h. The reaction mixture was cooled to ambient temperature and then added to ice water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient from CH2Cl2: to 4:1 2M NH3 in MeOH:CH2Cl2 to 80:20 CH2Cl2: 2M NH3 in MeOH to afford the title compound as a solid (156 mg, 0.393 mmol, 46%).

[0578]

[0456] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.42 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.21 (s, 2H), 4.69 - 4.61 (m, 1H), 4.13 (d, J = 12.7 Hz, 1H), 4.00 - 3.83 (m, 2H), 3.42 (s, 1H), 3.16 (dd, J = 11.8, 6.8 Hz, 1H), 3.11 - 2.99 (m, 2H), 1.81 (tt, J = 8.4, 5.1 Hz, 1H), 1.33 (d, J = 9.7 Hz, 10H), 0.86 (dd, J = 8.6, 2.1 Hz, 2H), 0.67 - 0.56 (m, 2H).

[0579]

[0457] UPLC-MS (basic method, 2 minutes): Rt: 1.04 minutes, m / z: 398.2 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(1S,5S)-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyrimidin-4-amine To a solution of tert-butyl (1R,5S)-3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (140 mg, 0.35 mmol) in CHCl (5 mL) was added trifluoroacetic acid (2 mL, 26 mmol) at ambient temperature, and the reaction mixture was stirred for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (84 mg, 0.268 mmol, 80%).

[0580]

[0459] 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.33 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.20 (s, 1H), 4.30 (dd, J = 6.6, 4.7 Hz, 1H), 3.93 - 3.79 (m, 2H), 3.60 (t, J = 7.7 Hz, 1H), 3.18 - 3.10 (m, 3H), 3.08 - 3.03 (m, 1H), 1.82 (tt, J = 8.4, 5.0 Hz, 1H), 0.91 - 0.79 (m, 2H), 0.66 - 0.54 (m, 2H).

[0581]

[0460] UPLC-MS (basic method, 4 minutes): Rt: 0.95 minutes, m / z: 298.1 [M+H] + . [Example]

[0582] Example 45. Synthesis of Compound 64

[0583] [ka]

[0584] tert-Butyl 3-[1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]azetidin-3-yl]azetidine-1-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (395 mg, 1.68 mmol), tert-butyl[3,3'-biazetidine]-1-carboxylate hydrochloride (1.20 equiv., 500 mg, 2.01 mmol), and N,N-diisopropylethylamine (1.0 mL, 3.5 mmol) in NMP (6 mL) was heated to 120°C and stirred for 20 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2 x 10 mL), and then dried under reduced pressure. The crude residue was purified by automated flash column chromatography eluting with a gradient of CH2Cl2 to 1:9 2M NH3 in CH2Cl2 to afford the title compound as a solid (205 mg, 0.478 mmol, 29%).

[0585]

[0462] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.43 (s, 1H), 7.84 (d, J = 5.8 Hz, 1H), 6.48 - 6.08 (m, 2H), 4.12 - 4.02 (m, 2H), 3.95 (s, 2H), 3.62 (dd, J = 8.6, 4.8 Hz, 2H), 3.53 (s, 2H), 2.99 - 2.75 (m, 2H), 1.89 - 1.72 (m, 1H), 1.46 - 1.29 (m, 9H), 0.98 - 0.83 (m, 2H), 0.75 - 0.56 (m, 2H).

[0586]

[0463] UPLC-MS (basic method, 4 minutes): Rt: 1.56 minutes, m / z: 412.5 [M+H] + . 2-[3-(azetidin-3-yl)azetidin-1-yl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl 3-[1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]azetidin-3-yl]azetidine-1-carboxylate (97 mg, 0.24 mmol) in CHCl (4 mL) was added trifluoroacetic acid (4 mL, 52 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes, after which the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluent was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (31 mg, 97 μmol, 41%).

[0587]

[0465] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.39 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.44 - 5.90 (m, 2H), 4.04 (t, J = 8.0 Hz, 2H), 3.67 (dd, J = 8.7, 4.5 Hz, 2H), 3.52 (t, J = 7.2 Hz, 2H), 3.20 (t, 2H), 2.86 (s, 2H), 1.91 - 1.79 (m, 1H), 1.65 (s, 1H), 0.98 - 0.81 (m, 2H), 0.74 - 0.52 (m, 2H).

[0588]

[0466] UPLC-MS (basic method, 4 minutes): Rt: 0.99 minutes, m / z: 312.2 [M+H] + . [Example]

[0589] Example 46. Synthesis of Compound 14

[0590] [ka]

[0591] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-amine A solution of benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (200 mg, 0.435 mmol) in a 30% w / v solution of hydrogen bromide in acetic acid (3 mL) was stirred at ambient temperature for 3 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC. The residue was then loaded onto an SCX cartridge, the cartridge was washed with methanol (10 mL), and the compound was then eluted with 2M NH3 in MeOH (20 mL). The eluent was concentrated under reduced pressure to give the title compound as a solid (77 mg, 0.23 mmol, 53%).

[0592]

[0468] 1 H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 5.9 Hz, 1H), 6.29 - 6.00 (m, 2H), 4.78 (s, 1H), 3.44 (s, 2H), 2.89 (s, 2H), 2.44 (s, 3H), 1.96 - 1.85 (m, 3H), 1.58 - 1.48 (m, 2H), 1.01 - 0.93 (m, 2H), 0.77 - 0.68 (m, 2H).

[0593]

[0469] UPLC-MS (basic method, 2 minutes): Rt: 1.19 minutes, m / z=326.1[M+H] + . [Example]

[0594] Example 47. Synthesis of Compound 14

[0595] [ka]

[0596] tert-Butyl 4-(methylaminomethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 2-Methyl-2-propanyl 4-{[(methylsulfonyl)oxy]methyl}-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.018 g, 3.49 mmol) was dissolved in a 2.0 M solution of methylamine in methanol (60 mL, 120 mmol) and distributed between three 15-20 mL microwave vials. The reaction mixture was sequentially heated to 70 °C under microwave irradiation for 2 h, then the vials were recombined and concentrated to dryness. The crude residue was diluted with 0.5 M NaOH (aq) (75 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated to dryness to give the title compound as an oil (802 mg, 3.37 mmol, 96%).

[0597]

[0471] 1 H NMR (400 MHz, chloroform-d) δ 4.45–4.21 (m, 1H), 3.23 (s, 2H), 2.83 (s, 2H), 2.46 (s, 3H), 1.78–1.73 (m, 2H), 1.48–1.44 (m, 11H).

[0472] UPLC-MS (2 minutes, basic): rt=0.93 minutes, m / z=227.1[M+H] + .

[0598] tert-Butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a solution of tert-butyl 4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (802 mg, 3.37 mmol) and triethylamine (0.74 mL, 5.31 mmol) in CHCl (45 mL) was added benzyl chloroformate (0.56 mL, 3.90 mmol), and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was then diluted with water (50 mL) and then extracted with CHCl (3 × 50 mL). The combined organic extracts were washed with saturated aqueous brine (50 mL) and then concentrated to dryness under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of 1:4 EtOAc:iso-hexane to 4:6 EtOAc:iso-hexane to give the title compound as an oil (776 mg, 2.07 mmol, 58%).

[0599]

[0474] 1 H NMR (400 MHz, chloroform-d) δ 7.38 - 7.28 (m, 5H), 5.11 (d, J = 9.1 Hz, 2H), 4.30 (d, J = 13.0 Hz, 1H), 3.53 (d, J = 16.2 Hz, 2H), 3.25 - 3.14 (d, 2H), 2.96 (d, J = 6.1 Hz, 3H), 1.80 - 1.66 (m, 2H), 1.51 - 1.39 (m, 11H).

[0600]

[0475] UPLC-MS (2 min, basic, ELSD): rt=1.26 min, m / z=361.2[M+H] + . Benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate To a solution of tert-butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (776 mg, 2.07 mmol) in CHCl (20 mL) was added trifluoroacetic acid (10.0 mL, 105 mmol), and the reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, and the cartridge was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as an oil (487 mg, 1.78 mmol, 83%).

[0601]

[0477] 1 H NMR (400 MHz, chloroform-d) δ 7.38 - 7.14 (m, 5H), 5.03 (d, J = 8.7 Hz, 2H), 3.59 (d, 1H), 3.47 (d, J = 14.4 Hz, 2H), 2.88 (s, 3H), 2.73 (d, 2H), 1.55 (d, 2H), 1.35 - 1.16 (m, 2H).

[0602]

[0478] UPLC-MS (basic method, 2 minutes): Rt: 0.89 minutes, m / z=261.1[M+H] + . Benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (479 mg, 2.03 mmol), benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (487 mg, 1.78 mmol), and N,N-diisopropylethylamine (0.77 mL, 4.44 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 24 h. The reaction mixture was cooled to ambient temperature and then added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (676 mg, 1.18 mmol, 66%).

[0603]

[0480] 1 H NMR (400 MHz, DMSO-d6) δ δ 7.99 (d, J = 5.7 Hz, 1H), 7.39 - 7.29 (m, 5H), 6.14 (s, 1H), 5.88 (s, 1H), 5.13 (s, 2H), 3.64 - 3.51 (m, 2H), 3.54 - 3.45 (m, 2H), 3.00 (d, J = 6.6 Hz, 3H), 1.86 (ddd, J = 13.5, 8.5, 5.1 Hz, 3H), 1.71 - 1.47 (m, 3H), 1.05 - 0.91 (m, 2H), 0.75 (dt, J = 6.6, 4.8 Hz, 2H).

[0604]

[0481] UPLC-MS (basic method, 2 minutes): Rt: 1.07 minutes, m / z=460.4[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-amine To a solution of benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (893 mg, 1.94 mmol) in methanol (25 mL) under a stream of nitrogen was added 10% w / w palladium on activated carbon (260 mg, 0.244 mmol). The reaction was then exchanged with hydrogen and the reaction mixture was stirred at room temperature for 6 hours. The atmosphere was exchanged with nitrogen and a suspension of 10% w / w palladium on activated carbon (282 mg, 0.265 mmol) in water (1 mL) was added under a stream of nitrogen. The atmosphere was exchanged with hydrogen and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a pad of Celite and the filter cake was washed with EtOAc (10 mL). The eluent was concentrated to dryness under reduced pressure. The residue was purified by reverse phase basic preparative HPLC to give the title compound as a solid (206 mg, 0.613 mmol, 32%).

[0605]

[0483] 1 H NMR (400 MHz, methanol-d4) δ 7.85 - 7.76 (m, 1H), 6.15 (s, 2H), 4.77 (q, J = 1.8 Hz, 1H), 3.44 (s, 2H), 2.88 (d, J = 3.7 Hz, 2H), 2.47 - 2.35 (m, 3H), 1.88 (dd, J = 8.3, 5.1 Hz, 3H), 1.52 (dd, J = 4.6, 1.9 Hz, 2H), 1.01 - 0.87 (m, 2H), 0.76 - 0.64 (m, 2H).

[0606]

[0484] UPLC-MS (basic method, 2 minutes): Rt: 1.13 minutes, m / z=326.0[M+H] + . [Example]

[0607] Example 48. Synthesis of Compound 14

[0608] [ka]

[0609] tert-Butyl 4-(methylsulfonyloxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-Butyl 4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5.00 g, 23.4 mmol) was dissolved in CHCl (190 mL) and cooled to 0 °C. Triethylamine (9.8 mL, 70.3 mmol) was added, followed by methanesulfonic anhydride (8.17 g, 46.9 mmol) in portions over 10 min, and the reaction was then warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with water (1 L), the organics were extracted with CHCl (3 × 100 mL), and the combined organic extracts were dried over NaSO and concentrated to dryness to give the title compound (8.00 g, 24.7 mmol) as an oil.

[0610]

[0486] 1 H NMR (400 MHz, chloroform-d) δ H 4.40 (s, 2H), 3.29 (s, 2H), 3.03 (s, 3H), 1.87 (dt, J = 4.3, 1.9 Hz, 2H), 1.54 (dd, J = 4.6, 1.9 Hz, 2H), 1.46 (s, 9H).

[0611] tert-Butyl 4-(methylaminomethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 2-Methyl-2-propanyl 4-{[(methylsulfonyl)oxy]methyl}-2-azabicyclo[2.1.1]hexane-2-carboxylate (8.70 g, 29.9 mmol) was dissolved in a 2.0 M solution of methylamine in methanol (400 mL) in a 1 L Parr vessel, and the sealed reaction was heated at 70° C. for 16 h. The vessel was cooled to room temperature, and the reaction mixture was concentrated to dryness under reduced pressure to give the title compound as an oil (5.6 g, 23.5 mmol, 78% yield).

[0612]

[0488] 1 H NMR (400 MHz, chloroform-d) δ 4.32 (s, 1H), 3.21 (s, 2H), 2.81 (s, 2H), 2.44 (s, 3H), 1.73 (dt, J = 4.1, 1.9 Hz, 2H), 1.44 (s, 9H), 1.50–1.38 (m, 2H).

[0613] tert-Butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a solution of tert-butyl 4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5.6 g, 24.7 mmol) and triethylamine (5.17 mL, 37.12 mmol) in CHCl (56 mL) was added benzyl chloroformate (3.89 mL, 27.2 mmol), and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was then diluted with water (200 mL) and then extracted with CHCl (3 × 50 mL). The combined organic extracts were washed with saturated aqueous brine (200 mL) and then concentrated to dryness under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of 1:4 EtOAc:iso-hexane to 6:4 EtOAc:iso-hexane to give the title compound as an oil (7.00 g, 16.51 mmol, 67%).

[0614]

[0490] 1 H NMR (400 MHz, chloroform-d) δ 7.38 - 7.27 (m, 5H), 5.10 (d, J = 8.4 Hz, 2H), 4.31 (s, 1H), 3.51 (d, J = 15.7 Hz, 2H), 3.23 - 3.13 (m, 2H), 2.95 (d, J = 5.3 Hz, 2H), 1.67 (m, 2H), 1.45 (s, 11H).

[0615]

[0491] UPLC-MS (basic method, 4 minutes, ELSD): Rt=2.03 minutes, m / z=261.2 [M-Boc+H] + . Benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate To a solution of tert-butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (7.00 g, 19.42 mmol) in CHCl (120 mL) was added trifluoroacetic acid (30 mL, 400 mmol) and the reaction mixture was stirred at room temperature for 1 h and then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as an oil (3.94 g, 14.4 mmol, 74%).

[0616]

[0493] 1 H NMR (400 MHz, chloroform-d) δ 7.41–7.27 (m, 5H), 5.15–5.07 (m, 2H), 3.70–3.60 (m, 1H), 3.59–3.50 (m, 2H), 3.01–2.90 (m, 3H), 2.85–2.73 (m, 2H), 1.68–1.55 (m, 2H), 1.39–1.25 (m, 2H).

[0617]

[0494] UPLC-MS (basic method, 2 minutes): Rt: 0.89 minutes, m / z=261.1[M+H] + . Benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (3.05 g, 12.94 mmol), benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (3.94 g, 14.38 mmol), and N,N-diisopropylethylamine (6.26 mL, 35.95 mmol) in NMP (38 mL) was heated to 102° C. and stirred for 67 hours. Additional N,N-diisopropylethylamine (6.26 mL, 36.0 mmol) was added, and the reaction was heated at 110° C. for 20 hours. The reaction mixture was cooled to ambient temperature and then added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under vacuum to give the title compound as a solid (676 mg, 1.18 mmol, 66%).

[0618]

[0496] 1 H NMR (400 MHz, DMSO-d6) δ H 11.87 (s, 1H), 9.31 (s, 1H), 7.79 (d, J = 5.7 Hz, 1H), 7.36 - 7.22 (m, 5H), 6.34 - 5.99 (m, 2H), 5.04 (d, J = 13.6 Hz, 2H), 4.63 (d, J = 12.1 Hz, 1H), 3.55 (s, 2H), 2.89 (d, J = 13.1 Hz, 3H), 1.79 (s, 2H), 1.72 (s, 1H), 1.39 (s, 1H), 1.34 (s, 1H), 0.86 (d, J = 8.1 Hz, 2H), 0.62 (s, 2H).

[0619]

[0497] UPLC-MS (basic method, 4 minutes): Rt: 1.74 minutes, m / z=460.4[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-amine To benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (4.77 g, 10.38 mmol) was added a 30% w / v solution of hydrogen bromide in acetic acid (95 mL, 1.7 mol) and the reaction mixture was stirred at ambient temperature for 1 h. The suspension was diluted with water (450 mL) and washed with CHCl (450 mL) and the aqueous layer was added dropwise to a suspension of NaCO (256 g) in water (730 mL). The solution was extracted with CHCl (3 × 500 mL) and the combined organics were dried over NaSO and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a gradient of 1:49 to 1:19 2M NH3 in MeOH:DCM to give the title compound as a solid (1.84 g, 5.65 mmol, 54% yield).

[0620]

[0499] 1 H NMR (400 MHz, DMSO-d6) δ H 11.86 (s, 1H), 9.28 (s, 1H), 7.79 (d, J = 5.7 Hz, 1H), 6.21 (s, 3H), 4.67 - 4.61 (m, 1H), 2.74 (s, 2H), 2.29 (s, 3H), 1.83 (ddd, J = 13.5, 8.6, 5.0 Hz, 1H), 1.76 (m, 2H), 1.33 (m, 2H), 0.87 (m, 2H), 0.66 - 0.58 (m, 2H).

[0621]

[0500] 1 H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 6.0 Hz, 1H), 6.16 (s, 2H), 4.78 (m, 1H), 3.44 (s, 2H), 2.92 (s, 2H), 2.46 (s, 3H), 1.97 - 1.85 (m, 3H), 1.53 (m, 2H), 0.97 (m, 2H), 0.77 - 0.68 (m, 2H).

[0622]

[0501] UPLC-MS (basic method, 2 minutes): Rt: 1.19 minutes, m / z=326.1[M+H] + . [Example]

[0623] Example 49. Synthesis of Compound 14

[0624] [ka]

[0625] tert-Butyl 4-(methylaminomethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 2-Methyl-2-propanyl 4-{[(methylsulfonyl)oxy]methyl}-2-azabicyclo[2.1.1]hexane-2-carboxylate (4.7 g, 16.1 mmol) was dissolved in a 2.0 M solution of methylamine in methanol (216 mL, 432 mmol) in a 300 mL Parr vessel, and the sealed reaction was heated at 70 °C for 16 h. The vessel was cooled to room temperature, and the reaction mixture was concentrated to dryness under reduced pressure. The residue was then dissolved in brine (30 mL) and Na2CO3 (5.0 g) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated to dryness under reduced pressure to give the title compound as an oil (2.60 g, 10.9 mmol, 67% yield).

[0626]

[0503] 1 H NMR (400 MHz, chloroform-d) δ 4.32 (s, 1H), 3.22 (s, 2H), 2.82 (s, 2H), 2.45 (s, 3H), 1.79–1.69 (m, 2H), 1.45 (s, 11H). tert-Butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a solution of tert-butyl 4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3.6 g, 15.9 mmol) and triethylamine (3.3 mL, 23.9 mmol) in CHCl (32 mL) was added benzyl chloroformate (2.5 mL, 17.5 mmol), and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was then diluted with water (100 mL) and then extracted with CHCl (3 × 50 mL). The combined organic extracts were washed with saturated aqueous brine (100 mL) and then concentrated to dryness under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of 1:4 EtOAc:iso-hexane to 6:4 EtOAc:iso-hexane to give the title compound as an oil (4.80 g, 12.5 mmol, 79%).

[0627]

[0505] 1 H NMR (400 MHz, chloroform-d) δ 7.40 - 7.27 (m, 5H), 5.11 (d, J = 8.2 Hz, 2H), 4.30 (s, 1H), 3.53 (d, J = 15.8 Hz, 2H), 3.31 - 3.08 (m, 2H), 2.99 - 2.93 (m, 3H), 1.80 - 1.67 (m, 2H), 1.55 - 1.36 (m, 11H).

[0628]

[0506] UPLC-MS (basic method, 2 minutes): Rt=1.22 minutes, m / z=361.2[M+H] + . Benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate To a solution of tert-butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4.80 g, 13.3 mmol) in CHCl (80 mL) was added trifluoroacetic acid (21 mL, 273 mmol) and the reaction mixture was stirred at room temperature for 30 min and then concentrated to dryness under reduced pressure. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH in methanol and the eluate was concentrated to dryness under reduced pressure to give the title compound as an oil (3.18 g, 12.2 mmol, 92%).

[0629]

[0508] 1 H NMR (400 MHz, chloroform-d) δ 7.41–7.27 (m, 5H), 5.15–5.07 (m, 2H), 3.70–3.60 (m, 1H), 3.59–3.50 (m, 2H), 3.01–2.90 (m, 3H), 2.85–2.73 (m, 2H), 1.68–1.55 (m, 2H), 1.39–1.25 (m, 2H).

[0630]

[0509] UPLC-MS (basic method, 2 minutes): Rt: 0.80 minutes, m / z=261.1[M+H] + . Benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (3.1 g, 13.3 mmol), benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (3.2 g, 11.6 mmol), and N,N-diisopropylethylamine (5.1 mL, 29.0 mmol) in NMP (32 mL) was heated to 102° C. and stirred for 68 h. Additional N,N-diisopropylethylamine (5.1 mL, 29.0 mmol) was added, and the reaction was heated at 110° C. for 20 h. The reaction mixture was cooled to ambient temperature and then added dropwise with stirring to ice water (600 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, then diluted with EtOAc (300 mL), and washed with saturated aqueous sodium bicarbonate (2×125 mL). The organics were separated, dried over NaSO, and then concentrated to dryness under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of EtOAc to ethanol / EtOAc / NHOH (1:3:0.02 v / v) to afford the title compound (4.40 g, 9.10 mmol, 69%) as a foam.

[0631]

[0511] 1 H NMR (400 MHz, chloroform-d, 50℃) δ 8.00 (d, J = 5.7 Hz, 1H), 7.40 - 7.27 (m, 6H), 6.75 (s, 1H), 6.13 (s, 1H), 5.89 (s, 1H), 5.15 (s, 2H), 4.81 (s, 1H), 3.61 (s, 2H), 3.53 - 3.40 (m, 2H), 3.01 (s, 3H), 1.91 - 1.78 (m, 3H), 1.46 - 1.35 (m, 2H), 1.01 - 0.89 (m, 2H), 0.78 - 0.71 (m, 2H).

[0632]

[0512] UPLC-MS (basic method, 2 minutes): Rt: 1.07 minutes, m / z=460.2[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-amine To benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (1.30 g, 2.83 mmol) was added a 30% w / v solution of hydrogen bromide in acetic acid (1.6 mL, 26.0 mmol), and the reaction mixture was stirred at ambient temperature for 80 min. The suspension was diluted with water (120 mL), washed with CHCl (120 mL), and the aqueous layer was added dropwise to a suspension of NaCO (70 g) in water (200 mL). The solution was extracted with CHCl (3 × 150 mL), and the combined organics were dried over NaSO and concentrated to dryness under reduced pressure. The crude compound was purified by reverse phase basic preparative HPLC to give the title compound as a solid (509 g, 1.55 mmol, 55% yield).

[0633]

[0514] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.34 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.42 - 5.94 (m, 2H), 4.68 (s, 1H), 2.75 (s, 2H), 2.31 (s, 3H), 1.86 (tt, J = 8.4, 5.1 Hz, 1H), 1.82 - 1.75 (m, 2H), 1.40 - 1.32 (m, 2H), 0.94 - 0.87 (m, 2H), 0.69 - 0.63 (m, 2H).

[0634]

[0515] 1H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 6.0 Hz, 1H), 6.32 - 5.96 (m, 2H), 4.78 (s, 1H), 3.44 (s, 2H), 2.89 (s, 2H), 2.44 (s, 3H), 1.98 - 1.85 (m, 3H), 1.56 - 1.48 (m, 2H), 1.01 - 0.93 (m, 2H), 0.75 - 0.69 (m, 2H).

[0635]

[0516] UPLC-MS (basic method, 4 minutes): Rt: 1.13 minutes, m / z=326.1[M+H] + . [Example]

[0636] Example 50: Synthesis of Compound 14

[0637] [ka]

[0638] tert-Butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate To a solution of tert-butyl 4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (815 mg, 3.60 mmol) and triethylamine (753 μL, 5.40 mmol) in CHCl (10 mL) was added benzyl chloroformate (565 μL, 3.96 mmol), and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was then diluted with water (50 mL) and then extracted with CHCl (3 × 50 mL). The combined organic extracts were washed with saturated aqueous brine (50 mL) and then concentrated to dryness under reduced pressure. The crude material was purified by automated flash column chromatography on silica gel eluting with a gradient of 1:4 EtOAc:iso-hexane to 4:6 EtOAc:iso-hexane to give the title compound (1.16 g, 3.12 mmol, 87%) as an oil.

[0639]

[0518] 1 H NMR (400 MHz, chloroform-d) δ 7.39–7.28 (m, 5H), 5.14–5.08 (m, 2H), 4.29 (s, 1H), 3.57–3.49 (m, 2H), 3.29–3.11 (m, 2H), 2.99–2.93 (m, 3H), 1.78–1.66 (m, 2H), 1.46 (s, 11H).

[0640]

[0519] UPLC-MS (basic method, 2 minutes): Rt: 1.26 minutes, m / z=361.1[M+H] + . Benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate To a solution of tert-butyl 4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.15 g, 3.19 mmol) in CHCl (10 mL) was added trifluoroacetic acid (5.0 mL, 65 mmol) and the reaction mixture was stirred at room temperature for 30 min. The crude residue was loaded onto an SCX cartridge, which was then washed with methanol, and the compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as an oil (760 mg, 2.92 mmol, 92%).

[0641]

[0521] 1 H NMR (400 MHz, chloroform-d) δ 7.39–7.29 (m, 5H), 5.15–5.08 (m, 2H), 3.60–3.51 (m, 2H), 2.99–2.93 (m, 3H), 2.84–2.72 (m, 2H), 1.65–1.55 (m, 2H), 1.36–1.23 (m, 2H).

[0642]

[0522] UPLC-MS (basic method, 2 minutes): Rt: 0.86 minutes, m / z=261.1[M+H]+ . Benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (570 mg, 2.42 mmol), benzyl ((2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (756 mg, 2.90 mmol), and N,N-diisopropylethylamine (0.93 mL, 5.3 mmol) in NMP (6 mL) was heated to 120° C. in a sealed tube and stirred for 18 h. The reaction mixture was cooled to ambient temperature and then added dropwise with stirring to ice water (200 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (970 mg, 2.11 mmol, 87%).

[0643]

[0524] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.34 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.45 - 7.25 (m, 5H), 6.26 (s, 1H), 6.16 (s, 1H), 5.12 - 5.04 (m, 2H), 4.71 - 4.63 (m, 1H), 3.59 (s, 2H), 2.97 - 2.89 (m, 3H), 1.96 - 1.72 (m, 3H), 1.45 - 1.36 (m, 2H), 0.98 - 0.86 (m, 2H), 0.71 - 0.64 (m, 2H).

[0644]

[0525] UPLC-MS (basic method, 2 minutes): Rt: 1.07 minutes, m / z=460.4[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((methylamino)methyl)-2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-amine To a solution of benzyl ((2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-4-yl)methyl)(methyl)carbamate (220 mg, 0.479 mmol) in methanol (5 mL) under a stream of nitrogen was added a suspension of 10% w / w palladium on activated carbon (51 mg, 48 μmol) in water (0.1 mL). The reaction vessel was then placed under vacuum and back-filled with nitrogen three times. The reaction vessel was then placed under vacuum and then back-filled with hydrogen a total of three times. The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was then filtered through a pad of Celite and the filter cake was washed with EtOAc (10 mL). The eluent was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (90 mg, 0.277 mmol, 58%).

[0645]

[0527] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.31 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.35 - 5.97 (m, 2H), 4.68 (s, 1H), 3.32 (s, 2H), 2.75 (s, 2H), 2.32 (s, 3H), 1.86 (tt, J = 8.5, 5.1 Hz, 1H), 1.82 - 1.76 (m, 2H), 1.42 - 1.31 (m, 2H), 0.95 - 0.86 (m, 2H), 0.69 - 0.62 (m, 2H).

[0646]

[0528] 1 H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 6.0 Hz, 1H), 6.27 - 5.92 (m, 1H), 4.78 (s, 1H), 3.44 (s, 2H), 2.89 (s, 2H), 2.44 (s, 3H), 1.97 - 1.84 (m, 3H), 1.58 - 1.47 (m, 1H), 1.02 - 0.92 (m, 2H), 0.77 - 0.68 (m, 2H).

[0647]

[0529] UPLC-MS (basic method, 2 minutes): Rt: 1.15 minutes, m / z=326.0[M+H] + . [Example]

[0648] Example 51: Synthesis of Compound 30

[0649] [ka]

[0650] tert-Butyl 4-[(1,3-dioxoisoindolin-2-yl)methyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate 2-Methyl-2-propanyl 4-{[(methylsulfonyl)oxy]methyl}-2-azabicyclo[2.1.1]hexane-2-carboxylate (600 mg, 2.06 mmol) and potassium phthalimide (458 mg, 2.47 mmol) were dissolved in DMF (6 mL), and the reaction mixture was heated at 90° C. under a nitrogen atmosphere for 4 hours. The reaction mixture was poured into ice water, and the precipitated solid was collected by filtration. The filter cake was washed with isohexane (20 mL) and evaporated to dryness in vacuo to give the title compound as a solid (590 mg, 1.72 mmol, 84%).

[0651]

[0531] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 - 7.74 (m, 4H), 4.07 (t, J = 1.8 Hz, 1H), 3.82 (s, 2H), 3.08 (s, 2H), 1.71 (dt, J = 4.2, 1.8 Hz, 2H), 1.33 (s, 9H), 1.31 - 1.27 (m, 2H).

[0652]

[0532] UPLC-MS analysis: (2 min, basic): rt = 1.18 min, no characteristic m / z observed. 2-(2-Azabicyclo[2.1.1]hexan-4-ylmethyl)isoindoline-1,3-dione;2,2,2-Trifluoroacetic acid tert-Butyl 4-[(1,3-dioxoisoindolin-2-yl)methyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (520 mg, 1.52 mmol) was dissolved in DCM (10 mL) and the reaction mixture was cooled to 0 °C. Trifluoroacetic acid (1.2 mL, 15 mmol) was added thereto and the reaction mixture was stirred for 4 hours. The solvent was evaporated to dryness under reduced pressure to give the title compound as a solid (505 mg, 1.42 mmol, 93%).

[0653]

[0534] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 2H), 7.89 - 7.76 (m, 4H), 4.02 (d, J = 1.8 Hz, 1H), 3.87 (s, 2H), 3.18 - 3.07 (m, 2H), 1.88 (d, J = 5.8 Hz, 2H), 1.52 - 1.37 (m, 2H).

[0654]

[0535] UPLC-MS analysis: (2 minutes, basic): rt=0.80 minutes, m / z=243.1 [M+H] + . 2-[[2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methyl]isoindoline-1,3-dione 2-(2-Azabicyclo[2.1.1]hexan-4-ylmethyl)isoindoline-1,3-dione; 2,2,2-trifluoroacetic acid (505 mg, 1.42 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (334 mg, 1.42 mmol), and N,N-diisopropylethylamine (0.74 mL, 4.25 mmol) were dissolved in n-butanol (6 mL), and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was evaporated, and ice water was added to it. The precipitated brown solid was filtered off and washed with 10% ethyl acetate / isohexane (2 × 10 mL). The precipitate was evaporated to dryness to give the title compound as a solid (460 mg, 1.04 mmol, 74%).

[0655]

[0537] 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 7.93 - 7.73 (m, 5H), 6.29 (s, 2H), 4.72 (d, J = 1.7 Hz, 1H), 3.97 (s, 2H), 3.43 (s, 2H), 1.95 (s, 2H), 1.92 - 1.83 (m, 1H), 1.54 (d, J = 4.6 Hz, 2H), 1.08 - 0.85 (m, 2H), 0.80 - 0.57 (m, 2H).

[0656]

[0538] UPLC-MS analysis: (2 minutes, basic): rt=1.03 minutes, m / z=442.3 [M+H] + . 2-[4-(aminomethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine 2-[[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methyl]isoindoline-1,3-dione (460 mg, 1.04 mmol) was dissolved in ethanol (14 mL), and hydrazine hydrate (0.20 mL, 4.2 mmol) was added. The reaction mixture was heated to reflux for 4 hours. The reaction mixture was cooled, and ethanol (20 mL) was added to it. The precipitated solid was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase preparative HPLC under basic conditions. The residue was then dissolved in MeOH and then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH, and the compound was then eluted with 2M NH3 in MeOH. The eluate was concentrated to dryness under reduced pressure to give the title compound as a solid. (107 mg, 0.344 mmol, 33%).

[0657]

[0540] 1 H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 5.9 Hz, 1H), 6.16 (s, 2H), 4.79 (t, J = 1.8 Hz, 1H), 3.42 (s, 2H), 3.00 (s, 2H), 1.95 - 1.85 (m, 3H), 1.50 (dd, J = 4.5, 1.9 Hz, 2H), 0.97 (d, J = 8.2 Hz, 2H), 0.76 - 0.68 (m, 2H).

[0658]

[0541] UPLC-MS analysis: (4 minutes, basic): rt=1.12 minutes, m / z=312.1 [M+H] + . 2-[4-(aminomethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of 2-[[2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methyl]isoindoline-1,3-dione (120 mg, 0.271 mmol) in EtOH (3 mL) was added hydrazine hydrate (40 μL, 0.41 mmol), and the reaction mixture was heated to 60° C. for 3 h. The reaction mixture was cooled to room temperature and then filtered through a pad of Celite. The filtrate was then concentrated to dryness under reduced pressure. The crude compound was loaded onto an SCX-2 cartridge, and the cartridge was then washed with methanol. The compound was then eluted with 2 M NH in methanol, and the eluate was concentrated to dryness under reduced pressure. The sample was further purified by reverse-phase basic preparative HPLC to give the title compound as a solid (21 mg, 69 μmol, 25%).

[0659]

[0543] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.29 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 4.71 - 4.66 (m, 1H), 2.85 (s, 2H), 1.92 - 1.81 (m, 1H), 1.80 - 1.75 (m, 2H), 1.36 - 1.30 (m, 2H), 0.94 - 0.87 (m, 2H), 0.70 - 0.62 (m, 2H).

[0660]

[0544] 1 H NMR (400 MHz, methanol-d4) δ 7.84 (d, J = 5.9 Hz, 1H), 6.16 (s, 2H), 4.82 - 4.77 (m, 1H), 3.42 (s, 2H), 3.06 - 3.01 (m, 2H), 1.95 - 1.92 (m, 2H), 1.91 - 1.87 (m, 1H), 1.56 - 1.48 (m, 2H), 1.00 - 0.94 (m, 2H), 0.76 - 0.68 (m, 2H).

[0661]

[0545] UPLC-MS (basic method, 4 minutes): Rt: 1.07 minutes, m / z=312.1[M+H] + . [Example]

[0662] Example 52: Synthesis of Compound 34

[0663] [ka]

[0664] tert-Butyl N-[3-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]amino]propyl]-N-methyl-carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.27 mmol), N-methylpropane-1,3-diamine, N-Boc protected (0.61 mL, 3.2 mmol), and N,N-diisopropylethylamine (0.78 mL, 4.5 mmol) in 1-butanol (7 mL) was heated to 100° C. and stirred for 96 h. The reaction mixture was then cooled to ambient temperature and the solvent removed under reduced pressure. The residue was dissolved in CHCl (20 mL) and washed with water (2×20 mL), and the organics were dried (NaSO) and concentrated to dryness under reduced pressure. The residue was purified by normal phase column chromatography on silica gel eluting with a gradient of CH2Cl2 to 0.1% NEt3 in 9:1 CH2Cl2:MeOH to afford the title compound as a solid (199 mg, 0.514 mmol, 40%).

[0665]

[0547] 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J = 5.8 Hz, 1H), 6.22 (s, 1H), 5.87 (s, 1H), 3.47–3.38 (m, 3H), 2.87 (s, 3H), 1.92–1.81 (m, 3H), 1.51–1.44 (m, 11H), 1.00–0.91 (m, 2H), 0.79–0.75 (m, 2H).

[0666]

[0548] UPLC-MS (basic method, 2 minutes): Rt: 1.00 minutes, m / z=388.2[M+H] + . N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 -[3-(methylamino)propyl]pyrimidine-2,4-diamine To a solution of tert-butyl N-[3-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]amino]propyl]-N-methyl-carbamate (196 mg, 0.506 mmol) in CHCl (4 mL) was added trifluoroacetic acid (1.0 mL, 26 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude compound was loaded onto an SCX-2 cartridge. The cartridge was then washed with methanol, and the compound was then eluted with 2M NH in methanol. The eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (114 mg, 0.397 mmol, 78%).

[0667]

[0550] 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 7.77 (d, J = 5.6 Hz, 1H), 6.71 (s, 1H), 6.11 (s, 2H), 3.30 - 3.22 (m, 2H), 2.53 - 2.51 (m, 2H), 2.26 (s, 3H), 1.89 - 1.78 (m, 1H), 1.70 - 1.58 (m, 2H), 0.94 - 0.84 (m, 2H), 0.70 - 0.60 (m, 2H).

[0668]

[0551] 1 H NMR (400 MHz, methanol-d4) δ 7.79 (d, J = 5.9 Hz, 1H), 6.10 (d, J = 5.9 Hz, 1H), 5.99 (s, 1H), 3.41 (t, J = 6.7 Hz, 2H), 2.67 (t, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.93 - 1.86 (m, 1H), 1.86 - 1.77 (m, 2H), 1.00 - 0.91 (m, 2H), 0.76 - 0.67 (m, 2H).

[0669]

[0552] UPLC-MS (basic method, 4 minutes): Rt: 0.97 minutes, m / z=288.1 [M+H] + . [Example]

[0670] Example 53: Synthesis of Compound 36

[0671] [ka]

[0672] tert-Butyl N-[[(3S)-1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate A solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (442 mg, 1.68 mmol), tert-butyl N-[(3R)-pyrrolidin-3-ylmethyl]carbamate hydrochloride (269 mg, 1.14 mmol), and N,N-diisopropylethylamine (1.0 mL, 5.9 mmol) in NMP (4 mL) was heated to 120° C. and stirred for 20 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude material was purified by flash column chromatography eluting with 2M NH3 in 9:1 CH2Cl2:MeOH to give the title compound as an oil (315 mg, 0.597 mmol, 79%).

[0673]

[0554] 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.36 (s, 1H), 7.82 (d, J = 5.8 Hz, 1H), 6.98 (s, 2H), 6.20 (s, 1H), 3.55 (s, 1H), 2.98 (s, 3H), 2.37 (s, 1H), 2.18 (t, J = 8.1 Hz, 1H), 2.05 - 1.82 (m, 4H), 1.75 - 1.53 (m, 8H), 1.38 (s, 9H).

[0674]

[0555] UPLC-MS (basic method, 2 minutes): Rt: 1.10 minutes, m / z: 428.4 [M+H] + . N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-[(3S)-3-(methylaminomethyl)pyrrolidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl N-[[(3S)-1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]methyl]carbamate (115 mg, 0.269 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.3 mL, 2.7 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was then cooled to 0° C. and then quenched with water (1.2 mL), followed by 15% w / v sodium hydroxide solution (1.2 mL), followed by water (3.6 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 10 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 10 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The filtrate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (6.4 mg, 18.2 μmol, 6.78%).

[0675]

[0557] 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.31 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.41 (s, 1H), 6.18 (s, 1H), 3.64 (t, J = 9.4 Hz, 1H), 3.59 - 3.54 (m, 1H), 3.44 - 3.35 (m, 1H), 3.22 - 3.11 (m, 1H), 3.03 - 2.96 (m, 1H), 2.41 - 2.32 (m, 1H), 2.29 (s, 3H), 2.08 - 1.90 (m, 4H), 1.76 - 1.53 (m, 8H).

[0676]

[0558] UPLC-MS (basic method, 4 minutes): Rt: 1.40 minutes, m / z: 342.2 [M+H] + . [Example]

[0677] Example 54: Synthesis of Compound 39

[0678] [ka]

[0679] (±)-tert-Butyl 3-[1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]azetidine-1-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (306 mg, 1.30 mmol), tert-butyl 3-(pyrrolidin-3-yl)azetidine-1-carboxylate (348 mg, 1.54 mmol), and N,N-diisopropylethylamine (0.57 mL, 3.3 mmol) in NMP (6 mL) was heated to 120° C. and stirred for 24 hours. The reaction mixture was then cooled to ambient temperature and added dropwise to ice water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (596 mg, 1.22 mmol, 94%).

[0680]

[0560] 1 H NMR (400 MHz, chloroform-d) δ 7.97 (d, J = 5.7 Hz, 1H), 6.04 (d, J = 5.5 Hz, 1H), 5.88 (s, 1H), 4.07 - 3.96 (m, 2H), 3.76 (dd, J = 10.7, 6.7 Hz, 1H), 3.73 - 3.64 (m, 3H), 3.56 (dt, J = 10.9, 7.6 Hz, 1H), 3.16 (dd, J = 10.8, 6.6 Hz, 1H), 2.58 - 2.47 (m, 2H), 2.15 - 2.05 (m, 1H), 1.86 (tt, J = 8.4, 5.1 Hz, 1H), 1.68 - 1.56 (m, 1H), 1.43 (s, 9H), 1.00 - 0.88 (m, 2H), 0.77 - 0.66 (m, 2H).

[0681]

[0561] UPLC-MS (basic method, 2 minutes): Rt: 1.06 minutes, m / z: 426.2 [M+H] + . (±)-2-[3-(azetidin-3-yl)pyrrolidin-1-yl]-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine To a solution of tert-butyl 3-[1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3-yl]azetidine-1-carboxylate (106 mg, 0.22 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then concentrated to dryness. The crude reaction mixture was then loaded onto an SCX-2 cartridge, the cartridge was washed with MeOH, and the compound was then eluted with 2M NH in MeOH. The eluate was concentrated under reduced pressure to give the title compound as a solid (38 mg, 0.12 mmol, 53%).

[0682]

[0563] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.33 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 6.19 (s, 2H), 3.74 - 3.49 (m, 4H), 3.49 - 3.21 (m, 4H), 3.09 - 2.96 (m, 1H), 2.07 - 1.94 (m, 1H), 1.91 - 1.79 (m, 1H), 1.64 - 1.43 (m, 1H), 0.98 - 0.81 (m, 3H), 0.71 - 0.55 (m, 2H).

[0683]

[0564] 1H NMR (400 MHz, methanol-d4) δ 7.81 (d, J = 5.7 Hz, 1H), 6.28 - 5.90 (m, 2H), 3.92 - 3.79 (m, 1H), 3.75 - 3.55 (m, 3H), 3.55 - 3.38 (m, 2H), 3.22 - 3.03 (m, 1H), 2.88 - 2.74 (m, 1H), 2.68 - 2.53 (m, 1H), 2.53 - 2.35 (m, 1H), 2.17 - 2.01 (m, 1H), 1.92 - 1.78 (m, 1H), 1.70 - 1.54 (m, 1H), 0.99 - 0.84 (m, 2H), 0.70 - 0.60 (m, 2H).

[0684]

[0565] UPLC-MS (basic method, 4 minutes): Rt: 1.04 minutes, m / z: 326.0 [M+H] + . [Example]

[0685] Example 55: Synthesis of Compound 40

[0686] [ka]

[0687] tert-Butyl (1R,5S)-3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate A solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (442 mg, 1.68 mmol), (1R,5S)-tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (379 mg, 1.91 mmol), and N,N-diisopropylethylamine (1.0 mL, 5.9 mmol) in NMP (4 mL) was heated to 120° C. and stirred for 20 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure. The crude residue was purified by automated flash column chromatography eluting with a gradient of CH2Cl2 to 9:1 CH2Cl2:2M NH3 in MeOH to afford the title compound as a solid (202 mg, 0.483 mmol, 38%).

[0688]

[0567] 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.42 (s, 1H), 7.88 (d, J = 5.7 Hz, 1H), 6.26 (s, 2H), 4.70 (t, J = 5.6 Hz, 1H), 4.18 (d, J = 12.5 Hz, 1H), 4.02 (d, J = 11.7 Hz, 2H), 3.45 - 3.39 (m, 1H), 3.26 - 3.16 (m, 1H), 3.13 (d, J = 7.4 Hz, 2H), 1.90 - 1.80 (m, 1H), 1.38 (s, 9H), 0.91 (d, J = 8.3 Hz, 2H), 0.67 (d, J = 5.5 Hz, 2H).

[0689]

[0568] UPLC-MS (basic method, 4 minutes): Rt: 1.56 minutes, m / z: 398.4 [M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(1S,5S)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyrimidin-4-amine To a solution of tert-butyl (1R,5S)-3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (189 mg, 0.476 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (2.0 mL, 4.76 mmol) was heated to reflux and stirred for 3 hours. The reaction mixture was then cooled to 0° C. and quenched with water (1.8 mL), followed by 15% w / v sodium hydroxide solution (1.8 mL), followed by water (5.4 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 10 minutes, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 10 minutes. The reaction mixture was passed through a pad of Celite, and the filter cake was washed with EtOAc (20 mL). The filtrate was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound (40 mg, 0.127 mmol, 27%) as a solid.

[0690]

[0570] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.34 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 6.24 (s, 2H), 3.87 - 3.77 (m, 2H), 3.74 (dd, J = 6.6, 4.1 Hz, 1H), 3.48 (t, J = 10.1 Hz, 1H), 3.11 - 3.06 (m, 3H), 3.06 - 2.81 (m, 1H), 2.22 (s, 3H), 1.86 (tt, J = 8.8, 5.0 Hz, 1H), 0.93 - 0.86 (m, 2H), 0.73 - 0.58 (m, 2H).

[0691]

[0571] UPLC-MS (basic method, 4 minutes): Rt: 1.16 minutes, m / z: 312.1 [M+H] + . [Example]

[0692] Example 56: Synthesis of Compound 44

[0693] [ka]

[0694] tert-Butyl 7-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.84 mmol), 2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane (288 mg, 1.27 mmol), and N,N-diisopropylethylamine (0.37 mL, 2.12 mmol) in NMP (5 mL) was heated to 120° C. and stirred for 20 hours. The reaction mixture was cooled to ambient temperature and then added dropwise to ice water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2×10 mL), and then dried under reduced pressure to give the title compound as a solid (300 mg, 0.705 mmol, 83%).

[0695]

[0573] 1 H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 5.9 Hz, 1H), 6.15 (s, 1H), 6.03 (s, 1H), 3.69 (s, 8H), 1.96–1.81 (m, 1H), 1.86–1.65 (m, 3H), 1.50–1.33 (m, 10H), 0.96 (d, J = 8.5 Hz, 2H), 0.77–0.61 (m, 2H).

[0696]

[0574] UPLC-MS (basic method, 4 minutes): Rt=1.84 minutes, m / z=426.3[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-amine To a solution of tert-butyl 7-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (150 mg, 0.35 mmol) in anhydrous THF (7 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.5 mL, 3.5 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was then cooled to 0° C. and quenched with water (1.3 mL), followed by 15% w / v sodium hydroxide solution (1.3 mL), followed by water (3.9 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 10 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 10 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The filtrate was then concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (22 mg, 63 μmol, 18% yield).

[0697]

[0576] 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.30 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 6.24 (s, 1H), 6.03 (s, 1H), 3.76 - 3.51 (m, 4H), 2.94 (s, 4H), 2.23 (s, 3H), 1.92 - 1.76 (m, 1H), 1.66 - 1.55 (m, 4H), 1.01 - 0.77 (m, 2H), 0.83 - 0.49 (m, 2H).

[0698]

[0577] UPLC-MS (basic method, 4 minutes): Rt=1.23 minutes, m / z=340.1[M+H] + . [Example]

[0699] Example 57: Synthesis of Compound 45

[0700] [ka]

[0701] tert-Butyl N-[[2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan-4-yl]methyl]carbamate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (202 mg, 0.764 mmol), tert-butyl N-({2-azabicyclo[2.2.1]heptan-4-yl}methyl)carbamate (190 mg, 0.840 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol) in n-butanol (5 mL) was heated to 100° C. and stirred for 24 h. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was then suspended in water (20 mL) and extracted with CHCl (3×20 mL). The combined organic extracts were dried over MgSO and then concentrated to dryness under reduced pressure. The crude material was purified by normal phase column chromatography on silica gel eluting with a gradient of CH2Cl2 to 1:9 2M NH3:CH2Cl2 in MeOH to afford the title compound as an oil (232 mg, 0.486 mmol, 64%).

[0702]

[0579] 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.26 (s, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.01 (s, 1H), 6.18 (s, 2H), 4.46 (s, 1H), 3.28 (d, J = 5.4 Hz, 2H), 3.20 (d, J = 6.2 Hz, 2H), 3.07 (s, 1H), 1.85 (s, 1H), 1.70 (s, 1H), 1.52 (d, J = 10.5 Hz, 2H), 1.39 (s, 9H), 1.36 (s, 2H), 0.90 (s, 2H), 0.78 - 0.56 (m, 2H).

[0703]

[0580] UPLC-MS (basic method, 4 minutes): Rt: 1.68 minutes, m / z=426.4[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methylaminomethyl)-2-azabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-amine To a solution of tert-butyl N-[[2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan-4-yl]methyl]carbamate (230 mg, 0.427 mmol) in anhydrous THF (7 mL) was added a 2.4 M solution of lithium aluminum hydride in THF (1.8 mL, 4.3 mmol) at 0° C. The reaction mixture was then heated to reflux and stirred for 3 h. The reaction was then cooled to 0° C. and quenched by the dropwise addition of water (1.7 mL), followed by a 15% w / v aqueous solution of NaOH (1.7 mL), followed by water (5.1 mL). The reaction mixture was allowed to warm to room temperature and stirred for 15 min. MgSO4 (approximately 1 g) was then added and the reaction mixture was stirred for 16 h. The reaction mixture was filtered through a pad of Celite, and the filter cake was washed with EtOAc (20 mL), and the filtrate was concentrated to dryness under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC to give the title compound (55 mg, 0.16 mmol, 38%) as a solid.

[0704]

[0582] 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.26 (s, 1H), 7.79 (d, J = 5.7 Hz, 1H), 6.17 (s, 2H), 4.48 (s, 1H), 3.14 (s, 1H), 2.71 (s, 2H), 2.35 (s, 3H), 1.93 - 1.46 (m, 6H), 1.39 (s, 2H), 0.91 (d, J = 8.3 Hz, 2H), 0.64 (dt, J = 6.8, 3.4 Hz, 2H).

[0705]

[0583] UPLC-MS (basic method, 4 minutes): Rt: 1.23 minutes, m / z=340.3[M+H] + . [Example]

[0706] Example 58: Synthesis of Compound 46

[0707] [ka]

[0708] tert-Butyl 3-[1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]azetidin-3-yl]azetidine-1-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (395 mg, 1.68 mmol), tert-butyl[3,3'-biazetidine]-1-carboxylate hydrochloride (500 mg, 2.01 mmol), and N,N-diisopropylethylamine (1.0 mL, 5.9 mmol) in NMP (6 mL) was heated to 120 °C and stirred for 20 h. The reaction mixture was then cooled to ambient temperature and added dropwise to ice-water (100 mL) with stirring, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2 × 10 mL), and then dried under reduced pressure. The crude material was purified by flash column chromatography using a gradient of CHCl to 9:1 CHCl:2M NHMeOH to give the title compound as a solid (205 mg, 0.478 mmol, 29%).

[0709]

[0585] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.43 (s, 1H), 7.84 (d, J = 5.8 Hz, 1H), 6.48 - 6.08 (m, 2H), 4.12 - 4.02 (m, 2H), 3.95 (s, 2H), 3.62 (dd, J = 8.6, 4.8 Hz, 2H), 3.53 (s, 2H), 2.99 - 2.75 (m, 2H), 1.89 - 1.72 (m, 1H), 1.46 - 1.29 (m, 9H), 0.98 - 0.83 (m, 2H), 0.75 - 0.56 (m, 2H).

[0710]

[0586] UPLC-MS (basic method, 4 minutes): Rt=1.56 minutes, m / z=412.5[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[3-(1-methylazetidin-3-yl)azetidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl 3-[1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]azetidin-3-yl]azetidine-1-carboxylate (65 mg, 0.158 mmol) in THF (10 mL) was added a 2.4 M solution of lithium aluminum hydride in THF (0.65 mL, 1.58 mmol) at 0° C. The reaction mixture was then heated to reflux and stirred for 3 h. The reaction mixture was cooled to 0° C. and then quenched with water (0.60 mL), followed by 15% w / v sodium hydroxide solution (0.60 mL), followed by water (1.8 mL). The reaction mixture was allowed to warm to room temperature and stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite, and the filter cake was washed with EtOAc (20 mL). The filtrate was concentrated to dryness under reduced pressure. The residue was purified by reverse phase basic preparative HPLC to give the title compound as a solid (22 mg, 67 mmol, 42%).

[0711]

[0588] 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.42 (s, 1H), 7.83 (d, J = 6.3 Hz, 1H), 6.53 - 5.71 (m, 2H), 4.16 - 3.93 (m, 2H), 3.74 - 3.55 (m, 2H), 3.28 - 3.18 (m, 2H), 2.86 - 2.78 (m, 3H), 2.62 (s, 1H), 2.22 - 2.15 (m, 3H), 1.91 - 1.79 (m, 1H), 0.97 - 0.73 (m, 2H), 0.68 - 0.57 (m, 2H).

[0712]

[0589] UPLC-MS (basic method, 4 minutes): Rt=1.16 minutes, m / z=326.2[M+H] + . [Example]

[0713] Example 59: Synthesis of Compound 53

[0714] [ka]

[0715] tert-Butyl (1S,5R)-3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.27 mmol), tert-butyl (1S,5R)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (303 mg, 1.53 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.18 mmol) in NMP (5 mL) was heated to 120° C. and stirred for 20 hours. The reaction mixture was then added dropwise to ice water (approximately 100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration and then washed with water (2×10 mL). The material was then dried under reduced pressure for 2 hours to give the title compound as a solid (390 mg, 0.981 mmol, 77%).

[0716]

[0591] 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.41 (s, 1H), 7.87 (d, J = 5.8 Hz, 1H), 6.43 - 6.10 (m, 2H), 4.69 (t, J = 5.5 Hz, 1H), 4.18 (d, J = 12.5 Hz, 1H), 4.05 - 3.87 (m, 2H), 3.53 - 3.36 (m, 1H), 3.25 - 3.03 (m, 3H), 1.85 (tt, J = 8.6, 4.9 Hz, 1H), 1.38 (s, 9H), 0.96 - 0.86 (m, 2H), 0.74 - 0.61 (m, 2H).

[0717]

[0592] UPLC-MS (basic method, 2 minutes): Rt: 1.03 minutes, m / z=398.2[M+H] + . N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(1R,5R)-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyrimidin-4-amine To a solution of tert-butyl (1S,5R)-3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (100 mg, 0.252 mmol) in CHCl (2 mL) was added trifluoroacetic acid (2.0 mL, 26.1 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness under reduced pressure. The crude residue was then loaded onto an SCX-2 cartridge, and the cartridge was then washed with water (20 mL), followed by MeOH (20 mL). The compound was eluted with 2M NH in MeOH (40 mL), and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (54 mg, 0.182 mmol, 72%).

[0718]

[0594] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.37 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 6.24 (s, 2H), 4.35 (dd, J = 6.6, 4.7 Hz, 1H), 3.92 (dd, J = 11.6, 1.4 Hz, 1H), 3.87 (d, J = 12.1 Hz, 1H), 3.65 (t, J = 7.7 Hz, 1H), 3.30 - 3.26 (m, 1H), 3.23 - 3.15 (m, 2H), 3.10 (dd, J = 7.9, 4.1 Hz, 1H), 1.86 (tt, J = 8.4, 5.1 Hz, 1H), 0.93 - 0.87 (m, 2H), 0.70 - 0.62 (m, 2H).

[0719]

[0595] 1H NMR (400 MHz, chloroform-d) δ 8.03 (d, J = 5.7 Hz, 1H), 7.16 (s, 1H), 6.11 (d, J = 4.5 Hz, 1H), 4.54 (dd, J = 6.6, 4.7 Hz, 1H), 4.11 (dd, J = 11.5, 1.4 Hz, 1H), 4.06 (d, J = 12.3 Hz, 1H), 3.85 (d, J = 7.9 Hz, 1H), 3.46 (dd, J = 11.3, 7.2 Hz, 1H), 3.40 - 3.23 (m, 3H), 1.86 (tt, J = 8.3, 4.8 Hz, 1H), 0.99 - 0.90 (m, 2H), 0.76 - 0.69 (m, 2H).

[0720]

[0596] UPLC-MS (basic method, 4 minutes): Rt: 0.93 minutes, m / z=298.1 [M+H] + . [Example]

[0721] Example 60: Synthesis of Compound 52

[0722] [ka]

[0723] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(1R,5R)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyrimidin-4-amine To a solution of tert-butyl (1S,5R)-3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (144 mg, 0.363 mmol) in anhydrous THF (3 mL) was added a 2.4 M solution of lithium aluminum hydride in THF (1.5 mL, 3.6 mmol) at 0° C., and the reaction mixture was heated to 75° C. for 3 h. The reaction mixture was cooled to room temperature and then quenched with water (0.15 mL), followed by 10% w / v sodium hydroxide solution (0.15 mL), followed by water (0.5 mL). The reaction mixture was stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added, and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite, and the filter cake was washed with EtOAc (20 mL). The eluate was concentrated to dryness under reduced pressure to give N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[(1R,5R)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl]pyrimidin-4-amine as a solid (82 mg, 0.25 mmol, 70%).

[0724]

[0598] 1 H NMR (400 MHz, DMSO-D6) δ 11.87 (s, 1H), 9.32 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 6.22 (s, 2H), 3.84 (dd, J = 12.0, 4.3 Hz, 2H), 3.75 (dd, J = 6.6, 4.2 Hz, 1H), 3.55 - 3.43 (m, 1H), 3.13 - 3.06 (m, 3H), 3.03 - 2.94 (m, 1H), 2.22 (s, 3H), 1.86 (tt, J = 8.4, 5.1 Hz, 1H), 0.98 - 0.84 (m, 2H), 0.73 - 0.59 (m, 2H).

[0725]

[0599] UPLC-MS (basic method, 4 minutes): Rt: 1.17 minutes, m / z=312.0[M+H] + . [Example]

[0726] Example 61: Synthesis of Compound 48

[0727] [ka]

[0728] N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 -[3-(dimethylamino)propyl]-N 2 -methyl-pyrimidine-2,4-diamine To a solution of tert-butyl N-[3-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-methyl-amino]propyl]-N-methyl-carbamate (230 mg, 0.573 mmol) in anhydrous THF (7 mL) was added a 2.4 M solution of lithium aluminum hydride in THF (4.06 mL, 9.74 mmol) at 0° C., and the reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was cooled to 0° C. and then quenched with water (3.2 mL), followed by 15% w / v sodium hydroxide solution (3.2 mL), followed by water (9.8 mL). The reaction mixture was stirred for 15 min, after which magnesium sulfate (approximately 1 g) was added, and the reaction mixture was stirred for an additional 15 min. The reaction mixture was passed through a pad of Celite, the filter cake was washed with EtOAc (20 mL), and the eluate was concentrated to dryness. The crude compound was loaded onto an SCX-2 cartridge, which was then washed with methanol (10 mL), and the compound was then eluted with 2M NH3 in methanol (20 mL), and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (170 mg, 0.539 mmol, 94%).

[0729]

[0601] 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 5.6 Hz, 1H), 6.21 - 6.05 (m, 2H), 3.55 (dd, J = 8.4, 6.4 Hz, 2H), 3.04 (s, 3H), 2.21 (t, J = 7.1 Hz, 2H), 2.11 (s, 6H), 1.90 - 1.79 (m, 1H), 1.73 - 1.60 (m, 2H), 1.00 - 0.82 (m, 2H), 0.67 - 0.54 (m, 2H).

[0730]

[0602] UPLC-MS (basic method, 4 minutes): Rt: 1.25 minutes, m / z=316.1[M+H] + . [Example]

[0731] Example 62: Synthesis of Compound 101

[0732] [ka]

[0733] tert-Butyl N-[3-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-methyl-amino]propyl]-N-methyl-carbamate A solution of tert-butyl methyl (3-(methylamino)propyl)carbamate (429 mg, 2.12 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.849 mmol), and N,N-diisopropylethylamine (0.52 mL, 2.97 mmol) in 1-butanol (7 mL) was heated to 100° C. and stirred for 20 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was diluted with water (20 mL) and extracted with CHCl (2×20 mL). The organic layer was then washed with brine (50 mL), dried over MgSO, and concentrated under reduced pressure to give the title compound as an oil (345 mg, 0.791 mmol, 93%).

[0734]

[0604] 1 H NMR (400 MHz, methanol-d4) δ 7.85 (d, J = 5.9 Hz, 1H), 6.13 (s, 2H), 3.61 (t, J = 7.2 Hz, 2H), 3.27 (t, J = 7.7 Hz, 2H), 3.12 (s, 3H), 2.85 (s, 3H), 1.93 - 1.85 (m, 3H), 1.51 - 1.37 (m, 9H), 1.01 - 0.94 (m, 2H), 0.76 - 0.68 (m, 2H).

[0735]

[0605] UPLC-MS (basic method, 4 minutes): Rt=1.73 minutes, m / z=402.3[M+H] + . N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 -methyl-N 2 -[3-(methylamino)propyl]pyrimidine-2,4-diamine To a solution of tert-butyl N-[3-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-methyl-amino]propyl]-N-methyl-carbamate (115 mg, 0.286 mmol) in CHCl (5 mL) was added trifluoroacetic acid (5.0 mL, 0.286 mmol) dropwise at 0° C., and the reaction was stirred for 30 minutes. The reaction mixture was concentrated to dryness under reduced pressure. The crude compound was loaded onto an SCX cartridge, and the cartridge was then washed with methanol. The compound was then eluted with 2M NH in methanol, and the eluate was concentrated to dryness under reduced pressure to give the title compound as a solid (50 mg, 0.17 mmol, 58%).

[0736]

[0607] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.32 (s, 1H), 7.85 - 7.78 (m, 1H), 6.42 - 6.07 (m, 2H), 3.61 - 3.55 (m, 2H), 3.02 (d, J = 4.8 Hz, 3H), 2.56 - 2.52 (m, 2H), 2.29 (d, J = 4.3 Hz, 3H), 1.88 - 1.80 (m, 1H), 1.74 - 1.68 (m, 2H), 0.93 - 0.85 (m, 2H), 0.68 - 0.58 (m, 2H).

[0737]

[0608] UPLC-MS (basic method, 6 minutes): Rt=1.68 minutes, m / z=302.1[M+H] + . [Example]

[0738] Example 63: Synthesis of Compound 65

[0739] [ka]

[0740] tert-Butyl 3-[1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]azetidin-3-yl]azetidine-1-carboxylate A solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (442 mg, 1.68 mmol), tert-butyl[3,3'-biazetidine]-1-carboxylate hydrochloride (500 mg, 2.01 mmol), and N,N-diisopropylethylamine (1.0 mL, 5.9 mmol) in NMP (4 mL) was heated to 120°C and stirred for 20 h. The reaction mixture was then cooled to ambient temperature and added dropwise with stirring to ice water (100 mL), resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (2 x 10 mL), and then dried under reduced pressure. The crude material was purified by normal phase flash column chromatography on silica gel eluting with a gradient of CH2Cl2 to 2M NH3 in 9:1 CH2Cl2:MeOH to afford the title compound as a solid (222 mg, 0.479 mmol, 29%).

[0741]

[0610] 1 H NMR (400 MHz, methanol-d4) δ 7.81 (s, 1H), 6.35 (s, 1H), 6.23 (s, 1H), 4.19 (d, J = 8.3 Hz, 2H), 4.06 (d, J = 8.2 Hz, 2H), 3.77 (s, 2H), 3.65 (s, 2H), 3.11 - 3.01 (m, 1H), 2.99 - 2.85 (m, 2H), 2.05 (s, 2H), 1.89 - 1.72 (m, 2H), 1.72 - 1.61 (m, 4H), 1.58 - 1.25 (m, 9H).

[0742]

[0611] UPLC-MS (basic method, 4 minutes): Rt: 1.79 minutes, m / z: 440.4 [M+H] + . N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-[3-(1-methylazetidin-3-yl)azetidin-1-yl]pyrimidin-4-amine To a solution of tert-butyl 3-[1-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]azetidin-3-yl]azetidine-1-carboxylate (199 mg, 0.453 mmol) in anhydrous THF (10 mL) was added dropwise at 0° C. A 2.4 M solution of lithium aluminum hydride in THF (1.86 mL, 4.53 mmol) was added dropwise. The reaction mixture was heated to reflux and stirred for 3 h. The reaction mixture was then cooled to 0° C. and quenched with water (1.6 mL), followed by 15% w / v sodium hydroxide solution (1.6 mL), followed by water (3.6 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 10 min, after which magnesium sulfate (approximately 1 g) was added and the reaction mixture was stirred for an additional 10 min. The reaction mixture was passed through a pad of Celite and the filter cake was washed with EtOAc (20 mL). The filtrate was then concentrated to dryness under reduced pressure. The residue was purified by reverse-phase basic preparative HPLC to give the title compound as a solid (37 mg, 0.11 mmol, 23%).

[0743]

[0613] 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.41 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.28 (s, 2H), 4.03 (d, J = 8.3 Hz, 2H), 3.66 (dd, J = 8.5, 5.4 Hz, 2H), 3.25 (t, J = 7.3 Hz, 2H), 3.08 - 2.92 (m, 1H), 2.88 - 2.76 (m, 3H), 2.64 - 2.58 (m, 1H), 2.18 (s, 3H), 2.06 - 1.91 (m, 2H), 1.72 - 1.48 (m, 6H).

[0744]

[0614] UPLC-MS (basic method, 4 minutes): Rt: 1.34 minutes, m / z: 354.1 [M+H] + . [Example]

[0745] Example 64: Synthesis of Compound 67

[0746] [ka]

[0747] 2-Azabicyclo[2.1.1]hexan-4-ylmethanol; Hydrochloride To a solution of tert-butyl 4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.00 g, 4.69 mmol) in 1,4-dioxane (20 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol) at room temperature, and the reaction was stirred for 6 h. The reaction mixture was then concentrated to dryness under reduced pressure to give the title compound (672 mg, 4.49 mmol, 98%) as a semisolid.

[0748]

[0616] 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 2H), 4.08 (t, J = 1.6 Hz, 1H), 3.60 (s, 2H), 3.10 - 3.01 (m, 2H), 1.86 - 1.78 (m, 2H), 1.51 - 1.43 (m, 2H).

[0617] UPLC-MS (basic method, 2 minutes): Rt: 0.38 minutes, m / z=114.0[M-Cl] + .

[0749] [2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-yl]methanol A solution of 2-azabicyclo[2.1.1]hexan-4-ylmethanol; hydrochloride (722 mg, 4.82 mmol), 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1.06 g, 4.02 mmol), and N,N-diisopropylethylamine (3.2 mL, 18 mmol) in NMP (10 mL) was heated to 120° C. in a sealed tube and stirred for 48 h. The reaction mixture was cooled to room temperature and then loaded ...

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof. [In the formula, W is selected from the group consisting of N, C—H, and C—F; Y is NH, N-CH ３ , O., S., C.H. ２ , C.H.F., C.F. ２ , CH(CH ３ ), C(CH ３ ) ２ , and C(CH ２ CH ２ ), CHCF ３ , CHCF ２ H, CH(OCF ２ H), CHOH, C(CH ３ )OH, and CH(OCH ３ ) selected from the group consisting of; Ring Z is a 4-10 membered N-linked monocyclic or bicyclic heterocycle, Z is halo, hydroxyl, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkoxy, and cyano; L １ is a bond or C １ ~C ６ Alkylene (1, 2 or 3 halogens, R ４ and optionally substituted by R ３ is H, C １ ~C ６ Alkyl, NR'R', S(O) ０～２ C １ ~C ４ Alkyl, SO ２ N (R Ｎ ) ２ , N(R Ｎ ) S.O. ２ -C １ ~C ４ alkyl, and heterocyclyl, where heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkoxy, and oxo; R ４ is halogen and C １ ~C ６ alkyl, or two R ４ is R ４ Together with the carbon to which it is bonded, C ３ ~C ５ forming a carbocyclic ring; R', each occurrence, is H, C １ ~C ６ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ６ Alkylene -O-C １ ~C ４ Alkyl, C １ ~C ６ Alkylene-SO ２ -C １ ~C ４ and heterocyclyl, wherein heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo; R Ｈ is H, C １ ~C ３ Alkyl, —C(O)—C １ ~C ３ Alkyl, and C(O)-O-C １ ~C ３ selected from the group consisting of alkyl; R Ｎ is H and C １ ~C ３ alkyl, or two R Ｎ is R Ｎ together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocycle; R １ is C ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ is selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ Bicycloalkyl, heterocyclyl, or heteroaryl are selected from halo and C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); R ２ H, F, CF ３ , —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, C ３ ~C ７ cycloalkyl, and heterocyclyl; R ５ H, halo, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); or R ２ and R ５ is R ２ and R ５ together with the carbon atom to which it is attached form a 5- to 6-membered carbocyclic ring; When ring Z is a 6-membered monocyclic heterocycle, L １ is C １ ~C ６ alkylene or L １ is a bond, R ３ is C ２ ~C ６ Alkyl, SO ２ C １ ~C ４ alkyl, and NHR′, where R′ is selected from １ ~C ６ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ６ Alkylene -O-C １ ~C ４ Alkyl, C １ ~C ６ Alkylene-SO ２ -C １ ~C ４ alkyl, and heterocyclyl, where heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ and optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo.

2. W is N, and the compound of formula Ia: 【Chemistry 2】 2. The compound of claim 1, having the formula: or a pharma- ceutically acceptable salt, stereoisomer and / or N-oxide thereof.

3. R １ is 5-6 membered heterocyclyl or C ３ ~C ６ 3. The compound of claim 1 or 2, which is cycloalkyl.

4. R １ But, C ３ ~C ６ The compound according to any one of claims 1 to 3, which is cycloalkyl.

5. R １ The compound according to any one of claims 1 to 4, wherein is cyclopropyl.

6. R １ The compound according to any one of claims 1 to 4, wherein is cyclopentyl.

7. Ring Z is selected from the group consisting of a 4-6 membered monocyclic heterocycle, a 6-10 membered spiro heterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle; Z is selected from halo, hydroxyl, C １ ~C ４ 7. The compound of any one of claims 1 to 6, optionally substituted with one or two substituents each independently selected from the group consisting of alkyl (optionally substituted with one, two or three halogens), and oxo.

8. Ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged cycloheteroalkyl; Ring Z is selected from the group consisting of halo, hydroxyl, C １ ~C ４ 7. The compound of any one of claims 1 to 6, optionally substituted with one or two substituents each independently selected from the group consisting of alkyl (optionally substituted with one, two or three halogens), and oxo.

9. Ring Z is 【Chemistry 3】 The compound according to any one of claims 1 to 6, selected from the group consisting of:

10. Formula Ib: 【Chemistry 4】 10. The compound of any one of claims 1 to 9, represented by: or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

11. Formula Ic: 【Chemistry 5】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein m is 0, 1, or 2.

12. Formula Id: 【Chemistry 6】 10. The compound of any one of claims 1 to 9, represented by: or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

13. Formula Ie: 【Chemistry 7】 10. The compound of any one of claims 1 to 9, represented by: or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

14. L １ The compound according to any one of claims 1 to 13, wherein is a bond.

15. L １ C １ ~C ６ The compound according to any one of claims 1 to 13, which is an alkylene.

16. L １ The compound of claim 15 , wherein is methylene.

17. L １ But one or two R ４ C replaced by １ ~C ４ The compound according to any one of claims 1 to 13, which is an alkylene.

18. L １ But one or two R ４ 18. The compound of any one of claims 1 to 13 and 17, wherein R is methylene substituted by:

19. R ４ But, C １ ~C ３ 20. The compound of claim 18 which is alkyl (optionally substituted with 1, 2 or 3 halogens).

20. Two R's ４ But, R ４ Together with the carbon to which it is bonded, C ３ ~C ４ The compound according to claim 18, which forms a carbocyclic ring.

21. R ３ is H or C １ ~C ６ The compound according to any one of claims 1 to 20, which is alkyl.

22. R ３ is H or methyl.

23. R ３ The compound according to any one of claims 1 to 20, wherein is NR'R'.

24. R ３ But NH ２ , NH(CH ３ ), or N(CH ３ ) ２ 24. The compound of claim 23, wherein

25. R ３ But halo, hydroxyl, C １ ~C ４ 21. The compound of any one of claims 1 to 20, which is a 4-6 membered heterocyclyl optionally substituted by 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted by 1, 2 or 3 halogen), and oxo.

26. R ２ The compound according to any one of claims 1 to 25, wherein is H or F.

27. R ２ The compound according to any one of claims 1 to 26, wherein is H.

28. R ５ The compound of claim 1 , wherein is H or methyl.

29. R ５ The compound of claim 1 or 28, wherein is H. 【Request 30】 【Chemical 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 【Chemistry 8-5】 【Chemistry 8-6】 【Chemistry 8-7】 【Chemistry 8-8】 【Chemistry 8-9】 【Chemistry 8-10】 【Chemistry 8-11】 【Chemistry 8-12】 【Chemistry 8-13】 【Chemistry 8-14】 【Chemistry 8-15】 【Chemistry 8-16】 【Chemistry 8-17】 【Chemistry 8-18】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

31. Compound of Formula II: 【Chemistry 9】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof, W is selected from the group consisting of N, C—H, and C—F; Y is NH, N-CH ３ , O., S., C.H. ２ , C.F.H., C.F. ２ , CH(CH ３ ), C(CH ３ ) ２ , C(CH ２ CH ２ ), CHCF ３ , CHCF ２ H, CH(OCF ２ H), CHOH, C(CH ３ )OH, and CH(OCH ３ ) selected from the group consisting of; Ring A is C １ ~C ４ is a 5-6 membered heteroaryl optionally substituted with alkyl; Ring Z is selected from the group consisting of 6-10 membered spiro heterocycles, 6-10 membered fused bicyclic heterocycles, and 6-10 membered bridged heterocycles, Z being selected from halo, hydroxyl, C １ ~C ４ Alkyl (optionally substituted with 1, 2 or 3 halogens), —C(O)OH, —C(O)—O—C １ ~C ４ Alkyl, oxo, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkoxy, and cyano; L １ is a bond or C １ ~C ６ Alkylene (one, two or three R ４ and optionally substituted by R ３ is H, C １ ~C ６ Alkyl, NR'R', S(O) ０～２ C １ ~C ４ Alkyl, SO ２ N (R Ｎ ) ２ , N(R Ｎ ) S.O. ２ -C １ ~C ４ alkyl, and heterocyclyl, where heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkoxy, and oxo; R ４ is halogen and C １ ~C ６ alkyl, or two R ４ is R ４ Together with the carbon to which it is bonded, C ３ ~C ５ forming a carbocyclic ring; R', each occurrence, is H, C １ ~C ６ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ６ Alkylene -O-C １ ~C ４ Alkyl, C １ ~C ６ Alkylene-SO ２ -C １ ~C ４ and heterocyclyl, wherein heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo; R Ｈ is H, C １ ~C ３ Alkyl, —C(O)—C １ ~C ３ Alkyl, and C(O)-O-C １ ~C ３ selected from the group consisting of alkyl; R Ｎ is H and C １ ~C ３ alkyl, or two R Ｎ is R Ｎ together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocycle; R １ is C ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ is selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ Bicycloalkyl, heterocyclyl, or heteroaryl are selected from halo and C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); R ２ H, F, CF ３ , —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, C ３ ~C ７ cycloalkyl, and heterocyclyl; R ５ H, halo, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); or R ２ and R ５ is R ２ and R ５ together with the carbon atom to which it is attached form a 5- or 6-membered carbocyclic ring. 【Chemistry 10-1】 【Chemistry 10-2】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

32. Compound of Formula III: 【Chemistry 11】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof, W is selected from the group consisting of N, C—H, and C—F; Y is NH, N-CH ３ , O., S., C.H. ２ , C.F.H., C.F. ２ , CH(CH ３ ), C(CH ３ ) ２ , C(CH ２ CH ２ ), CHCF ３ , CHCF ２ H, CH(OCF ２ H), CHOH, C(CH ３ )OH, and CH(OCH ３ ) selected from the group consisting of; Ring Z is selected from the group consisting of 6-10 membered spiro heterocycles, 6-10 membered fused bicyclic heterocycles, and 6-10 membered bridged heterocycles, Z being selected from halo, hydroxyl, C １ ~C ４ Alkyl (optionally substituted with 1, 2 or 3 halogens), —C(O)OH, —C(O)—O—C １ ~C ４ Alkyl, oxo, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkoxy, and cyano; L １ is a bond or C １ ~C ６ Alkylene (one, two or three R ４ and optionally substituted by R ３ is H, C １ ~C ６ Alkyl, NR'R', S(O) ０～２ C １ ~C ４ Alkyl, SO ２ N (R Ｎ ) ２ , N(R Ｎ ) S.O. ２ -C １ ~C ４ alkyl, and heterocyclyl, where heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkoxy, and oxo; R ４ is halogen and C １ ~C ６ alkyl, or two R ４ is R ４ Together with the carbon to which it is bonded, C ３ ~C ５ forming a carbocyclic ring; R', each occurrence, is H, C １ ~C ６ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ６ Alkylene -O-C １ ~C ４ Alkyl, C １ ~C ６ Alkylene-SO ２ -C １ ~C ４ and heterocyclyl, wherein heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo; R Ｈ is H, C １ ~C ３ Alkyl, —C(O)—C １ ~C ３ Alkyl, and C(O)-O-C １ ~C ３ selected from the group consisting of alkyl; R Ｎ is H and C １ ~C ３ alkyl, or two R Ｎ is R Ｎ together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocycle; R １ is C ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ is selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ Bicycloalkyl, heterocyclyl, or heteroaryl are selected from halo and C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); R ２ H, F, CF ３ , —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, C ３ ~C ７ cycloalkyl, and heterocyclyl; R ５ H, halo, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); or R ２ and R ５ is R ２ and R ５ together with the carbon atom to which it is attached form a 5- or 6-membered carbocyclic ring.

33. W is N and has formula IIIa: 【Chemistry 12】 33. The compound of claim 32, or a pharma- ceutically acceptable salt, stereoisomer and / or N-oxide thereof, having the formula:

34. R １ is 5-6 membered heterocyclyl or C ３ ~C ６ The compound of any one of claims 31 to 33, which is cycloalkyl.

35. R １ C ３ ~C ６ The compound according to any one of claims 31 to 34, which is a chloroalkyl.

36. R １ The compound of any one of claims 31 to 35, wherein is cyclopropyl.

37. R １ The compound of any one of claims 31 to 35, wherein is cyclopentyl.

38. Ring Z is 【Chemistry 13】 The compound according to any one of claims 31 to 37, selected from the group consisting of:

39. L １ The compound of any one of claims 31 to 38, wherein is a bond.

40. L １ C １ ~C ６ The compound of any one of claims 31 to 38, which is an alkylene.

41. L １ The compound of claim 40, wherein is methylene.

42. L １ But one or two R ４ C replaced by １ ~C ４ The compound of any one of claims 31 to 38, which is an alkylene.

43. L １ But one or two R ４ 43. The compound of any one of claims 31 to 38 and 42, wherein R is methylene substituted by:

44. R ４ But, C １ ~C ３ 44. The compound of claim 43, which is alkyl (optionally substituted with 1, 2 or 3 halogens).

45. Two R's ４ But, R ４ Together with the carbon to which it is bonded, C ３ ~C ４ 44. The compound of claim 43 which forms a carbocyclic ring.

46. R ３ is H or C １ ~C ６ The compound of any one of claims 31 to 45, which is alkyl.

47. R ３ is H or methyl.

48. R ３ The compound of any one of claims 31 to 45, wherein is NR'R'.

49. R ３ But NH ２ , NH(CH ３ ), or N(CH ３ ) ２ 49. The compound of claim 48, wherein:

50. R ３ But halo, hydroxyl, C １ ~C ４ 46. ​​The compound of any one of claims 31-45, which is a 4-6 membered heterocyclyl optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo.

51. R ２ The compound according to any one of claims 31 to 50, wherein is H or F.

52. R ２ The compound according to any one of claims 31 to 51, wherein is H.

53. R ５ is H or methyl.

54. R ５ 54. The compound of any one of claims 31, 32 and 53, wherein is H.

55. Compound of Formula VI: 【Chemistry 14】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof, W is selected from the group consisting of N, C—H, and C—F; Y is NH, N-CH ３ , O., S., C.H. ２ , C.F. ２ , CH(CH ３ ), C(CH ３ ) ２ , and C(CH ２ CH ２ ) selected from the group consisting of; Ring Z is a 4-10 membered N-linked heterocycle, Z is halo, hydroxyl, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo; L １ is a bond or C １ ~C ６ alkylene (optionally substituted with 1, 2 or 3 halogen); R ３ is H, C １ ~C ６ is selected from the group consisting of alkyl, NR′R′, and heterocyclyl, wherein heterocyclyl is selected from halo, hydroxyl, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo; R', each occurrence, is H, C １ ~C ６ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ６ Alkylene -O-C １ ~C ４ Alkyl, C １ ~C ６ Alkylene-SO ２ -C １ ~C ４ and heterocyclyl, wherein heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo; R Ｈ is H, C １ ~C ３ Alkyl, —C(O)—C １ ~C ３ Alkyl, and C(O)-O-C １ ~C ３ selected from the group consisting of alkyl; R １ is C ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ is selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; ３ ~C １０ Cycloalkyl, heterocyclyl, or heteroaryl are selected from halo and C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); R ２ H, F, CF ３ , —C(O)—O-methyl, —C(O)OH, —O-methyl, C ３ ~C ７ cycloalkyl, and heterocyclyl; When ring Z is a 6-membered monocyclic heterocycle, L １ is C １ ~C ６ alkylene or L １ is a bond, R ３ is C １ ~C ６ alkyl and NHR'. The compound is selected from

56. A method of treating a proliferative disease comprising administering to a patient a therapeutically effective amount of a compound of formula IV: 【Chemistry 15】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof. [In the formula, W is selected from the group consisting of N, C—H, and C—F; Y is NH, N-CH ３ , O., S., C.H. ２ , C.F.H., C.F. ２ , CH(CH ３ ), C(CH ３ ) ２ , C(CH ２ CH ２ ), CHCF ３ , CHCF ２ H, CH(OCF ２ H), CHOH, C(CH ３ )OH, and CH(OCH ３ ) selected from the group consisting of; Ring Z is a 4-10 membered N-linked heterocycle, Z is halo, hydroxyl, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogens), oxo, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkoxy, and cyano; L １ is a bond or C １ ~C ６ Alkylene (one, two or three R ４ and optionally substituted by R ３ is H, C １ ~C ６ Alkyl, NR'R', S(O) ０～２ C １ ~C ４ Alkyl, SO ２ N (R Ｎ ) ２ , N(R Ｎ ) S.O. ２ -C １ ~C ４ alkyl, and heterocyclyl, where heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkoxy, and oxo; R ４ is halogen and C １ ~C ６ alkyl, or two R ４ is R ４ Together with the carbon to which it is bonded, C ３ ~C ５ forming a carbocyclic ring; R', each occurrence, is H, C １ ~C ６ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ６ Alkylene -O-C １ ~C ４ Alkyl, C １ ~C ６ Alkylene-SO ２ -C １ ~C ４ and heterocyclyl, wherein heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogen), and oxo; R Ｈ is H, C １ ~C ３ Alkyl, —C(O)—C １ ~C ３ Alkyl, and C(O)-O-C １ ~C ３ selected from the group consisting of alkyl; R Ｎ is H and C １ ~C ３ alkyl, or two R Ｎ is R Ｎ together with the nitrogen atom to which it is attached form a 4- to 6-membered heterocycle; R １ is C １ ~C ６ Alkyl, C ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ is selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; １ ~C ６ Alkyl, C ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ Bicycloalkyl, heterocyclyl, or heteroaryl are selected from halo and C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); R ２ H, F, CF ３ , —C(O)—O-methyl, —C(O)OH, —O-methyl, —O-ethyl, methyl, C ３ ~C ７ cycloalkyl, and heterocyclyl; R ５ H, halo, C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); or R ２ and R ５ is R ２ and R ５ together with the carbon atom to which it is attached form a 5- or 6-membered carbocyclic ring. to a subject having a proliferative disease.

57. W is N, and the compound of formula IVa: 【Chemistry 16】 57. The method of claim 56, or a pharma- ceutically acceptable salt, stereoisomer and / or N-oxide thereof, having the formula:

58. R １ is 5-6 membered heterocyclyl or C ３ ~C ６ 58. The method of claim 56 or 57, wherein said alkyl group is cycloalkyl.

59. R １ But, C ３ ~C ６ The method of any one of claims 56 to 58, wherein the is cycloalkyl.

60. R １ The method of any one of claims 56 to 59, wherein is cyclopropyl.

61. R １ The method of any one of claims 56 to 59, wherein is cyclopentyl.

62. Ring Z is selected from the group consisting of a 4-6 membered monocyclic heterocycle, a 6-10 membered spiro heterocycle, a 6-10 membered fused bicyclic heterocycle, and a 6-10 membered bridged heterocycle; Z is selected from halo, hydroxyl, C １ ~C ４ 62. The method of any one of claims 56 to 61, optionally substituted with one or two substituents each independently selected from the group consisting of alkyl (optionally substituted with one, two or three halogens), and oxo.

63. Ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged cycloheteroalkyl; Z is selected from halo, hydroxyl, C １ ~C ４ 63. The method of any one of claims 56 to 62, optionally substituted with one or two substituents each independently selected from the group consisting of alkyl (optionally substituted with one, two or three halogens), and oxo.

64. Ring Z is 【Chemistry 17】 The method of any one of claims 56 to 62, selected from the group consisting of:

65. Formula IVb: 【Chemistry 18】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

66. Formula IVc: 【Chemistry 19】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein m is 0, 1, or 2.

67. Formula IVd: 【Chemistry 20】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

68. Formula IVe: 【Chemistry 21】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

69. L １ The method of any one of claims 56 to 68, wherein is a bond.

70. L １ C １ ~C ６ The method of any one of claims 56 to 68, wherein the alkylene is alkylene.

71. L １ The method of claim 70, wherein is methylene.

72. L １ But one or two R ４ C replaced by １ ~C ４ The method of any one of claims 56 to 68, wherein the alkylene is alkylene.

73. L １ But one or two R ４ The method of any one of claims 56 to 68 and 72, wherein methylene is substituted by:

74. R ４ But, C １ ~C ３ 74. The method of claim 73, wherein said alkyl is optionally substituted with 1, 2 or 3 halogens.

75. Two R's ４ But, R ４ Together with the carbon to which it is bonded, C ３ ~C ４ 74. The method of claim 73, wherein a carbocyclic ring is formed.

76. R ３ is H or C １ ~C ６ The method of any one of claims 56 to 75, wherein the alkyl group is alkyl.

77. R ３ is H or methyl.

78. R ３ The method of any one of claims 56 to 75, wherein is NR'R'.

79. R ３ But NH ２ , NH(CH ３ ), or N(CH ３ ) ２ 79. The method of claim 78, wherein:

80. R ３ But halo, hydroxyl, C １ ~C ４ 76. The method of any one of claims 56-75, wherein the heterocyclyl is a 4-6 membered heterocyclyl optionally substituted by 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted by 1, 2 or 3 halogen), and oxo.

81. R ２ The method of any one of claims 56 to 80, wherein is H, F, or methyl.

82. R ２ The method of any one of claims 56 to 81, wherein is H.

83. R ５ is H or methyl.

84. R ５ The method of claim 56 or 83, wherein is H.

85. 【Chemical 22】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

86. Formula V: 【Chemistry 23】 or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof [ During the ceremony, W' is selected from the group consisting of N, C-H, and C-F; Y' is NH, N-CH ３ , O., S., C.H. ２ , C.F.H., C.F. ２ , CH(CH ３ ), C(CH ３ ) ２ , C(CH ２ CH ２ ), CHCF ３ , CHCF ２ H, CH(OCF ２ H), CHOH, C(CH ３ )OH, and CH(OCH ３ ) selected from the group consisting of; R Ｌ is H or C １ ~C ６ is alkyl; L ２ is a bond or C １ ~C ６ Alkylene (one, two or three R ２４ and optionally substituted by R ２３ is NR'R'; R ２４ is halogen and C １ ~C ６ alkyl, or two R ４ is R ４ Together with the carbon to which it is bonded, C ３ ~C ５ forming a carbocyclic ring; R', each occurrence, is H, C １ ~C ６ alkyl (optionally substituted with 1, 2 or 3 halogens), C １ ~C ６ Alkylene -O-C １ ~C ４ Alkyl, C １ ~C ６ Alkylene-SO ２ -C １ ~C ４ and heterocyclyl, wherein heterocyclyl is selected from the group consisting of halo, hydroxyl, C １ ~C ４ optionally substituted with 1 or 2 substituents each independently selected from the group consisting of alkyl (optionally substituted with 1, 2 or 3 halogens), and oxo, or two R' together with the nitrogen to which they are attached form a heterocyclyl, which may be optionally substituted with methyl, halo, cyano, oxo, or hydroxyl; R Ｈ ' is H, C １ ~C ３ Alkyl, —C(O)—C １ ~C ３ Alkyl, and C(O)-O-C １ ~C ３ selected from the group consisting of alkyl; R ２１ is C １ ~C ６ Alkyl, C ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ is selected from the group consisting of bicycloalkyl, heterocyclyl, cyano, halo, heteroaryl, and H; １ ~C ６ Alkyl, C ３ ~C １０ Cycloalkyl, Spiro C ５ ~C １０ Bicycloalkyl, heterocyclyl, or heteroaryl are selected from halo and C １ ~C ４ alkyl (optionally substituted with 1, 2 or 3 halogen); R ２２ is H, F, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, methyl, C ３ ~C ７ cycloalkyl, and heterocyclyl.

87. W′ is N, and the compound of formula Va: 【Chemistry 24】 87. The compound of claim 86, or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof, having the formula:

88. R ２１ is 5-6 membered heterocyclyl or C ３ ~C ６ 87. The compound of claim 85 or 86, which is cycloalkyl.

89. R ２１ C ３ ~C ６ 88. The compound of any one of claims 85 to 87, which is a chloroalkyl.

90. R ２１ The compound of any one of claims 85 to 88, wherein is cyclopropyl.

91. R ２１ The compound of any one of claims 85 to 88, wherein is cyclopentyl.

92. L ２ C １ ~C ６ The compound of any one of claims 85 to 90, which is an alkylene.

93. L ２ The compound according to any one of claims 85 to 91, wherein is propylene.

94. R ２３ But NH ２ , NH(CH ３ ), or N(CH ３ ) ２ The compound according to any one of claims 85 to 92,

95. The compound of any one of claims 85-93, wherein two R' together with the nitrogen to which they are attached form a 4-6 membered heterocyclyl.

96. R ２２ The compound of any one of claims 85 to 94, wherein is H, F, or methyl.

97. R ２２ The compound according to any one of claims 85 to 95, wherein is H.

98. 【Catalogue 25】 87. The compound of claim 86, which is selected from the group consisting of: or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

99. A pharmaceutical composition comprising a compound according to any one of claims 1 to 55 and 85 to 97, or a pharma- ceutically acceptable salt, stereoisomer, and / or N-oxide thereof, and at least one pharma- ceutically acceptable carrier or diluent.

100. 99. The pharmaceutical composition of claim 98, formulated for parenteral administration.

101. 99. The pharmaceutical composition of claim 98, formulated for intravenous administration.

102. 99. The pharmaceutical composition of claim 98, formulated for subcutaneous administration.

103. A method of treating a proliferative disease comprising administering to a subject having a proliferative disease a therapeutically effective amount of a compound according to any one of claims 1 to 55 and 85 to 97, or a pharma- ceutically acceptable salt, stereoisomer and / or N-oxide thereof, or a therapeutically effective amount of a pharmaceutical composition according to any one of claims 98 to 101.

104. The method of any one of claims 56 to 84 and 102, wherein the proliferative disease is cancer.

105. The method of claim 103, wherein the cancer is selected from the group consisting of head and neck cancer, nervous system cancer, brain cancer, neuroblastoma, lung / mediastinal cancer, breast cancer, esophageal cancer, gastric cancer, liver cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer, colorectal cancer, gynecological cancer, genitourinary cancer, ovarian cancer, thyroid cancer, adrenal cancer, skin cancer, melanoma, osteosarcoma, soft tissue sarcoma, pediatric malignancies, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, leukemia, and metastasis from an unknown primary site.

106. A method of modulating MycN in a cell of a subject in need of MycN modulation, comprising administering to a subject in need thereof an amount of a compound of any one of claims 1 to 55 and 85 to 97, or a pharma- ceutically acceptable salt, stereoisomer and / or N-oxide thereof, or a pharmaceutical composition of any one of claims 98 to 101, effective to effect MycN modulation in the cell of the subject.

107. The method of any one of claims 56-84 and 102-104, further comprising administering a second treatment to the subject.

108. The method of claim 106, wherein the second treatment is an anti-neoplastic treatment.

109. The method of claim 107, wherein the anti-cancer treatment is the administration of one or more agents selected from DNA topoisomerase I or II inhibitors, DNA damaging agents, immunotherapeutic agents, metabolic antagonists or thymidylate synthase (TS) inhibitors, microtubule targeting agents, ionizing radiation, inhibitors of mitotic regulators or mitotic checkpoint regulators, inhibitors of DNA damage signal transduction factors, and inhibitors of DNA damage repair enzymes.

110. The method of claim 107, wherein the anti-cancer treatment is selected from the group consisting of immunotherapy, radiation therapy, photodynamic therapy, gene-directed enzyme prodrug therapy (GDEPT), antibody-directed enzyme prodrug therapy (ADEPT), gene therapy, and nutritionally restricted diet.

Images