2,6,9 trisubstituted purines

Abstract

Compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof (wherein R 1 , R 2 , R 3 , R 4 , and R 5 as defined herein), pharmaceutical compositions comprising such compounds and salts, uses of such compounds and salts for treating or preventing conditions mediated by cyclin-dependent kinase 2 (CDK2), kits comprising such compounds and salts, and methods for making such compounds and salts. [Formula 1] JPEG2026500305000305.jpg63128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 387,734, filed December 16, 2022, which is incorporated by reference in its entirety for all purposes.

[0002] FIELD OF THE INVENTION This disclosure relates generally to 2,6,9 trisubstituted purines and pharmaceutically acceptable salts thereof. The disclosure further relates to pharmaceutical compositions containing such compounds and salts, the use of such compounds and salts for treating or preventing conditions mediated by cyclin-dependent kinase 2 (CDK2), kits containing such compounds and salts, and methods for making such compounds and salts. [Background technology]

[0003] Cyclin-dependent kinases (CDKs), including CDK2, are serine / threonine protein kinases involved in cell cycle regulation. CDK2 drives cell progression through the S and M phases of the cell cycle. Overexpression of CDK2 is associated with cell cycle dysregulation and tumor growth in several cancer types. While the monomeric form of CDK2 is inactive, CDK2 is activated when it forms a heterodimeric complex with one of its two regulatory partners, cyclin A or cyclin E. Binding of cyclin E to CDK2 in late G1 of the cell cycle is required for the transition from G1 to S phase of the cell cycle. Binding of cyclin A to CDK2 is required for progression through S phase of the cell cycle. Activated CDK2-cyclin A / E complexes direct the phosphorylation of a wide range of transcription factors that regulate various oncogenic signaling pathways that affect cell cycle progression. CDK2 activation also leads to the hyperphosphorylation and inactivation of retinoblastoma protein (pRB), a tumor suppressor protein that helps maintain cells in a quiescent state (ie, the G0 phase of the cell cycle).

[0004] Overexpression of the CCNE1 gene, which produces cyclin E, occurs in many tumor cells, making them CDK2 and cyclin E dependent. Abnormal cyclin E activity has been observed in, for example, solid tumor cancers, such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, endometrial cancer, and bone cancer, as well as blood cancers, such as leukemia and lymphoma. In addition, amplification and / or overexpression of cyclin E has been reported as a potential mechanism for resistance to CDK4 / 6 therapy in ER-positive, HER2-negative breast cancer. Similarly, aberrant expression of cyclin A is associated with chromosomal instability and tumor proliferation, while inhibition of cyclin A results in reduced tumor growth.

[0005] Inhibition of CDK2 activity is a currently underexplored therapeutic approach for treating cancer and other diseases associated with CDK2 activity. Despite significant efforts, there are currently no approved pharmacological agents available that broadly or specifically inhibit CDK2 activity. Attempts to identify such inhibitors have been difficult, in part, due to two major hurdles. First, the mechanism of CDK2 degradation remains poorly understood. Second, CDK2 inhibitors developed to date generally lack the required specificity or exhibit off-target toxicity otherwise caused by the CDK. Sequence and structural similarity between various CDKs is generally high, and similarities between CDK binding sites render most CDK2 inhibitors either insufficiently specific and / or highly toxic. Therefore, there is a need for CDK2 inhibitors, particularly those with pharmacologically relevant properties, including selectivity, that are suitable for administration to subjects in need of such treatment. The present disclosure addresses this significant unmet need by providing such compounds, along with corresponding pharmaceutical compositions and methods for the treatment of cancer and other CDK2-mediated conditions. Summary of the Invention

[0006] In one aspect, the present disclosure provides a compound of formula (I):

[0007] [ka] or a pharmaceutically acceptable salt thereof, R 1 is C 1~6 -Alkyl, Halo-C 1~6 -alkyl, and cyclopropyl; R 2 -NHR 6 ,

[0008] [ka] is selected from the group consisting of R3 and R 4 is hydrogen, and R 3 and R 4 The other is hydrogen, halogen, C 1~3 -Alkyl, Halo-C 1~3 -alkyl, and C 1~3 -alkoxy, R 5 is C 1~6 -Alkyl, C 3~6 -cycloalkyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; 1~6 -alkyl and C 3~6 -Cycloalkyl is halogen and C 1~3 -alkoxy; pyrazolyl and imidazolyl are optionally substituted with one or more substituents independently selected from C 1~3 -alkyl; R 6 is C 1~10 -alkyl or

[0009] [ka] and C 1~10 -Alkyl is substituted with hydroxy or oxo, halogen, C 3~6 -optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl ... R 7 is hydrogen or C 1~3 -alkyl, R 8 is hydrogen, R 9 is hydrogen, C 1~6 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -Alkoxy-C 1~6 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl, C 1~6-Alkyl, C 3~6 -cycloalkyl, C 1~6 -Alkoxy-C 1~6 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen, or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, and the monocyclic ring being optionally substituted with one or more substituents independently selected from halogen.

[0010] In another aspect, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In another aspect, the disclosure provides a method for treating or preventing a CDK2-mediated condition in a subject suffering from or susceptible to such a condition by administering to the subject a therapeutically effective amount of a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof. In one aspect, the condition is cancer. In another aspect, the condition is cancer characterized by amplification or overexpression of the cyclin E1 (CCNE1) gene and / or the cyclin E2 (CCNE2) gene.

[0012] In another aspect, the disclosure provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament for treating or preventing a condition mediated by CDK2.

[0013] In another aspect, the disclosure provides the use of a compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a condition mediated by CDK2.

[0014] In another aspect, the disclosure provides a method for treating or preventing a CDK2-mediated condition in a subject suffering from or susceptible to such a condition by administering to the subject a therapeutically effective amount of a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof, and a second pharmacological agent. In one aspect, the second pharmacological agent is a CDK4 / 6 inhibitor.

[0015] In another aspect, the disclosure provides a kit comprising a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof. In one aspect, the kit further comprises a second pharmacological agent.

[0016] In another aspect, the disclosure provides methods for preparing compounds having the structure of formula (I) or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0017] [Figure 1A] 1 shows the effect of treatment with a CDK2 inhibitor on the cell cycle of OVCAR3 cells, corresponding to treatment with the compound of Example 6. [Figure 1B] 1 shows the effect of treatment with a CDK2 inhibitor on the cell cycle of OVCAR3 cells, corresponding to treatment with the compound of Example 20. [Figure 2-1] Figure 2 shows Western blots (pRB) of OVCAR3 cells after treatment with CDK2 inhibitors. Figure 2A corresponds to treatment with the compound of Example 6. Figure 2B corresponds to treatment with the compound of Example 20. [Figure 2-2] Figure 2 shows Western blots (pRB) of OVCAR3 cells after treatment with CDK2 inhibitors. Figure 2A corresponds to treatment with the compound of Example 6. Figure 2B corresponds to treatment with the compound of Example 20. [Figure 3A]FIG. 1 shows a combination signal heat map (% inhibition of proliferation signal) in palbociclib-resistant MCF7-PC1 cells after treatment with a CDK2 inhibitor (compound of Example 6), a CDK4 / 6 inhibitor (palbociclib), or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib). [Figure 3B] FIG. 1 shows a combination signal heat map (% inhibition of proliferation signal) in palbociclib-resistant MCF7-PC1 cells after treatment with a CDK2 inhibitor (compound of Example 6), a CDK4 / 6 inhibitor (abemaciclib), or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (abemaciclib). [Figure 3C] FIG. 1 shows a combination signal heat map (% inhibition of proliferation signal) in palbociclib-resistant MCF7-PC1 cells after treatment with a CDK2 inhibitor (compound of Example 20), a CDK4 / 6 inhibitor (palbociclib), or a combination of a CDK2 inhibitor (compound of Example 20) and a CDK4 / 6 inhibitor (palbociclib). [Figure 4A] FIG. 1 shows a combination signal heat map (% induction of senescence) in palbociclib-resistant MCF7-PC1 cells after treatment with a CDK2 inhibitor (compound of Example 6), a CDK4 / 6 inhibitor (palbociclib), or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib). [Figure 4B] FIG. 1 shows a combination signal heat map (% induction of senescence) in palbociclib-resistant MCF7-PC1 cells after treatment with a CDK2 inhibitor (compound of Example 6), a CDK4 / 6 inhibitor (abemaciclib), or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (abemaciclib). [Figure 5A] 1 shows a combination signal heat map (% induction of senescence) in MCF7 cells after treatment with a CDK2 inhibitor (compound of Example 6), a CDK4 / 6 inhibitor (palbociclib), or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib). [Figure 5B]1 shows a combination signal heat map (% induction of senescence) in MCF7 cells after treatment with a CDK2 inhibitor (compound of Example 6), a CDK4 / 6 inhibitor (abemaciclib), or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (abemaciclib). [Figure 6] FIG. 1 shows a combination signal heat map (% induction of senescence) in OVAR3 cells after treatment with a CDK2 inhibitor (compound of Example 6), a CDK4 / 6 inhibitor (palbociclib), or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib). [Figure 7A] 1 shows the effect on body weight of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) in an OVCAR3 human ovarian cancer xenograft mouse model as a whole. [Figure 7B] 1 shows the effect on body weight of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) in an OVCAR3 human ovarian cancer xenograft mouse model as a whole. [Figure 8] 1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on tumor volume in an OVCAR3 human ovarian cancer xenograft mouse model. [Figure 9] 1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on pRB levels in an OVCAR3 human ovarian cancer xenograft mouse model. [Figure 10] 1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on pRB levels in the MCF7-PC1 human palbociclib-resistant ER+ breast cancer xenograft mouse model. [Figure 11]1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on tumor volume in a CTG-3298 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model. [Figure 12] 1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on pRB levels in a CTG-3298 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model. [Figure 13] 1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on pHH3 levels in a CTG-3298 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model. [Figure 14] 1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on pRB levels in a T47D P1 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model. [Figure 15] 1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on tumor volume in the CTG-3283 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model. [Figure 16] 1 shows the effect of treatment with a CDK2 inhibitor (compound of Example 6) or a combination of a CDK2 inhibitor (compound of Example 6) and a CDK4 / 6 inhibitor (palbociclib) on pRB levels in the CTG-3283 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model. DETAILED DESCRIPTION OF THE INVENTION

[0018] Many embodiments are detailed throughout this specification and will be apparent to those skilled in the art, and this specification should not be construed as being limited to any particular embodiment described herein.

[0019] I. Definition With respect to the embodiments disclosed herein, the following terms have the meanings set forth below.

[0020] References to "a" or "an" mean "one or more." Throughout, plural and singular forms should be treated as interchangeable except for references to number.

[0021] Unless the context requires otherwise, the words "comprise" or "comprises" or "comprising" are to be interpreted inclusively and not exclusively, and are used with the understanding and express understanding that Applicant intends each of these words to be so interpreted in interpreting this patent, including the claims that follow.

[0022] The term "halogen" (alone or in combination with another term(s)) means a fluorine radical (which may be represented as -F), a chlorine radical (which may be represented as -Cl), a bromine radical (which may be represented as -Br), or an iodine radical (which may be represented as -I).

[0023] The term "hydroxy" (alone or in combination with another term(s)) means --OH.

[0024] The term "oxo" (alone or in combination with another term(s)) means an oxo radical, which may be represented as ═O.

[0025] The term "alkyl" (alone or in combination with another term) means a straight-chain or branched-chain saturated hydrocarbyl substituent (i.e., a substituent containing only carbon and hydrogen). Alkyl typically contains 1 to about 20 carbon atoms, more typically 1 to about 10 carbon atoms, even more typically 1 to about 8 carbon atoms, and even more typically 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, iso-amyl, and 2,2-dimethylpropyl), and hexyl.

[0026] The term "cycloalkyl" (alone or in combination with another term) means a saturated carbocyclyl substituent containing 3 to about 14 carbon ring atoms, more typically 3 to about 12 carbon ring atoms, and even more typically 3 to about 8 carbon ring atoms. Cycloalkyls typically contain a single carbon ring containing 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0027] The term "alkoxy" (alone or in combination with another term(s)) means an alkyl ether substituent, i.e., alkyl-O-. Examples of alkoxy include methoxy (CH3-O-), ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. Thus, for example, the term "alkoxyalkyl" (alone or in combination with another term(s)) means an alkyl substituted with an alkoxy, such as "methoxymethyl," which means

[0028] [ka] It can be expressed as:

[0029] The prefix "halo" indicates that the substituent to which the prefix is ​​attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl refers to an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. When two or more hydrogens are replaced with halogens, the halogens can be the same or different. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, difluoropropyl, heptafluoropropylchloromethyl, dichloromethyl, trichloromethyl, difluorochloromethyl, dichlorofluoromethyl, and dichloropropyl. Similarly, "haloalkoxy" refers to an alkoxy substituent in which at least one hydrogen radical is replaced with a halogen radical. When two or more hydrogens are replaced with halogens, the halogens can be the same or different. Examples of haloalkoxy substituents include fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), 1,1,1-trifluoroethoxy, and chloromethoxy.

[0030] In some cases, the number of carbon atoms in a substituent (e.g., alkyl, cycloalkyl, etc.) is indicated by the prefix "Cx-y-" where x is the minimum number of carbon atoms in the substituent and y is the maximum number. Thus, for example, "C 1~6 "-alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. 3~6 -Cycloalkyl refers to a cycloalkyl substituent containing from 3 to 6 carbon ring atoms.

[0031] A substituent is "substitutable" if it contains at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano are not included in this definition.

[0032] When a substituent is described as "substituted," a non-hydrogen radical is present in place of a hydrogen radical on the carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is present in place of a hydrogen radical on the alkyl substituent. For example, a monofluoroalkyl is an alkyl substituted with a fluoro radical, and a difluoroalkyl is an alkyl substituted with two fluoro radicals. When two or more substitutions are present on a substituent, it should be recognized that each non-hydrogen radical may be the same or different (unless otherwise specified).

[0033] When a substituent is described as being "optionally substituted," the substituent can be either (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent present) can be replaced separately and / or together with any independently selected substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent present) can each be replaced with any independently selected substituents.

[0034] When substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent can be the same or different from the other substituents.

[0035] The term "pharmaceutically acceptable" is used adjectively herein to mean that the modified noun is appropriate for use as a pharmaceutical product or part of a pharmaceutical product. For example, a "pharmaceutically acceptable salt" is a salt that is suitable for use in mammals, particularly humans, and includes salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids that are suitable for use in mammals, particularly humans.

[0036] A "therapeutically effective amount" refers to that amount of compound administered that will relieve to some extent one or more of the symptoms of the condition being treated, or otherwise bring about a beneficial or desirable result with respect to that condition. When a pharmacological agent is administered to treat cancer, a therapeutically effective amount refers to, for example, an amount that has the following effects: (1) reducing tumor size; (2) inhibiting (i.e., slowing to some extent, and preferably stopping) tumor metastasis; (3) inhibiting to some extent (i.e., slowing to some extent, and preferably stopping) tumor growth or tumor invasiveness; (4) reducing to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer; (5) reducing the dose of other drugs needed to treat the disease; (6) enhancing the effect of another drug; and / or (7) slowing the progression of the disease in a patient.

[0037] The terms "treat," "treating," and "treatment" are readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can encompass (1) reducing the extent or cause of the condition being treated, and / or (2) alleviating or ameliorating one or more symptoms associated with the condition. Treating a subject having or diagnosed with cancer can include, for example, reducing the number of cancer cells, reducing tumor size, reducing the rate of cancer cell invasion into peripheral organs, reducing the rate of tumor metastasis or tumor growth, or otherwise reversing, attenuating, or inhibiting the progression of the cancer.

[0038] II. Compounds A. Compounds of Formula (I) In one embodiment, the present disclosure provides a compound of formula (I):

[0039] [ka] and pharmaceutically acceptable salts thereof, wherein R 1 is C 1~6 -Alkyl, Halo-C 1~6-alkyl, and cyclopropyl; R 2 -NHR 6 ,

[0040] [ka] is selected from the group consisting of R 3 and R 4 is hydrogen, and R 3 and R 4 The other is hydrogen, halogen, C 1~3 -Alkyl, Halo-C 1~3 -alkyl, and C 1~3 -alkoxy, R 5 is C 1~6 -Alkyl, C 3~6 -cycloalkyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; 1~6 -alkyl and C 3~6 -Cycloalkyl is halogen and C 1~3 -alkoxy; pyrazolyl and imidazolyl are optionally substituted with one or more substituents independently selected from C 1~3 -alkyl; R 6 is C 1~10 -alkyl or

[0041] [ka] and C 1~10 -Alkyl is substituted with hydroxy or oxo, halogen, C 3~6 -optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl ... R 7 is hydrogen or C 1~3 -alkyl, R 8is hydrogen, R 9 is hydrogen, C 1~6 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -Alkoxy-C 1~6 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl, C 1~6 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -Alkoxy-C 1~6 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen, or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, and the monocyclic ring being optionally substituted with one or more substituents independently selected from halogen.

[0042] In some embodiments, the present disclosure provides a compound of formula (IA):

[0043] [ka] Compounds of formula (I) having the structure: 1 , R 2 , R 3 , R 4 , and R 5 is as defined above).

[0044] R 1 substituent In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 1 is C 1~3 -Alkyl, Halo-C 1~3 In one aspect, R is selected from the group consisting of -alkyl, and cyclopropyl.1 is C 1~3 -Alkyl and halo-C 1~3 In another embodiment, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, fluoromethyl, and difluoromethyl. 1 is selected from the group consisting of ethyl and isopropyl. 1 is C 1~3 In another embodiment, R 1 is methyl. In another embodiment, R 1 is ethyl. In another embodiment, R 1 is n-propyl. In another embodiment, R 1 is isopropyl. In another embodiment, R 1 is Halo-C 1~3 In another embodiment, R 1 Fluoro-C 1~3 In another embodiment, R 1 is selected from the group consisting of fluoromethyl and difluoromethyl. 1 is fluoromethyl. In another embodiment, R 1 is difluoromethyl. In another embodiment, R 1 is cyclopropyl.

[0045] R 2 substituent In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 is.

[0046] In some embodiments, R 2 -NHR 6 and R 6 is C 1~10 -alkyl, C 1~10 -Alkyl is substituted with hydroxy and halogen, C 3~6In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl, cyclopropyl, tetrahydrofuranyl, and tetrahydrofuranyl. 6 is C 2~6 -alkyl, C 2~6 -Alkyl is substituted with hydroxy and halogen, C 3~6 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cycloalkyl, cyclopropyl, cyclopropyl, tetrahydrofuranyl, and tetrahydrofuranyl. 6 is C 1~10 -alkyl, C 1~10 In another aspect, R -alkyl is substituted with hydroxy and optionally with one or more substituents independently selected from the group consisting of fluoro, cyclopropyl, and tetrahydrofuranyl. 6 is C 2~6 -alkyl, C 2~6 In another aspect, R -alkyl is substituted with hydroxy and optionally with one or more substituents independently selected from the group consisting of fluoro, cyclopropyl, and tetrahydrofuranyl. 6 is C 1~10 -alkyl, C 1~10 In another aspect, R -alkyl is substituted with hydroxy and optionally with one or more substituents independently selected from the group consisting of fluoro and cyclopropyl. 6 is C 2~6 -alkyl, C 2~6 The -alkyl is substituted with hydroxy and optionally substituted with one or more substituents independently selected from the group consisting of fluoro and cyclopropyl.

[0047] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 is C 1~10 -alkyl, C 1~10 -alkyl is substituted with hydroxy. 6 is C2~6 -alkyl, C 2~6 In another embodiment, R 6 is a C4-alkyl, wherein the C4-alkyl is substituted with hydroxy. 6 is a C5-alkyl, wherein the C5-alkyl is substituted with hydroxy. 6 is a C6-alkyl, wherein the C6-alkyl is substituted with hydroxy. 6 teeth,

[0048] [ka] is. In another embodiment, R 6 teeth,

[0049] [ka] is selected from the group consisting of: In another embodiment, R 6 teeth,

[0050] [ka] is. In another embodiment, R 6 teeth,

[0051] [ka] is selected from the group consisting of: In another embodiment, R 6 teeth,

[0052] [ka] is. In another embodiment, R 6 teeth,

[0053] [ka] is selected from the group consisting of:

[0054] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 is C 1~10 -alkyl, C 1~10 -alkyl is substituted with hydroxy and one or more halogens. 6 is C 2~6 -alkyl, C 2~6 In another embodiment, R -alkyl is substituted with hydroxy and one or more halogens. 6 is a C4-alkyl, wherein the C4-alkyl is substituted with hydroxy and one or more halogens. 6 is a C5-alkyl, wherein the C5-alkyl is substituted with hydroxy and one or more halogens. 6 is a C6-alkyl, wherein the C6-alkyl is substituted with hydroxy and one or more halogens. In a further embodiment, the halogen is fluoro. In another embodiment, R 6 teeth,

[0055] [ka] is. In another embodiment, R 6 teeth,

[0056] [ka] is. In another embodiment, R 6 teeth,

[0057] [ka] is. In another embodiment, R6 teeth,

[0058] [ka] is.

[0059] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 is C 1~10 -alkyl, C 1~10 -Alkyl is hydroxy and C 3~6 -cycloalkyl. In one aspect, R 6 is C 2~6 -alkyl, C 2~6 -Alkyl is hydroxy and C 3~6 In another embodiment, R 6 is a C2-alkyl, which is a hydroxyl and C 3~6 In another embodiment, R 6 is a C3-alkyl, which is a hydroxyl and C 3~6 -substituted with cycloalkyl.

[0060] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 is C 1~10 -alkyl, C 1~10 -alkyl is substituted with hydroxy and cyclopropyl. 6 is C 2~6 -alkyl, C 2~6 In another embodiment, R -alkyl is substituted with hydroxy and cyclopropyl. 6 is a C2-alkyl, wherein the C2-alkyl is substituted with hydroxy and cyclopropyl.6 is a C3-alkyl, wherein the C3-alkyl is substituted with hydroxy and cyclopropyl. 6 teeth,

[0061] [ka] is. In another embodiment, R 6 teeth,

[0062] [ka] is selected from the group consisting of: In another embodiment, R 6 teeth,

[0063] [ka] is. In another embodiment, R 6 teeth,

[0064] [ka] is selected from the group consisting of:

[0065] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 is C 1~10 -alkyl, C 1~10 -alkyl is substituted with hydroxy and cyclopentyl. 6 is C 2~6 -alkyl, C 2~6 In another embodiment, R -alkyl is substituted with hydroxy and cyclopentyl. 6 is a C2-alkyl, wherein the C2-alkyl is substituted with hydroxy and cyclopentyl. 6is a C3-alkyl, wherein the C3-alkyl is substituted with hydroxy and cyclopentyl. 6 teeth,

[0066] [ka] is. In another embodiment, R 6 teeth,

[0067] [ka] is.

[0068] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 is C 1~10 -alkyl, C 1~10 -alkyl is substituted with hydroxy and tetrahydrofuranyl. 6 is C 2~6 -alkyl, C 2~6 In another embodiment, R -alkyl is substituted with hydroxy and tetrahydrofuranyl. 6 is a C2-alkyl, wherein the C2-alkyl is substituted with hydroxy and tetrahydrofuranyl. 6 is a C3-alkyl, wherein the C3-alkyl is substituted with hydroxy and tetrahydrofuranyl. 6 teeth,

[0069] [ka] is. In another embodiment, R 6 teeth,

[0070] [ka] is.

[0071] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 teeth,

[0072] [ka] and R 10 is C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 3~6 -cycloalkyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl, and tetrahydrofuranyl; R 11 is hydrogen and C 1~3 -alkyl, and R 12 is hydrogen, C 1~3 -Alkyl and halo-C 1~3 For clarity, the R groups described above for the broadest embodiment of compounds having the structure of Formula (I) are selected from the group consisting of: 6 The first definition of R can be chosen 10 , R 11 , and R 12 The combination of substituents is further limited. 10 is C 1~3 -Alkyl and halo-C 1~3 -alkyl, and R 11 is hydrogen and C 1~3 -alkyl, and R 12 is hydrogen, C 1~3 -Alkyl and halo-C 1~3 In another embodiment, R 10 is C 3~6 -cycloalkyl, C 3~6 -Cycloalkyl-C 1~3-alkyl, and tetrahydrofuranyl; R 11 is hydrogen and C 1~3 -alkyl, and R 12 is hydrogen, C 1~3 -Alkyl and halo-C 1~3 In another embodiment, R 10 is selected from the group consisting of methyl, ethyl, fluoroethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, and tetrahydrofuranyl; R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen, methyl, and trifluoromethyl. 10 is selected from the group consisting of methyl, ethyl, and fluoroethyl; R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen, methyl, and trifluoromethyl. 10 is methyl and R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen, methyl, and trifluoromethyl. 10 is ethyl, and R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen, methyl, and trifluoromethyl. 10 is fluoroethyl, and R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen, methyl, and trifluoromethyl. 10 is selected from the group consisting of cyclopropyl and cyclopropylmethyl; R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen and methyl. 10 is cyclohexyl and R 11 is selected from the group consisting of hydrogen and methyl; R12 is selected from the group consisting of hydrogen and methyl. 10 is tetrahydrofuranyl and R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen and methyl. 6 teeth,

[0073] [ka] is. In another embodiment, R 6 teeth,

[0074] [ka] is selected from the group consisting of: In another embodiment, R 6 teeth,

[0075] [ka] is. In another embodiment, R 6 teeth,

[0076] [ka] is selected from the group consisting of:

[0077] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 is C 1~10 -alkyl, C 1~10 -Alkyl is substituted with oxo and halogen, C 3~6 In one aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl, cyclopropyl, tetrahydrofuranyl, and tetrahydrofuranyl. 6 is C 2~5-alkyl, C 2~5 -Alkyl is substituted with oxo and halogen, C 3~6 In another aspect, R is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cycloalkyl, cyclopropyl, cyclopropyl, tetrahydrofuranyl, and tetrahydrofuranyl. 6 is C 1~10 -alkyl, C 1~10 In another embodiment, R -alkyl is substituted with oxo. 6 is C 1~5 -alkyl, C 2~5 In another embodiment, R -alkyl is substituted with oxo. 6 teeth,

[0078] [ka] is. In another embodiment, R 6 teeth,

[0079] [ka] is selected from the group consisting of:

[0080] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 -NHR 6 and R 6 teeth,

[0081] [ka] is.

[0082] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 teeth,

[0083] [ka] and R 7 is hydrogen or C 1~3 In another embodiment, R 7 is hydrogen or methyl. In another embodiment, R 7 is hydrogen. In another embodiment, R 7 is methyl.

[0084] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 2 teeth,

[0085] [ka] is.

[0086] R 3 and R 4 substituent In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 3 is hydrogen, halogen, C 1~3 -Alkyl, Halo-C 1~3 -alkyl, and C 1~3 -alkoxy, and R 4 is hydrogen. In another embodiment, R 3 is selected from the group consisting of hydrogen, fluoro, methyl, and methoxy; R 4 is hydrogen. In another embodiment, R 3 is selected from the group consisting of hydrogen, methyl, and fluoro; R 4 is hydrogen. In another embodiment, R 3 is fluoro and R 4 is hydrogen. In another embodiment, R 3 is methyl and R 4 is hydrogen.

[0087] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 3is hydrogen and R 4 is hydrogen, halogen, C 1~3 -Alkyl, Halo-C 1~3 -alkyl, and C 1~3 -alkoxy. In one aspect, R 3 is hydrogen and R 4 is selected from the group consisting of hydrogen, fluoro, methyl, and methoxy. 3 is hydrogen and R 4 is selected from the group consisting of hydrogen and methyl. 3 is hydrogen and R 4 is methyl.

[0088] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 3 and R 4 are hydrogen atoms.

[0089] R 5 substituent In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is C 1~6 -Alkyl, C 3~6 -cycloalkyl, and -NR 8 R 9 C 1~6 -alkyl and C 3~6 -Cycloalkyl is halogen and C 1~3 In one aspect, R is optionally substituted with one or more substituents independently selected from: 5 is C 1~3 -Alkyl, C 3~6 -cycloalkyl, and -NR 8 R 9 C 1~3 -alkyl and C 3~6 -Cycloalkyl is halogen and C 1~3 -optionally substituted with one or more substituents independently selected from: -alkoxy.

[0090] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is C 1~6 -alkyl and C 3~6 -cycloalkyl, C 1~6 -alkyl and C 3~6 -Cycloalkyl is halogen and C 1~3 -optionally substituted with one or more substituents independently selected from: -alkoxy.

[0091] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is C 1~6 -alkyl, C 1~6 -Alkyl is halogen and C 1~3 In one aspect, R is optionally substituted with one or more substituents independently selected from: 5 is C 1~3 -alkyl, C 1~3 -Alkyl is halogen and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from: 5 is methyl, and methyl is a halogen and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from: 5 is ethyl, and ethyl is a halogen and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from: 5 is propyl, and propyl is a halogen and C 1~3 In a further aspect, the halogen is fluoro and the C 1~3 -alkoxy is methoxy.

[0092] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is C 3~6 -cycloalkyl, C 3~6 -Cycloalkyl is halogen and C 1~3 In one aspect, R is optionally substituted with one or more substituents independently selected from: 5 is cyclopropyl, and cyclopropyl is a halogen and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from: 5 is cyclobutyl, and cyclobutyl is a halogen and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from: 5 is cyclopentyl, and cyclopentyl is a halogen and C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from: 5 is cyclohexyl, and cyclohexyl is a halogen and C 1~3 -alkoxy. In a further embodiment, halogen is fluoro. In a further embodiment, C 1~3 -alkoxy is methoxy. In a further embodiment, halogen is fluoro and C 1~3 -alkoxy is methoxy.

[0093] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is selected from the group consisting of pyrazolyl and imidazolyl, wherein pyrazolyl and imidazolyl are C 1~3 In one aspect, R is optionally substituted with one or more substituents independently selected from -alkyl. 5 is selected from the group consisting of pyrazolyl and imidazolyl, wherein pyrazolyl and imidazolyl are optionally substituted with one or more methyl. 5is pyrazolyl, and pyrazolyl is C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from -alkyl. 5 is pyrazolyl, which is optionally substituted with one or more methyl. 5 is imidazolyl, and imidazolyl is C 1~3 In another aspect, R is optionally substituted with one or more substituents independently selected from -alkyl. 5 is imidazolyl, which is optionally substituted with one or more methyl.

[0094] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is selected from the group consisting of methyl, fluoromethyl, trifluoromethyl, methoxyethyl, cyclopropyl, imidazolyl, pyrazolyl, methylimidazolyl, and methylpyrazolyl.

[0095] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 and R 8 is hydrogen and R 9 is hydrogen, C 1~6 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -Alkoxy-C 1~6 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl, C 1~6 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -Alkoxy-C 1~6 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is hydrogen, C1~3 -Alkyl, C 3~6 -cycloalkyl, C 1~3 -Alkoxy-C 1~3 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl, C 1~3 -Alkyl, C 3~6 -cycloalkyl, C 1~3 -Alkoxy-C 1~3 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is hydrogen, C 1~3 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl, C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. In a further embodiment, halogen is fluoro.

[0096] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 and R 8 is hydrogen and R 9 is hydrogen.

[0097] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 and R 8 is hydrogen and R 9 is C 1~6 -alkyl, C 1~6 -alkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is C 1~3 -alkyl, C 1~3-alkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is methyl, which is optionally substituted with one or more substituents independently selected from halogen. 9 is ethyl, which is optionally substituted with one or more substituents independently selected from halogen. 9 is propyl, which is optionally substituted with one or more substituents independently selected from halogen. In a further embodiment, halogen is fluoro.

[0098] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 and R 8 is hydrogen and R 9 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is cyclopropyl, which is optionally substituted with one or more substituents independently selected from halogen. 9 is cyclobutyl, which is optionally substituted with one or more substituents independently selected from halogen. 9 is cyclopentyl, wherein the cyclopentyl is optionally substituted with one or more substituents independently selected from halogen. 9 is cyclohexyl, wherein the cyclohexyl is optionally substituted with one or more substituents independently selected from halogen. In a further embodiment, the halogen is fluoro.

[0099] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is -NR8 R 9 and R 8 is hydrogen and R 9 is C 1~6 -Alkoxy-C 1~6 -alkyl, C 1~6 -Alkoxy-C 1~6 -alkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is C 1~3 -Alkoxy-C 1~3 -alkyl, C 1~3 -Alkoxy-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is methoxy-C 1~3 -alkyl and methoxy-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is methoxymethyl, which is optionally substituted with one or more substituents independently selected from halogen. 9 is methoxyethyl, which is optionally substituted with one or more substituents independently selected from halogen. In a further embodiment, halogen is fluoro.

[0100] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 and R 8 is hydrogen and R 9 Tetrahydrofuranyl and 1,4-dioxanyl-C 1~3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. 9 is tetrahydrofuranyl. In another embodiment, R 9is 1,4-dioxanyl-C 1~3 In another embodiment, R 9 is 1,4-dioxanylmethyl. In a further embodiment, the halogen is fluoro.

[0101] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 and R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 4-, 5-, or 6-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, and the monocyclic ring being optionally substituted with one or more substituents independently selected from halogen. 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a four-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, and the monocyclic ring is optionally substituted with one or more substituents independently selected from halogen. 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a five-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, and the monocyclic ring is optionally substituted with one or more substituents independently selected from halogen. 8 and R 9 together with the nitrogen atom to which they are attached form a 6-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, and the monocyclic ring being optionally substituted with one or more substituents independently selected from halogen. In a further embodiment, the halogen is fluoro.

[0102] In some embodiments, the disclosure provides compounds having the structure of Formula (I) or Formula (IA), and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 and R 8 is hydrogen and R 9is selected from the group consisting of hydrogen, methyl, ethyl, difluoroethyl, trifluoroethyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form an azetidinyl ring, which is optionally substituted with one or more substituents independently selected from halogen. In a further embodiment, halogen is fluoro. In another embodiment, R 5 is -NR 8 R 9 and R 8 is hydrogen and R 9 is selected from the group consisting of methyl, ethyl, difluoroethyl, trifluoroethyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl.

[0103] B. Additional Embodiments In some embodiments, the disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds have a structure selected from the structures of Formulas I-1 to I-117 shown in Table 1.

[0104] [Table 1-1]

[0105] [Table 1-2]

[0106] [Table 1-3]

[0107] [Table 1-4]

[0108] [Table 1-5]

[0109] Table 1-6

[0110] Table 1-7

[0111] Table 1-8

[0112] Table 1-9

[0113] Table 1-10

[0114] Table 1-11

[0115] Table 1-12

[0116] Table 1-13

[0117] Table 1-14

[0118] Table 1-15 (In the formula, applicable to possible occasions, R1 is C 1~6 -Alkyl, Halo-C 1~6 -alkyl, and cyclopropyl; R 2 -NHR 6 ,

[0119] [ka] is selected from the group consisting of R 3 and R 4 is hydrogen, and R 3 and R 4 The other is hydrogen, halogen, C 1~3 -Alkyl, Halo-C 1~3 -alkyl, and C 1~3 -alkoxy, R 5 is C 1~6 -Alkyl, C 3~6 -cycloalkyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; 1~6 -alkyl and C 3~6 -Cycloalkyl is halogen and C 1~3 -alkoxy; pyrazolyl and imidazolyl are optionally substituted with one or more substituents independently selected from C 1~3 -alkyl; R 6 is C 1~10 -alkyl or

[0120] [ka] and C 1~10 -Alkyl is substituted with hydroxy or oxo, halogen, C 3~6 -optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl ... R 7is hydrogen or C 1~3 -alkyl, R 8 is hydrogen, R 9 is hydrogen, C 1~6 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -Alkoxy-C 1~6 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl, C 1~6 -Alkyl, C 3~6 -cycloalkyl, C 1~6 -Alkoxy-C 1~6 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen, or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, and the monocyclic ring being optionally substituted with one or more substituents independently selected from halogen; R 10 is C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 3~6 -cycloalkyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl, and tetrahydrofuranyl; R 11 is hydrogen and C 1~3 -alkyl, R 12 is hydrogen, C 1~3 -Alkyl and halo-C 1~3 -alkyl, R 13 is hydrogen and C 1~3 -alkyl).

[0121] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein, where applicable, R 1 is C 1~3 -Alkyl, Halo-C 1~3 -alkyl, and cyclopropyl; R 2 -NHR 6 and R 3 is hydrogen and R 4 is hydrogen and C 1~3 -alkyl, or R 4 is hydrogen and R 3 is hydrogen, halogen, and C 1~3 -alkyl, R 5 is C 1~6 -Alkyl, C 3~6 -cycloalkyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; 1~6 -alkyl and C 3~6 -Cycloalkyl is halogen and C 1~3 -alkoxy; pyrazolyl and imidazolyl are optionally substituted with one or more substituents independently selected from C 1~3 -alkyl; R 6 is C 1~10 -alkyl, C 1~10 -Alkyl is substituted with hydroxy and halogen, C 3~6 -optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl ... R 8 is hydrogen, R 9 is hydrogen, C 1~3 -Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl, C 1~3-Alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1~3 -alkyl is optionally substituted with one or more substituents independently selected from halogen, or R 8 and R 9 together with the nitrogen atom to which they are attached form an azetidinyl ring, the azetidinyl ring being optionally substituted with one or more substituents independently selected from halogen; R 10 is C 1~3 -Alkyl, Halo-C 1~3 -Alkyl, C 3~6 -cycloalkyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl, and tetrahydrofuranyl; R 11 is hydrogen and C 1~3 -alkyl, R 12 is hydrogen, C 1~3 -Alkyl and halo-C 1~3 -alkyl, R 13 is hydrogen and C 1~3 -alkyl. In one embodiment, the compound has a structure selected from the structures of formulae I-1 through I-117 shown in Table 1.

[0122] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein, where applicable, R 1 is C 1~3 -Alkyl and Fluoro-C 1~3 -alkyl, R 2 -NHR 6 and R 3 is hydrogen and R 4 is selected from the group consisting of hydrogen and methyl, or R 4 is hydrogen and R 3is selected from the group consisting of hydrogen, fluoro, and methyl; R 5 is C 1~3 -Alkyl, C 3~6 -cycloalkyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; 1~6 -alkyl and C 3~6 -cycloalkyl is optionally substituted with one or more substituents independently selected from fluoro and methoxy; pyrazolyl and imidazolyl are optionally substituted with one or more methyl; R 6 is C 2~6 -alkyl, C 2~6 -Alkyl is substituted with hydroxy and fluoro, C 3~6 -optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl ... R 8 is hydrogen, R 9 is hydrogen, C 1~3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl; 1~3 - alkyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl are optionally substituted with one or more substituents independently selected from halogen; R 10 is C 1~3 -Alkyl, Fluoro-C 1~3 -Alkyl, C 3~6 -cycloalkyl, C 3~6 -cycloalkylmethyl, and tetrahydrofuranyl; R 11 is hydrogen and C 1~3 -alkyl, R 12 is hydrogen, C 1~3 -Alkyl and halo-C 1~3 -alkyl, R 13 is hydrogen and C 1~3-alkyl. In one embodiment, the compound has a structure selected from the structures of formulae I-1 through I-117 shown in Table 1.

[0123] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein, where applicable, R 1 is C 1~3 -Alkyl and Fluoro-C 1~3 -alkyl, R 2 -NHR 6 and R 3 is selected from the group consisting of hydrogen and fluoro; R 4 is hydrogen, R 5 is C 1~3 -Alkyl, cyclopropyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; 1~6 - alkyl and cyclopropyl are optionally substituted with one or more substituents independently selected from fluoro and methoxy, and pyrazolyl and imidazolyl are optionally substituted with one or more methyl; R 6 is C 2~6 -alkyl, C 2~6 -Alkyl is substituted with hydroxy and fluoro, C 3~6 -optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl ... R 8 is hydrogen, R 9 is hydrogen, C 1~3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl; 1~3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl are optionally substituted with one or more fluoro; R 10is selected from the group consisting of methyl, ethyl, fluoroethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, and tetrahydrofuranyl; R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen, methyl, and fluoromethyl. In one embodiment, the compound has a structure selected from the structures of formulae I-1 through I-117 shown in Table 1.

[0124] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein, where applicable, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, fluoromethyl, and difluoromethyl; R 2 -NHR 6 and R 3 and R 4 is hydrogen, R 5 is methyl, fluoromethyl, trifluoromethyl, methoxyethyl, cyclopropyl, -NR 8 R 9 , imidazolyl, pyrazolyl, methylimidazolyl, and methylpyrazolyl; R 6 is C 2~6 -alkyl, C 2~6 -Alkyl is substituted with hydroxy and fluoro, C 3~6 -optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl ... R 8 is hydrogen, R 9 is selected from the group consisting of hydrogen, methyl, ethyl, difluoroethyl, trifluoroethyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl; R 10is selected from the group consisting of methyl, ethyl, fluoroethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, and tetrahydrofuranyl; R 11 is selected from the group consisting of hydrogen and methyl; R 12 is selected from the group consisting of hydrogen, methyl, and fluoromethyl. In one embodiment, the compound has a structure selected from the structures of formulae I-1 through I-117 shown in Table 1.

[0125] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-61):

[0126] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0127] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-62):

[0128] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0129] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-63):

[0130] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0131] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-64):

[0132] [ka] wherein R 5 , R 10 , R 11 , and R 12 is as defined in any of the embodiments disclosed herein.

[0133] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-65):

[0134] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0135] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-66):

[0136] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0137] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-67):

[0138] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0139] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-68):

[0140] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0141] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-69):

[0142] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0143] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-70):

[0144] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0145] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-71):

[0146] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0147] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-72):

[0148] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0149] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-73):

[0150] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0151] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-74):

[0152] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0153] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-75):

[0154] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0155] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-76):

[0156] [ka] wherein R 5 , R 10 , R 11 , and R 12 is as defined in any of the embodiments disclosed herein.

[0157] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-77):

[0158] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0159] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-78):

[0160] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0161] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-79):

[0162] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0163] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-80):

[0164] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0165] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-81):

[0166] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0167] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-82):

[0168] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0169] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-83):

[0170] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0171] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the formula (I-84):

[0172] [ka] wherein R 5 is as defined in any of the embodiments disclosed herein.

[0173] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds have a structure selected from the structures of formulae I-1 to I-117 shown in Table 1, wherein, where applicable, R 5 is C 1~3 -alkyl, C 1~3 -Alkyl is fluoro and C 1~3 -optionally substituted with one or more substituents independently selected from: -alkoxy.

[0174] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds have a structure selected from the structures of formulae I-1 to I-117 shown in Table 1, wherein, where applicable, R 5 is C 3~6 -cycloalkyl, C 3~6 -cycloalkyl is optionally substituted with one or more fluoro substituents. 5 is cyclopropyl, which is optionally substituted with one or more fluoro substituents. 5is cyclobutyl, which is optionally substituted with one or more fluoro substituents. 5 is cyclopentyl, which is optionally substituted with one or more fluoro substituents. 5 is cyclohexyl, which is optionally substituted with one or more fluoro substituents.

[0175] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds have a structure selected from the structures of formulae I-1 to I-117 shown in Table 1, wherein, where applicable, R 5 is pyrazolyl, and pyrazolyl is C 1~3 In one aspect, R is optionally substituted with one or more substituents independently selected from -alkyl. 5 is pyrazolyl, which is optionally substituted with one or more methyl.

[0176] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds have a structure selected from the structures of formulae I-1 to I-117 shown in Table 1, wherein, where applicable, R 5 is imidazolyl, and imidazolyl is C 1~3 In one aspect, R is optionally substituted with one or more substituents independently selected from -alkyl. 5 is imidazolyl, which is optionally substituted with one or more methyl.

[0177] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds have a structure selected from the structures of formulae I-1 to I-117 shown in Table 1, wherein, where applicable, R 5 is -NR 8 R 9 In one aspect, R 9 is C 1~3 -alkyl, C 1~3In another aspect, R 9 is tetrahydrofuranyl. In another embodiment, R 9 is 1,4-dioxanyl-C 1~3 In another embodiment, R 9 is 1,4-dioxanylmethyl.

[0178] In some embodiments, the disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds are (S)-3-((9-ethyl-2-(1-oxoisoindolin-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 1], (S)-3-((9-ethyl-2-((R)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 2], (S)-3-((9-ethyl-2-((R * )-1-hydroxy-1-methyl-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)-amino)-N-methylpyrrolidine-1-sulfonamide [Example 3], (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-sulfonamide [Example 4], (S)—N-(2,2-difluoroethyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 5], (S)—N-ethyl-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 6], (S)—N-ethyl-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-pyrrolidine-1-sulfonamide [Example 7], (S)—N-ethyl-3-((9-ethyl-2-(((2S,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)-amino)pyrrolidine-1-sulfonamide [Example 8], (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 9], (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 10], (S)—N-ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)-amino)pyrrolidine-1-sulfonamide [Example 11], (S)—N-ethyl-3-((9-ethyl-2-(((R)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 12], (S)—N-ethyl-3-((9-ethyl-2-(((2R,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 13], (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)-amino)-N-ethylpyrrolidine-1-sulfonamide [Example 14], 2-Cyclopentyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol [Example 15], 2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-2-(tetrahydrofuran-2-yl)ethan-1-ol [Example 16], (R)-2-((6-(((3R * ,4R * )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-2-cyclopropylethan-1-ol [Example 17], (S)-3-((2-(((2S,3R)-1,3-dihydroxybutan-2-yl)amino)-9-ethyl-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide [Example 18], (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide [Example 19], (R)-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)-amino)-3-methylbutan-1-ol [Example 20], (S)-3-((9-ethyl-2-(((3S,4R)-1,1,1-trifluoro-4-hydroxypentan-3-yl-)-amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 21], (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide [Example 22], (S)—N-(((S)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 23], (2R,3S)-3-((9-ethyl-6-(((S)-1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol [Example 24], (S)—N-(((R)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 25], (3R * ,4R * )-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)-amino)-N-ethyl-4-fluoropyrrolidine-1-sulfonamide [Example 26], (R)-2-(6-((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-ylamino)-3-methylbutan-1-ol [Example 27], (R)-2-(9-ethyl-6-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 28], (R)-2-(9-cyclopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 29], (R)-2-cyclopropyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol [Example 30], (2R,3S)-3-((9-isopropyl-6-(((S)-1-(1-methyl-1H-pyrazol-4-yl-sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol [Example 31], (2R,3S)-3-((9-isopropyl-6-(((S)-1-(1-methyl-1H-imidazol-4-yl-sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol [Example 32], (R)-2-((6-(((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 33], (R)-2-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 34], (R)-2-((9-isopropyl-6-(((3S,5S)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 35], (R)-2-((9-isopropyl-6-(((3S,4R)-4-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 36], (2R,3S)-3-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol [Example 37], (R)-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol [Example 38], (R)-2-cyclopropyl-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol [Example 39], (R)-2-((9-ethyl-6-(((S)-1-(2,2,2-trifluoroethylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 40], (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 41], (R)-2-((9-ethyl-6-(((S)-1-((2-methoxyethyl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 42], (R)-2-((9-ethyl-6-(((S)-1-(fluoromethylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 43], (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 44], (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 45], (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 46], (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 47], (S)-3-((9-ethyl-2-(((S)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 48], (S)-3-((9-ethyl-2-(((2R * ,3S * )-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 49 / 50], (S)-3-((9-ethyl-2-(((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 51], (3R * ,4R * )-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-4-fluoro-N-methylpyrrolidine-1-sulfonamide [Example 52], (S)—N-ethyl-3-((2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 53], (S)-3-((9-(fluoromethyl)-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 54], (S)-3-((9-(difluoromethyl)-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 55], (2R,3S)-3-((6-(((3R * ,4R * )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)-amino)-9-methyl-9H-purin-2-yl)amino)pentan-2-ol [Example 56], (2R,3S)-3-((6-(((3R * ,4R * )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)-amino)-9-(difluoromethyl)-9H-purin-2-yl)amino)-1,1,1-trifluorobutan-2-ol [Example 57], (S)-3-((2-(((R *)-1-cyclopropyl-3-hydroxypropan-2-yl)amino)-9-ethyl-9H-purin-6-yl)-amino)-N-ethylpyrrolidine-1-sulfonamide [Example 58], (S)-N-ethyl-3-((9-ethyl-2-(((R * )-3-hydroxy-3-methylbutan-2-yl)-amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 59], (S)—N-ethyl-3-((3-ethyl-5-(((2R,3S)-2-hydroxypentan-3-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)pyrrolidine-1-sulfonamide [Example 60], (R)-2-((6-(((3R * ,4R * )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoro-pyrrolidin-3-yl)amino)-9-(difluoromethyl)-9H-purin-2-yl)amino)-2-cyclopropylethan-1-ol [Example 61], and (2R,3S)-3-((6-(((S)-1-((1H-pyrazol-5-yl)sulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)pentan-2-ol [Example 62].

[0179] C. Combination of Embodiments Any embodiment of the compounds described in this disclosure may be combined with any other suitable embodiment described herein to provide additional embodiments. For example, one embodiment may include a compound having R 1 , R 2 , R 3 , R 4 , and / or R 5 The possible groups for R are described individually or collectively, and separate embodiments are 5 When describing possible groups for R 1 , R 3 , R 4 , and / or R 5 The possible groups described for R5 It will be understood that the possible groups described for R may be combined to provide additional embodiments as described. In other words, for any of the compound embodiments described in this disclosure, R 5 The substituents may be any of the R groups described herein. 5 may be as defined in any of the embodiments.

[0180] D. Further Embodiments In some embodiments, compounds of the disclosure have an IC of less than about 200 nM for CDK2 inhibition as measured by the NanoBRET assay described in Example 63 below. 50 In one aspect, IC 50 In another embodiment, the IC 50 In another embodiment, the IC 50 In another embodiment, the IC 50 The value is less than about 25 nM.

[0181] In some embodiments, compounds of the present disclosure have an IC of less than about 1 μM for inhibiting NPM phosphorylation, as measured in the pNPM phosphorylation assay described in Example 64 below. 50 In one embodiment, the IC 50 In another embodiment, the IC value in the assay is less than about 750 nM. 50 In another embodiment, the IC value in the assay is less than about 500 nM. 50 In another embodiment, the IC value in the assay is less than about 250 nM. 50 The value is less than about 100 nM.

[0182] In some embodiments, compounds of the present disclosure are selective inhibitors of CDK2, i.e., they have a lower inhibition constant (e.g., Ki or IC) for CDK2 compared to other enzymatic targets. 50). Compounds that are selective CDK2 inhibitors generally have an improved safety profile, improved administration schedule, and / or enhanced overall efficacy compared to non-selective CDK2 inhibitors. In one embodiment, the compound has a corresponding inhibition constant for CDK2 that is at least 10-fold lower than the inhibition constant for at least one of CDK1, CDK4, CDK6, and / or CDK9. In another embodiment, the compound has a corresponding inhibition constant for CDK2 that is at least 10-fold lower than the inhibition constant for at least two of CDK1, CDK4, CDK6, and / or CDK9. In another embodiment, the compound has a corresponding inhibition constant for CDK2 that is at least 10-fold lower than the inhibition constant for at least three of CDK1, CDK4, CDK6, and / or CDK9. In another embodiment, the compound has a corresponding inhibition constant for CDK2 that is at least 10-fold lower than the inhibition constant for CDK1, CDK4, CDK6, and CDK9.

[0183] In some embodiments, compounds of the present disclosure are at least about 5-fold more selective for CDK2 compared to CDK1 as measured by the NanoBRET assay described below in Example 63. In one aspect, the compounds are at least about 10-fold more selective for CDK2 compared to CDK1. In another aspect, the compounds have an IC for CDK1 inhibition of greater than about 0.1 μM. 50 In another embodiment, the compound has an IC value for CDK1 inhibition of greater than about 0.2 μM. 50 In another embodiment, the compound has an IC value for CDK1 of greater than about 0.3 μM. 50 It has a value.

[0184] In some embodiments, compounds of the present disclosure are at least about 30-fold more selective for CDK2 over CDK4 as measured by the NanoBRET assay described in Example 63 below. In one aspect, a compound is at least about 100-fold more selective for CDK2 over CDK4. In another aspect, a compound is at least about 500-fold more selective for CDK2 over CDK4. In another aspect, a compound has an IC for CDK4 inhibition of greater than about 0.7 μM. 50 In another embodiment, the compound has an IC value for CDK4 inhibition of greater than about 1.0 μM. 50 In another embodiment, the compound has an IC value for CDK4 inhibition of greater than about 5.0 μM. 50 It has a value.

[0185] In some embodiments, compounds of the present disclosure are at least about 100-fold more selective for CDK2 over CDK9 as measured in the POLR2A Ser2 phosphorylation assay described in Example 65 below. In one aspect, a compound is at least about 100-fold more selective for CDK2 over CDK9. In another aspect, a compound is at least about 500-fold more selective for CDK2 over CDK9. In another aspect, a compound is at least about 1000-fold more selective for CDK2 over CDK9. In another aspect, a compound has an IC of greater than about 1.0 μM in an assay. 50 In another embodiment, the compound has an IC value of greater than about 5.0 μM in the assay. 50 In another embodiment, the compound has an IC value of greater than about 10.0 μM in the assay. 50 It has a value.

[0186] In some embodiments, compounds of the present disclosure inhibit MCF7 cell proliferation as measured in the EdU assay described below in Example 66. In one aspect, the compound has an IC of less than about 2.0 μM in the assay. 50 In another aspect, IC 50 In another embodiment, the IC 50 In another embodiment, the IC 50The value is less than about 500 nM.

[0187] In some embodiments of the present disclosure, the compound inhibits OVCAR3 cell proliferation as measured by the EdU assay described below in Example 66. In one aspect, the compound has an IC of less than about 1.0 μM in the assay. 50 In another aspect, IC 50 In another embodiment, the IC 50 In another embodiment, the IC 50 The value is less than about 250 nM.

[0188] In some embodiments, compounds of the present disclosure have pharmaceutically acceptable metabolic stability as measured as described in the human liver microsome (HLM) assay reported in Example 83 below. In one aspect, the compound has an HLM CL of less than about 300 μL / min / mg. int In another aspect, HLM CL int In another embodiment, the HLM CL is less than about 200 μL / min / mg. int In another embodiment, the HLM CL is less than about 100 μL / min / mg. int Values ​​are less than about 50 μL / min / mg.

[0189] E. Salt The compounds of the present disclosure may exist in a salt form or a non-salt form (i.e., as a free base), and the present disclosure encompasses both salt and non-salt forms. The compounds may form acid addition salts or base addition salts. Generally, acid addition salts can be prepared using various inorganic or organic acids. Such salts can typically be formed, for example, by mixing the compound with an acid (e.g., a stoichiometric amount of the acid) using various methods known in the art. This mixing can be carried out in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or an aqueous / organic mixture. In another embodiment, the acid addition salt is, for example, a trifluoroacetate salt, a formate salt, an acetate salt, or a hydrochloride salt. Generally, base addition salts can be prepared using salts with various inorganic or organic bases, such as alkali metal or alkaline earth metal salts, e.g., sodium, calcium, or magnesium salts, or other metal salts, e.g., potassium or zinc, or ammonium salts, or organic bases, such as methylamine, dimethylamine, trimethylamine, piperidine, or morpholine. Those skilled in the art will be aware of the general principles and techniques for preparing pharmaceutical salts, such as those described in J. Pharm. Sci. 1977 66, 1. Examples of pharmaceutically acceptable salts are also described in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0190] F. Isomers The compounds and salts of the present disclosure may exist in one or more geometric, optical, enantiomeric, and diastereomeric forms, including, but not limited to, cis- and trans-forms, E- and Z-forms, and R-, S-, and meso-forms. Unless otherwise specified, reference to a particular compound encompasses all such isomeric forms, including racemates and other mixtures. Where appropriate, such isomers may be separated from their mixtures by the application or adaptation of known methods (e.g., chromatographic and recrystallization techniques). Where appropriate, such isomers may be prepared by the application or adaptation of known methods. In some embodiments, a single stereoisomer is obtained by isolation from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by, for example, direct synthesis from chiral starting materials.

[0191] A particular enantiomer of a compound described herein may be more active than other enantiomers of the same compound. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is a single enantiomer with an enantiomeric excess (%ee) of 90% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater. In one aspect, the single enantiomer is present in an enantiomeric excess (%ee) of 99% or greater.

[0192] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, that is a single enantiomer in an enantiomeric excess (%ee) of 90% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater, together with one or more pharmaceutically acceptable excipients. In one aspect, the single enantiomer is present in an enantiomeric excess (%ee) of 99% or greater.

[0193] G. Further Forms The compounds and salts of the present disclosure may exist in various tautomeric forms, and the present specification includes all such tautomeric forms. "Tautomers" are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom.

[0194] The compounds of the present disclosure and their pharmaceutically acceptable salts may exist in solvated (such as hydrated) as well as unsolvated forms, and the present specification includes all such solvates.

[0195] The compounds of the present disclosure and their pharmaceutically acceptable salts may exist in crystalline or amorphous form, and the present specification encompasses all such forms.

[0196] The compounds and salts of the present disclosure may be isotopically labeled (or "radiolabeled"). In that case, 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. The present disclosure encompasses isotopically labeled forms of the compounds disclosed herein. Examples of isotopes that may be incorporated include: 2 H (also written as "D" for deuterium), 3 H (also written as "T" for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O, and 36 The isotope used will depend on the specific application of the radiolabeled derivative. For example, in in vitro receptor labeling and competition assays, 3 H or 14 C is often useful. For radioactive imaging applications, 11 C is often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 It is C.

[0197] H. Intermediates In some embodiments, the present disclosure provides additional compounds and pharmaceutically acceptable salts thereof that are useful as intermediates for preparing the disclosed compounds.

[0198] III. How to use The compounds of the present disclosure and their pharmaceutically acceptable salts are inhibitors of cyclin-dependent kinase 2 (CDK2) activity.

[0199] Thus, in some embodiments, the present disclosure provides methods for treating or preventing a CDK2-mediated condition in a subject suffering from or susceptible to a CDK2-mediated condition by administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the present disclosure provides methods for inhibiting CDK2 activity in a subject suffering from or susceptible to a condition mediated by CDK2 by administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the present disclosure provides methods for treating cancer in a subject suffering from or susceptible to cancer by administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the subject. In one aspect, the cancer is a solid tumor cancer. In another aspect, the cancer is a hematological cancer. In another aspect, the cancer is mediated in whole or in part by CDK2.

[0202] In some embodiments, the present disclosure provides methods for treating cancer in a subject suffering from or susceptible to a cancer characterized by amplification or overexpression of the cyclin E (CCNE) gene by administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the subject. In one aspect, the cancer is characterized by amplification or overexpression of CCNE1. In another aspect, the cancer is characterized by amplification or overexpression of CCNE2. In another aspect, the cancer is characterized by amplification or overexpression of CCNE1 and CCNE2. In another aspect, the cancer is a solid tumor cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In another aspect, the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, and lung cancer. In another aspect, the solid tumor cancer is breast cancer or ovarian cancer. In another aspect, the cancer is a hematological cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0203] In some embodiments, the present disclosure provides a method for treating or preventing solid tumor cancer in a subject suffering from or susceptible to cancer by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, cervical cancer, uterine cancer, gastric cancer, prostate cancer, bladder cancer, lung cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, pancreatic cancer, thyroid cancer, colorectal cancer, and skin cancer. In one aspect, the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, colorectal cancer, and skin cancer. In another aspect, the solid tumor cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, and lung cancer. In another aspect, the solid tumor cancer is breast cancer or ovarian cancer.

[0204] In some embodiments, the cancer is breast cancer. In one aspect, the breast cancer is selected from the group consisting of hormone receptor positive (HR+) breast cancer, hormone receptor negative (HR-) breast cancer, and triple-negative breast cancer. In another aspect, the breast cancer is HR+HER2- breast cancer. In another aspect, the breast cancer is chemotherapy-resistant breast cancer. In another aspect, the breast cancer is radiotherapy-resistant breast cancer. In another aspect, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. In another aspect, the breast cancer is advanced or metastatic breast cancer. In another aspect, the subject afflicted with breast cancer has previously been treated with a CDK4 / 6 inhibitor.

[0205] In some embodiments, the cancer is ovarian cancer. In one aspect, the ovarian cancer is platinum-sensitive or platinum-resistant ovarian cancer. In another aspect, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. In another aspect, the cancer is epithelial ovarian cancer. In another aspect, the ovarian cancer is serous ovarian cancer. In another aspect, the ovarian cancer is high-grade serous ovarian cancer (HGSOC). In another aspect, the ovarian cancer is advanced ovarian cancer or metastatic ovarian cancer. In another aspect, the ovarian cancer is metastatic high-grade serous ovarian cancer (HGSOC). In another aspect, the subject with ovarian cancer has previously been treated with platinum-based chemotherapy.

[0206] In some embodiments, the cancer condition is lung cancer. In one aspect, the lung cancer is small cell lung cancer (SCLC). In another aspect, the lung cancer is non-small cell lung cancer (NSCLC). In another aspect, the non-small cell lung cancer (NSCLC) is squamous cell carcinoma. In another aspect, the non-small cell lung cancer (NSCLC) is adenocarcinoma. In another aspect, the non-small cell lung cancer (NSCLC) is large cell carcinoma.

[0207] In some embodiments, the present disclosure provides a method for treating or preventing a hematological cancer in a subject suffering from or susceptible to cancer by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the hematological cancer is selected from the group consisting of non-Hodgkin's lymphoma, leukemia, multiple myeloma (MM), and myelodysplastic syndrome (MDS). In one aspect, the hematological cancer is non-Hodgkin's lymphoma (NHL). In another aspect, the non-Hodgkin's lymphoma (NHL) is selected from diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma (MCL), and marginal zone lymphoma. In another aspect, the hematological cancer is leukemia. In another aspect, the leukemia is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). In another aspect, the hematological cancer is multiple myeloma (MM). In another aspect, the hematological cancer is myelodysplastic syndrome (MDS).

[0208] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered as a first line treatment.

[0209] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered as a second (or subsequent) line of treatment.

[0210] In some embodiments, a subject administered a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, exhibits a partial response (PR) in response to such treatment.

[0211] In some embodiments, a subject administered a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, exhibits a complete response (CR) in response to such treatment.

[0212] In some embodiments, subjects administered a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, exhibit improved progression-free survival (PFS) in response to such treatment.

[0213] In some embodiments, subjects administered a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, exhibit improved overall survival (OR) in response to such treatment.

[0214] PR, CR, PFS, and OR can be evaluated, for example, according to the RECIST (Response Evaluation Criteria in Solid Tumors) guidelines (version 1.1).

[0215] The subject to be treated is usually a human or non-human mammal, particularly a human. Suitable subjects may also include domestic or wild animals; companion animals (including dogs, cats, etc.); livestock (including horses, cows, and other ruminants, pigs, poultry, rabbits, etc.); primates (including monkeys, such as rhesus monkeys, cynomolgus monkeys (also known as club-eating monkeys or long-tailed monkeys), marmosets, tamarins, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[0216] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use as a medicament for treating a cancer mediated in whole or in part by CDK2.

[0217] In some embodiments, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating a cancer that is mediated in whole or in part by CDK2.

[0218] In some embodiments, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer mediated in whole or in part by CDK2.

[0219] IV. Combination Therapy and Fixed-Dose Combinations The compounds and pharmaceutically acceptable salts of the present disclosure can be used in the above methods either as single pharmacological agents or in combination with other pharmacological agents or techniques. Such combination therapy can be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment. These combination therapies (and corresponding combination products) employ the compounds and pharmaceutically acceptable salts of the present disclosure within the dosage ranges described herein, as well as other pharmacological agents, typically within their approved dosage ranges.

[0220] In some embodiments, the present disclosure provides a suitable combination for use in treating cancer mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In one aspect, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, relociclib (G1T38), trilaciclib (G1T28), dalpiciclib (SHR-6390), and BPI-16350. In another aspect, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, and dalpiciclib. In another aspect, the CDK4 / 6 inhibitor is palbociclib. In another aspect, the CDK4 / 6 inhibitor is abemaciclib. In another embodiment, the CDK4 / 6 inhibitor is ribociclib.In another embodiment, the CDK4 / 6 inhibitor is dalpiciclib.

[0221] In some embodiments, the present disclosure provides suitable combinations for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and endocrine therapy. In one aspect, the cancer is breast cancer.

[0222] In some embodiments, the present disclosure provides suitable combinations for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and an aromatase inhibitor. In one aspect, the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole. In another aspect, the combination further comprises everolimus. In another aspect, the cancer is breast cancer.

[0223] In some embodiments, the present disclosure provides a suitable combination for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a selective estrogen receptor degrader (SERD). In one aspect, the SERD is selected from the group consisting of fulvestrant, gildedestrant (GDC-9545), amsenestrant (SAR439859), camizestrant (AZD9833), lintodestrant (G1T48), imrunestrant (LY3484356), elakestrant (RAD-1901), taragarestrant (D-0502), OP1250 (Olema), LSZ102 (Novartis), ZN-c5 (Zentalis), and SHR9549 (Jiangsu Hengrui Medicine). In another embodiment, the SERD is selected from the group consisting of fulvestrant, giledestrant, camizestrant, imrunestrant, and elaquestrant. In another embodiment, the SERD is fulvestrant. In another embodiment, the SERD is fulvestrant and the administered combination further comprises alpelisib. In another embodiment, the SERD is camizestrant (AZD9833). In another embodiment, the SERD is camizestrant and the administered combination further comprises alpelisib. In another embodiment, the cancer is breast cancer.

[0224] In some embodiments, the present disclosure provides suitable combinations for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, a selective estrogen receptor degrader (SERD), and a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In one aspect, the SERD is selected from the group consisting of fulvestrant, gildedestrant (GDC-9545), amsenestrant (SAR439859), camizestrant (AZD9833), lindestrant (G1T48), imrunestrant (LY3484356), elakestrant (RAD-1901), taragarestrant (D-0502), OP1250 (Olema), LSZ102 (Novartis), ZN-c5 (Zentalis), and SHR9549 (Jiangsu Hengrui and the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, relociclib (G1T38), trilaciclib (G1T28), dalpiciclib (SHR-6390), and BPI-16350. In another embodiment, the SERD is selected from the group consisting of fulvestrant, giledestrant, camizestrant, imrunestrant, and elaquestrant, and the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, and dalpiciclib. In another embodiment, the SERD is selected from the group consisting of fulvestrant and camizestrant, and the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, and ribociclib. In another embodiment, the SERD is kamizestrant and the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, and ribociclib. In another embodiment, the cancer is breast cancer.

[0225] In some embodiments, the present disclosure provides suitable combinations for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a PROTAC estrogen receptor degrader (PROTAC ER (PROTAC estrogen receptor) degrader). In one aspect, the PROTAC ER degrader is bepdegestrant. In another aspect, the cancer is breast cancer.

[0226] In some embodiments, the present disclosure provides a suitable combination for use in treating cancer mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a selective estrogen receptor modulator (SERM). In one aspect, the SERM is selected from the group consisting of anordrin, bazedoxifene, broparestrol, clomiphene, cyclophen, lasofoxifene, ormeloxifene, ospemifene, raloxifene, tamoxifen, and toremifene. In another aspect, the SERM is tamoxifen. In another aspect, the SERM is toremifene. In another aspect, the SERM is selected from the group consisting of acolbifene, afimoxifene, enclomiphene, endoxifen, and zuclomiphene. In another embodiment, the SERM is selected from the group consisting of arzoxifene, brillanestran, clomifenoxide, droloxifene, etacstil, fispemifene, idoxifene, levormeloxifene, miproxifene, nafoxidine, nitromiphene, panomiphene, pipendoxifene, trioxifene, zindoxifene, GW-7604 (Glaxo Wellcome), and NNC 45-0095 (Novo Nordisk). In another embodiment, the cancer is breast cancer.

[0227] In some embodiments, the present disclosure provides suitable combinations for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and an anti-HER2 agent. In one aspect, the anti-HER2 agent is an anti-HER2 monoclonal antibody. In another aspect, the anti-HER2 monoclonal antibody is trastuzumab or pertuzumab. In another aspect, the cancer is breast cancer.

[0228] In some embodiments, the present disclosure provides a suitable combination for use in treating a cancer mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a poly ADP ribose polymerase (PARP) inhibitor. In one aspect, the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, and AZD5305 (CAS Number: 2589531-76-8). In another aspect, the PARP inhibitor is olaparib. In another aspect, the PARP inhibitor is AZD5305. In another aspect, the cancer is breast cancer. In another aspect, the cancer is ovarian cancer.

[0229] In some embodiments, the present disclosure provides suitable combinations for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a protein kinase B (Akt) inhibitor. In one aspect, the Akt inhibitor is selected from the group consisting of capivasertib (AZD5363) and ipatasertib (RG7440). In another aspect, the Akt inhibitor is capivasertib. In another aspect, the Akt inhibitor is ipatasertib. In another aspect, the cancer is breast cancer.

[0230] In some embodiments, the present disclosure provides suitable combinations for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and radiation therapy.

[0231] In some embodiments, the present disclosure provides suitable combinations for use in treating cancers mediated in whole or in part by CDK2, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and chemotherapy.

[0232] In some embodiments, the present disclosure provides suitable combinations for use in treating breast cancer, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and chemotherapy. In one aspect, the chemotherapy comprises administration of a combination of cyclophosphamide and doxorubicin ("AC"). In another aspect, the chemotherapy comprises administration of a combination of cyclophosphamide, doxorubicin, and a taxane, such as paclitaxel or docetaxel ("CAT"). In another aspect, the chemotherapy comprises administration of a combination of cyclophosphamide, methotrexate, and fluorouracil (or "CMF (cyclophosphamide, methotrexate, and fluorouracil)").

[0233] In some embodiments, the present disclosure provides a suitable combination for use in treating ovarian cancer, the combination comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and chemotherapy. In one aspect, the chemotherapy comprises the administration of one or more chemotherapeutic agents selected from the group consisting of cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, doxorubicin, epirubicin, and gemcitabine. In another aspect, the chemotherapy comprises the administration of a combination of carboplatin and any of doxorubicin, gemcitabine, paclitaxel, or docetaxel. In another embodiment, the chemotherapy comprises the administration of a combination of carboplatin and either paclitaxel or docetaxel. In another embodiment, the chemotherapy comprises the administration of topotecan. In another embodiment, the chemotherapy comprises the administration of a combination of bleomycin, etoposide, and cisplatin (BEP). In another embodiment, the chemotherapy comprises the administration of vincristine, dactinomycin, and cyclophosphamide (VAC). In another embodiment, the chemotherapy comprises the administration of a combination of paclitaxel, gemcitabine, and oxaliplatin.

[0234] V. Pharmaceutical Compositions The compounds of the present disclosure and their pharmaceutically acceptable salts can be administered as pharmaceutical compositions containing one or more pharmaceutically acceptable excipients. Thus, in some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0235] The excipients selected for inclusion in a particular composition depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; and Quinn, Marian. Pharmaceutically acceptable excipients can function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickeners, and coating agents. As those skilled in the art will understand, a particular pharmaceutically acceptable excipient can perform more than one function, and may perform different functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

[0236] The composition may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions, or suspensions), inhalation (e.g., as finely divided powders or liquid aerosols), insufflation (e.g., as finely divided powders), parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, or intramuscular administration), or rectal administration as a suppository. The composition may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0237] The total daily dose will necessarily vary depending on the subject being treated, the particular route of administration, any co-administered therapies, and the severity of the disease being treated, and may include single or multiple doses. The specific dosage may be adjusted depending, for example, on the condition being treated; the subject's age, weight, general health, sex, and diet; the route of administration; the interval between doses; the rate of excretion; and other drugs co-administered to the subject. A physician of ordinary skill, given the disclosure of this application, can determine the appropriate dosage and regimen for administering a therapeutic agent to a subject, and adjust such dosage and regimen as necessary during the course of treatment, according to methods well known in the therapeutic arts. The compounds of the present disclosure or pharmaceutically acceptable salts thereof are typically administered in a dose range of 2.5 to 5,000 mg / m of an animal. 2 It is administered to warm-blooded animals at a unit dose in the range of about 0.05 to 100 mg / kg body area, which will usually provide a therapeutically effective dose.

[0238] In some embodiments, the present disclosure provides a pharmaceutical composition for use in therapy, comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0239] In some embodiments, the present disclosure provides a pharmaceutical composition for use in treating a condition mediated by CDK2, comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. In a further aspect, the CDK2-mediated condition is selected from the conditions disclosed herein. In one aspect, the CDK2-mediated condition is breast cancer. In another aspect, the CDK2-mediated condition is ovarian cancer. In another aspect, the CDK2-mediated condition is endometrial cancer. In another aspect, the CDK2-mediated condition is lung cancer.

[0240] VI. Kits The present disclosure further provides kits comprising a unit dosage form comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof contained within packaging material, and a label or package insert indicating that the unit dosage form can be used to treat one or more of the conditions described above.

[0241] In some embodiments, the kit comprises a unit dosage form comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof contained within packaging material, and a label or package insert indicating that the pharmaceutical composition can be used to treat a condition mediated by CDK2. In further aspects, the CDK2-mediated condition is selected from the conditions disclosed herein. In one aspect, the CDK2-mediated condition is breast cancer. In another aspect, the CDK2-mediated condition is ovarian cancer. In another aspect, the CDK2-mediated condition is endometrial cancer. In another aspect, the CDK2-mediated condition is lung cancer.

[0242] In some embodiments, the kit comprises (a) a first unit dosage form comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, (b) a second unit dosage form comprising a pharmacological agent selected from the group consisting of a CDK4 / 6 inhibitor, an aromatase inhibitor, a selective estrogen receptor degrader, a PROTAC estrogen receptor degrader, a selective estrogen receptor modulator, an anti-HER2 agent, a poly ADP-ribose polymerase inhibitor, and a protein kinase B inhibitor, (c) container means for containing the first and second dosage forms, and (d) a label or package insert indicating that the first unit dosage form and the second unit dosage form can be used to treat a condition mediated by CDK2. In one aspect, the second unit dosage form comprises a CDK4 / 6 inhibitor.

[0243] VII. Preparation method The present disclosure further provides processes for the preparation of the disclosed compounds and pharmaceutically acceptable salts thereof. Reaction Schemes 1-8 show synthetic routes to these compounds, where, unless otherwise indicated, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 is as defined in formula (I). One of ordinary skill in the art will appreciate that these methods are representative and do not encompass all possible methods for preparing the compounds of the present disclosure.

[0244] Scheme 1

[0245] [ka] Scheme 1 shows a synthetic route to a particular compound of formula (I). A compound of formula A can be reacted with a compound of formula B (where X is a leaving group such as I, Br, etc.) to give a compound of formula C. The reaction can be carried out in the presence of a base (usually an inorganic base such as K2CO3, NaH, etc.) using a solvent (e.g., DMSO), and at a temperature typically ranging from 0°C to 60°C.

[0246] A compound of formula C can be reacted with an amine of formula D to give a compound of formula E. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., ethanol) and at a temperature typically ranging from 0°C to 80°C.

[0247] A compound of formula E can be reacted with an amine of formula F to give a compound of formula G. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., n-butanol, DMF, DMSO, NMP, 3-ethyl-3-pentanol, or a mixture thereof), and at a temperature typically ranging from 80°C to 160°C.

[0248] Compounds of formula G can be converted to compounds of formula H by deprotection of the Boc using a suitable reagent (eg, 4M HCl in 1,4-dioxane) in a solvent (eg, DCM) at 23°C.

[0249] A compound of formula H can be reacted with a compound of formula I to give a compound of formula (I). The reaction can be carried out in the presence of a base (usually an organic base, such as TEA, DIPEA, etc.), using a solvent (e.g., DCM), and typically at a temperature ranging from -78°C to 23°C.

[0250] Scheme 2

[0251] [ka] Scheme 2 shows a synthetic route to a particular compound of formula G. A compound of formula J can be reacted with a compound of formula B (X is a leaving group such as I, Br, etc.) to give a compound of formula K. The reaction can be carried out in the presence of a base (usually an inorganic base such as K2CO3, NaH, etc.) using a solvent (e.g., DMSO), and at a temperature typically ranging from 0°C to 60°C.

[0252] A compound of formula K can be reacted with an amine of formula D to give a compound of formula L. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., ethanol) and at a temperature typically ranging from 0°C to 80°C.

[0253] A compound of formula L can be reacted with an amine of formula F to give a compound of formula G. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., n-butanol, DMF, DMSO, NMP, 3-ethyl-3-pentanol, or a mixture thereof), and at a temperature typically ranging from 80°C to 160°C.

[0254] Scheme 3

[0255] [ka] Scheme 3 shows a synthetic route to certain compounds of formula (I). Compounds of formula K can be reacted with amines of formula M to give compounds of formula N. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., ethanol) and at temperatures typically ranging from 0°C to 80°C.

[0256] A compound of formula N can be reacted with an amine of formula F to give a compound of formula (I). The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., n-butanol, DMF, DMSO, NMP, 3-ethyl-3-pentanol, or a mixture thereof), and at a temperature typically ranging from 80°C to 160°C.

[0257] Scheme 4

[0258] [ka] Scheme 4 shows a synthetic route to certain compounds of formula (I). Compounds of formula C can be reacted with amines of formula M to give compounds of formula O. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., ethanol) and at temperatures typically ranging from 0°C to 80°C.

[0259] A compound of formula O can be reacted with an amine of formula F to give a compound of formula (I). The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., n-butanol, DMF, DMSO, NMP, 3-ethyl-3-pentanol, or a mixture thereof), and at a temperature typically ranging from 80°C to 160°C.

[0260] Scheme 5

[0261] [ka] Scheme 5 shows a synthetic route to certain compounds of formula T. Compounds of formula L can be converted to compounds of formula P by deprotection of the Boc using a suitable reagent (e.g., 4 M HCl in 1,4-dioxane) in a solvent (e.g., DCM) at 23°C.

[0262] The compound of formula P can be reacted with 2,3-dimethyl-1-((2-methyl-1H-imidazol-1-yl)sulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate to give the compound of formula Q. The reaction can be carried out using a solvent such as acetonitrile, THF, etc., and at 23° C.

[0263] A compound of formula Q can be reacted with an amine of formula R to give a compound of formula S. The reaction can be carried out in the presence of methyl trifluoromethanesulfonate using a solvent such as DCM, acetonitrile, etc., and at a temperature typically ranging from -20°C to 70°C.

[0264] A compound of formula S can be reacted with an amine of formula F to give a compound of formula T. The reaction can be catalyzed by a suitable Pd pre-catalyst (e.g., Pd(OAc)) and a phosphine ligand (e.g., BrettPhos) in the presence of a base (e.g., CsCO) using a suitable solvent (e.g., t-BuOH) and at temperatures typically in the range of 80°C to 100°C.

[0265] Scheme 6

[0266] [ka] Scheme 6 shows a synthetic route to a particular compound of formula (I). A compound of formula P can be reacted with a compound of formula I to give a compound of formula U. The reaction can be carried out in the presence of a base (usually an organic base, such as TEA, DIPEA, etc.), using a solvent (e.g., DCM), and typically at a temperature ranging from -78°C to 23°C.

[0267] A compound of formula U can be reacted with an amine of formula F to give a compound of formula (I). The reaction can be catalyzed by a suitable Pd catalyst (e.g., Pd-PEPPSI-IPentCl-o-picoline(2-methylpyridine)) in the presence of a base (e.g., NatBuO) using a suitable solvent (e.g., 1,4-dioxane) and at a temperature typically ranging from 80°C to 120°C.

[0268] Scheme 7

[0269] [ka] Scheme 7 shows a synthetic route to certain compounds of formula (I). Compounds of formula A can be reacted with amines of formula D to give compounds of formula V. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (e.g., tert-amyl alcohol), and at 100°C.

[0270] A compound of formula V can be reacted with a compound of formula B to give a compound of formula E. The reaction can be carried out in the presence of a base (usually an inorganic base such as K2CO3), using a solvent (e.g., DMSO), and at a temperature typically ranging from 0°C to 60°C.

[0271] Compounds of formula E can be converted to compounds of formula W by deprotection of the Boc using a suitable reagent (eg, 4M HCl in 1,4-dioxane) in a solvent (eg, DCM) at 23°C.

[0272] Compounds of formula W can be converted to compounds of formula Y using a suitable reagent (Ac2O) in the presence of a base (eg, TEA) in a solvent (eg, DCM) at 23°C.

[0273] A compound of formula Y can be reacted with an amine of formula F to give a compound of formula Z. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (e.g., 3-ethyl-3-pentanol), and at 160°C.

[0274] Compounds of formula Z can be converted to compounds of formula A1 using a suitable reagent (eg, LiOH) in a solvent (eg, an ethanol / water mixture) at 80°C.

[0275] A compound of formula A1 can be reacted with a compound of formula I to give a compound of formula (I). The reaction can be carried out in the presence of a base (usually an organic base, such as TEA, DIPEA, etc.) using a solvent (e.g., DCM), and typically at a temperature ranging from -78°C to 23°C.

[0276] Scheme 8

[0277] [ka] Scheme 8 shows a synthetic route to certain compounds of formula L. Compounds of formula J can be reacted with amines of formula D to give compounds of formula B1. The reaction can be carried out in the presence of a base (usually an organic base such as DIPEA) using a solvent (e.g., IPA) and at 100°C.

[0278] A compound of formula B1 can be reacted with a compound of formula B to give a compound of formula L. The reaction can be carried out in the presence of a base (usually an inorganic base such as K2CO3), using a solvent (e.g., DMSO), and at a temperature typically ranging from 0°C to 80°C.

[0279] It is understood that the organic reactions described herein are carried out according to experimental standards known to those skilled in the art. It is understood that some of the reactions described herein can optionally be carried out in a different order than that shown herein. It is understood that the chiral isomers of the compounds herein can be resolved at any stage of the synthetic process using chiral resolving agents known to those skilled in the art as described in the literature, or chiral chromatography methods known to those skilled in the art as described in the literature, or can be resolved at any stage of the synthetic process as further described in the Examples.

[0280] It will be further understood that additional protecting groups may optionally be required in some of the above steps. Accordingly, it will be further understood that deprotection steps may optionally be performed using methods known to those skilled in the art and described in the literature. Protection and deprotection of functional groups are described in "Protective Groups in Organic Synthesis," 3rd Ed., T.W. Greene and P.G.M. Hutz, Wiley-Interscience (1999), which is incorporated herein by reference.

[0281] VIII. Working Examples The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate embodiments of the present disclosure. They are not intended to be limiting in any way. Other compounds of the present disclosure can be prepared using the methods illustrated in these examples, either alone or in combination with techniques generally known in the art.

[0282] A. General Conditions Unless otherwise specified,

[0283] 1 H NMR spectra were obtained using a Bruker 300 MHz, 400 MHz, or 500 MHz spectrometer at 27° C. unless otherwise stated. Chemical shifts are expressed in parts per million (ppm) and are relative to residual solvent monolayers. 1 The H isotopologues are used as the reference (CHCl3: 7.24 ppm; CHDCl2: 5.32 ppm; CD3S(=O)CD2H: 2.49 ppm). Coupling constants are given in units of hertz (Hz). Splitting patterns indicate apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br s (broad singlet).

[0284] LC-MS was performed using a Waters UPLC equipped with a Waters SQD mass spectrometer or a Shimadzu LC-20AD, LC-20XR, or LC-30AD equipped with a Shimadzu 2020 mass spectrometer. Molecular ions reported are [M+H] unless otherwise stated. + For molecules with multiple isotopic patterns (e.g., Br, Cl), the reported value is that obtained for the lowest isotopic mass unless otherwise stated.

[0285] Flash chromatography was performed on a Biotage™ SP1™ purification system, an ISCO CombiFlash® Rf, or a Thermo Fisher Gilson system using normal phase silica FLASH+™ (40M, 25M, or 12M) or SNAP™ KP-Sil cartridges (340, 100, 50, or 10), straight phase flash chromatography using an Agela Flash Column silica-CS column with a C18 flash column, or standard flash chromatography. Generally, all solvents used were commercially available analytical grade. Anhydrous solvents were routinely used for reactions. The phase separator used in the examples was an ISOLUTE® Phase Separator column. The intermediates and examples named below were named using ACD / Name 12.01 from Advanced Chemistry Development, Inc. (ACD / Labs). Starting materials were obtained from commercial sources or prepared by literature routes.

[0286] In general, the examples and intermediate compounds are named using ChemDraw Professional version 21.0.0.28 from PerkinElmer. ChemDraw Professional version 21.0.0.28 generates names of chemical structures using Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are distinguished from one another by stereodescriptors that are specified in the name and assigned according to CIP rules. (a) In depicting stereocenters, ChemDraw arbitrarily uses labels such as "&" and "or" to represent the configuration of stereochemical centers present in a structure. In general, chemical structures of examples and intermediates with the label "&" at a stereocenter mean that the configuration of such example or intermediate at that stereocenter is a mixture of both (R) and (S), and the label "or" means that the configuration of such example or intermediate at that stereocenter is either (S) or (R). Absolute stereocenters, unassigned stereocenters, "&" stereocenters, and "or" stereocenters may all be present in a single structure. (b) In general, for examples and intermediate structures where all of the stereocenters are designated as "&", the structures are named using the prefix "rac-". For examples and intermediate structures where all of the stereocenters are designated as "or", the structures are named using the prefix "rel-". (c) In general, examples and intermediate compounds are named using the descriptors (RS) and (SR) to represent the generic "&" center for chemical structures having multiple chiral centers, only some of which are designated as "&". The descriptor (R) is used to represent the generic "or" center for chemical structures having multiple chiral centers, only some of which are designated as "or". * ) and (S * ) is used. (d) In general, the label "Isomeric 1" corresponds to the isomer eluted first on a given chiral HPLC column and eluent, and "Isomeric 2" corresponds to the isomer eluted second on a given chiral HPLC column and eluent, and is used to distinguish between two isomers containing one or more stereocenters with unknown absolute configuration at one or more stereocenters.

[0287] In addition to those mentioned above, the following abbreviations were used: ACN = acetonitrile; Ac2O = acetic anhydride; AcOH = acetic acid; aq. = aqueous; BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc = t-butyloxycarbonyl; Boc2O = di-tert-butyl dicarbonate; cataCXium® A Pd G3 = [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]-palladium(II) methanesulfonate; CDCl3 = deuterated chloroform; CD3OD = deuterated methanol; CH3NO2 = nitromethane; CO2 = carbon dioxide; Cs2CO3 = cesium carbonate; DCE = 1,2-dichloroethane; DCM = dichloromethane; DEA = diethylamine; DEAD = diethyl azodicarboxylate; Dess-Martin periodinane = 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DIEA = N,N-diisopropylethylamine; DMAP = 2,6-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d6 = deuterated dimethyl sulfoxide; DIAD = diisopropyl (E)-diazene-1,2-dicarboxylate; DIBAL-H = diisobutylaluminum hydride; DSC = differential scanning calorimetry; DTAD = di-tert-butyl (E)-diazene-1,2-dicarboxylate; EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; ee = enantiomeric excess; eq=equivalency; ESI = electrospray ionization; Et2O = diethyl ether; EtOAc = ethyl acetate; EO = diethyl ether; EtOH = ethanol; FA = formic acid; h=time; HATU = (dimethylamino)-N,N-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridinyl)-methanaminium hexafluorophosphate; HBr = hydrobromic acid; HCl = hydrochloric acid; H2O = water; H2O2 = hydrogen peroxide; HOBt = 1-hydroxybenzotriazole; HP = high pressure; IPA or iPrOH = isopropanol; IPAmine = isopropylamine; KHSO4 = potassium hydrogen sulfate; LAH = lithium aluminum hydride; LC = liquid chromatography; LC-MS / MS = Liquid Chromatography-Tandem Mass Spectrometry LiClO4 = lithium perchlorate; LiOH = lithium hydroxide; mCPBA = meta-chloroperoxybenzoic acid; MeCN or CH3CN = acetonitrile; MeMgBr = methylmagnesium bromide; MeNO2 = nitromethane; MeOH = methanol; MgSO4 = magnesium sulfate; min=minutes; mmol = millimoles; MP Carbonate = tetraalkylammonium carbonate, polymer-supported, loading of 2.5–3.5 mmol / g; MS=mass spectrometry; MTBE = tert-butyl methyl ether; Na2CO3 = sodium carbonate; NaCl = sodium chloride; NaH = sodium hydride; NaHCO3 = sodium bicarbonate; Na2SO4 = sodium sulfate; NH3 = ammonia; NH4Cl = ammonium chloride; NH4HCO3 = ammonium bicarbonate; NMP = N-methyl-2-pyrrolidone; NMR=nuclear magnetic resonance; Pd / C = palladium on carbon; PdCl2(dppf) = 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride; Pd2dba3 = tris(dibenzylideneacetone)dipalladium(0); Pd(OH)2 = palladium hydroxide; Pd-PEPPSI-IPentCl-o-picoline(2-methylpyridine) precatalyst = (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium; PE = petroleum ether; PPh3 = triphenylphosphine; rt=room temperature; Rt or RT = retention time; Ruphos Pd G3 = (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; sat=saturated; SFC = supercritical fluid chromatography; SOCl2 = thionyl chloride; TBAF = tetrabutylammonium fluoride; tBuBrettPhos = 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl; tBuBrettPhos Pd G3 = [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; tBuOH = tert-butanol; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TMS = trimethylsilyl; T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide; and UPLC = Ultra-High Performance Liquid Chromatography

[0288] B. Compound Example 1: (S)-3-((9-ethyl-2-(1-oxoisoindolin-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0289] [ka] Intermediate 2: 2,6-dichloro-9-ethyl-9H-purine 2,6-Dichloro-9H-purine (Intermediate 1, 15.10 g, 79.89 mmol) and potassium carbonate (13.80 g, 99.87 mmol) were suspended in DMSO (67.1 mL) and treated with iodoethane (7.10 mL, 87.88 mmol) under nitrogen. The reaction was stirred at room temperature over the weekend. The reaction was diluted with water, adjusted to pH 7 with acetic acid, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica (elution gradient 0 to 100% EtOAc in hexanes). The product fractions were concentrated under reduced pressure to give 2,6-dichloro-9-ethyl-9H-purine (Intermediate 2, 10.40 g, 60.0%) as a white solid.1 H NMR(500MHz,DMSO-d6)1.43(3H,t),4.27(2H,q),8.75(1H,s);m / z(ES + ) [M+H] + =217.

[0290] Intermediate 3: (S)-tert-butyl 3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-pyrrolidine-1-carboxylate 2,6-Dichloro-9-ethyl-9H-purine (Intermediate 2, 5.69 g, 26.21 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (5.85 g, 30.15 mmol) were dissolved in ethanol (100 mL) under nitrogen and cooled to 0° C., then N,N-diisopropylethylamine (13.74 ml, 78.64 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 2 days. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc and washed with water. The aqueous layer was re-extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give (S)-tert-butyl 3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate as a white solid (Intermediate 3, 8.00 g, 83%). 1 H NMR(500MHz,DMSO-d6)1.32-1.47(12H,m),1.86-2.09(1H,m),2.08-2.25(1 H,m),3.15-3.27(1H,m),3.35-3.41(1H,m),3.41-3.51(1H,m),3.60(1H,br dd),4.15(2H,q),4.50-4.70(1H,m),8.22(1H,s),8.49(1H,br s). m / z(ES - )[MH] - =365.

[0291] Intermediate 4: (S)-2-chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride To a 30 mL scintillation vial was added (S)-tert-butyl 3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 3, 1.029 g, 2.80 mmol), dichloromethane (10 mL), and hydrogen chloride (3.51 mL, 14.02 mmol) (4 M solution in 1,4-dioxane). The vial was sealed and stirred at room temperature for 3 hours. The reaction mixture was filtered, and the precipitate was washed with DCM and dried under vacuum to give the product (S)-2-chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 4, 0.850 g, 100%) as a white solid. m / z (ES + ) [M+H] + =267.

[0292] Intermediate 5: (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (S)-2-Chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 4, 0.850 g, 2.80 mmol) was weighed into a 40 mL scintillation vial, and dichloromethane (30 mL) and triethylamine (1.943 mL, 14.02 mmol) were added. The reaction was cooled to −40° C. A solution of methylsulfamoyl chloride (0.454 g, 3.36 mmol) in dichloromethane (5 mL) was added to the reaction mixture, stirred for 1 hour, and then allowed to warm to room temperature. The reaction was quenched by the addition of aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The resulting white solid was purified by silica flash chromatography using 0-10% MeOH in DCM to give (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Intermediate 5, 0.442 g, 43.8%) as a white solid. 1H NMR (500 MHz, dichloromethane-d2) 1.52 (3H, t), 2.04-2.22 (1H, m), 2.42 (1H, dq), 2.79 (3H, d), 3.36-3.48 (2H, m), 3.61 (1H, dt), 3.70 (1H, dd), 4.22 (2H, q), 4.74-5.13 (1H, m), 5.44 (1H, br s), 6.55 (1H, br s), 7.80 (1H, s). m / z (ES) + ) [M+H] + =360.

[0293] Example 1: (S)-3-((9-ethyl-2-(1-oxoisoindolin-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0294] [ka] (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Intermediate 5, 50 mg, 0.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (54.0 mg, 0.21 mmol), cesium carbonate (136 mg, 0.42 mmol), and cataCXium® A Pd G3 (10.12 mg, 0.01 mmol) were weighed into a 20 mL scintillation vial, evacuated, backfilled with N2, and sealed. 1,4-Dioxane (2 mL) and water (0.500 mL) were added. The reaction vial was placed in a heating block preheated to 100 °C and stirred for 16 h. The reaction mixture was cooled, quenched with brine, and attempted extraction with DCM (a solid precipitated), followed by the addition of a DCM:MeOH mixture (resulting in a clear biphasic mixture). The organic layer was separated, dried over Na2SO4, and concentrated under vacuum onto silica gel. The resulting solid was purified by silica flash chromatography using 0-10% MeOH in DCM to give a light brown solid. The brown solid was further purified by C18 flash chromatography using 0-100% ACN in water (0.1% NH4OH) to give (S)-3-((9-ethyl-2-(1-oxoisoindolin-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 1, 0.040 g, 63.1%). 1 H NMR(500MHz,DMSO-d6)1.50(3H,t),2.12-2.22(1H,m),2.28-2.36(1H,m),2.57(3H,d),3.23-3.30(2H,m),3.43- 3.51(1H,m),3.65(1H,dd),4.29(2H,q),4.87-4.98(3H,m),7.03(1H,q),7.64(1H,t),7.78(1H,dd),8.11(1H,br s),8.27(1H,s),8.62-8.73(2H,m). m / z(ES + ) [M+H] + =457.

[0295] Example 2: (S)-3-((9-ethyl-2-((R)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0296] [ka] Intermediate 6: (S)-3-((9-ethyl-2-(1-oxo-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Intermediate 5, 50 mg, 0.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (43.0 mg, 0.17 mmol), cesium carbonate (136 mg, 0.42 mmol), and cataCXium® A Pd G3 (10.12 mg, 0.01 mmol) were weighed into a 20 mL scintillation vial, evacuated, backfilled with N2, sealed, and 1,4-dioxane (2 mL) and water (0.500 mL) were added. The reaction vial was placed in a heating block preheated to 100 °C and stirred for 16 h. The reaction mixture was cooled, quenched with brine, and attempted extraction with DCM (a solid precipitated), followed by the addition of a DCM:MeOH mixture. The organic layer was separated, dried over Na2SO4, and concentrated onto silica gel in vacuo. The resulting solid was purified by silica flash chromatography using 0-10% MeOH in DCM to give an off-white solid. This solid was further purified by C18 flash chromatography using 0-100% ACN in water (0.1% NH4OH) to give (S)-3-((9-ethyl-2-(1-oxo-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Intermediate 6, 0.050 g, 79%) as a white solid. 1H NMR(500MHz,DMSO-d6)1.49(3H,t),2.15-2.37(2H,m),2.53-2.59(3H,m),2.61-2.72(2 H,m),3.09-3.26(2H,m),3.34-3.49(1H,m),3.63-3.72(3H,m),4.28(2H,q),4.87(1H,br s),7.02(1H,br s),7.58(1H,t),7.74(1H,d),7.96-8.16(1H,m),8.27(1H,s),8.61-8.68(1H,m). m / z(ES + ) [M+H] + =456.

[0297] Example 2: (S)-3-((9-ethyl-2-((R)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0298] [ka] (S)-3-((9-ethyl-2-(1-oxo-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Intermediate 6, 44 mg, 0.10 mmol) was added to a 20 mL vial and methanol (1 mL) was added. Sodium tetrahydroborate (7.31 mg, 0.19 mmol) was added to the reaction mixture at room temperature and stirred for 1 hour. The reaction was concentrated and quenched with saturated aqueous NH4Cl. The reaction was extracted with DCM and the combined organic layers were dried over Mg2SO4, filtered, and concentrated under reduced pressure. The crude product containing a mixture of diastereomers was purified by chiral SFC (Whelk-O column 4.6 mm × 100 mm 5 μm) using MeOH containing 0.2% NH 4 OH to give (S)-3-((9-ethyl-2-((R)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 2, Isomer 1, 14.00 mg, 31.7%); 1H NMR(500MHz,DMSO-d6)1.47(3H,t),1.76-1.84(1H,m),2.07-2.21(1H,m),2.23-2.38(2H,m) ,2.60(3H,s),3.16-3.25(2H,m),3.38-3.56(3H,m),3.63(1H,dd),4.25(2H,q),4.86(1H,br m / z(ES) + ) [M+H] + = 458; and (S)-3-((9-ethyl-2-((S)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (isomer 2, 14.00 mg, 31.7%).

[0299] Example 3: (S)-3-((9-ethyl-2-((R * )-1-hydroxy-1-methyl-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0300] [ka] (S)-3-((9-ethyl-2-(1-oxo-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Intermediate 6, 0.040 g, 0.09 mmol) was weighed into a 20 mL scintillation vial, evacuated, backfilled with N, sealed, and tetrahydrofuran (2 mL) was added. The reaction vial was cooled to 0 °C, and methylmagnesium bromide (0.146 ml, 0.44 mmol, 1 M solution in EtO) was added dropwise and stirred for 1.5 h. An additional 2 equivalents of MeMgBr was added and stirred for 1.5 h. The reaction mixture was quenched with brine and extracted with DCM. The organic layer was separated, dried over NaSO, and concentrated. The crude product containing a mixture of diastereomers was purified by chiral SFC (Whelk-O column 4.6 mm × 100 mm 5 μm) using MeOH containing 0.2% NH 4 OH to give (S)-3-((9-ethyl-2-((R * )-1-hydroxy-1-methyl-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 3, Isomer 1, 0.013 g, 30.2%); 1 H NMR(500MHz,DMSO-d6)1.41-1.50(6H,m),2.07(2H,t),2.11-2.20(1H,m),2.22-2.36(1H,m) ,2.56(3H,s),3.17-3.29(2H,m),3.40-3.55(3H,m),3.63(1H,dd),4.24(2H,q),4.99(2H,br s),6.84-7.15(1H,m),7.30-7.40(2H,m),7.93(1H,br s),8.14(1H,br d),8.22(1H,s);m / z(ES + ) [M+H] + = 472; and isomer 2 (0.012 g, 29.0%).

[0301] Example 4: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-sulfonamide

[0302] [ka] Intermediate 8: 6-chloro-9-ethyl-2-fluoro-9H-purine Iodoethane (5.15 mL, 63.75 mmol) was added to a stirred suspension of 6-chloro-2-fluoro-9H-purine (Intermediate 7, 10 g, 57.96 mmol) and potassium carbonate (10.01 g, 72.44 mmol) in DMSO (52.8 mL) at 23 °C. The resulting suspension was stirred at 23 °C for 20 hours. The reaction was diluted with water, adjusted to pH 7-8 with glacial acetic acid, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes). The product fractions were concentrated to give 6-chloro-9-ethyl-2-fluoro-9H-purine (Intermediate 8, 7.00 g, 60.2%); 1 H NMR (chloroform-d, 300 MHz) δ 1.58 (3H, t), 4.31 (2H, q), 8.11 (1H, s); m / z (ES + ) [M+H] + = 201; and 6-chloro-7-ethyl-2-fluoro-7H-purine, both as off-white solids.

[0303] Intermediate 9: (S)-tert-butyl 3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)-pyrrolidine-1-carboxylate 6-Chloro-9-ethyl-2-fluoro-9H-purine (Intermediate 8, 2.30 g, 11.47 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (2.093 g, 11.24 mmol) were dissolved in DMF (15 mL) under nitrogen and cooled to 0 °C, then N,N-diisopropylethylamine (4.01 mL, 22.93 mmol) was added dropwise. The reaction was warmed to 80 °C and stirred for 1 h. The solvent was removed under reduced pressure and the white residue was purified by silica flash chromatography (elution gradient 50–100% EtOAc in hexanes, followed by 15% MeOH in DCM). The product fractions were concentrated under reduced pressure to give tert-butyl (S)-3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 2.37 g, 59.1%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 1.37-1.45(12H,m),2.00(1H,s),2.14(1H,s),3.16-3.31(2H,m),3.38-3.66(2H,m),4.12(2H,q),4.58(1H,s),8.18(1H,s),8.56(1H,s). m / z(ES + ) [M+H] + =351.

[0304] Intermediate 10: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate tert-butyl (S)-tert-Butyl 3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 0.903 g, 2.58 mmol), (2R,3S)-3-aminopentan-2-ol (0.857 ml, 7.73 mmol), and DIEA (1.350 ml, 7.73 mmol) were dissolved in n-butanol (6.13 mL) / dimethyl sulfoxide (0.613 mL) and the reaction was heated to 100° C. The reaction was stirred at 100° C. for 65 hours, then continued stirring at 120° C. for an additional 16 hours. The reaction was concentrated and purified by C18 flash chromatography (elution gradient 0-100% acetonitrile in water (containing 0.1% formic acid additive)) to afford tert-butyl (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 10, 0.700 g, 62.7%) as a white solid. m / z (ES + ) [M+H] + =434.

[0305] Intermediate 11: (2R,3S)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol hydrochloride To a scintillation vial was added tert-butyl (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 10, 0.240 g, 0.55 mmol), dichloromethane (3 mL), and hydrogen chloride (0.692 ml, 2.77 mmol) (4 M solution in 1,4-dioxane). The vial was sealed and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give (2R,3S)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol.HCl (Intermediate 11, 0.205 g, 100%) as a white solid. m / z (ES + ) [M+H] + =334.

[0306] Example 4: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-sulfonamide

[0307] [ka] (2R,3S)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol hydrochloride (Intermediate 11, 94 mg, 0.25 mmol) was weighed into a scintillation vial, dichloromethane (5 mL) and triethylamine (195 μL, 1.40 mmol) were added, and the reaction was cooled to 0° C. (2,2,2-trifluoroethyl)sulfamoyl chloride (55.2 mg, 0.28 mmol) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated and purified by C18 flash chromatography using 0-100% ACN in water (0.1% NH4OH) followed by SFC purification to give (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-sulfonamide (Example 4, 40 mg, 0.081 mmol, 31.8%). 1 H NMR(500MHz,DMSO-d6)0.86(3H,t),1.06(3H,d),1.30-1.43(4H,m),1.69(1H,ddd ),2.00-2.09(1H,m),2.17-2.24(1H,m),2.52-2.57(1H,m),3.13-3.30(1H,m),3.3 7-3.45(1H,m),3.57(1H,dd),3.61-3.68(1H,m),3.72-3.80(3H,m),3.99(2H,q), 4.56-4.76(2H,m),5.89-6.03(1H,m),7.29-7.46(1H,m),7.74(1H,s),8.03(1H,br s); 19 F NMR(471MHz,DMSO-d6)-71.28(3F,s). m / z(ES+ ) [M+H] + =495.

[0308] Example 5: (S)—N-(2,2-difluoroethyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0309] [ka] (2R,3S)-3-((9-Ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol hydrochloride (Intermediate 11, 80 mg, 0.22 mmol) was weighed into a 20 mL scintillation vial, dichloromethane (5 mL) and triethylamine (165 μl, 1.19 mmol) were added, and the reaction was cooled to 0° C. (2,2-Difluoroethyl)sulfamoyl chloride (42.7 mg, 0.24 mmol) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated and purified by C18 flash chromatography followed by SFC to give (S)—N-(2,2-difluoroethyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 5, 0.031 g, 30.1%). 1 H NMR(500MHz,DMSO-d6)0.86(3H,t),1.06(3H,d),1.30-1.43(4H,m),1.64-1 .77(1H,m),1.98-2.12(1H,m),2.15-2.26(1H,m),3.11-3.29(3H,m),3.34- 3.43(3H,m),3.56(1H,dd),3.61-3.69(1H,m),3.77(1H,tdd),3.99(2H,q), 4.56-4.77(1H,m),5.91-6.13(2H,m),7.26-7.48(1H,m),7.65-7.79(2H,m). 19 F NMR(471MHz,DMSO-d6)-122.03(2F,s). m / z(ES +) [M+H] + =477.

[0310] Example 6: (S)—N-ethyl-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0311] [ka] (2R,3S)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol.HCl (Intermediate 11, 0.482 g, 1.30 mmol) was weighed into a 40 mL scintillation vial, dichloromethane (20 mL) and triethylamine (0.903 mL, 6.52 mmol) were added, and the reaction was cooled to −78° C. Ethylsulfamoyl chloride (0.177 g, 1.17 mmol) was added to the reaction mixture and stirred for 2 hours. Additional ethylsulfamoyl chloride (0.030 g, 0.20 mmol) was added and stirred for 1 hour. The reaction was quenched with aqueous NaHCO, warmed to 25°C, stirred for 15 minutes, extracted with DCM, and the organic layer separated, dried over MgSO, and concentrated to give a white foam. The solid was purified by flash chromatography on silica using 0-20% MeOH in DCM to give (S)-N-ethyl-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 6, 0.302 g, 52.6%). 1H NMR(400MHz,DMSO-d6)0.86(3H,t),0.97-1.1(6H,m),1.27-1.49(4H,m),1.69 (1H,ddd),2.05(1H,dt),2.20(1H,td),2.95(2H,qd),3.09(1H,dd),3.21(1H, dt),3.33-3.42(1H,m),3.54(1H,dd),3.58-3.66(1H,m),3.71-3.82(1H,m),3 .98(2H,q),4.64(2H,s),5.96(1H,s),6.93-7.62(2H,m),7.73(1H,s);m / z(ES + ) [M+H] + =441.

[0312] Example 7: (S)—N-ethyl-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0313] [ka] 3-Oxo-115-benzo[d][1,2]iodaoxol-1,1,1(3H)-triyl triacetate (42.4 mg, 0.10 mmol) was added to (S)-N-ethyl-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 6, 40 mg, 0.09 mmol) in dichloromethane (0.5 mL). The resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated and purified by C18 flash chromatography using 0-100% ACN in HO to give (S)-N-ethyl-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 7, 0.026 g, 64.3%). 1H NMR(500MHz,DMSO-d6)0.92(3H,t),1.07(3H,t),1.34(3H,t),1.61-1.78(2H,m),1.95-2.19(5H,m),2.92-3.01(2H,m),3.10(1H ,dd),3.17-3.29(2H,m),3.33-3.40(1H,m),3.52(1H,dd),3.96-4.05(2H,m),4.05-4.15(1H,m),6.67-6.89(1H,m),7.08(1H,br t),7.42-7.57(1H,m),7.78(1H,s). m / z(ES + ) [M+H] + =439.

[0314] Example 8: (S)—N-ethyl-3-((9-ethyl-2-(((2S,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0315] [ka] (S)-N-Ethyl-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-pyrrolidine-1-sulfonamide (Example 7, 0.193 g, 0.44 mmol) was dissolved in THF (4.58 ml) / MeOH (0.917 ml) and treated with sodium tetrahydroborate (0.027 g, 0.70 mmol). The reaction mixture was stirred under nitrogen for 45 minutes. The reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was applied to silica and purified by silica flash chromatography (elution gradient 0-10% MeOH in DCM). The product fractions were concentrated under reduced pressure to give the crude product (0.152 g, 78%) as a white solid. The solid was purified by chiral SFC (IH column 4.6 × 150 mm, 5 μm) using 0.2% NHOH in MeOH to give (S)-N-ethyl-3-((9-ethyl-2-(((2S,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 8, 0.016 g, 8.46%) as the minor regioisomer. 1 H NMR(500MHz,DMSO-d6)0.88(3H,t),1.02-1.09(6H,m),1.35(3H,t),1.42-1.53(1H,m),1.55-1.64(1H,m),2.05(1H,br dd),2.16-2.25(1H,m),2.88-3.04(2H,m),3.11(1H,dd),3.18-3.29(1H,m),3.35-3.4 1(1H,m),3.55(1H,dd),3.74-3.82(2H,m),4.00(2H,q),4.45-4.59(1H,m),4.65(1H,br s),5.59-5.79(1H,m),7.07(1H,t),7.21-7.60(1H,m),7.75(1H,br s). m / z(ES + ) [M+H] + =441.

[0316] Example 9: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0317] [ka] Intermediate 12: tert-butyl (((S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamate (2R,3S)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol, HCl (Intermediate 11, 0.520 g, 1.41 mmol) was weighed into a 30 mL scintillation vial, dichloromethane (12.77 ml) and triethylamine (0.974 ml, 7.03 mmol) were added, and the reaction was cooled to −40° C. A solution of tert-butyl (chlorosulfonyl)carbamate (0.303 g, 1.41 mmol) in dichloromethane (12.77 ml) (poorly soluble) was added to the reaction mixture and stirred for 1 hour. The reaction was quenched by the addition of aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The resulting white solid was purified by silica flash chromatography using 0-10% MeOH in DCM to afford tert-butyl (((S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamate (Intermediate 12, 0.455 g, 63.1%) as a white solid. 1H NMR(500MHz,DMSO-d6)0.86(3H,t),1.06(3H,d),1.28-1.45(13H,m),1.69 (1H,ttd),1.96-2.11(1H,m),2.11-2.26(1H,m),3.22-3.30(2H,m),3.35- 3.46(1H,m),3.54-3.60(1H,m),3.62-3.80(3H,m),3.99(2H,q),4.54-4.7 6(1H,m),5.82-6.03(1H,m),7.24-7.56(1H,m),7.73(1H,s),10.91(1H,br s). m / z(ES + ) [M+H] + =513.

[0318] Example 9: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0319] [ka] tert-Butyl (((S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamate (Intermediate 12, 0.121 g, 0.24 mmol) was weighed into a 20 mL scintillation vial, and dichloromethane and hydrochloric acid (0.236 mL, 0.94 mmol) (4 M solution in 1,4-dioxane) were added and stirred at room temperature for 1.5 hours (LCMS showed no remaining SM). The reaction was concentrated to give a white foam as the HCl salt of the desired product. A portion of the solid was dissolved in ethyl acetate, and aqueous NaHCO was added. The organic layer was separated, dried, and concentrated to give (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 9, 33 mg, 33.9%) as the free base. 1H NMR(500MHz,DMSO-d6)0.79-0.93(3H,m),0.96-1.16(3H,m),1.29-1.44(4H,m),1.62-1.84(1H,m),2.01(1H,br dd),2.12-2.27(1H,m),3.05(1H,br dd),3.14-3.29(3H,m),3.51(1H,dd),3.59-3.68(1H,m),3.74-3.80(1H,m),3.99(2H,q),4.66(1H,br s),5.88-6.04(1H,m),6.77(2H,s),7.33(1H,br s),7.73(1H,s). m / z(ES + ) [M+H] + =413.

[0320] Example 10: (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0321] [ka] Intermediate 13: tert-butyl (((S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamate tert-Butyl (((S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamate (Intermediate 12, 0.457 g, 0.89 mmol) was suspended in DCM (25.4 ml), cooled to 0° C., and treated with DMSO (3.35 ml, 47.25 mmol) and DIEA (0.934 ml, 5.35 mmol). The reaction was then treated with sulfur trioxide pyridine (0.568 g, 3.57 mmol) and stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred for 20 minutes. The reaction was quenched with water, diluted with EtOAc, and the organic layer separated. The organic layer was washed with water, brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes followed by 2% MeOH in EtOAc). The product fractions were concentrated under reduced pressure to give tert-butyl (((S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamate (Intermediate 13, 0.326 g, 71.6%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 0.92(3H,t),1.34(3H,t),1.43(9H,s),1.61-1.77(2H,m),1.97-2.17(5H,m),3.26-3.30( 1H,m),3.38-3.44(1H,m),3.53-3.59(1H,m),3.70(1H,dd),3.96-4.13(3H,m),4.55(1H,br s),6.77(1H,br s),7.55(1H,br s),7.78(1H,s),10.90(1H,s). m / z(ES+)[M+H] + =511.

[0322] Example 10: (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0323] [ka] tert-Butyl (((S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamate (Intermediate 13, 191 mg, 0.37 mmol) was weighed into a 20 mL scintillation vial, and dichloromethane (5 mL) and hydrochloric acid (0.374 mL, 1.50 mmol) (4 M solution in 1,4-dioxane) were added and stirred at room temperature for 1.5 hours. The reaction was concentrated to give a white foam. The solid was purified by C18 flash chromatography using 0-100% ACN in HO (with 0.1% NH4OH additive) and the product fractions were directly lyophilized to give (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 10, 60.0 mg, 39.1%). 1 H NMR(500MHz,DMSO-d6)δ ppm 0.93(3H,t),1.34(3H,t),1.62-1.80(2H,m),1.93-2.06(1H,m),2.08(3H,s),2.11-2.22(1H ,m),3.00-3.10(1H,m),3.12-3.24(1H,m),3.41-3.54(2H,m),3.96-4.15(3H,m),4.58(1H,br s),6.70-6.84(3H,m),7.47(1H,br s),7.80(1H,s). m / z(ES+)[M+H] + =411.

[0324] Example 11: (S)—N-ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0325] [ka] Intermediate 14: (S)-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate tert-butyl (S)-tert-Butyl 3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 2.5 g, 7.13 mmol), (2S,3R)-3-aminopentan-2-ol (2.94 g, 28.54 mmol), and DIEA (12.46 ml, 71.35 mmol) were dissolved in dimethyl sulfoxide (12.31 ml) and the reaction was heated to 140° C. The reaction was stirred at 140° C. for 65 hours, cooled, concentrated in vacuo, and purified by C18 flash column chromatography using 0-100% acetonitrile in water (0.1% formic acid) to give tert-butyl (S)-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 14, 3.00 g, 97%) as a white solid. 1 H NMR(500MHz,DMSO-d6)0.86(3H,t),1.06(3H,d),1.32-1.42(13H,m),1.65-1.74(1H,m),1.95-2.05(1H,m),2.05- 2.15(1H,m),3.15-3.31(3H,m),3.41-3.48(1H,m),3.57-3.68(2H,m),3.73-3.79(1H,m),3.99(2H,q),4.64(1H,br s),5.96(1H,br s),7.39(1H,br s),7.73(1H,s);m / z(ES + ) [M+H] + =434.

[0326] Intermediate 15: (2S,3R)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol hydrochloride To a reaction flask was added tert-butyl (S)-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 14, 3.09 g, 7.13 mmol), dichloromethane (5 mL), and hydrogen chloride (8.91 mL, 35.64 mmol) (4 M in 1,4-dioxane). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a white solid as (2S,3R)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol hydrochloride (Intermediate 15, 2.65 g, 101%). m / z (ES + ) [M+H] + =334.

[0327] Example 11: (S)—N-ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0328] [ka] (2S,3R)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol, HCl (Intermediate 15, 1.60 g, 4.33 mmol) was weighed into a reaction flask, dichloromethane (50 mL) and triethylamine (3.00 mL, 21.63 mmol) were added, and the reaction was cooled to −78° C. Ethylsulfamoyl chloride (0.686 g, 4.54 mmol) was added as a solution in DCM to the reaction mixture and stirred for 2 hours. The reaction was quenched with aqueous NaHCO, stirred for 15 minutes, extracted with DCM, and the organic layer was separated, dried over MgSO, and concentrated to give a white foam. The solid was purified by silica flash chromatography using 0-20% MeOH in DCM to give (S)-N-ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 11, 1.100 g, 57.7%). 1 H NMR(500MHz,DMSO-d6)0.86(3H,t),1.04-1.08(6H,m),1.31-1.44(4H,m),1.70(1H,ddd),2.05(1H,br dd),2.16-2.24(1H,m),2.93-2.99(2H,m),3.10(1H,dd),3.16-3.25(1H,m),3.33-3.42(1H,m),3.54(1H,dd),3.62-3.68 (1H,m),3.76(1H,tdd),3.99(2H,q),4.56-4.75(2H,m),5.90-6.03(1H,m),7.07(1H,t),7.27-7.47(1H,m),7.73(1H,s). m / z(ES + ) [M+H] + =441.

[0329] Example 12: (S)—N-ethyl-3-((9-ethyl-2-(((R)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0330] [ka] (S)-N-ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 11, 0.873 g, 1.98 mmol) was suspended in DCM (56.5 ml), cooled to 0° C., and treated with DMSO (7.45 ml, 105.02 mmol) and DIEA (2.077 ml, 11.89 mmol). The reaction was treated with sulfur trioxide pyridine (1.262 g, 7.93 mmol), stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred for 20 minutes. The reaction was quenched with water, diluted with EtOAc, and the layers separated. The organic portion was washed with water, brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by C18 flash chromatography using 0 to 100% acetonitrile in HO (0.1% formic acid). The product fractions were concentrated under reduced pressure to give (S)-N-ethyl-3-((9-ethyl-2-(((R)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 12, 0.687 g, 79%). 1 H NMR(500MHz,DMSO-d6)0.92(3H,t),1.07(3H,t),1.34(3H,t),1.62-1.79(2H,m) ,1.99-2.06(1H,m),2.07(3H,s),2.15-2.24(1H,m),2.97(2H,quin),3.07(1H,br dd),3.17-3.26(1H,m),3.39(1H,td),3.44-3.49(1H,m),3.99(2H,q),4.05-4.12(1H,m),4.45-4.79(1H,m),6.77(1H,br s),7.07(1H,t),7.49(1H,br s), 7.78 (1H, s); m / z (ES + ) [M+H] + =439.

[0331] Example 13: (S)-N-ethyl-3-((9-ethyl-2-(((2RS,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0332] [ka] (S)-N-ethyl-3-((9-ethyl-2-(((R)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 12, 0.200 g, 0.46 mmol) was dissolved in THF (4.75 ml) / MeOH (0.950 ml) and treated with sodium tetrahydroborate (0.028 g, 0.73 mmol). The reaction mixture was stirred under nitrogen for 35 minutes. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a 2.2:1 mixture of diastereomers. The diastereomers were separated by SFC purification (IH column 21 × 250 mm, 5 μm) using 0.2% NHOH in MeOH to give (S)-N-ethyl-3-((9-ethyl-2-(((2R,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 13, 28 mg, 0.064 mmol, 13.94%) as the minor isomer. 1 H NMR(500MHz,DMSO-d6)0.88(3H,t),1.02-1.09(6H,m),1.35(3H,t),1.43-1.52(1H,m),1.55-1.63(1H,m),2.00-2.08(1H,m),2.17-2.24( 1H,m),2.93-2.99(2H,m),3.09(1H,dd),3.19-3.29(1H,m),3.33-3.40(1H,m),3.55(1H,dd),3.74-3.81(2H,m),3.99(2H,q),4.50(1H,br s),4.65(1H,br s),5.66(1H,br s),7.08(1H,t),7.38(1H,br s),7.74(1H,s). m / z(ES + ) [M+H] + =441.

[0333] Example 14: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide

[0334] [ka] Intermediate 16: 2,6-Dichloro-9-(difluoromethyl)-9H-purine 2,6-Dichloro-9H-purine (Intermediate 1, 8.18 g, 43.28 mmol), diethyl (bromodifluoromethyl)phosphonate (16.85 g, 60.59 mmol), and potassium fluoride (5.03 g, 86.56 mmol) in MeCN (160 mL) were stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was quenched with water, extracted with EtOAc, and the EtOAc layer was dried and concentrated. The colorless liquid was purified by flash chromatography on silica using hexane:EtOAc to give 2,6-dichloro-9-(difluoromethyl)-9H-purine (Intermediate 16, 9.80 g, 95%) contaminated with residual diethyl (bromodifluoromethyl)phosphonate. 1 H NMR (500 MHz, dichloromethane-d2) 7.66 (1H, t), 8.51 (1H, s). m / z (ES + ) [M+H] + =239.

[0335] Intermediate 17: (S)-tert-butyl 3-((2-chloro-9-(difluoromethyl)-9H-purin-6-yl)-amino)pyrrolidine-1-carboxylate 2,6-Dichloro-9-(difluoromethyl)-9H-purine (Intermediate 16, 4.00 g, 4.18 mmol, 25 wt%), (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.812 g, 4.18 mmol) were dissolved in acetonitrile (30 mL) under N2, and N,N-diisopropylethylamine (2.192 mL, 12.55 mmol) was added and stirred at room temperature for 16 hours. 0.3 equivalents of additional tert-butyl (S)-3-aminopyrrolidine-1-carboxylate were added and stirred for 6 hours. The solvent was removed under reduced pressure, and the residue was dissolved in DCM and washed with aqueous NaHCO3. The aqueous layer was extracted again with DCM and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil which was purified by silica flash chromatography to give tert-butyl (S)-3-((2-chloro-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 17, 0.706 g, 43.4%). m / z (ES + ) [M+H] + =389.

[0336] Intermediate 18: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate tert-butyl (S)-tert-Butyl 3-((2-chloro-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 17, 706 mg, 1.82 mmol), (R)-2-amino-2-cyclopropylethan-1-ol, HCl (500 mg, 3.63 mmol), cesium carbonate (2071 mg, 6.36 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6',-tri-i-propyl-1,1'-biphenyl (292 mg, 0.54 mmol), and palladium(II) acetate (40.8 mg, 0.18 mmol) were placed in an oven-dried vial. The vial was evacuated and backfilled with nitrogen twice, then tBuOH (5.19 mL) was added, and the reaction was sealed and heated at 90 °C for 16 h. The reaction was concentrated and the resulting residue was purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes followed by 0-10% MeOH in DCM). The product fractions were concentrated under reduced pressure to give tert-butyl (3S)-3-((2-((1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 18, 0.361 g, 43.9%) as a dry yellow film. 1 H NMR(500MHz, dichloromethane-d2)0.34-0.46(2H,m),0.49-0.61(2H,m),1.02(1H,br s),1.47(9H,br s),1.98(1H,br s),2.24(1H,br s),3.28-3.37(1H,m),3.37-3.53(3H,m),3.75(2H,br dd),3.92(1H,br d),4.23(1H,br s),4.56-4.79(1H,m),5.43-5.55(1H,m),6.22(1H,br s),7.36(1H,t),7.77(1H,s). m / z(ES + ) [M+H] + =454.

[0337] Intermediate 19: (R)-2-Cyclopropyl-2-((9-(difluoromethyl)-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol hydrochloride To a 30 mL scintillation vial was added tert-butyl (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 18, 0.3612 g, 0.80 mmol), dichloromethane (2 mL), and hydrogen chloride (0.996 mL, 3.98 mmol) (4 M in 1,4-dioxane). The vial was sealed and stirred at room temperature for 16 h. The reaction mixture was concentrated and dried under vacuum to give (R)-2-cyclopropyl-2-((9-(difluoromethyl)-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol 4HCl (Intermediate 19, 0.406 g, 102%) as a white solid.

[0338] Example 14: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide

[0339] [ka] (R)-2-Cyclopropyl-2-((9-(difluoromethyl)-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol, 4HCl (Intermediate 19, 0.116 g, 0.23 mmol) was weighed into a 20 mL scintillation vial, dichloromethane (5 mL) and triethylamine (0.129 mL, 0.93 mmol) were added, and the reaction was cooled to −78° C. Ethylsulfamoyl chloride (0.039 g, 0.26 mmol) was added to the reaction mixture and stirred for 60 minutes. Additional ethylsulfamoyl chloride (5.34 mg, 0.04 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction was quenched with aqueous NaHCO, extracted with DCM, and the organic layer was dried and concentrated. The crude product was purified by silica flash chromatography using 0-20% MeOH in DCM to give (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide (Example 14, 0.037 g, 34.6%) as a colorless film. 1 H NMR(500MHz, dichloromethane-d2)0.37-0.46(2H,m),0.52-0.67(2H,m),0.92-1.08(1H,m),1.21(3H,t),1.90(1H,br s),2.03-2.12(1H,m),2.38(1H,dq),3.12-3.21(2H,m),3.27-3.46(3H,m),3.54(1H,ddd),3.65-3.80(2H,m),3.92(1H,dd),4.77(1H,br s),4.84(1H,br s),5.31-5.35(1H,m),6.13(1H,br s), 7.36(1H,t), 7.78(1H,s). 19 F NMR (471 MHz, dichloromethane-d2) -96.02 (2F, s). m / z (ES + ) [M+H] + =461.

[0340] Example 15: 2-Cyclopentyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol

[0341] [ka] Intermediate 20: 2,6-dichloro-9-isopropyl-9H-purine DIAD (20.57 mL, 105.82 mmol) was slowly added to 2,6-dichloro-9H-purine (Intermediate 1, 10 g, 52.91 mmol), IPA (16.31 mL, 211.64 mmol), and triphenylphosphine (27.8 g, 105.82 mmol) in THF (30 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (500 mL) and washed sequentially with saturated aqueous NaCO (300 mL × 3) and aqueous brine (300 mL × 2). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica flash chromatography (elution gradient 0–50% EtOAc in petroleum ether). Pure fractions were evaporated to dryness to give 2,6-dichloro-9-isopropyl-9H-purine (Intermediate 20, 7.00 g, 57.3%) as a white solid (contaminated with triphenylphosphine oxide). This compound was carried on to the next step without further purification. m / z (ES + ) [M+H] + =231.

[0342] Intermediate 21: (S)-2-chloro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine DIEA (2.72 mL, 15.58 mmol) was added to 2,6-dichloro-9-isopropyl-9H-purine (Intermediate 20, 1.2 g, 3.12 mmol, 60 wt%) and (S)-1-(methylsulfonyl)pyrrolidin-3-amine hydrochloride (0.625 g, 3.12 mmol) in iPrOH (4 mL). The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted with DCM (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by C18 flash chromatography (elution gradient: 5–70% MeCN in water (0.1% NH4HCO3)). Pure fractions were evaporated to dryness to afford (S)-2-chloro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (intermediate 21, 0.750 g, 67.1%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 1.50(6H,d),2.04(1H,s),2.23(1H,s),2.92(3H,s),3.24(1H,s),3.33-3.3 9(2H,m),3.48(1H,s),3.60(1H,s),4.68(1H,p),8.33(1H,s),8.52(1H,s). m / z(ES + ) [M+H] + =359.

[0343] Example 15: 2-Cyclopentyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol

[0344] [ka] 2-Amino-2-cyclopentylethan-1-ol (194 mg, 1.50 mmol) and (S)-2-chloro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 21, 360 mg, 1.00 mmol) were placed in a vial, and the reaction mixture was dissolved in 1 mL of anhydrous NMP. N-ethyl-N-isopropylpropan-2-amine (648 mg, 5.02 mmol) was then added. The reaction mixture was heated with stirring at 140° C. for 16 hours. After cooling to ambient temperature, the mixture was evaporated in vacuo. The residue was purified by C18 flash chromatography using water (containing NH3) and methanol as eluents to give 2-cyclopentyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol (Example 15, 4.70 mg, 1.037%). m / z (ES + ) [M+H] + =452.

[0345] Example 16: 2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-2-(tetrahydrofuran-2-yl)ethan-1-ol

[0346] [ka] 2-Amino-2-(tetrahydrofuran-2-yl)ethan-1-ol (197 mg, 1.50 mmol) and (S)-2-chloro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 21, 360 mg, 1.00 mmol) were placed in a vial, and the reaction mixture was dissolved in 1 mL of anhydrous NMP. N-Ethyl-N-isopropylpropan-2-amine (648 mg, 5.02 mmol) was then added. The reaction mixture was heated with stirring at 140° C. for 16 hours. After cooling to ambient temperature, the mixture was evaporated in vacuo. The residue was purified by C18 flash chromatography using water (containing NH3) and methanol as eluents to give 2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-2-(tetrahydrofuran-2-yl)ethan-1-ol (Example 16, 4.60 mg, 1.011%). m / z (ES + ) [M+H] + =454.

[0347] Example 17: (R)-2-((6-(((3R * ,4R * )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-2-cyclopropylethan-1-ol

[0348] [ka] Intermediate 22: tert-butyl rac-(3R,4R)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate 2,6-Dichloro-9-ethyl-9H-purine (Intermediate 2, 0.32 g, 1.47 mmol) and trans-1-Boc-3-amino-4-fluoropyrrolidine (0.361 g, 1.77 mmol) were placed in a 20 mL reaction vial under nitrogen and dissolved in acetonitrile (8.44 mL). The reaction was treated with DIEA (0.772 mL, 4.42 mmol), sealed, and heated at 100 °C for 16 h. The reaction was concentrated under reduced pressure, and the resulting residue was purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes (EtOAc containing 6% MeOH)). The product fractions were concentrated under reduced pressure to give tert-butyl rac-(3R,4R)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 22, 0.529 g, 93%) as a beige foam. 1 H NMR(DMSO-d6)1.35-1.44(12H,m),3.40-3.78(4H,m),4.14(2H,q),4.55-4.81(1H,m),5.08-5.29(1H,m),8.25(1H,s),8.68(1H,br d);m / z(ES + ) [M+H] + =385.

[0349] Intermediate 23: tert-butyl (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate tert-Butyl rac-(3R,4R)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 22, 0.529 g, 1.37 mmol), (R)-2-amino-2-cyclopropylethan-1-ol, HCl (0.378 g, 2.75 mmol), cesium carbonate (1.568 g, 4.81 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (0.221 g, 0.41 mmol), and palladium(II) acetate (0.031 g, 0.14 mmol) were placed in an oven-dried microwave vial under nitrogen. The vial was evacuated and filled with nitrogen twice, then tBuOH (6.87 mL) was added, and the reaction was sealed and heated in an oil bath at 90 °C overnight. LC / MS indicated a complete reaction. The reaction was diluted with EtOAc / HO. The layers were separated, the organic component was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0 to 100% EtOAc in hexanes (EtOAc containing 7% MeOH)). Product fractions were concentrated under reduced pressure to give tert-butyl (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 23, 0.308 g, 49.8%) as a beige solid. 1 H NMR(DMSO-d6)0.14-0.44(4H,m),0.91-1.04(1H,m),1.32(3H,t),1.41(9H,s),3.40-3.73(7H,m),3.97(2H,q),4.57(1H,br s),4.63-4.82(1H,m),5.06-5.38(1H,m),6.04(1H,br d),7.50-7.69(1H,m),7.74(1H,s);m / z(ES + ) [M+H] + =450.

[0350] Intermediate 24: (R)-2-Cyclopropyl-2-((9-ethyl-6-(((3RS,4RS)-4-fluoropyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol hydrochloride tert-Butyl (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 23, 0.308 g, 0.69 mmol) was dissolved in MeOH (2.57 mL) and treated with HCl (4.0 M in dioxane) (1.713 ml, 6.85 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction was concentrated under reduced pressure to give (R)-2-cyclopropyl-2-((9-ethyl-6-(((3RS,4RS)-4-fluoropyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol.4HCl (Intermediate 24, 0.315 g, 93%) as a yellow foam. m / z (ES + ) [M+H] + =350.

[0351] Example 17: (R)-2-((6-(((3R * ,4R * )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-2-cyclopropylethan-1-ol

[0352] [ka] (R)-2-Cyclopropyl-2-((9-ethyl-6-(((3RS,4RS)-4-fluoropyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol, 4HCl (Intermediate 24, 315 mg, 0.64 mmol) was suspended in DCM (15.37 mL) and treated with TEA (532 μL, 3.82 mmol). The reaction was cooled to −78° C. and treated with a suspension of 1H-imidazole-2-sulfonyl chloride (106 mg, 0.64 mmol) in 3 mL of DCM. The reaction was stirred at that temperature for 30 minutes and then allowed to warm slowly to room temperature. The reaction was concentrated under reduced pressure and the resulting residue was purified by silica flash chromatography (elution gradient 0-15% MeOH in DCM) followed by preparative SFC (Chiralpak AD column, 5 μm, 21 mm diameter, 250 mm length) eluting with 15% MeOH (containing 0.2% NH4OH) in CO2 (column temperature: 40 °C, outlet pressure: 100 bar, flow rate: 70 mL / min) to give (R)-2-((6-(((3R * ,4R * )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-2-cyclopropylethan-1-ol (Example 17, Isomer 1, 0.100 g, 32.8%); 1 H NMR(DMSO-d6)0.15-0.23(1H,m),0.25-0.33(1H,m),0.33-0.44(2H,m),0.91-1.02(1H,m),1.32(3H,t),3.43-3.75(6H,m),3.81(1H,br dd),3.97(2H,q),4.57(1H,br s),4.65-4.89(1H,m),5.07-5.30(1H,m),6.07(1H,br d),7.38(2H,s),7.76(1H,s),7.92-8.37(1H,m),13.66(1H,br s);m / z(ES + ) [M+H] + = 480 as a white dry film and Isomer 2 (106 mg, 34.8%) as a dry film.

[0353] Example 18: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide

[0354] [ka] Intermediate 26: 2,3-dimethyl-1-((2-methyl-1H-imidazol-1-yl)sulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate 1,1'-Sulfonylbis(2-methyl-1H-imidazole) (Intermediate 25, 3.00 g, 13.26 mmol) was dissolved in DCM (53.8 mL) and cooled in a dry ice / MeOH bath (-20 °C) under nitrogen. Methyl trifluoromethanesulfonate (1.460 ml, 13.26 mmol) was dissolved in DCM (17.95 mL) and added dropwise to the chilled solution. The reaction was allowed to warm to 20 °C and stirred for 1.5 h. A white precipitate was allowed to settle and the supernatant was decanted. The solid was washed with 30 mL of DCM and dried under vacuum to give 2,3-dimethyl-1-((2-methyl-1H-imidazol-1-yl)sulfonyl)-1H-imidazol-3-ium (Intermediate 26, 4.63 g, 89%) as a white solid. 1 H NMR (methanol-d4) 2.64 (3H,s), 2.88 (3H,s), 3.89 (3H,s), 7.09 (1H,d), 7.77 (1H,d), 7.90 (1H,d), 8.29 (1H,d).

[0355] Intermediate 3: (S)-tert-butyl 3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-pyrrolidine-1-carboxylate 2,6-Dichloro-9-ethyl-9H-purine (Intermediate 2, 2.024 g, 9.32 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.628 mL, 9.32 mmol) were dissolved in DMF (10.66 mL) and cooled to 0 °C under nitrogen. The reaction was then treated with DIEA (3.26 mL, 18.65 mmol), allowed to warm to room temperature, and stirred for 48 h. The reaction was diluted with 50% saturated sodium chloride solution and extracted with DCM. The extract was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was applied to silica and purified by silica flash chromatography (elution gradient 0–100% EtOAc in hexanes, followed by 10% MeOH in EtOAc). The product fractions were concentrated under reduced pressure to give tert-butyl (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 3, 3.56 g, 104%) as a white foam that solidified upon standing. NMR indicated the presence of residual DMF. 1 H NMR(DMSO-d6)1.31-1.50(12H,m),1.83-2.27(2H,m),3.16-3.29(2H,m),3.44(1H,br s),3.58(1H,br dd),4.13(2H,q),4.48-5.44(1H,m),8.21(1H,s),8.47(1H,br s);m / z(ES + ) [M+H] + =367.

[0356] Intermediate 4: (S)-2-chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine (S)-tert-Butyl 3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 3, 1.52 g, 4.14 mmol) was dissolved in MeOH (15.52 mL) and treated with HCl (4.0 M in dioxane) (10.34 ml, 41.38 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with methanol and concentrated under reduced pressure. The residue was diluted with 20% i-PrOH in DCM and treated with a solution of sodium bicarbonate (1.043 g, 12.41 mmol) in 10 mL of water. The layers were separated and the aqueous layer was extracted with 20% i-PrOH in DCM. The combined extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (S)-2-chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 4, 1.08 g, 98%) as a beige solid. 1 H NMR(DMSO-d6)1.37(3H,t),1.74-1.93(1H,m),2.06-2.20(1H,m),2.82-3.03(2H,m),3.05-3.16(1H,m),3.20(1H,br m / z(ES + ) [M+H] + =267.

[0357] Intermediate 27: (S)-2-chloro-9-ethyl-N-(1-((2-methyl-1H-imidazol-1-yl)sulfonyl)-pyrrolidin-3-yl)-9H-purin-6-amine (S)-2-Chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 4, 1.08 g, 4.05 mmol) was suspended in acetonitrile (57.8 mL) / THF (9.64 mL) and treated with 2,3-dimethyl-1-((2-methyl-1H-imidazol-1-yl)sulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate (Intermediate 26, 2.371 g, 6.07 mmol). Once the reaction was homogeneous, it was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, and the resulting residue was purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes (EtOAc containing 15% MeOH)). The product fractions were concentrated under reduced pressure to afford (S)-2-chloro-9-ethyl-N-(1-((2-methyl-1H-imidazol-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 27, 1.467 g, 88%) as a beige foam. 1 H NMR (methanol-d4) 1.48 (3H, t), 2.08-2.19 (1H, m), 2.32-2.44 (1H, m), 2.56 (3H, s), 3.51-3.66 (2H, m), 3.68-3.85 (2H, m), 4.23 (2H, q), 4.48-4.75 (1H, m), 6.75 (1H, br s), 7.39 (1H, s), 8.07 (1H, s); NH was not observed; m / z (ES + ) [M+H] + =411.

[0358] Intermediate 28: (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (S)-2-Chloro-9-ethyl-N-(1-((2-methyl-1H-imidazol-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 27, 310 mg, 0.75 mmol) was dissolved in DCM (3.07 mL) and cooled in a dry ice / MeOH bath (-20 °C) under nitrogen. Methyl trifluoromethanesulfonate (74.8 μl, 0.68 mmol) was dissolved in DCM (1.023 mL) and added dropwise to the chilled solution. The reaction was allowed to warm to 20 °C and stirred for 1 h. The solvent was removed under reduced pressure to give (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (434 mg, 100%) as a white foam. m / z (ES + )[M] +=425. (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (216 mg, 0.38 mmol) and (R)-tetrahydrofuran-3-amine (39.3 mg, 0.45 mmol) were dissolved in acetonitrile (6.26 mL) and heated at 70° C. for 16 h. The reaction was concentrated under reduced pressure and purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes (EtOAc containing 15% MeOH)). The product fractions were concentrated under reduced pressure to give (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (Intermediate 28, 0.115 g, 73.6%) as a white solid. 1H NMR(DMSO-d6)1.38(3H,t),1.80(1H,dq),2.01-2.14(2H,m),2.15-2.31(1H,m),3.07-3.14(1H,m),3.21-3 .29(1H,m),3.36-3.48(2H,m),3.49-3.68(2H,m),3.74(2H,q),3.80-3.91(1H,m),4.13(2H,q),4.63(1H,br d),7.41(1H,br d),8.22(1H,br s),8.35-8.62(1H,m);m / z(ES + ) [M+H] + =416.

[0359] Example 18: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide

[0360] [ka] (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (Intermediate 28, 114 mg, 0.27 mmol), (2R,3S)-3-aminopentan-2-ol (56.6 mg, 0.55 mmol), cesium carbonate (268 mg, 0.82 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (44.1 mg, 0.08 mmol), and palladium(II) acetate (6.15 mg, 0.03 mmol) were placed in an oven-dried microwave vial under nitrogen. The vial was evacuated and backfilled with nitrogen twice, then tBuOH (1.371 mL) was added, the reaction sealed, and heated to 100° C. for 3 h. The reaction was diluted with EtOAc / HO. The layers were separated, the organic component dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0–20% MeOH in DCM). Product fractions were concentrated under reduced pressure to afford (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (Example 18, 0.053 g, 40.0%) as a white foam. 1 H NMR(DMSO-d6)0.85(3H,br t),1.04(3H,br d),1.28-1.48(4H,m),1.68(1H,br s),1.79(1H,dq),1.95-2.13(2H,m),2.14-2.27(1H,m),3.05-3.16(1H,m),3.22(1H,q),3.34-3.42(1H,m),3.46(1H,br dd),3.53(1H,br t),3.62(2H,q),3.69-3.80(3H,m),3.80-3.88(1H,m),3.97(2H,q),4.42-4.88(2H,m),5.95(1H,br s),7.22-7.52(2H,m),7.72(1H,s);m / z(ES + ) [M+H] + =483.

[0361] Example 19: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(methyl)-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide

[0362] [ka] Intermediate 29: (S)-tert-butyl 3-((2-chloro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (S)-tert-Butyl 3-aminopyrrolidine-1-carboxylate (10.58 ml, 58.20 mmol) was added to a solution of 2,6-dichloro-9H-purine (Intermediate 1, 10 g, 52.91 mmol) and N,N-diisopropylethylamine (10.17 ml, 58.20 mmol) dissolved in 2-methyl-2-butanol (140 mL) at room temperature under nitrogen. The reaction mixture was heated at 100° C. for 90 minutes. The reaction was cooled and concentrated to give an oily solid. Water (200 mL) was added, the product was extracted with ethyl acetate (200 mL), and the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give (S)-tert-butyl 3-((2-chloro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 29, 17.20 g, 96%) as a yellow solid. 1 H NMR(DMSO-d6)1.32-1.50(9H,m),1.95-2.04(2H,m),2.06-2.25(1H,m),3.15-3.27(1H,m),3.42-3.51(1H,m),3.61(1H,br dd), 4.51-4.72(1H,m),8.17(1H,s),8.26-8.47(1H,m),11.80-13.36(1H,m); + ) [M+H] + =339.

[0363] Intermediate 30: (S)-tert-butyl 3-((2-chloro-9-methyl-9H-purin-6-yl)-amino)pyrrolidine-1-carboxylate Iodomethane (3.48 ml, 55.84 mmol) was added to a stirred suspension of (S)-tert-butyl 3-((2-chloro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 29, 17.2 g, 50.77 mmol) and potassium carbonate (8.77 g, 63.46 mmol) in DMSO (190 mL), and the reaction was stirred at room temperature for 20 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was applied to silica and purified by silica flash chromatography (elution gradient 0 to 100% ethyl acetate in hexanes). The product fractions were concentrated under reduced pressure to give tert-butyl (S)-3-((2-chloro-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 30, 8.50 g, 47.5%) as a white solid. 1 H NMR(DMSO-d6)1.40(9H,br d),1.92-2.05(1H,m),2.14(1H,br d),3.15-3.25(1H,m),3.27-3.35(1H,m),3.45(1H,br s),3.55-3.67(1H,m),3.66-3.76(3H,m),4.58-5.29(1H,m),8.14(1H,br s),8.47(1H,br s);m / z(ES + ) [M+H] + =353.

[0364] Intermediate 31: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate tert-butyl (S)-tert-Butyl 3-((2-chloro-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 30, 2 g, 5.67 mmol), (R)-2-amino-2-cyclopropylethan-1-ol, HCl (1.56 g, 11.33 mmol), cesium carbonate (6.47 g, 19.84 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl (0.913 g, 1.71 mmol), and palladium(II) acetate (0.127 g, 0.57 mmol) were placed in an oven-dried vial under nitrogen. The vial was evacuated and backfilled with nitrogen twice, then tBuOH (28 mL) was added and the reaction was heated in an oil bath at 100 °C for 3.5 h. The reaction was diluted with EtOAc / HO and the layers were separated. The organic portion was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0 to 100% EtOAc in hexanes (EtOAc containing 17% MeOH)). The product fractions were concentrated under reduced pressure to afford tert-butyl (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 31, 1.408 g, 59%) as a yellow foam. 1 H NMR(DMSO-d6)0.11-0.46(4H,m),0.91-1.06(1H,m),1.38(8H,br d),1.85-1.98(1H,m),2.02-2.23(1H,m),3.11-3.28(3H,m),3.36-3.69(1H,m),3.39-3.64(7H,m),4.35-4.81(2H,m),5.94(1H,br d),7.21-7.49(1H,m),7.66(1H,s);m / z(ES + ) [M+H] + =418.

[0365] Intermediate 32: (R)-2-Cyclopropyl-2-((9-methyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol hydrochloride (S)-tert-Butyl 3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 31, 1.40 g, 3.35 mmol) was dissolved in MeOH (14.7 mL) and treated with HCl (4 M in dioxane) (6.33 ml, 25.15 mmol). The reaction was stirred at room temperature for 3.5 hours, at which point it was concentrated under reduced pressure to give (R)-2-cyclopropyl-2-((9-methyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol hydrochloride (Intermediate 32, 1.436 g, 99%) as a beige solid. m / z (ES + ) [M+H] + =318.

[0366] Example 19: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(methyl)-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide

[0367] [ka] (R)-2-Cyclopropyl-2-((9-methyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol, 4HCl (Intermediate 32, 1.229 g, 2.65 mmol) was suspended in DCM (59 mL) and treated with TEA (2.22 ml, 15.91 mmol). The reaction was cooled to −60° C. and treated dropwise over 20 minutes with a solution of ethylsulfamoyl chloride (0.381 g, 2.65 mmol) in 20 mL of DCM. The reaction was allowed to warm to −35° C. over 3 hours, at which point it was concentrated under reduced pressure and the resulting residue was applied to silica and purified by silica flash chromatography (elution gradient 0–100% EtOAc in hexanes (EtOAc containing 20% ​​MeOH)). The product fractions were concentrated under reduced pressure to give (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide (Example 19, 0.500 g, 44.5%) as a white foam. 1 H NMR(DMSO-d6)0.15-0.24(1H,m),0.26-0.33(1H,m),0.34-0.46(2H,m),0.91-1.02(1H,m),1.05(3H,t),1.98-2.08(1H,m),2.11 -2.26(1H,m),2.88-3.00(2H,m),3.07(1H,dd),3.20(1H,dt),3.36(1H,ddd),3.42-3.61(7H,m),4.36-4.91(2H,m),5.95(1H,br d),7.07(1H,t),7.22-7.47(1H,m),7.66(1H,s);m / z(ES + ) [M+H] + =425.

[0368] Example 20: (R)-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0369] [ka] Intermediate 34: (S)-(1-(methylsulfonyl)pyrrolidin-3-yl)carbamate tert-butyl (S)-tert-Butyl pyrrolidin-3-ylcarbamate (Intermediate 33, 14.17 g, 76.08 mmol) was dissolved in DCM (200 mL) under nitrogen. The solution was treated with DIEA (20 mL, 114.51 mmol) and cooled to 0 °C. Methanesulfonyl chloride (5.93 mL, 76.08 mmol) was added dropwise over approximately 5 min, the cooling bath was allowed to expire, and the reaction was stirred overnight, slowly warming to room temperature. The reaction was concentrated under reduced pressure, and the mixture was diluted with EtOAc and stirred for 5 min. The mixture was filtered, and the solid was washed with copious amounts of EtOAc. The filtrate was washed with 1 M aqueous HCl (2 × 100 mL), water, and saturated aqueous NaCl. The organic portion was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl (S)-(1-(methylsulfonyl)pyrrolidin-3-yl)carbamate (Intermediate 34, 15.91 g, 79%) as an off-white solid. 1 H NMR(DMSO-d6)1.38(9H,s),1.76(1H,dq),2.03(1H,dq),2.86(3H,s),3.00(1H,dd), 3.16-3.26(1H,m),3.28-3.35(1H,m),3.40(1H,dd),3.93-4.04(1H,m),7.16(1H,br d);m / z(ES + )[M-Boc] + =165.

[0370] Intermediate 35: (S)-1-(methylsulfonyl)pyrrolidin-3-amine HCl (4.0 M in dioxane) (100 mL, 400.00 mmol) was added slowly via cannula to a stirred solution of tert-butyl (S)-(1-(methylsulfonyl)pyrrolidin-3-yl)carbamate (Intermediate 34, 15.91 g, 60.19 mmol) in 1,4-dioxane (150 mL). The reaction was stirred at room temperature for 18 hours (the reaction became a suspension). The solvent was removed under reduced pressure, and the solid residue was washed with EtO and filtered to give the HCl salt of (S)-1-(methylsulfonyl)pyrrolidin-3-amine (Intermediate 35, 11.92 g, 99%) as an off-white solid. 1 H NMR (DMSO-d6) 1.91-2.03(1H,m),2.21(1H,dq),2.95(3H,s),3.24-3.35(2H,m),3.44(1H,dt),3.51(1H,dd),3.82(1H,br d),8.40(3H,br s).

[0371] Intermediate 36: 6-chloro-2-fluoro-9-isopropyl-9H-purine 6-Chloro-2-fluoro-9H-purine (Intermediate 7, 8.00 g, 46.36 mmol) was dissolved in THF (300 mL) in an oven-dried 1 L flask under nitrogen. The solution was treated with 2-propanol (14.29 mL, 185.46 mmol), followed by triphenylphosphine (24.32 g, 92.73 mmol) and dihydrogen iodide (18.03 mL, 92.73 mmol), with the dihydrogen iodide added dropwise over 20 min. After the addition, the reaction was allowed to stir at room temperature for 17 h. The reaction was poured into water and extracted with EtOAc. The extract was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (elution gradient 0–80% EtOAc in hexanes). The product fractions were concentrated under reduced pressure to give 6-chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 7.40 g, 74.4%) as a white solid. 1 H NMR(DMSO-d6)1.54(6H,d),4.73-4.84(1H,m),8.81(1H,s);m / z(ES + ) [M+H] +=215.

[0372] Intermediate 37: (S)-2-Fluoro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine 6-Chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 6.4 g, 29.82 mmol) and (S)-1-(methylsulfonyl)pyrrolidin-3-amine.HCl (Intermediate 35, 7.18 g, 35.78 mmol) were dissolved in EtOH (150 mL) under nitrogen, cooled in an ice-water bath, and treated with N,N-diisopropylethylamine (20.83 mL, 119.28 mmol) in a 500 mL round-bottom flask. The reaction was allowed to warm to room temperature and stirred for 4 days (usually requiring 48 h). The solvent was removed under reduced pressure, and the residue was dissolved in DCM, washed with water, dried over sodium sulfate / magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was applied to silica and purified by silica flash chromatography (elution gradient 50–100% EtOAc in hexanes, followed by 8% MeOH in DCM). The product fractions were concentrated under reduced pressure to give (S)-2-fluoro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 37, 6.46 g, 63.3%) as a beige solid. 1 H NMR(DMSO-d6)1.49(6H,d),2.05(1H,br d),2.15-2.32(1H,m),2.91(3H,s),3.24(1H,br s),3.30-3.38(1H,m),3.40-3.52(1H,m),3.59(1H,br s),4.63(2H,quin),8.26(1H,s),8.56(1H,br s);m / z(ES + ) [M+H] + =343.

[0373] Example 20: (R)-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0374] [ka] (S)-2-Fluoro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 37, 3.0 g, 8.76 mmol), (R)-2-amino-3-methylbutan-1-ol (3.24 mL, 29.20 mmol), and DIEA (3.83 mL, 29.20 mmol) were dissolved in n-butanol (18 mL) / dimethyl sulfoxide (2.25 mL), and the reaction was placed in a preheated oil bath at 140 °C. The reaction was heated for 64 h. The reaction was concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with water, brine, dried over sodium sulfate / magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 40–100% EtOAc in hexanes, followed by 5% MeOH in DCM). The product fractions were concentrated under reduced pressure to give impure product. The residue was repurified by silica flash chromatography (elution gradient 0 to 10% MeOH in EtOAc). The product fractions were concentrated under reduced pressure to give (R)-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 20, 3.09 g, 83%) as a dry white film. 1 H NMR(DMSO-d6)0.89(6H,t),1.45(6H,t),1.86-2.09(2H,m),2.12-2.25(1H,m),2.90(3H,s),3.14-3.29(2H ,m),3.40-3.53(3H,m),3.58(1H,dd),3.73-3.88(1H,m),4.36-4.58(2H,m),4.59-4.90(1H,m),5.79(1H,br s),7.39(1H,br s),7.79(1H,s);m / z(ES + ) [M+H] + =426.

[0375] Example 21: (S)-3-((9-ethyl-2-(((3S * ,4R *)-1,1,1-trifluoro-4-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0376] [ka] Intermediate 39: 2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutanoic acid 2-Amino-4,4,4-trifluorobutanoic acid (Intermediate 38, 2.51 g, 15.98 mmol) was suspended in DCM (64.1 mL) and cooled to 0° C. in an ice bath. Boc anhydride (4.08 mL, 17.58 mmol) and TEA (4.45 mL, 31.96 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was extracted with water, and the aqueous extract was acidified with 1N HCl and extracted with DCM. The combined extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutanoic acid (Intermediate 39, 3.19 g, 78%) as a white foam. 1 H NMR(DMSO-d6)1.37(9H,s),2.53-2.65(1H,m),2.66-2.80(1H,m),4.07-4.19(1H,m),7.12(1H,br d),11.78-13.76(1H,m).

[0377] Intermediate 40: tert-butyl (4,4,4-trifluoro-1-(methoxyamino)-1-oxobutan-2-yl)-carbamate 2-((tert-Butoxycarbonyl)amino)-4,4,4-trifluorobutanoic acid (Intermediate 39, 3.19 g, 12.40 mmol) and HOBt (2.279 g, 14.88 mmol) were dissolved in DCM (31.8 mL) / THF (7.94 mL) and cooled to 0 °C under nitrogen. The reaction was then treated with EDC (2.85 g, 14.88 mmol), N,O-dimethylhydroxylamine.HCl (1.452 g, 14.88 mmol), and N-methylmorpholine (1.636 mL, 14.88 mmol). The reaction was allowed to slowly warm to room temperature and stirred overnight. The reaction was concentrated under reduced pressure, and the residue was partitioned between EtOAc and 5% KHSO in water (50 mL). The organic layer was then washed with 5% KHSO (50 mL), saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient: 0 to 100% EtOAc in hexanes). The product fractions were concentrated under reduced pressure to give tert-butyl (4,4,4-trifluoro-1-(methoxy(methyl)amino)-1-oxobutan-2-yl)carbamate (Intermediate 40, 2.80 g, 75%) as a white solid. 1 H NMR(DMSO-d6)1.36(9H,s),2.51-2.60(2H,m),3.11(3H,s),3.71(3H,s),4.73(1H,br d),7.35(1H,br d);m / z(ES + ) [M+H] + =301.

[0378] Intermediate 41: tert-butyl (4,4,4-trifluoro-1-oxobutan-2-yl)carbamate tert-Butyl (4,4,4-trifluoro-1-(methoxy(methyl)amino)-1-oxobutan-2-yl)carbamate (Intermediate 40, 2.8 g, 9.32 mmol) was dissolved in THF (54.9 mL) in an oven-dried flask under nitrogen. The solution was cooled to 0° C. in an ice bath for 15 minutes, at which point the solution was treated with LAH (2.0 M in THF) (7.23 ml, 14.45 mmol). The reaction was stirred at 0° C. for 1 hour. A solution of potassium hydrogen sulfate (2.54 g, 18.65 mmol) in 28 mL of water was added slowly at 0° C. and allowed to stir for 15 minutes. The organic solvents in the reaction mixture were concentrated under reduced pressure. An additional 28 mL of water was added to the aqueous residue and extracted with DCM (3×). The combined extracts were then washed with 1 N HCl, saturated NaHCO3, brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (4,4,4-trifluoro-1-oxobutan-2-yl)carbamate (Intermediate 41, 2.150 g, 96%) as a white solid. 1 H NMR (DMSO-d6) 1.39 (9H, s), 2.38-2.43 (1H, m), 2.73-2.86 (1H, m), 4.15 (1H, br t), 7.62 (1H, br d), 9.36 (1H, s).

[0379] Intermediate 42: tert-butyl (1,1,1-trifluoro-4-hydroxypentan-3-yl)carbamate tert-Butyl (4,4,4-trifluoro-1-oxobutan-2-yl)carbamate (Intermediate 41, 2.15 g, 8.91 mmol) was dissolved in DCM (34.2 mL) and cooled in a dry ice / MeOH bath. The solution was treated with MeMgBr (3.0 M in EtO) (10.40 mL, 31.20 mmol) and stirred at that temperature for 20 min. The reaction was then warmed to room temperature and stirred overnight, at which point it was quenched with saturated ammonium chloride (34 mL, slowly), diluted with EtOAc, and the layers separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0–80% EtOAc in hexanes). The product fractions were concentrated under reduced pressure to give tert-butyl (1,1,1-trifluoro-4-hydroxypentan-3-yl)carbamate (Intermediate 42, 1.510 g, 66.0%) as a colorless oil. 1 H NMR(DMSO-d6)0.87-1.07(3H,m),1.32-1.42(9H,m),2.14-2.46(2H,m),3.33-3.82(2H,m),4.71-4.97(1H,m),6.59-6.87(1H,m).

[0380] Intermediate 43: 3-amino-5,5,5-trifluoropentan-2-ol tert-Butyl (1,1,1-trifluoro-4-hydroxypentan-3-yl)carbamate (Intermediate 42, 1.51 g, 5.87 mmol) was dissolved in 1,4-dioxane (22.01 mL) and treated with HCl (4.0 M in dioxane) (14.67 ml, 58.70 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to give 3-amino-5,5,5-trifluoropentan-2-ol (Intermediate 43, 1.200 g, 106%) as a pale yellow oil and the HCl salt, which solidified upon placing in the freezer. 1 H NMR(DMSO-d6)1.02-1.22(3H,m),2.53-2.88(2H,m),3.21-3.38(1H,m),3.75-3.87(1H,m),5.28-5.82(1H,m),8.03-8.43(3H,m).

[0381] Intermediate 44: tert-butyl (3S)-3-((9-ethyl-2-((1,1,1-trifluoro-4-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (S)-tert-Butyl 3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 3, 408 mg, 1.11 mmol), 3-amino-5,5,5-trifluoropentan-2-ol.HCl (Intermediate 43, 532 mg, 2.74 mmol), cesium carbonate (1812 mg, 5.56 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6',-tri-i-propyl-1,1'-biphenyl (179 mg, 0.33 mmol), and palladium(II) acetate (25 mg, 0.11 mmol) were placed in an oven-dried vial under nitrogen. The vial was evacuated and backfilled with nitrogen, then tBuOH (2.009 mL) was added. The reaction was sealed and heated at 100 °C over the weekend. The reaction was diluted with EtOAc / HO. The layers were separated, the organic component was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes (EtOAc containing 6 percent MeOH)). The product fractions were concentrated under reduced pressure to give tert-butyl (3S)-3-((9-ethyl-2-((1,1,1-trifluoro-4-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 44, 0.434 g, 80%) as a dry yellow film. m / z (ES + ) [M+H] + =488.

[0382] Intermediate 45: 3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-5,5,5-trifluoropentan-2-ol tert-Butyl (3S)-3-((9-ethyl-2-((1,1,1-trifluoro-4-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 44, 0.434 g, 0.89 mmol) was dissolved in 1,4-dioxane (3.39 mL) and treated with HCl (4.0 M in 1,4-dioxane) (2.25 ml, 8.90 mmol). The reaction was stirred at room temperature for 16 hours, resulting in the formation of a gum. The reaction was diluted with methanol until homogeneous and then concentrated under reduced pressure. The residue was dissolved in methanol and treated with 1.1 g of MP Carbonate (3.12 mmol / g) and stirred gently for 1 hour to generate the free base of the product. The MP Carbonate was filtered, and the filtrate was concentrated under reduced pressure to give 3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-5,5,5-trifluoropentan-2-ol (Intermediate 45, 0.343 g, 99%) as a dry yellow film. m / z (ES + ) [M+H] + =388.

[0383] Example 21: (S)-3-((9-ethyl-2-(((3S * ,4R * )-1,1,1-trifluoro-4-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0384] [ka] 3-((9-Ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-5,5,5-trifluoropentan-2-ol (Intermediate 45, 0.342 g, 0.88 mmol) was dissolved in DCM (14.10 mL) and treated with TEA (0.615 mL, 4.41 mmol). The reaction was cooled in a dry ice / MeOH bath and treated with methylsulfamoyl chloride (0.117 g, 0.91 mmol). The reaction was stirred at that temperature for 2 h. The reaction was concentrated under reduced pressure, applied to silica, and the resulting residue was purified by silica flash chromatography (elution gradient 0–10% MeOH in DCM). Product fractions were concentrated under reduced pressure, and the sample was subjected to chiral separation. Two methods were used to separate the four isomers. Isomers 1 and 2 were purified by preparative SFC (Chiralpak IG column, 5 μm, diameter 21 mm, length 250 mm) eluting with 17% MeOH (containing 0.2% NH4OH) in CO2 (column temperature: 40 °C, outlet pressure: 100 bar, flow rate: 70 mL / min). Isomers 3 and 4 were purified by preparative SFC (Chiralpak IC column, 5 μm, diameter 21 mm, length 250 mm) eluting with 20% IPA (containing 0.2% NH4OH) in CO2 (column temperature: 40 °C, outlet pressure: 100 bar, flow rate: 70 mL / min) to give (S)-3-((9-ethyl-2-(((3S * ,4R * )-1,1,1-trifluoro-4-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 21, Isomer 4, 0.0286 g, 15.0%); 1 H NMR (methanol-d4) 1.23 (3H, d), 1.44 (3H, t), 2.02-2.12 (1H, m), 2.33-2.49 (2H, m), 2.59-2.74 (4H, m), 3.20-3.29 (1H, m), 3.38-3.46 (1H, m), 3.48-3.57 (1H, m), 3.68 (1H, dd), 3.87 (1H, quin), 4.10 (2H, q), 4.30-4.45 (1H, m), 4.73-4.82 (1H, m), 7.73 (1H, br s); NH not observed; m / z (ES)+ ) [M+H] + = 481 was obtained as a colorless dry film along with isomers 1, 2, and 3 as colorless films.

[0385] Example 22: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide

[0386] [ka] Intermediate 46: (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (S)-2-Chloro-9-ethyl-N-(1-((2-methyl-1H-imidazol-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 27, 310 mg, 0.75 mmol) was dissolved in DCM (3.07 mL) and cooled in a dry ice / MeOH bath (-20 °C) under nitrogen. Methyl trifluoromethanesulfonate (74.8 μl, 0.68 mmol) was dissolved in DCM (1.023 mL) and added dropwise to the chilled solution. The reaction was allowed to warm to 20 °C and stirred for 1 h. The solvent was removed under reduced pressure to give (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (434 mg, 100%) as a white foam. (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (216 mg, 0.38 mmol) and (S)-tetrahydrofuran-3-amine (39.3 mg, 0.45 mmol) were dissolved in acetonitrile (6.26 mL) and heated at 70° C. for 16 h. The reaction was concentrated under reduced pressure and purified by silica flash chromatography (elution gradient 0 to 100% EtOAc in hexanes (EtOAc containing 15% MeOH)). Product fractions were concentrated under reduced pressure to give (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (Intermediate 46, 0.134 g, 86%) as a white solid. 1H NMR(DMSO-d6)1.38(3H,t),1.71-1.82(1H,m),1.99-2.16(2H,m),2.16-2.30(1H,m),3.13(1H,br s),3.21-3.28(1H,m),3.36-3.44(1H,m),3.47(1H,br dd),3.50-3.67(2H,m),3.67-3.80(2H,m),3.81-3.91(1H,m),4.13(2H,q),4.44-4.85(1H,m),7.41(1H,br d),8.22(1H,br s),8.37-8.58(1H,m);m / z(ES + ) [M+H] + =416.

[0387] Example 22: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide

[0388] [ka] (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (Intermediate 46, 129 mg, 0.31 mmol), (2R,3S)-3-aminopentan-2-ol (64.0 mg, 0.62 mmol), cesium carbonate (303 mg, 0.93 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (49.9 mg, 0.09 mmol), and palladium(II) acetate (6.96 mg, 0.03 mmol) were placed in an oven-dried microwave vial under nitrogen. The vial was evacuated and backfilled with nitrogen twice, then tBuOH (1.551 mL) was added, the reaction sealed, and heated to 100° C. for 3 h. The reaction was diluted with EtOAc / HO. The layers were separated, the organic component dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0–20% MeOH in DCM). Product fractions were concentrated under reduced pressure to afford (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (Example 22, 0.069 g, 46.4%) as a white foam. 1 H NMR(DMSO-d6)0.84(3H,br t),1.04(3H,br d),1.28-1.44(4H,m),1.59-1.73(1H,m),1.73-1.83(1H,m),1.99-2.10(2H,m),2.15-2.24 (1H,m),3.07-3.15(1H,m),3.21(1H,q),3.34-3.41(1H,m),3.44-3.50(1H,m),3.53(1H,br t),3.58-3.66(2H,m),3.68-3.79(3H,m),3.80-3.89(1H,m),3.97(2H,q),4.41-4.90(2H,m),5.95(1H,br d),7.25-7.52(2H,m),7.72(1H,s);m / z(ES + ) [M+H] + =416.

[0389] Example 23: (S)—N-(((S)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0390] [ka] Intermediate 47: (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide (S)-2-Chloro-9-ethyl-N-(1-((2-methyl-1H-imidazol-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 27, 154 mg, 0.37 mmol) was dissolved in DCM (1.525 mL) and cooled in a dry ice / MeOH bath (-20 °C) under nitrogen. Methyl trifluoromethanesulfonate (37.2 μl, 0.34 mmol) was dissolved in DCM (0.508 mL) and added dropwise to the chilled solution. The reaction was allowed to warm to 20 °C and stirred for 1 h. The solvent was removed under reduced pressure to give (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (216 mg, 100%) as a white foam. (S)-(1,4-Dioxan-2-yl)methanamine·HCl (68.1 mg, 0.44 mmol) was dissolved in acetonitrile (1.675 mL) and treated with TEA (61.8 μl, 0.44 mmol), and the reaction was stirred for 10 min. This solution was then added to a solution of (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (216 mg, 0.38 mmol) in acetonitrile (4.52 mL). The reaction was then heated at 70° C. for 16 h. The reaction was concentrated under reduced pressure and purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes (EtOAc containing 15% MeOH)). The product fractions were concentrated under reduced pressure to give (S)—N-(((S)-1,4-dioxan-2-yl)methyl)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Intermediate 47, 0.122 g, 72.8%) as a pale yellow solid. 1H NMR(DMSO-d6)1.37(3H,t),2.00-2.31(2H,m),2.92(2H,br t),3.07-3.20(2H,m),3.21-3.28(1H,m),3.36-3.46(2H,m),3.48-3.63(4H,m),3.69(2H,br t),4.13(2H,q),4.39-4.88(1H,m),7.24(1H,br s),8.21(1H,s),8.45(1H,br s);m / z(ES + ) [M+H] + =446.

[0391] Example 23: (S)—N-(((S)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0392] [ka] (S)—N-(((S)-1,4-dioxan-2-yl)methyl)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Intermediate 47, 118.5 mg, 0.27 mmol), (2R,3S)-3-aminopentan-2-ol (54.8 mg, 0.53 mmol), cesium carbonate (260 mg, 0.80 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (42.8 mg, 0.08 mmol), and palladium(II) acetate (5.97 mg, 0.03 mmol) were placed in an oven-dried vial under nitrogen. The vial was evacuated and backfilled with nitrogen, then tBuOH (1.329 mL) was added, and the reaction was sealed and heated at 100° C. for 5.5 hours. The reaction was diluted with EtOAc / HO. The layers were separated, the organic component was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient of 0 to 15 percent MeOH in DCM). Product fractions were concentrated under reduced pressure to afford (S)—N-(((S)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 23, 0.077 g, 56.7%) as a yellow foam. 1 H NMR(DMSO-d6)0.85(3H,br t),1.04(3H,br d),1.30-1.45(4H,m),1.57-1.76(1H,m),1.94-2.11(1H,m),2.11-2.25(1H,m),2.86-2.99(2H,m),3.06-3.26 (3H,m),3.33-3.45(2H,m),3.48-3.57(3H,m),3.57-3.66(2H,m),3.66-3.80(3H,m),3.97(2H,q),4.63(2H,br s),5.94(1H,br s),7.22(1H,br t),7.36(1H,br s), 7.72 (1H, s); m / z (ES + ) [M+H] + =513.

[0393] Example 24: (2R,3S)-3-((9-ethyl-6-(((S)-1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0394] [ka] Intermediate 48: (S)-2-chloro-9-ethyl-N-(1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (S)-2-Chloro-9-ethyl-N-(1-((2-methyl-1H-imidazol-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 27, 158 mg, 0.38 mmol) was dissolved in DCM (1.565 mL) and cooled in a dry ice / MeOH bath (-20 °C) under nitrogen. Methyl trifluoromethanesulfonate (38.1 μl, 0.35 mmol) was dissolved in DCM (0.522 mL) and added dropwise to the chilled solution. The reaction was allowed to warm to 20 °C and stirred for 1 h. The solvent was removed under reduced pressure to give (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (221 mg, 100%) as a white foam. 3-Fluoroazetidine HCl (60.0 mg, 0.54 mmol) was dissolved in acetonitrile (3.17 mL) and treated with TEA (75 μL, 0.54 mmol), and the reaction was stirred for 10 min. A solution of (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (221 mg, 0.38 mmol) in acetonitrile (3.17 mL) was then added, and the reaction was then heated at 70° C. for 3 hours. The reaction was concentrated under reduced pressure and purified by silica flash chromatography (elution gradient 0 to 100% EtOAc in hexanes (EtOAc containing 15% MeOH)). Product fractions were concentrated under reduced pressure to give (S)-2-chloro-9-ethyl-N-(1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 48, 0.114 g, 73.1%) as a white solid. 1H NMR(DMSO-d6)1.38(3H,t),2.00-2.14(1H,m),2.16-2.29(1H,m),3.17-3.38(3H,m),3.43-3.54(1H,m),3.54-3. 72(1H,m),3.83-3.97(2H,m),4.07-4.17(3H,m),4.46-4.83(1H,m),5.24-5.48(1H,m),8.22(1H,s),8.49(1H,br d);m / z(ES + ) [M+H] + =404.

[0395] Example 24: (2R,3S)-3-((9-ethyl-6-(((S)-1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0396] [ka] (S)-2-Chloro-9-ethyl-N-(1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 48, 105 mg, 0.26 mmol), (2R,3S)-3-aminopentan-2-ol (53.6 mg, 0.52 mmol), cesium carbonate (254 mg, 0.78 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (41.9 mg, 0.08 mmol), and palladium(II) acetate (5.84 mg, 0.03 mmol) were placed in an oven-dried microwave vial under nitrogen. The vial was evacuated and backfilled with nitrogen, then tBuOH (1.300 mL) was added, and the reaction was sealed and heated at 100° C. for 5.5 h. The reaction was diluted with EtOAc / HO. The layers were separated, the organic component was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0–20% MeOH in DCM). Product fractions were concentrated under reduced pressure to afford (2R,3S)-3-((9-ethyl-6-(((S)-1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol (Example 24, 0.099 g, 81%) as a pale yellow foam. 1 H NMR(DMSO-d6)0.84(3H,t),1.04(3H,d),1.30-1.44(4H,m),1.63-1.75(1H,m),2.00-2.12(1H,m),2.14-2.23(1H,m),3.20(1H,br dd),3.30-3.35(1H,m),3.43-3.51(1H,m),3.56-3.67(2H,m),3.72-3.81(1H,m),3.8 5-4.02(4H,m),4.04-4.16(2H,m),4.37-4.86(2H,m),5.23-5.46(1H,m),5.98(1H,br s),7.23-7.59(1H,m),7.73(1H,s);m / z(ES + ) [M+H] + =471.

[0397] Example 25: (S)—N-(((R)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0398] [ka] Intermediate 49: (S)—N-(((R)-1,4-dioxan-2-yl)methyl)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (S)-2-Chloro-9-ethyl-N-(1-((2-methyl-1H-imidazol-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 27, 154 mg, 0.37 mmol) was dissolved in DCM (1.525 mL) and cooled in a dry ice / MeOH bath (-20 °C) under nitrogen. Methyl trifluoromethanesulfonate (37.2 μl, 0.34 mmol) was dissolved in DCM (0.508 mL) and added dropwise to the chilled solution. The reaction was allowed to warm to 20 °C and stirred for 1 h. The solvent was removed under reduced pressure to give (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (216 mg, 100%) as a white foam. (R)-(1,4-Dioxan-2-yl)methanamine·HCl (75 mg, 0.49 mmol) was dissolved in acetonitrile (1.720 mL) and treated with TEA (68.1 μL, 0.49 mmol), and the reaction was stirred for 10 min. This solution was then added to a solution of (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (216 mg, 0.38 mmol) in acetonitrile (4.47 mL). The reaction was then heated at 70° C. for 16 h. The reaction was concentrated under reduced pressure and purified by silica flash chromatography (elution gradient 0-100% EtOAc in hexanes (EtOAc containing 15% MeOH)). The product fractions were concentrated under reduced pressure to give (S)—N-(((R)-1,4-dioxan-2-yl)methyl)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Intermediate 49, 0.087 g, 51.9%) as a white foam. 1H NMR(DMSO-d6)1.37(3H,t),1.98-2.32(2H,m),2.84-3.01(2H,m),3.07-3.20 (2H,m),3.20-3.28(1H,m),3.34-3.45(2H,m),3.46-3.64(4H,m),3.70(2H,br d),4.13(2H,q),4.47-4.84(1H,m),7.24(1H,br s),8.21(1H,s),8.45(1H,br s);m / z(ES + ) [M+H] + =446.

[0399] Example 25: (S)—N-(((R)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0400] [ka] (S)—N-(((R)-1,4-dioxan-2-yl)methyl)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Intermediate 49, 83.8 mg, 0.19 mmol), (2R,3S)-3-aminopentan-2-ol (38.8 mg, 0.38 mmol), cesium carbonate (184 mg, 0.56 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′,-tri-i-propyl-1,1′-biphenyl (30.3 mg, 0.06 mmol), and palladium(II) acetate (4.22 mg, 0.02 mmol) were placed in an oven-dried vial. The vial was evacuated and backfilled with nitrogen, then tBuOH (0.940 mL) was added, and the reaction was sealed and heated at 100° C. for 5.5 hours. The reaction was diluted with EtOAc / HO. The layers were separated, the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient of 0 to 15 percent MeOH in DCM). Product fractions were concentrated under reduced pressure to afford (S)—N-(((R)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide (Example 25, 0.053 g, 54.5%) as a yellow foam. 1 H NMR(500MHz,DMSO-d6)0.85(3H,t),1.04(3H,d),1.30-1.45(4H,m),1.63-1.75(1H,m),1.96-2.08(1H,m),2.13-2.23(1H,m),2.85-3 .00(2H,m),3.05-3.25(3H,m),3.33-3.45(2H,m),3.47-3.56(3H,m),3.57-3.66(2H,m),3.67-3.82(3H,m),3.97(2H,q),4.63(2H,br s),5.95(1H,br s),7.22(1H,br t),7.37(1H,br s), 7.72 (1H, s); m / z (ES + ) [M+H] + =513.

[0401] Example 26: (3R * ,4R * )-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethyl-4-fluoropyrrolidine-1-sulfonamide

[0402] [ka] Intermediate 50: tert-butyl rac-(3R,4R)-3-((2-chloro-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate DIEA (1.525 mL, 8.73 mmol) was added to a stirred solution of 2,6-dichloro-9H-purine (Intermediate 1, 1.5 g, 7.94 mmol) and tert-butyl rac-(3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (1.783 g, 8.73 mmol) in 2-methylbutan-2-ol (22 mL, 7.94 mmol), and the vial was heated at 100 °C for 1.5 h. The solvent was removed under reduced pressure, and the resulting residue was purified by silica flash chromatography (elution gradient: 0 to 10% MeOH in DCM). Product fractions were concentrated under reduced pressure to give tert-butyl rac-(3R,4R)-3-((2-chloro-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 50, 2.260 g, 80%) as a pale yellow solid.

[0403] Intermediate 51: tert-butyl rac-(3R,4R)-3-((2-chloro-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate Iodomethane (0.432 mL, 6.91 mmol) was added to a stirred solution of tert-butyl rac-(3R,4R)-3-((2-chloro-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 50, 2.24 g, 6.28 mmol) and K2CO3 (1.085 g, 7.85 mmol) in DMSO (20.50 mL). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was applied to silica and purified by silica flash chromatography (elution gradient 0 to 100% ethyl acetate in hexanes). The product fractions were concentrated under reduced pressure to give tert-butyl rac-(3R,4R)-3-((2-chloro-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 51, 1.56 g, 67%). 1 H NMR (DMSO-d6) 1.43 (9H, s), 3.39-3.57 (2H, m), 3.58-3.69 (1H, m), 3.72 (4H, s), 4.56-4.86 (1H, m), 5.08-5.29 (1H, m), 8.18 (1H, br s), 8.53-8.76 (1H, m); one proton not observed.

[0404] Intermediate 52: tert-butyl (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate tert-Butyl rac-(3R,4R)-3-((2-chloro-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 51, 800 mg, 2.16 mmol), (R)-2-amino-2-cyclopropylethan-1-ol.HCl (594 mg, 4.31 mmol), cesium carbonate (2460 mg, 7.55 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6',-tri-i-propyl-1,1'-biphenyl (232 mg, 0.43 mmol), and palladium(II) acetate (48.4 mg, 0.22 mmol) were placed in an oven-dried vial. The vial was evacuated and backfilled with nitrogen twice, then tBuOH (6.16 mL) was added, the reaction sealed, and heated at 96 °C for 16 h. The reaction was diluted with EtOAc / HO. The layers were separated, the organic component dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica flash chromatography (elution gradient 0 to 100% EtOAc in hexanes (EtOAc containing 6 percent MeOH)). Product fractions were concentrated under reduced pressure to afford tert-butyl (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 52, 0.530 g, 56.4%) as a dry yellow film.

[0405] Intermediate 53: (R)-2-Cyclopropyl-2-((6-(((3RS,4RS)-4-fluoropyrrolidin-3-yl)-amino)-9-methyl-9H-purin-2-yl)amino)ethan-1-ol hydrochloride HCl (4 M in 1,4-dioxane) (689 μl, 2.76 mmol) was added to a stirred solution of tert-butyl (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 52, 200 mg, 0.46 mmol) in MeOH (0.5 ml) and 1,4-dioxane (1 ml) at 20° C. The resulting solution was stirred at room temperature for 1 hour. The reaction was concentrated to give (R)-2-cyclopropyl-2-((6-(((3RS,4RS)-4-fluoropyrrolidin-3-yl)amino)-9-methyl-9H-purin-2-yl)amino)ethan-1-ol hydrochloride (Intermediate 53, 170 mg, 100%).

[0406] Example 26: (3R * ,4R * )-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethyl-4-fluoropyrrolidine-1-sulfonamide

[0407] [ka] (R)-2-Cyclopropyl-2-((6-(((3RS,4RS)-4-fluoropyrrolidin-3-yl)amino)-9-methyl-9H-purin-2-yl)amino)ethan-1-ol.HCl (Intermediate 53, 140 mg, 0.38 mmol) was weighed into a 40 mL scintillation vial, dichloromethane (5 mL), triethylamine (261 μL, 1.88 mmol) were added, and the reaction mixture was cooled to −78° C. Ethylsulfamoyl chloride (51.2 mg, 0.34 mmol) was added to the reaction mixture and stirred for 2 hours. Additional ethylsulfamoyl chloride (17.08 mg, 0.12 mmol) was added to the reaction mixture and stirred for 1 hour. The reaction was quenched with aqueous NaHCO3, stirred for 15 min, extracted with DCM, and the organic layer was separated, dried over MgSO4, and concentrated to give a white foam. The resulting residue was purified by silica flash chromatography (elution gradient 0-20% MeOH in DCM). The product fractions were concentrated under reduced pressure to give the racemic product, which was subjected to chiral separation. The product was purified by preparative SFC (AD column, 5 μm, diameter 4.6 mm, length 100 mm) eluting with 10-60% methanol in CO2 (column temperature: 40 °C, outlet pressure: 120 bar, flow rate: 4.0 mL / min) to give (3R * ,4R * )-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethyl-4-fluoropyrrolidine-1-sulfonamide (Example 26, Isomer 1, 33 mg, 20%); 1 H NMR(DMSO-d6)0.15-0.24(m,1H)0.32(dt,1H)0.36-0.45(m,2H)1.00(br d,1H)1.07(t,3H)2.93-3.05(m,2H)3.23-3.29(m,1H)3.37-3.46(m,1H)3.49-3.73(m,8H)4.58(br s,1H)4.64-4.85(m,1H)5.22-5.47(m,1H)6.07(br s,1H)7.25(t,1H)7.53(br s,1H)7.71(s,1H);m / z(ES + ) [M+H] += 443; and isomer 2 (37 mg, 22.2%).

[0408] Example 27: (R)-2-(6-((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-ylamino)-3-methylbutan-1-ol

[0409] [ka] Intermediate 36: 6-chloro-2-fluoro-9-isopropyl-9H-purine DIAD (22.54 mL, 115.91 mmol) was added to 6-chloro-2-fluoro-9H-purine (Intermediate 7, 10 g, 57.96 mmol), IPA (8.93 mL, 115.91 mmol), and PPh (30.4 g, 115.91 mmol) in THF (200 mL) under nitrogen at 0 °C over 30 min. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO (200 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated to give a yellow solid. The crude product was purified by silica flash chromatography (elution gradient 0–90% EtOAc in petroleum ether). Pure fractions were evaporated to dryness to give 6-chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 10.00 g, 80%) as a yellow solid (contains triphenylphosphine oxide and is difficult to separate). 1 H NMR(400MHz,DMSO-d6)1.18(3H,d),1.55(3H,d),4.69-4.85(1H,m),8.84(1H,d);m / z(ES + ) [M+H] + =215.

[0410] Intermediate 54: (S)-N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-2-fluoro-9-isopropyl-9H-purin-6-amine DIEA (0.488 mL, 2.80 mmol) was added to 6-chloro-2-fluoro-9-isopropyl-9H-purine (200 mg, 0.56 mmol, 60 wt%) and (S)-1-(cyclopropylsulfonyl)pyrrolidin-3-amine (Intermediate 36, 213 mg, 1.12 mmol) in MeCN (5 mL). The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and washed sequentially with saturated aqueous NH Cl (20 mL × 1), saturated aqueous Na CO (20 mL), and saturated aqueous brine (20 mL). The organic layer was dried over Na SO , filtered, and evaporated to give the crude product. The residue was purified by preparative TLC (EtOAc) to give (S)—N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-2-fluoro-9-isopropyl-9H-purin-6-amine (Intermediate 54, 110 mg, 53.4%) as a colorless oil (contains triphenylphosphine oxide). 1 H NMR(300MHz,DMSO-d6)0.95(4H,dq),1.51(6H,d),2.09(1H,d),2.24(1H,d),2.73(1H,ddd),3.29 (1H,s),3.35-3.50(1H,m),3.50-3.62(1H,m),3.67(1H,s),4.65(2H,p),8.28(1H,s),8.59(1H,br s);m / z(ES + ) [M+H] + =369.

[0411] Example 27: (R)-2-(6-((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-ylamino)-3-methylbutan-1-ol

[0412] [ka] DIEA (0.474 mL, 2.71 mmol) was added to (S)—N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-2-fluoro-9-isopropyl-9H-purin-6-amine (Intermediate 54, 100 mg, 0.27 mmol) and (R)-2-amino-3-methylbutan-1-ol (140 mg, 1.36 mmol) in NMP (4 mL). The resulting mixture was stirred at 140° C. for 5 days. The reaction mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μ silica, 50 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.01% NH4HCO3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 27, 45.0 mg, 36.7%). 1 H NMR(400MHz,DMSO-d6)0.86-1.02(10H,m),1.46(6H,t),1.96(1H,dt),2.07(1H,p),2.22(1H,dq),2.65-2.73(1H,m ),3.27(1H,dd),3.33-3.39(1H,m),3.46-3.56(3H,m),3.62-3.67(1H,m),3.82(1H,dq),4.52(2H,dq),4.71(1H,br s),5.79(1H,br s),7.38(1H,br s),7.80(1H,s);m / z(ES + ) [M+H] + =452.

[0413] Example 28: (R)-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0414] [ka] Intermediate 8: 6-chloro-9-ethyl-2-fluoro-9H-purine DIAD (0.845 mL, 4.35 mmol) was added dropwise to 6-chloro-2-fluoro-9H-purine (Intermediate 7, 0.5 g, 2.90 mmol), ethanol (0.400 g, 8.69 mmol), and PPh3 (2.280 g, 8.69 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was purified by silica flash chromatography (elution gradient 0–80% EtOAc in petroleum ether). Pure fractions were evaporated to dryness to give 6-chloro-9-ethyl-2-fluoro-9H-purine (Intermediate 8, 0.400 g, 68.8%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)1.18(3H,d),4.72-4.84(2H,m),8.86(1H,s);m / z(ES + ) [M+H] + =201.

[0415] Intermediate 55: (S)-9-Ethyl-2-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine TEA (1.042 mL, 7.48 mmol) was added to 6-chloro-9-ethyl-2-fluoro-9H-purine (0.5 g, 2.49 mmol) and (S)-1-(methylsulfonyl)pyrrolidin-3-amine hydrochloride (Intermediate 8, 0.500 g, 2.49 mmol) in MeCN (20 mL). The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into saturated aqueous NaCO (100 mL) and extracted with DCM (3 × 100 mL), and the organic layer was dried over NaSO. The crude product was purified by silica flash chromatography (elution gradient 0–80% EtOAc in petroleum ether). Pure fractions were evaporated to dryness to give (S)-9-ethyl-2-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 55, 0.400 g, 48.9%) as a pale yellow solid. m / z (ES + ) [M+H] + =329.

[0416] Example 28: (R)-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0417] [ka] (S)-9-Ethyl-2-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (150 mg, 0.46 mmol), (R)-2-amino-3-methylbutan-1-ol (Intermediate 55, 236 mg, 2.28 mmol), and DIEA (0.798 mL, 4.57 mmol) in NMP (5 mL) were stirred at 140° C. for 3 days. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 * Purification was performed using a 150 mm column, 5 μm column; mobile phase A: water (0.05% NH3HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18B to 38B in 7 min. Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 28, 123 mg, 65.4%). 1 H NMR(400MHz,DMSO-d6)0.86-0.93(6H,m),1.34(3H,t),1.89-2.10(2H,m),2.13-2.26(1H,m),2.91(3H,s),3.17-3.25(1H,m ),3.25-3.35(1H,m),3.42-3.54(3H,m),3.55-3.63(1H,m),3.77-3.88(1H,m),3.94-4.04(2H,m),4.49(1H,t),4.71(1H,br s),5.84(1H,br s),7.41(1H,br s),7.74(1H,s);m / z(ES + ) [M+H] + =412.

[0418] Example 29: (R)-2-((9-cyclopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0419] [ka] Intermediate 57: 6-chloro-N-cyclopropyl-2-(methylthio)-5-nitropyridin-4-amine 4,6-Dichloro-2-(methylthio)-5-nitropyrimidine (Intermediate 56, 5 g, 20.83 mmol) was added to cyclopropanamine (1.070 g, 18.75 mmol) and TEA (8.71 mL, 62.48 mmol) in THF (100 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 1 day. The crude product was purified by silica flash chromatography (elution gradient 0 to 60 percent EtOAc in petroleum ether). Pure fractions were evaporated to dryness to give 6-chloro-N-cyclopropyl-2-(methylthio)-5-nitropyridin-4-amine (Intermediate 57, 3.00 g, 55.3%) as a yellow solid. m / z (ES + ) [M+H] + =261.

[0420] Intermediate 58: 6-chloro-N 4 -Cyclopropyl-2-(methylthio)pyrimidine-4,5-diamine 6-Chloro-N-cyclopropyl-2-(methylthio)-5-nitropyridin-4-amine (Intermediate 57, 3 g, 11.51 mmol) was added to iron (3.21 g, 57.54 mmol) in iPrOH (100 mL) and saturated aqueous NH4Cl (100 mL) at 25 °C. The resulting mixture was stirred at 50 °C for 1 day. The reaction mixture was filtered through Celite. The reaction mixture was diluted with DCM (300 mL) and washed sequentially with saturated aqueous NH4Cl (200 mL × 3) and saturated aqueous brine (300 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by silica flash chromatography (elution gradient 0 to 50% EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford 6-chloro-N4-cyclopropyl-2-(methylthio)pyrimidine-4,5-diamine (Intermediate 58, 2.000 g, 75%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)0.44-0.53(2H,m),0.66-0.80(2H,m),2.40(3H,s),2.77-2.88(1H,m),4.74(2H,s),7.07(1H,d);m / z(ES + ) [M+H] + =231.

[0421] Intermediate 59: 6-chloro-9-cyclopropyl-2-(methylthio)-9H-purine Methanesulfonic acid (1.250 g, 13.00 mmol) was added to 6-chloro-N4-cyclopropyl-2-(methylthio)pyrimidine-4,5-diamine (Intermediate 58, 1 g, 4.33 mmol) in triethyl orthoformate (15 mL, 4.33 mmol). The resulting mixture was stirred at 100 °C for 16 h. The solvent was removed under reduced pressure. The crude product was purified by C18 flash chromatography (elution gradient: 5–60% MeCN in water (0.1% NH4HCO3)). Pure fractions were evaporated to dryness to give 6-chloro-9-cyclopropyl-2-(methylthio)-9H-purine (Intermediate 59, 0.600 g, 57.5%) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)1.06-1.13(2H,m),1.13-1.20(2H,m),2.60(3H,s),3.51-3.61(1H,m),8.51(1H,s);m / z(ES + ) [M+H] + =241.

[0422] Intermediate 60: (S)-9-Cyclopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-2-(methylthio)-9H-purin-6-amine DIEA (4.35 mL, 24.93 mmol) was added to 6-chloro-9-cyclopropyl-2-(methylthio)-9H-purine (Intermediate 59, 600 mg, 2.49 mmol) and (S)-1-(methylsulfonyl)pyrrolidin-3-amine hydrochloride (750 mg, 3.74 mmol) in iPrOH (60 mL). The resulting mixture was stirred at 100 °C for 2 hours. The reaction mixture was poured into saturated aqueous NaCO (100 mL) and extracted with DCM (3 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated to give a pale yellow solid. The crude product was purified by silica flash chromatography (elution gradient 0 to 60 percent EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford (S)-9-cyclopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-2-(methylthio)-9H-purin-6-amine (intermediate 60, 400 mg, 43.6%) as an off-white solid. 1 H NMR (400 MHz, methanol-d4) 1.06-1.21 (4H, m), 2.07-2.20 (1H, m), 2.34-2.47 (1H, m), 2.58 (3H, s), 2.90 (3H, s), 3.33-3.42 (1H, m), 3.39-3.54 (2H, m), 3.54-3.64 (1H, m), 3.70-3.78 (1H, m), 4.84 (1H, br s), 7.92 (1H, s); one exchangeable H was not shown. m / z (ES + ) [M+H] + =369.

[0423] Intermediate 61: (S)-9-Cyclopropyl-2-(methylsulfonyl)-N-(1-(methylsulfonyl)-pyrrolidin-3-yl)-9H-purin-6-amine mCPBA (562 mg, 3.26 mmol) was slowly added to (S)-9-cyclopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-2-(methylthio)-9H-purin-6-amine (Intermediate 59, 400 mg, 1.09 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The crude product was purified by silica flash chromatography (elution gradient of 0 to 60 percent EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford (S)-9-cyclopropyl-2-(methylsulfonyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 61, 160 mg, 36.8%) as a white solid. m / z (ES + ) [M+H] + =401.

[0424] Example 29: (R)-2-((9-cyclopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0425] [ka] (S)-9-Cyclopropyl-2-(methylsulfonyl)-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 61, 80 mg, 0.20 mmol) was added to (R)-2-amino-3-methylbutan-1-ol (1 mL, 0.60 mmol). The resulting mixture was stirred at 140° C. for 2 days. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 *Purification was performed using a 150 mm column, 5 μm column; mobile phase A: water (0.05% NH3HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20B to 40B in 7 min. Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-cyclopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 29, 70.0 mg, 83%). 1 H NMR(400MHz,DMSO-d6)0.79-0.93(6H,m),0.91-1.06(4H,m),1.90-2.09(2H,m),2.12-2.25(1H,m),2.90(3H,s),3.1 5-3.24(1H,m),3.25-3.32(2H,m),3.41-3.52(3H,m),3.54-3.62(1H,m),3.77-3.87(1H,m),4.52(1H,s),4.68(1H,br s),5.95(1H,br s),7.43(1H,br s),7.68(1H,s);m / z(ES + ) [M+H] + =424.

[0426] Example 30: (R)-2-Cyclopropyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol

[0427] [ka] Intermediate 37: (S)-2-Fluoro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine 6-Chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 500 mg, 2.33 mmol) was added to (S)-1-(methylsulfonyl)pyrrolidin-3-amine hydrochloride (468 mg, 2.33 mmol) and DIEA (2.034 mL, 11.65 mmol) in EtOH (5 mL) at 80° C. over 2 hours. The resulting mixture was stirred at 80° C. for 2 hours. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc:petroleum ether=1:0) to give (S)-2-fluoro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 37, 310 mg, 38.9%) as a white solid. 1 H NMR(300MHz,DMSO-d6)1.5(6H,d),2.1(1H,br s),2.2(1H,br m / z(ES) + ) [M+H] + =343.

[0428] Example 30: (R)-2-Cyclopropyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol

[0429] [ka] N-Ethyl-N-isopropylpropan-2-amine (566 mg, 4.38 mmol) was added to (R)-2-amino-2-cyclopropylethan-1-ol hydrochloride (201 mg, 1.46 mmol) and (S)-2-fluoro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 37, 100 mg, 0.29 mmol) in NMP (1 mL). The resulting mixture was stirred at 140° C. for 4 days. The reaction mixture was filtered through Celite. The crude product was purified by preparative HPLC (column: Xselect CSH OBD column 30 * Purification was performed on a 150 mm column (5 μm); mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 14B to 24B in 7 min). Fractions containing the desired compound were evaporated to dryness to give (R)-2-cyclopropyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol (Example 30, 30.0 mg, 22.77%). 1 H NMR(400MHz,DMSO-d6)0.18-0.26(1H,m),0.29-0.45(3H,m),0.95-1.04(1H,m),1.46(6H,d),1.99-2.08(1 H,m),2.15-2.24(1H,m),2.91(3H,s),3.15-3.33(2H,m),3.40-3.64(5H,m),4.48-4.61(1H,m),4.69(1H,br s),5.96(1H,br d),7.41(1H,br s),7.81(1H,s),8.17(1H,s). m / z(ES + ) [M+H] + =424.

[0430] Example 31: (2R,3S)-3-((9-isopropyl-6-(((S)-1-(1-methyl-1H-pyrazol-4-yl-sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0431] [ka] Intermediate 62: (S)-tert-butyl 3-(2-fluoro-9-isopropyl-9H-purin-6-ylamino)-pyrrolidine-1-carboxylate DIEA (1.221 mL, 6.99 mmol) was added to 6-chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 500 mg, 1.40 mmol, 60 wt%) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (521 mg, 2.80 mmol) in MeCN (5 mL). The resulting mixture was stirred at 100 °C for 2 hours. The crude product was purified by silica flash chromatography (elution gradient of 0 to 100 percent EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford (S)-tert-butyl 3-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 62, 200 mg, 39.3%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)1.40(9H,br d),1.50(6H,d),1.93-2.07(1H,m),2.14(1H,br d),3.21-3.29(2H,m),3.39-3.50(1H,m),3.54-3.66(1H,m),4.58-4.70(2H,m),8.26(1H,s),8.56(1H,br s);m / z(ES + ) [M+H] + =365.

[0432] Intermediate 63: (S)-2-Fluoro-9-isopropyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride HCl in 1,4-dioxane (3 ml, 98.74 mmol, 4 M) was added dropwise to tert-butyl (S)-3-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 62, 200 mg, 0.55 mmol) in MeOH (3 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give (S)-2-fluoro-9-isopropyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 63, 190 mg, 115.3%) as a white solid. The product was used directly in the next step without further purification.

[0433] Intermediate 64: (S)-2-Fluoro-9-isopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl-sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine A solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (156 mg, 0.86 mmol) in DCM (2 mL) was added dropwise to a stirred solution of (S)-2-fluoro-9-isopropyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 63, 190 mg, 0.72 mmol) and TEA (0.301 mL, 2.16 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed successively with saturated aqueous NH4Cl (20 mL), saturated aqueous NaHCO3 (20 mL), and saturated aqueous brine (20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give (S)-2-fluoro-9-isopropyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 64, 210 mg, 71.5%) as the desired product. m / z (ES + ) [M+H] + =409.

[0434] Example 31: (2R,3S)-3-((9-isopropyl-6-(((S)-1-(1-methyl-1H-pyrazol-4-ylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0435] [ka] DIEA (0.812 mL, 4.65 mmol) was added to (S)-2-fluoro-9-isopropyl-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 64, 190 mg, 0.47 mmol) and (2R,3S)-3-aminopentan-2-ol.HCl (194.7 mg, 1.41 mmol) in NMP (4 mL). The resulting mixture was stirred at 140° C. for 4 days. The reaction mixture was filtered through Celite. The crude product was purified by preparative HPLC (column: Xselect CSH OBD column 30). * Purification was performed using a 150 mm column (5 μm); mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16B to 26B in 7 min). Fractions containing the desired compound were evaporated to dryness to give (2R,3S)-3-((9-isopropyl-6-(((S)-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol (Example 31, 85 mg, 37.2%). 1 H NMR (300 MHz, DMSO-d6) 0.9 (3H, t), 1.0 (3H, d), 1.5 (7H, d, overlapped), 1.7 (1H, s), 1.9 (1H, s), 2.0-2.1 (1H, m), 3.0-3.1 (1H, m), 3.2 (1H, q), 3.3 (1H, d), 3.5 (1H, m), 3.6-3.7 (2H, m), 3.9 (3H, s), 4.5-4.6 (2H, m), 4.6 (1H, s), 5.9 (1H, br s), 7.3 (1H, br s), 7.8 (2H, d), 8.3 (1H, s); m / z (ES) + ) [M+H] + =492.

[0436] Example 32: (2R,3S)-3-((9-isopropyl-6-(((S)-1-(1-methyl-1H-imidazol-4-yl-sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0437] [ka] Intermediate 65: (S)-2-Fluoro-9-isopropyl-N-(1-(1-methyl-1H-imidazol-4-yl-sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine A solution of 1-methyl-1H-imidazole-4-sulfonyl chloride (353 mg, 1.96 mmol) in DCM (2 mL) was added dropwise to a stirred solution of (S)-2-fluoro-9-isopropyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride (Intermediate 63, 490 mg, 1.63 mmol) and TEA (0.681 mL, 4.89 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed successively with saturated aqueous NH4Cl (20 mL), saturated aqueous NaHCO3 (20 mL), and saturated aqueous brine (20 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give (S)-2-fluoro-9-isopropyl-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 65, 600 mg, 90%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) 1.50 (6H, d), 1.92-2.16 (2H, m), 3.26-3.47 (4H, m, overlapped), 3.56-3.65 (1H, m), 3.71-3.82 (2H, m), 4.44 (1H, br d), 4.65 (1H, quin), 7.78 (1H, s), 7.80-7.85 (1H, m), 8.26 (1H, s), 8.42-8.52 (1H, m); m / z (ES) + ) [M+H] + =409.

[0438] Example 32: (2R,3S)-3-((9-isopropyl-6-(((S)-1-(1-methyl-1H-imidazol-4-yl-sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0439] [ka] DIEA (0.641 mL, 3.67 mmol) was added dropwise to (S)-2-fluoro-9-isopropyl-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 65, 150 mg, 0.37 mmol) and (2R,3S)-3-aminopentan-2-ol (189 mg, 1.84 mmol) in NMP (4 mL). The resulting mixture was stirred at 140° C. for 2 days. The reaction mixture was filtered through Celite. The crude product was purified by preparative column: XBridge Shield RP18 OBD column, 30 * Purification was performed using 23B-63B on a 150 mm column, 5 μm column; mobile phase A: water (0.05% NHOH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7 min. Fractions containing the desired compound were evaporated to dryness to give (2R,3S)-3-((9-isopropyl-6-(((S)-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol (Example 32, 50.0 mg, 27.7%). 1 H NMR(600MHz,DMSO-d6)0.86(3H,t),1.05(3H,d),1.36-1.44(1H,m),1.46(6H,dd),1.71(1H,ddd),1.88-1.99(1H,m),2.07(1H,dq),3.24(1H,br dd),3.29-3.33(1H,m),3.40-3.45(1H,m),3.59-3.66(2H,m),3.69(3H,s),3.73(1H,tdd),4.42-4.56(2H,m),4.66(1H,br s),5.94(1H,br s),7.32(1H,br s),7.78-7.83(3H,m). m / z(ES +) [M+H] + =492.

[0440] Example 33: (R)-2-((6-(((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)-9-isopropyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0441] [ka] Intermediate 66: (3R,4R)-3-fluoro-4-(2-fluoro-9-isopropyl-9H-purin-6-yl-amino)pyrrolidine-1-carboxylate tert-butyl 6-Chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 0.300 g, 1.40 mmol) was added to tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (0.314 g, 1.54 mmol) and DIEA (0.732 mL, 4.19 mmol) in MeCN (3 mL) at 25 °C. The resulting mixture was stirred at 80 °C for 1 day. The reaction was concentrated, and the crude product was purified by silica flash chromatography (elution gradient 0 to 60% EtOAc in petroleum ether). Pure fractions were evaporated to dryness to give tert-butyl (3R,4R)-3-fluoro-4-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 66, 0.280 g, 52.4%) as a white solid. 1 H NMR(400MHz,DMSO-d6)1.41(9H,s),1.47-1.53(6H,m),3.43-3.76(4H,m),4.58-4.74(2H,m),5.20(1H,d),8.30(1H,s),8.77(1H,br s);m / z(ES + ) [M+H] + =383.

[0442] Intermediate 67: 2-Fluoro-N-((3R,4R)-4-fluoropyrrolidin-3-yl)-9-isopropyl-9H-purin-6-amine hydrochloride tert-Butyl (3R,4R)-3-fluoro-4-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 66, 0.200 g, 0.52 mmol) was added to HCl (18 mL, 4 M) in 1,4-dioxane at 25° C. The resulting mixture was stirred at 25° C. for 1 day. The solvent was removed under reduced pressure. The product, 2-fluoro-N-((3R,4R)-4-fluoropyrrolidin-3-yl)-9-isopropyl-9H-purin-6-amine.HCl (Intermediate 67, 0.120 g, 72.1%) as a colorless gum, was used directly in the next step without further purification. m / z (ES + ) [M+H] + =283.

[0443] Intermediate 68: 2-Fluoro-N-((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)-9-isopropyl-9H-purin-6-amine 2-Fluoro-N-((3R,4R)-4-fluoropyrrolidin-3-yl)-9-isopropyl-9H-purin-6-amine·HCl (Intermediate 67, 0.110 g, 0.35 mmol) was added to methanesulfonic anhydride (0.081 g, 0.47 mmol) and triethylamine (0.118 g, 1.17 mmol) in DCM (20 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction was concentrated, and the residue was purified by preparative TLC (EtOAc) to give 2-fluoro-N-((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)-9-isopropyl-9H-purin-6-amine (Intermediate 68, 0.090 g, 72.3%) as a white solid. 1 H NMR(300MHz,DMSO-d6)1.50(6H,d),2.98(3H,s),3.40-3.88(4H,m),4.56-4.86(2H,m),5.30(1H,d),8.32(1H,s),8.75(1H,br s);m / z(ES + ) [M+H] + =361.

[0444] Example 33: (R)-2-((6-(((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0445] [ka] 2-Fluoro-N-((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)-9-isopropyl-9H-purin-6-amine (Intermediate 68, 0.060 g, 0.17 mmol) was added to (R)-2-amino-3-methylbutan-1-ol (0.086 g, 0.83 mmol) and DIEA (0.145 mL, 0.83 mmol) in NMP (2 mL) at 25 °C. The resulting mixture was stirred at 140 °C for 1 day. The reaction was concentrated, and the crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 * Purification was performed using a 150 mm column, 5 μm column; mobile phase A: water (0.05% NH3HO), mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 46B to 54B in 7 min. Fractions containing the desired compound were evaporated to dryness to give (R)-2-((6-(((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 33, 0.013 g, 18.25%). 1 H NMR(400MHz,DMSO-d6)0.89-0.98(6H,m),1.45-1.53(6H,m),1.91-1.99(1H,m),2.98(3H,s),3.44-3.53(3H,m),3.58(1H,br d),3.65-3.69(1H,m),3.72-3.78(1H,m),3.84-3.89(1H,m),4.48-4.57(2H,m),4.80-4.85(1H,m),5.28(1H,d),5.96(1H,br s),7.67(1H,br s),7.87(1H,s); 19 F NMR(376MHz,DMSO-d6)-177.52. m / z(ES + ) [M+H]+ =444.

[0446] Example 34: (R)-2-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0447] [ka] Intermediate 69: (2R,4S)-4-(2-fluoro-9-isopropyl-9H-purin-6-ylamino)-2-methylpyrrolidine-1-carboxylate tert-butyl 6-Chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 0.300 g, 1.40 mmol) was added to tert-butyl (2R,4S)-4-amino-2-methylpyrrolidine-1-carboxylate (0.308 g, 1.54 mmol) and DIEA (0.732 mL, 4.19 mmol) in MeCN (5 mL) at 25 °C. The resulting mixture was stirred at 100 °C for 1 day. The crude product was purified by silica flash chromatography (elution gradient of 0 to 100 percent EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford tert-butyl (2R,4S)-4-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)-2-methylpyrrolidine-1-carboxylate (Intermediate 69, 0.240 g, 45.4%) as a white solid. m / z (ES + ) [M+H] + =379.

[0448] Intermediate 70: 2-Fluoro-9-isopropyl-N-((3S,5R)-5-methylpyrrolidin-3-yl)-9H-purin-6-amine hydrochloride tert-Butyl (2R,4S)-4-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)-2-methylpyrrolidine-1-carboxylate (Intermediate 69, 0.230 g, 0.61 mmol) was added to HCl in 1,4-dioxane (15 mL, 4 M) at 25 °C. The resulting mixture was stirred at 25 °C for 1 day. The reaction mixture was evaporated to give the crude product, 2-fluoro-9-isopropyl-N-((3S,5R)-5-methylpyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 70, 0.140 g, 73.3%). m / z (ES + ) [M+H] + =279.

[0449] Intermediate 71: 2-Fluoro-9-isopropyl-N-((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)-9H-purin-6-amine 2-Fluoro-9-isopropyl-N-((3S,5R)-5-methylpyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 70, 0.130 g, 0.41 mmol) was added to TEA (0.195 mL, 1.40 mmol) and methanesulfonic anhydride (0.098 g, 0.56 mmol) in DCM (15 mL) at 20 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction was concentrated, and the residue was purified by preparative TLC (EtOAc:petroleum ether = 5:1) to give 2-fluoro-9-isopropyl-N-((3S,5R)-5-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 71, 0.130 g, 78%) as a white solid. 1 H NMR(300MHz,DMSO-d6)1.29(3H,d),1.50(6H,d),1.66-1.80(1H,m),1.99(1H,s),3.02(3H, d),3.64-3.97(2H,m),3.99-4.09(1H,m),4.41-4.60(1H,m),4.60-4.71(1H,m),8.31(1H,br d),8.53(1H,d);m / z(ES + ) [M+H] + =357.

[0450] Example 34: (R)-2-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0451] [ka] 2-Fluoro-9-isopropyl-N-((3S,5R)-5-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 71, 60.0 mg, 0.17 mmol) was added to DIEA (0.147 mL, 0.84 mmol) and (R)-2-amino-3-methylbutan-1-ol (87 mg, 0.84 mmol) in NMP (2 mL) at 20° C. The resulting mixture was stirred at 140° C. for 2 days. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 * Purification was performed using a 150 mm column, 5 μm column; mobile phase A: water (0.05% NH3HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35B to 35B in 6 min. Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 34, 63.0 mg, 85%). 1 H NMR(400MHz,DMSO-d6)0.88-0.93(6H,m),1.29(3H,d),1.46(6H,t),1.72-1.81(1H,m),1.95(1H,dq),2.41-2.48(1H,m),2.98(3H,br s),3.10-3.21(1H,m),3.31-3.32(1H,m),3.46-3.54(2H,m),3.73-3.84(3 H,m),4.46-4.61(2H,m),5.76-5.91(1H,m),7.28-7.45(1H,m),7.82(1H,br s);m / z(ES + ) [M+H] + =440.

[0452] Example 35: (R)-2-((9-isopropyl-6-(((3S,5S)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0453] [ka] Intermediate 72: (2S,4S)-4-(2-fluoro-9-isopropyl-9H-purin-6-ylamino)-2-methylpyrrolidine-1-carboxylate tert-butyl 6-Chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 0.300 g, 1.40 mmol) was added to tert-butyl (2S,4S)-4-amino-2-methylpyrrolidine-1-carboxylate (0.308 g, 1.54 mmol) and DIEA (0.732 mL, 4.19 mmol) in MeCN (5 mL) at 25 °C. The resulting mixture was stirred at 100 °C for 1 day. The reaction was concentrated, and the crude product was purified by silica flash chromatography (elution gradient of 0 to 100 percent EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford tert-butyl (2S,4S)-4-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)-2-methylpyrrolidine-1-carboxylate (Intermediate 72, 0.240 g, 45.4%) as a yellow solid. m / z (ES + ) [M+H] + =379.

[0454] Intermediate 73: 2-Fluoro-9-isopropyl-N-((3S,5S)-5-methylpyrrolidin-3-yl)-9H-purin-6-amine hydrochloride tert-Butyl (2S,4S)-4-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)-2-methylpyrrolidine-1-carboxylate (Intermediate 72, 0.230 g, 0.61 mmol) was added to HCl in 1,4-dioxane (3 mL, 4 M) at 25 °C. The resulting mixture was stirred at 25 °C for 1 day. The reaction mixture was filtered and evaporated to give crude product 2-fluoro-9-isopropyl-N-((3S,5S)-5-methylpyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 73, 0.140 g, 73.3%). m / z (ES + ) [M+H] + =279.

[0455] Intermediate 74: 2-Fluoro-9-isopropyl-N-((3S,5S)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)-9H-purin-6-amine 2-Fluoro-9-isopropyl-N-((3S,5S)-5-methylpyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 73, 0.130 g, 0.41 mmol) was added to TEA (0.195 mL, 1.40 mmol) and methanesulfonic anhydride (0.098 g, 0.56 mmol) in DCM (15 mL) at 20 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction was concentrated, and the residue was purified by preparative TLC (EtOAc:petroleum ether = 5:1) to give 2-fluoro-9-isopropyl-N-((3S,5S)-5-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 74, 0.130 g, 88.2%) as a white solid. 1 H NMR(300MHz,DMSO-d6)1.25(3H,d),1.51(6H,d),1.88-1.96(1H,m),2.19-2.30(1H,m),2.88(3H,s), 3.29-3.30(1H,m),3.59-3.68(1H,m),3.98-4.07(1H,m),4.6-4.65(2H,m),8.29(1H,s),8.52(1H,br s);m / z(ES + ) [M+H] + =357.

[0456] Example 35: (R)-2-((9-isopropyl-6-(((3S,5S)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0457] [ka] 2-Fluoro-9-isopropyl-N-((3S,5S)-5-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 74, 60.0 mg, 0.17 mmol) was added to DIEA (0.147 mL, 0.84 mmol) and (R)-2-amino-3-methylbutan-1-ol (87 mg, 0.84 mmol) in NMP (2 mL) at 20° C. The resulting mixture was stirred at 140° C. for 2 days. The reaction was concentrated, and the crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 34B to 39B in 7 min). Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-isopropyl-6-(((3S,5S)-5-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 35, 62.0 mg, 84%). 1 H NMR(400MHz,DMSO-d6)0.90(6H,dd),1.24(3H,d),1.46(6H,t),1.83-2.02(2H,m),2.20(1H,dt),2.87(3H,s),3. 30-3.32(1H,m),3.50(2H,t),3.59(1H,dd),3.78-3.86(1H,m),3.94-4.02(1H,m),4.47-4.58(2H,m),4.81(1H,br s),5.89(1H,br s),7.37(1H,br s),7.81(1H,s);m / z(ES + ) [M+H] + =440.

[0458] Example 36: (R)-2-((9-isopropyl-6-(((3S,4R)-4-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0459] [ka] Intermediate 75: (3S,4R)-3-(2-fluoro-9-isopropyl-9H-purin-6-ylamino)-4-methylpyrrolidine-1-carboxylate tert-butyl 6-Chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 0.300 g, 1.40 mmol) was added to tert-butyl (3S,4R)-3-amino-4-methylpyrrolidine-1-carboxylate (0.308 g, 1.54 mmol) and DIEA (0.732 mL, 4.19 mmol) in MeCN (5 mL) at 20 °C. The resulting mixture was stirred at 80 °C for 1 day. The reaction was concentrated, and the residue was purified by preparative TLC (EtOAc:petroleum ether = 1:1) to give tert-butyl (3S,4R)-3-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)-4-methylpyrrolidine-1-carboxylate (Intermediate 75, 0.300 g, 56.7%) as a white gum. m / z (ES + ) [M+H] + =379.

[0460] Intermediate 76: 2-Fluoro-9-isopropyl-N-((3S,4R)-4-methylpyrrolidin-3-yl)-9H-purin-6-amine hydrochloride tert-Butyl (3S,4R)-3-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)-4-methylpyrrolidine-1-carboxylate (Intermediate 75, 0.280 g, 0.74 mmol) was added to HCl in 1,4-dioxane (15 mL, 4 M) at 20° C. The resulting mixture was stirred at 20° C. for 1 day. The solvent was evaporated to give the crude product, 2-fluoro-9-isopropyl-N-((3S,4R)-4-methylpyrrolidin-3-yl)-9H-purin-6-amine.HCl (Intermediate 76, 0.100 g, 43.0%). m / z (ES + ) [M+H] + =279.

[0461] Intermediate 77: 2-Fluoro-9-isopropyl-N-((3S,4R)-4-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)-9H-purin-6-amine 2-Fluoro-9-isopropyl-N-((3S,4R)-4-methylpyrrolidin-3-yl)-9H-purin-6-amine, HCl (Intermediate 76, 0.090 g, 0.29 mmol) was added to methanesulfonic anhydride (0.068 g, 0.39 mmol) and TEA (0.225 mL, 1.62 mmol) in DCM (2 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 1 day. The reaction was concentrated to give the crude product, which was purified by preparative TLC (EtOAc:petroleum ether = 10:1) to give 2-fluoro-9-isopropyl-N-((3S,4R)-4-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 77, 0.100 g, 98%) as a white solid. 1 H NMR(300MHz,DMSO-d6)0.93(3H,t),1.50(6H,d),2.55-2.67(1H,m),2.93(3H,s),3.20 (1H,t),3.44-3.46(1H,m),3.47(1H,dd),3.63(1H,t),4.60-4.70(1H,m),4.79(1H,br s),8.28(1H,s),8.51(1H,d);m / z(ES + ) [M+H] + =357.

[0462] Example 36: (R)-2-((9-isopropyl-6-(((3S,4R)-4-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0463] [ka] 2-Fluoro-9-isopropyl-N-((3S,4R)-4-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 77, 0.050 g, 0.14 mmol) was added to (R)-2-amino-3-methylbutan-1-ol (0.072 g, 0.70 mmol) and DIEA (0.123 mL, 0.70 mmol) in NMP (2 mL) at 25 °C. The resulting mixture was stirred at 120 °C for 1 day. The reaction was concentrated, and the residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 * Purification was performed using a 150 mm column, 5 μm column; mobile phase A: water (0.05% NH3HO), mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 48B to 50B in 7 min. Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-isopropyl-6-(((3S,4R)-4-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 36, 0.022 g, 35.2%). 1 H NMR(300MHz,DMSO-d6)0.90(6H,dd),1.03(3H,d),1.47(6H,dd),1.90-2.00(1H,m),2.27-2.48(1H,m),2.89-2. 93(1H,m),2.94(3H,s),3.05-3.17(1H,m),3.45-3.70(4H,m),3.78-3.87(1H,m),4.33-4.59(3H,m),5.83(1H,br s),7.42(1H,br s),7.83(1H,s);m / z(ES + ) [M+H] + =440.

[0464] Example 37: (2R,3S)-3-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0465] [ka] 2-Fluoro-9-isopropyl-N-((3S,5R)-5-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 71, 60.0 mg, 0.17 mmol) was added to DIEA (147 μl, 0.84 mmol) and (2R,3S)-3-aminopentan-2-ol hydrochloride (118 mg, 0.84 mmol) in NMP (2 mL) at 20° C. The resulting mixture was stirred at 140° C. for 2 days. The reaction mixture was loaded onto a preparative column: XBridge Shield RP18 OBD column, 30 * Purification was performed on a 150 mm column, 5 μm column; mobile phase A: water (0.05% NH3HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45B to 60B in 7 min. Fractions containing the desired compound were evaporated to dryness to give (2R,3S)-3-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol (Example 37, 0.040 g, 54.1%). 1 H NMR (400 MHz, DMSO-d6): 0.86 (3H, t), 1.06 (3H, d), 1.30 (3H, d), 1.37-1.50 (7H, m, overlapped), 1.63-1.81 (2H, m), 2.41-2.48 (1H, m), 2.98 (3H, br s), 3.07-3.18 (1H, m), 3.61-3.69 (1H, m), 3.74-3.84 (3H, m), 4.40-4.62 (2H, m), 4.68 (1H, br s), 5.97 (1H, br s), 7.39 (1H, br s), 7.82 (1H, br s). m / z (ES) + ) [M+H] + =440.

[0466] Example 38: (R)-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol

[0467] [ka] DIEA (0.532 mL, 3.05 mmol) was added to (S)-9-ethyl-2-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (Intermediate 55, 100 mg, 0.30 mmol) and (R)-2-aminobutan-1-ol (136 mg, 1.52 mmol) in NMP (3 mL) under nitrogen. The resulting mixture was stirred at 140° C. for 4 days. The reaction was concentrated and the crude product was purified by preparative column: XBridge Shield RP18 OBD column, 30 * Purification was performed using 17B to 37B on a 150 mm column, 5 μm column; mobile phase A: water (0.05% NH3HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7 min. Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol (Example 38, 45.0 mg, 37.2%). 1 H NMR (400 MHz, DMSO-d6) 0.88 (3H, t), 1.34 (3H, t), 1.39-1.51 (1H, m), 1.57-1.70 (1H, m), 2.00-2.11 (1H, m), 2.13-2.24 (1H, m), 2.90 (3H, s), 3.15-3.24 (2H, m), 3.35-3.64 (4H, m, overlapped), 3.82 (1H, d), 4.02 (2H, q), 4.57 (1H, s), 4.68 (1H, br s), 5.94 (1H, br s), 7.44 (1H, br s), 7.75 (1H, s); m / z (ES) + ) [M+H] + =398.

[0468] Example 39: (R)-2-Cyclopropyl-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol

[0469] [ka] (S)-9-Ethyl-2-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (5.60 g, 17.05 mmol) was added to (R)-2-amino-2-cyclopropylethan-1-ol hydrochloride (Intermediate 55, 11.73 g, 85.27 mmol) and DIEA (29.8 ml, 170.54 mmol) in DMSO (6 mL). The resulting mixture was stirred at 140° C. for 2 days. The reaction was concentrated and the crude product was purified by preparative SFC (column: GreenSep Basic, 30 * Purification was performed on a 150 mm 5 μm column; mobile phase A: CO, mobile phase B: MeOH (0.5% of 2 M NH-MeOH); flow rate: 50 mL / min; gradient: 30% B. Fractions containing the desired compound were evaporated to dryness to give (R)-2-cyclopropyl-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol (Example 39, 3.30 g, 47.3%). 1 H NMR(300MHz,DMSO-d6)0.19-0.45(4H,m),0.94-1.07(1H,m),1.34(3H,t),1.98-2.26(2H,m),2.91(3H,s),3 .20(1H,dd),3.27-3.35(1H,m),3.44-3.53(2H,m),3.53-3.61(3H,m),3.99(2H,q),4.63(1H,t),4.70(1H,br s),5.99(1H,br d),7.42(1H,s),7.75(1H,s);m / z(ES + ) [M+H] + =410.

[0470] Example 40: (R)-2-((9-ethyl-6-(((S)-1-(2,2,2-trifluoroethylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0471] [ka] Intermediate 9: (S)-tert-butyl 3-(9-ethyl-2-fluoro-9H-purin-6-ylamino)pyrrolidine-1-carboxylate DIEA (5.75 ml, 32.90 mmol) was added to 6-chloro-9-ethyl-2-fluoro-9H-purine (Intermediate 8, 2.200 g, 10.97 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (2.043 g, 10.97 mmol) in IPA (20 mL). The resulting mixture was stirred at 100° C. for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by silica flash chromatography (elution gradient of 0 to 100 percent EtOAc in petroleum ether). Pure fractions were evaporated to dryness to afford (S)-tert-butyl 3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 3.00 g, 78%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) 1.40-1.33 (12H, m), 1.97 (1H, br s), 2.12 (1H, br s), 3.19-3.24 (2H, m, overlapped), 3.39-3.47 (1H, m), 3.54-3.60 (1H, m), 4.10 (2H, q), 4.57 (1H, br s), 8.16 (1H, s), 8.46 (1H, br s); m / z (ES) + ) [M+H] + =351.

[0472] Intermediate 78: (S)-3-(9-ethyl-2-((R)-1-hydroxy-3-methylbutan-2-yl-amino)-9H-purin-6-ylamino)pyrrolidine-1-carboxylate tert-butyl (S)-tert-Butyl 3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 1.200 g, 3.42 mmol) was added to (R)-2-amino-3-methylbutan-1-ol (3.89 g, 37.67 mmol) in NMP (0.5 mL) at 20° C. The resulting mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with DCM (300 mL) and subsequently washed with water (200 mL × 3). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The product, tert-butyl (S)-3-((9-ethyl-2-(((R)-1-hydroxy-3-methylbutan-2-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 78, 1.200 g, 81%), was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)0.88-0.92(6H,m),1.32-1.42(12H,m),1.90-2.04(2H,m),2.07-2.13(1H,m),3.14-3.2 8(2H,m),3.40-3.53(3H,m),3.55-3.63(1H,m),3.78-3.86(1H,m),3.93-4.04(2H,m),4.45(1H,s),4.55(1H,br s),5.78(1H,br s),7.36(1H,br s),7.73(1H,s);m / z(ES + ) [M+H] + =434.

[0473] Intermediate 79: (R)-2-(9-ethyl-6-((S)-pyrrolidin-3-ylamino)-9H-purin-2-yl-amino)-3-methylbutan-1-ol hydrochloride (S)-tert-Butyl 3-((9-ethyl-2-(((R)-1-hydroxy-3-methylbutan-2-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 78, 1.200 g, 2.77 mmol) was added to HCl in dioxane (20 mL, 4 M) at 20° C. The resulting mixture was stirred at 20° C. for 16 hours. The reaction mixture was evaporated to give the crude product. The product, (R)-2-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol.HCl (Intermediate 79, 0.800 g, 78%) as a solid was used directly in the next step without further purification. m / z (ES + ) [M+H] + =334.

[0474] Example 40: (R)-2-((9-ethyl-6-(((S)-1-(2,2,2-trifluoroethylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0475] [ka] (R)-2-((9-Ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol.HCl (Intermediate 79, 150 mg, 0.41 mmol) was added to 2,2,2-trifluoroethane-1-sulfonyl chloride (74 mg, 0.41 mmol) and TEA (170 μl, 1.22 mmol) in DCM (1 mL) at −20° C. The resulting mixture was stirred at −20° C. for 2 h. The reaction was concentrated and the crude product was purified by preparative HPLC (column: Sunfire Prep C18 column, 30 *Purification was performed using a HPLC column (150, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20B to 42B in 7 min). Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-ethyl-6-(((S)-1-((2,2,2-trifluoroethyl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 40, 10.00 mg, 5.14%). 1 H NMR(400MHz,DMSO-d6)0.89-0.92(6H,m),1.35(3H,t),1.93-1.99(1H,m),2.03-2.10(1H,m),2.17-2.24(1H,m),3 .37-3.61(5H,m),3.72(1H,dd),3.81-3.87(1H,m),4.00(2H,q),4.49-4.62(3H,m),4.71-4.80(1H,m),5.87(1H,br s),7.47(1H,br s),7.76(1H,s); 19 F NMR(376MHz,DMSO-d6)-60.04. m / z(ES + ) [M+H] + =480.

[0476] Example 41: (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0477] [ka] Intermediate 80: (S)-N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-9-ethyl-2-fluoro-9H-purin-6-amine DIEA (0.918 mL, 5.26 mmol) was added to 6-chloro-9-ethyl-2-fluoro-9H-purine (Intermediate 8, 300 mg, 1.50 mmol) and (S)-1-(cyclopropylsulfonyl)pyrrolidin-3-amine (0.2 g, 1.05 mmol) in iPrOH (5 mL). The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by C18 flash chromatography (elution gradient: 20–50% MeCN in water (0.1% NH4HCO3)). Pure fractions were evaporated to dryness to afford (S)-N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-9-ethyl-2-fluoro-9H-purin-6-amine (Intermediate 80, 300 mg, 81%) as a brown gum. m / z (ES + ) [M+H] + =355.

[0478] Example 41: (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0479] [ka] (R)-2-Amino-3-methylbutan-1-ol (0.2 mL, 1.80 mmol) was added to (S)—N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-9-ethyl-2-fluoro-9H-purin-6-amine (Intermediate 80, 0.1 g, 0.28 mmol) in NMP (0.5 mL). The resulting mixture was stirred at 120° C. for 16 hours. The reaction mixture was diluted with DCM (50 mL) and washed successively with saturated aqueous NaCO (50 mL) and saturated brine (50 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 *150 mm, 5 μm; Mobile phase A: water (0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25B to 40B in 7 min), followed by preparative chiral HPLC (Column: CHIRALPAK IA, 2 * Purification was performed by HPLC (25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (10 mM NH3-MeOH), mobile phase B: IPA; flow rate: 20 mL / min; gradient: 10B to 10B in 12 min). Fractions containing the target compound were evaporated to dryness to give (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 41, 0.012 g, 9.72%). 1 H NMR(400MHz,DMSO-d6)0.86-1.02(10H,m),1.34(3H,t),1.89-2.02(1H,m),2.00-2.13(1H,m),2.15-2.28(1H,m),2.64-2.75(1H,m), 3.23-3.32(1H,m),3.32-3.40(1H,m),3.45-3.58(3H,m),3.60-3.69(1H,m),3.79-3.87(1H,m),4.04(2H,q),4.49(1H,s),4.68(1H,br s),5.86(1H,br s),7.43(1H,br s), 7.74 (1H, s); m / z (ES + ) [M+H] + =438.

[0480] Example 42: (R)-2-((9-ethyl-6-(((S)-1-((2-methoxyethyl)sulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0481] [ka] (R)-2-((9-Ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol hydrochloride (Intermediate 79, 60 mg, 0.18 mmol) was added to 2-methoxyethane-1-sulfonyl chloride (14.27 mg, 0.09 mmol) and TEA (0.050 mL, 0.36 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19 * Purification was performed using a 250 mm column, 10 μm column; mobile phase A: water (10 mmol / L NHHCO + 0.1% NH HO), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 43B to 48B in 7 min. Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-ethyl-6-(((S)-1-((2-methoxyethyl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 42, 20.67 mg, 25.2%). 1 H NMR(400MHz,DMSO-d6)0.89(6H,dd),1.34(3H,t),1.88-2.08(2H,m),2.11-2.24(1H,m),3.22(1H,dd),3.28(3H, s),3.34-3.41(3H,m),3.47(3H,d),3.56-3.70(3H,m),3.76-3.90(1H,m),3.99(2H,q),4.49(1H,s),4.68(1H,br s),5.71-5.96(1H,m),7.38(1H,br s),7.74(1H,s);m / z(ES + ) [M+H] + =456.

[0482] Example 43: (R)-2-((9-ethyl-6-(((S)-1-(fluoromethylsulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0483] [ka] Fluoromethanesulfonyl chloride (31.8 mg, 0.24 mmol) was added dropwise to (R)-2-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol hydrochloride (Intermediate 79, 80 mg, 0.24 mmol) and TEA (100 μl, 0.72 mmol) in DCM (1 mL) at 20° C. The resulting mixture was stirred at −20° C. for 75 min. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 23B to 30B in 7 min). Fractions containing the desired compound were evaporated to dryness to give (R)-2-((9-ethyl-6-(((S)-1-((fluoromethyl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol (Example 43, 0.055 g, 53.4%). 1 H NMR(400MHz,DMSO-d6)0.86-0.94(6H,m),1.34(3H,t),1.91-2.00(1H,m),2.07(1H,br s),2.17-2.27(1H,m),3.26-3.37(1H,m),3.39-3.52(3H,m),3.55-3.63(1H ,m),3.70-3.78(1H,m),3.82(1H,t),3.98(2H,q),4.47(1H,s),4.73(1H,br s),5.53(1H,s),5.65(1H,s),5.84(1H,br s),7.44(1H,br s),7.74(1H,s); 19 F NMR(376MHz,DMSO-d6)-214.373. m / z(ES + ) [M+H] + =430.

[0484] Example 44: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0485] [ka] Intermediate 81: (S)-tert-butyl 3-(2-fluoro-9H-purin-6-ylamino)pyrrolidine-1-carboxylate 6-Chloro-2-fluoro-9H-purine (Intermediate 7, 50 g, 289.78 mmol) was dissolved in tert-amyl alcohol (1200 mL) at room temperature under nitrogen and then heated to 100° C. (Solution 1). In a separate vessel, (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (59.4 g, 318.75 mmol), DIEA (55.7 ml, 318.75 mmol), and tert-amyl alcohol (100 mL) were added at room temperature under nitrogen (Solution 2). Solution 2 was added dropwise to Solution 1, and the reaction mixture was heated at 100° C. for 90 minutes. LCMS after 1 hour showed the reaction was complete, with a substitution of Cl:F=13:1. The mixture was poured into ice water (2 L), the aqueous phase was extracted with EtOAc (2 × 1 L), and the organic phase was washed with NaSO, filtered, and evaporated to give (S)-tert-butyl 3-((2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 81, 105 g, 91%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)1.41(9H,s),1.91-2.07(1H,m),2.11-2.29(1H,m),3.15-3.73(5H,m),8.12(1H,s),8.39(1H,s),10.39(1H,br s);(ES + ) [M+H] + =323.

[0486] Intermediate 9: (S)-tert-butyl 3-(9-ethyl-2-fluoro-9H-purin-6-ylamino)pyrrolidine-1-carboxylate Iodoethane (22.34 ml, 276.41 mmol) was added dropwise to tert-butyl (S)-3-((2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 81, 100 g, 251.29 mmol, 81 wt%) in DMSO (1500 mL) at room temperature. The resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into ice water. The precipitate was collected by filtration, washed with water, and dried under vacuum to give the crude product. The crude product was triturated with MeCN to give tert-butyl (S)-3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 60.0 g, 68%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)1.32-1.47(12H,m),1.90-2.07(1H,m),2.08-2.23(1H,m),3.16-3.30(2H,m),3. 38-3.53(1H,m),3.55-3.68(1H,m),4.13(2H,q),4.51-5.30(1H,m),8.19(1H,s),8.35-8.61(1H,m);(ES + ) [M+H] + =351.

[0487] Intermediate 82: (S)-9-Ethyl-2-fluoro-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride (S)-tert-Butyl 3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 54 g, 154.11 mmol) was added to HCl in 1,4-dioxane (385 ml, 1540.76 mmol, 4 M). The resulting mixture was stirred at 25° C. for 6 hours. The solid that formed was collected, washed with MTBE, and air-dried to give (S)-9-ethyl-2-fluoro-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride (Intermediate 82, 50.0 g, 100%) as a white solid. (ES + ) [M+H] + =251.

[0488] Intermediate 83: (S)-1-(3-(9-ethyl-2-fluoro-9H-purin-6-ylamino)pyrrolidin-1-yl)-ethanone AcO (19.70 ml, 208.85 mmol) was added dropwise to (S)-9-ethyl-2-fluoro-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride (Intermediate 82, 50 g, 139.23 mmol) and TEA (77.6 ml, 556.93 mmol) in DCM (1000 mL) at 0° C. The resulting mixture was stirred at 25° C. for 12 h. The mixture was poured into saturated aqueous NHCl (2 L) and the aqueous phase was extracted with DCM (2 × 1 L). The organic phase was washed with saturated aqueous NaHCO3, saturated aqueous brine, then dried over Na2SO4, filtered and evaporated to give (S)-1-(3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 83, 39.0 g, 95%) as a pale yellow solid. 1 H(300MHz,DMSO-d6)1.36(3H,t),1.90-2.26(5H,m),3.25-3.55(2H,m),3.58-3 .85(2H,m),4.12(2H,q),4.54-5.36(1H,m),8.18(1H,s),8.36-8.65(1H,m);(ES + ) [M+H] + =293.

[0489] Intermediate 84: 1-((S)-3-(9-ethyl-2-((2R,3S)-2-hydroxypentan-3-ylamino)-9H-purin-6-ylamino)pyrrolidin-1-yl)ethanone 28 g of Intermediate 83 was divided equally into four portions. In each portion, DIEA (25.09 ml, 143.68 mmol) was added to (S)-1-(3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 83, 7 g, 23.95 mmol), (2R,3S)-3-aminopentan-2-ol hydrochloride (6.69 g, 47.89 mmol), and lithium chloride (2.030 g, 47.89 mmol) in 3-ethyl-3-pentanol (50 mL) and stirred at room temperature for 20 minutes. The resulting mixture was stirred at 160° C. for 96 hours. The four batches were combined. The reaction mixture was poured into DCM / MeOH (10:1) (2.5 L) and washed with saturated aqueous NH4Cl (300 mL × 1). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by silica flash chromatography (elution gradient 0-8% MeOH in DCM). Pure fractions were evaporated to dryness to give 1-((S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 84, 26.0 g, 72.2%) as a brown oil. m / z (ES + ) [M+H] + =376.

[0490] Intermediate 11: (2R,3S)-3-(9-ethyl-6-((S)-pyrrolidin-3-ylamino)-9H-purin-2-yl-amino)pentan-2-ol hydrochloride 1-((S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-pyrrolidin-1-yl)ethan-1-one (Intermediate 84, 30 g, 79.91 mmol) was added to LiOH (22.97 g, 958.79 mmol) in 1:1 EtOH:HO (300 mL). The resulting mixture was stirred at 80 °C for 16 h. The solvent was removed under reduced pressure. The crude product was purified by silica flash chromatography (elution gradient 0-10% MeOH(NH) in DCM). Pure fractions were evaporated to dryness to afford (2R,3S)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol (Intermediate 11, 14.50 g, 54.4%) as a pale yellow solid. 1H (300MHz, DMSO-d6) 0.87 (3H, t), 1.06 (3H, d), 1.34 (3H, t), 1.38-1.49 (1H, m), 1.69 (2H, ddt), 2.02 (1H, dtd), 2.65-2.80 (2H, m), 2.96 (2H, ddd), 3.63-3.68 (1H, m), 3.76-3.80 (1H, m), 3.98 (2H, q), 4.57 (1H, s), 5.82-6.00 (1H, m), 7.08 (1H, s), 7.70 (1H, s); two exchangeable protons were not observed; m / z (ES + ) [M+H] + =334.

[0491] Example 44: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0492] [ka] Methylsulfamoyl chloride (0.474 g, 3.6 mmol) was added to (2R,3S)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol (Intermediate 11, 1.2 g, 3.6 mmol) and TEA (1.50 ml, 10.8 mmol) in THF (48 mL). The resulting mixture was stirred at −78° C. for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl (75 mL) and extracted with DCM (3 × 75 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give a pale yellow solid. The crude product was purified by silica flash chromatography (elution gradient 0–10% MeOH in DCM). Pure fractions were evaporated and repurified by flash C18 flash chromatography (elution gradient 2 to 50% MeCN in water (0.1% NH4HCO3)). Pure fractions were evaporated to dryness to give (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 44, 0.760 g, 49.7%). 1 H NMR(400Hz,DMSO-d6)0.86(3H,t),1.06(3H,d),1.34(3H,t),1.38-1.46(1 H,m),1.65-1.74(1H,m),2.01-2.10(1H,m),2.17-2.25(1H,m),2.55-2.56 (3H,m),3.10-3.14(1H,m),3.20-3.26(1H,m),3.37-3.43(1H,m),3.53-3. 57(1H,m),3.61-3.68(1H,m),3.74-3.81(1H,m),3.98(2H,q),4.65(2H,br s),5.99(1H,br s),7.00(1H,s),7.39(1H,br s),7.73(1H,s);m / z(ES + ) [M+H] + =427.

[0493] Example 45: (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)-amino)-N-methylpyrrolidine-1-sulfonamide

[0494] [ka] Dess-Martin periodinane (497 mg, 1.17 mmol) was added to (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 44, 500 mg, 1.17 mmol) in THF (10 mL). The resulting mixture was stirred at 25 °C for 4 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 30:1) to give the crude product. The crude product was purified using a preparative column: Xselect CSH OBD column 30 * Purification was performed using a 150 mm column, 5 μm column; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; 5-35% ACN in water. Fractions containing the desired compound were evaporated to dryness to give (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 45, 0.051 g, 10.25%). 1 H NMR(400MHz,DMSO-d6)0.92(3H,t),1.33(3H,t),1.59-1.79(2H,m),1.95-2.04(1H,m),2.06(3H,s),2.16(1H,br s),2.55(3H,d),3.07-3.16(1H,m),3.17-3.27(1H,m),3.34-3.44(1H,m),3.47-3.56(1H,m),3.99(2H,q),4.06(1H,br s),4.57(1H,br s),6.82(1H,br s),7.01(1H,q),7.54(1H,br s),7.78(1H,s);m / z(ES + ) [M+H] + =425.

[0495] Example 46: (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0496] [ka] Methylmagnesium bromide (1.413 mL, 3.53 mmol) was added to (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 45, 150 mg, 0.35 mmol) in THF (3 mL) cooled to 0 °C. The resulting mixture was stirred at 0 °C for 5 h. The reaction mixture was quenched with water (1 mL). The reaction mixture was diluted with DCM (200 mL) and washed successively with saturated aqueous NH4Cl (250 mL x 3) and saturated aqueous brine (250 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC (column: Xselect CSH OBD column 30 * Purification was performed on a 150 mm column (5 μm); mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; 12-25% ACN in water). Fractions containing the desired compound were evaporated to dryness to give (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 46, 57.0 mg, 36.6%). 1H NMR (300 MHz, DMSO-d6) 0.84 (3H, t), 1.08 (6H, d), 1.31-1.36 (4H, m, overlapped), 1.72-1.78 (1H, br m), 2.03-2.09 (1H, br m), 2.12-2.29 (1H, br m), 2.54 (3H, d), 3.06-3.17 (1H, m), 3.17-3.28 (2H, m), 3.50-3.62 (1H, m), 3.78-3.91 (1H, br m), 3.98 (2H, q), 4.32-4.90 (2H, br m), 5.85 (1H, br s), 7.00 (1H, q), 7.40 (1H, br s), 7.73 (1H, s); m / z (ES + ) [M+H] + =441.

[0497] Example 47: (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0498] [ka] Intermediate 85: 1-((S)-3-(9-ethyl-2-((R)-1-hydroxybutan-2-ylamino)-9H-purin-6-ylamino)pyrrolidin-1-yl)ethanone (R)-2-Aminobutan-1-ol (229 mg, 2.57 mmol) was added to (S)-1-(3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 83, 150 mg, 0.51 mmol), DIEA (0.448 mL, 2.57 mmol), and lithium chloride (43.5 mg, 1.03 mmol) in 3-ethylpentan-3-ol (1.5 mL). The resulting mixture was stirred at 160° C. for 16 hours. The reaction mixture was diluted with DCM (100 mL) and washed successively with saturated aqueous NH4Cl (125 mL × 1) and saturated aqueous brine (125 mL). The organic layer was filtered and evaporated to give the crude product. The crude product was purified by C18 flash chromatography (elution gradient 0 to 50% MeCN in water (0.05% FA)). Pure fractions were evaporated to dryness to afford 1-((S)-3-((9-ethyl-2-(((R)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 85, 167 mg, 90%) as a yellow gum. 1 H NMR(300MHz,DMSO-d6)0.84-0.93(3H,m),1.34(3H,t),1.40-1.51(1H,m),1.60-1.68(1H,m),1.93(3H,d ),1.98-2.25(2H,m),3.42-3.53(3H,m),3.59-3.70(2H,m),3.76-3.87(2H,m),3.99(2H,q),4.61(2H,br s),5.93(1H,br s),7.43(1H,br s),7.74(1H,d);m / z(ES + ) [M+H] + =362.

[0499] Intermediate 86: (R)-2-(9-ethyl-6-((S)-pyrrolidin-3-ylamino)-9H-purin-2-yl-amino)butan-1-ol LiOH (103 mg, 4.29 mmol) was added to 1-((S)-3-((9-ethyl-2-(((R)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 85, 155 mg, 0.43 mmol) in EtOH (4 mL) and water (1 mL). The resulting mixture was stirred at 80° C. for 16 hours. THF was removed under reduced pressure, and the resulting residue was diluted with water (100 mL) and extracted with DCM (125 mL×5). The organic layer was dried over NaSO, filtered, and evaporated to give (R)-2-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol (Intermediate 86, 125 mg, 91%) as a white solid. 1 H NMR (300 MHz, DMSO-d6): 0.86 (3H, t), 1.33 (3H, t), 1.39-1.53 ​​(1H, m), 1.53-1.84 (2H, m), 1.96-2.07 (1H, m), 2.72-2.86 (2H, m), 2.92-3.09 (2H, m), 3.35-3.53 (3H, m), 3.82 (1H, br s), 3.98 (2H, q), 4.45-4.69 (1H, m), 5.87 (1H, br s), 7.15 (1H, br s), 7.71 (1H, s). One proton was missing; m / z (ES + ) [M+H] + =320.

[0500] Example 47: (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0501] [ka] Methylsulfamoyl chloride (54.8 mg, 0.42 mmol) was added to (R)-2-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol (Intermediate 86, 135 mg, 0.42 mmol) and TEA (0.295 mL, 2.11 mmol) in DCM (10 mL) cooled to −78° C. The resulting mixture was stirred at −78° C. for 3 h. The reaction mixture was diluted with DCM (125 mL) and washed successively with saturated aqueous NH4Cl (125 mL × 3) and saturated aqueous brine (125 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified using a preparative column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·HO), mobile phase B: MeOH; flow rate: 60 mL / min; 32–52% MeOH in water. Fractions containing the desired compound were evaporated to dryness to give (S)-3-((9-ethyl-2-(((R)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 47, 30.0 mg, 17.21%). 1 H NMR (400 MHz, methanol-d4) 1.02 (3H, t), 1.45 (3H, t), 1.50-1.66 (1H, m), 1.68-1.81 (1H, m), 2.01-2.14 (1H, m), 2.32-2.45 (1H, m), 2.67 (3H, s), 3.24-3.32 (1H, m), 3.34-3.48 (1H, m), 3.48-3.58 (1H, m), 3.60-3.74 (3H, m), 3.94-4.04 (1H, m), 4.11 (2H, q), 4.78 (1H, br s), 7.73 (1H, s). Four exchangeable protons were not observed; m / z (ES) + ) [M+H] + =413.

[0502] Example 48: (S)-3-((9-ethyl-2-(((S)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)-amino)-N-methylpyrrolidine-1-sulfonamide

[0503] [ka] Intermediate 87: 1-((S)-3-(9-ethyl-2-((S)-1-hydroxybutan-2-ylamino)-9H-purin-6-ylamino)pyrrolidin-1-yl)ethanone (S)-2-Aminobutan-1-ol (110 mg, 1.23 mmol) was added to (S)-1-(3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 83, 120 mg, 0.41 mmol), DIEA (358 μL, 2.05 mmol), and lithium chloride (34.8 mg, 0.82 mmol) in 3-ethylpentan-3-ol (1 mL). The resulting mixture was stirred at 160 °C for 16 h. The solvent was removed under reduced pressure. The crude product was purified by C18 flash chromatography (elution gradient: 0 to 50% MeCN in water (0.1% FA)). Pure fractions were evaporated to dryness to afford 1-((S)-3-((9-ethyl-2-(((S)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (intermediate 87, 0.125 g, 84%) as a pale yellow gum. 1 H NMR (400 MHz, DMSO-d6): 0.87 (3H, td), 1.33 (3H, t), 1.38-1.50 (1H, m), 1.58-1.69 (1H, m), 1.92 (3H, d), 2.01-2.25 (2H, m), 3.17-3.39 (2H, m), 3.59-3.70 (1H, m), 3.73-3.86 (2H, m), 3.98 (2H, q), 4.63 (2H, br s), 5.92 (1H, br s), 7.44 (1H, br d), 7.73 (1H, d); two protons overlapped with the water peak; m / z (ES) + ) [M+H] + =362.

[0504] Intermediate 88: (S)-2-(9-ethyl-6-((S)-pyrrolidin-3-ylamino)-9H-purin-2-yl-amino)butan-1-ol LiOH (114 mg, 4.77 mmol) was added to 1-((S)-3-((9-ethyl-2-(((S)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 87, 115 mg, 0.32 mmol) in EtOH (4 mL) and water (4.00 mL). The resulting mixture was stirred at 80° C. for 4 hours. The solvent was removed under reduced pressure. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL×7). The organic layer was dried over Na2SO4, filtered and evaporated to give crude (S)-2-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol (Intermediate 88, 0.097 g, 95%) product as a white solid. 1 H NMR(300MHz,DMSO-d6)0.86(3H,t),1.32(3H,t),1.36-1.49(1H,m),1.54-1.79(2H,m),1.93-2.10(1H,m),2.6 8-2.82(2H,m),2.89-3.05(2H,m),3.35(2H,s),3.42-3.52(1H,m),3.77-3.85(1H,m),3.96(2H,q),4.54(2H,br s),5.86(1H,br s),7.14(1H,br s),7.69(1H,s);m / z(ES + ) [M+H] + =320.

[0505] Example 48: (S)-3-((9-ethyl-2-(((S)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)-amino)-N-methylpyrrolidine-1-sulfonamide

[0506] [ka] Methylsulfamoyl chloride (43.4 mg, 0.33 mmol) was added to (S)-2-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol (Intermediate 88, 107 mg, 0.33 mmol) and TEA (0.233 mL, 1.67 mmol) in DCM (10 mL). The resulting mixture was stirred at −78° C. for 5 h. The reaction mixture was diluted with DCM (100 mL) and washed successively with saturated aqueous NH4Cl (125 mL×3) and saturated aqueous brine (125 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by chromatography on a preparative column: XBridge Shield RP18 OBD column, 30 mL. * Purification was performed using a 150 mm column, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 HO), mobile phase B: ACN; flow rate: 60 mL / min; 20-32% ACN in water. Fractions containing the target compound were evaporated to dryness to give (S)-3-((9-ethyl-2-(((S)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 48, 32.0 mg, 23.16%). 1 H NMR(400MHz,DMSO-d6)0.87(3H,t),1.34(3H,t),1.38-1.50(1H,m),1.57-1.69(1H,m),2.06(1H,s),2.14-2.25(1H,m),2.54(3H, d),3.06-3.14(1H,m),3.17-3.26(1H,m),3.34-3.43(2H,m),3.43-3.58(2H,m),3.79-3.86(1H,m),3.99(2H,q),4.53-4.71(2H,br m),5.94(1H,br s),7.01(1H,q),7.42(1H,br s), 7.74 (1H, s); m / z (ES + ) [M+H] + =413.

[0507] Examples 49 and 50: (S)-3-((9-ethyl-2-(((2R * ,3S *)-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0508] [ka] Intermediate 89: 1-((S)-3-(9-ethyl-2-(4,4,4-trifluoro-3-hydroxybutan-2-ylamino)-9H-purin-6-ylamino)pyrrolidin-1-yl)ethanone Lithium chloride (87 mg, 2.05 mmol) was added to (S)-1-(3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 83, 300 mg, 1.03 mmol), rac-(2R,3S)-3-amino-1,1,1-trifluorobutan-2-ol (441 mg, 3.08 mmol), and DIEA (0.896 mL, 5.13 mmol) in 3-methyl-3-pentanol (5 mL). The resulting mixture was stirred at 160 °C for 4 days. The reaction mixture was diluted with DCM (200 mL) and washed successively with saturated aqueous NH4Cl (250 mL × 3) and saturated aqueous brine (250 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by C18 flash chromatography (elution gradient 5–100% MeCN in water (0.05% NH4HCO3)). Pure fractions were evaporated to dryness to afford 1-((S)-3-((9-ethyl-2-(((2RS,3SR)-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 89, 400 mg, 94%) as a white solid. 1H NMR(300MHz,DMSO-d6)1.18(3H,d),1.32(3H,t),1.83-1.94(3H,m),1.97-2.21(2H,m),3.21-3.2 8(1H,m),3.36-3.50(2H,m),3.58-3.64(1H,m),3.68-3.81(1H,m),3.98(2H,q),4.15-4.31(2H,br m),4.61(1H,br s),6.29(1H,d),7.58(1H,br s),7.76(1H,d);m / z(ES + ) [M+H] + =416.

[0509] Intermediate 90: 3-(9-ethyl-6-((S)-pyrrolidin-3-ylamino)-9H-purin-2-ylamino)-1,1,1-trifluorobutan-2-ol LiOH (450 mg, 18.78 mmol) was added to 1-((S)-3-((9-ethyl-2-(((2RS,3SR)-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one (Intermediate 89, 390 mg, 0.94 mmol) in EtOH (4 mL) and water (1.00 mL). The resulting mixture was stirred at 80° C. for 16 hours. The solvent was removed under reduced pressure. The reaction mixture was diluted with water (25 mL) and subsequently washed with DCM (50 mL×5). The organic layer was dried over Na2SO4, filtered and evaporated to give crude (2RS,3SR)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-1,1,1-trifluorobutan-2-ol (Intermediate 90, 320 mg, 91%) product as a white solid. 1H NMR (DMSO-d6, 300 MHz) 1.18 (3H, d), 1.34 (3H, t), 1.62-1.74 (1H, m), 1.99 (1H, s), 2.63-2.78 (2H, m), 2.87-2.99 (2H, m), 3.99 (2H, q), 4.22-4.28 (2H, m), 4.51 (1H, br s), 5.77 (1H, s), 6.27 (1H, br d), 7.22 (1H, br s), 7.74 (1H, s). One proton overlapped with the solvent peak; m / z (ES + ) [M+H] + =374.

[0510] Examples 49 and 50: (S)-3-((9-ethyl-2-(((2R * ,3S * )-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0511] [ka] Methylsulfamoyl chloride (108 mg, 0.83 mmol) was added to (2RS,3SR)-3-((9-ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-1,1,1-trifluorobutan-2-ol (Intermediate 90, 310 mg, 0.83 mmol) and TEA (0.579 mL, 4.15 mmol) in DCM (30 mL). The resulting mixture was stirred at −70° C. for 3 h. The reaction mixture was diluted with DCM (150 mL) and washed successively with saturated aqueous NH4Cl (200 mL × 3) and saturated aqueous brine (200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30 mm × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; 18–43% ACN in water) to give a mixture of isomer 1 and isomer 2 as a white solid and a mixture of isomer 3 and isomer 4 as a pale yellow solid. The mixture of isomer 1 and isomer 2 was purified by preparative chiral HPLC (column: CHIRALPAK IG-3, 4.6 μm). * Purification was performed using a 50 mm column, 3 μm column; mobile phase A: (hexane:DCM=3:1) (0.3% IPAmine):EtOH=90:10; flow rate: 1 mL / min. Fractions containing the desired compound were evaporated to dryness to give isomer 1 (0.017 g, 4.86%) and (S)-3-((9-ethyl-2-(((2R * ,3S * )-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide (Example 49, Isomer 2, 0.020 g, 5.71%) was obtained....

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein R １ is C １～６ -Alkyl, halo-C １～６ - selected from the group consisting of alkyl, and cyclopropyl; R ２ is -NHR ６ , 【Chemistry 2】 is selected from the group consisting of R ３ and R ４ is hydrogen, and R ３ and R ４ The other of these is hydrogen, halogen, C １～３ -Alkyl, halo-C １～３ - alkyl, and C １～３ -alkoxy, R ５ is C １～６ -Alkyl, C ３～６ -cycloalkyl, -NR ８ R ９ , pyrazolyl, and imidazolyl, １～６ -Alkyl and C ３～６ -Cycloalkyl is a halogen and C １～３ -alkoxy, wherein the pyrazolyl and imidazolyl are optionally substituted with one or more substituents independently selected from C １～３ - optionally substituted with one or more substituents independently selected from alkyl; R ６ is C １～１０ - alkyl or 【Transformation 3】 and said C １～１０ - alkyl is substituted with hydroxy or oxo, halogen, C ３～６ - optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and tetrahydrofuranyl; R ７ is hydrogen or C １～３ - alkyl, R ８ is hydrogen, R ９ is hydrogen, C １～６ -Alkyl, C ３～６ -cycloalkyl, C １～６ -alkoxy-C １～６ -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C １～３ -alkyl, wherein said C １～６ -Alkyl, C ３～６ -cycloalkyl, C １～６ -alkoxy-C １～６ -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C １～３ - alkyl is optionally substituted with one or more substituents independently selected from halogen, or R ８ and R ９ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, said monocyclic ring being optionally substituted with one or more substituents independently selected from halogens.

2. The compound has formula (IA): 【Chemistry 4】 wherein R １ , R ２ , R ３ , R ４ , and R ５ 2. The compound of claim 1, wherein:

3. R １ But C １～３ -Alkyl and halo-C １～３ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: -alkyl.

4. R ２ But, -NHR ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

5. R ６ But C １～１０ -alkyl, and said C １～１０ - alkyl is substituted with hydroxy and halogen, C ３～６ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and tetrahydrofuranyl.

6. R ６ But C ２～６ -alkyl, and said C ２～６ 5. The compound of claim 4, wherein - alkyl is substituted with hydroxy, or a pharmaceutically acceptable salt thereof.

7. R ６ but, 【Transformation 5】 5. The compound of claim 4, wherein:

8. R ６ but, 【Transformation 6】 5. The compound of claim 4, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

9. R ６ but, 【Transformation 7】 (In the formula, R １０ is C １～３ -Alkyl, halo-C １～３ -Alkyl, C ３～６ -cycloalkyl, C ３～６ -cycloalkyl-C １～３ - selected from the group consisting of alkyl, and tetrahydrofuranyl; R １１ is hydrogen and C １～３ - alkyl, R １２ is hydrogen, C １～３ -Alkyl and halo-C １～３ -alkyl).

10. R ３ and R ４ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each of

11. R ５ But, -NR ８ R ９ and R ８ is hydrogen, and R ９ But hydrogen, C １～６ -Alkyl, C ３～６ -cycloalkyl, C １～６ -alkoxy-C １～６ -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C １～３ -alkyl, wherein said C １～６ -Alkyl, C ３～６ -cycloalkyl, C １～６ -alkoxy-C １～６ -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C １～３ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more substituents independently selected from halogen.

12. R ９ But C １～６ -alkyl, and said C １～６ 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein - alkyl is optionally substituted with one or more substituents independently selected from halogen.

13. The compound is Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 (wherein, where applicable, R １ is C １～６ -Alkyl, halo-C １～６ - selected from the group consisting of alkyl, and cyclopropyl; R ２ is -NHR ６ , 【Transformation 8】 is selected from the group consisting of R ３ and R ４ is hydrogen, and R ３ and R ４ The other of these is hydrogen, halogen, C １～３ -Alkyl, halo-C １～３ - alkyl, and C １～３ -alkoxy, R ５ is C １～６ -Alkyl, C ３～６ -cycloalkyl, -NR ８ R ９ , pyrazolyl, and imidazolyl, １～６ -Alkyl and C ３～６ -Cycloalkyl is a halogen and C １～３ -alkoxy, wherein the pyrazolyl and imidazolyl are optionally substituted with one or more substituents independently selected from C １～３ - optionally substituted with one or more substituents independently selected from alkyl; R ６ is C １～１０ - alkyl or 【Chemistry 9】 and said C １～１０ - alkyl is substituted with hydroxy or oxo, halogen, C ３～６ - optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and tetrahydrofuranyl; R ７ is hydrogen or C １～３ - alkyl, R ８ is hydrogen, R ９ is hydrogen, C １～６ -Alkyl, C ３～６ -cycloalkyl, C １～６ -alkoxy-C １～６ -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C １～３ -alkyl, wherein said C １～６ -Alkyl, C ３～６ -cycloalkyl, C １～６ -alkoxy-C １～６ -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C １～３ - alkyl is optionally substituted with one or more substituents independently selected from halogen, or R ８ and R ９ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered saturated monocyclic ring, the remaining ring atoms being carbon atoms, said monocyclic ring being optionally substituted with one or more substituents independently selected from halogen; R １０ is C １～３ -Alkyl, halo-C １～３ -Alkyl, C ３～６ -cycloalkyl, C ３～６ -cycloalkyl-C １～３ - selected from the group consisting of alkyl, and tetrahydrofuranyl; R １１ is hydrogen and C １～３ - alkyl, R １２ is hydrogen, C １～３ -Alkyl and halo-C １～３ - alkyl, R １３ is hydrogen and C １～３ -alkyl).

14. Where applicable, R １ But C １～３ -Alkyl, halo-C １～３ - selected from the group consisting of alkyl, and cyclopropyl; R ２ But, -NHR ６ and R ３ is hydrogen, and R ４ is hydrogen and C １～３ -alkyl or R ４ is hydrogen, and R ３ is hydrogen, halogen, and C １～３ - alkyl, R ５ But C １～６ -Alkyl, C ３～６ -cycloalkyl, -NR ８ R ９ , pyrazolyl, and imidazolyl, １～６ -Alkyl and C ３～６ - cycloalkyl is halogen and C １～３ -alkoxy, wherein the pyrazolyl and imidazolyl are optionally substituted with one or more substituents independently selected from C １～３ - optionally substituted with one or more substituents independently selected from alkyl; R ６ But C １～１０ -alkyl, and said C １～１０ - alkyl is substituted with hydroxy and halogen, C ３～６ - optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and tetrahydrofuranyl; R ８ is hydrogen, R ９ But hydrogen, C １～３ -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C １～３ -alkyl, wherein said C １～３ -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C １～３ - alkyl is optionally substituted with one or more substituents independently selected from halogen, or or R ８ and R ９ together with the nitrogen atom to which they are attached form an azetidinyl ring, said azetidinyl ring being optionally substituted with one or more substituents independently selected from halogen; R １０ But C １～３ -Alkyl, halo-C １～３ -Alkyl, C ３～６ -cycloalkyl, C ３～６ -cycloalkyl-C １～３ - selected from the group consisting of alkyl, and tetrahydrofuranyl; R １１ is hydrogen and C １～３ - alkyl, R １２ But hydrogen, C １～３ -Alkyl and halo-C １～３ - alkyl, R １３ is hydrogen and C １～３ 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: - alkyl.

15. Where applicable, R １ But C １～３ -Alkyl and fluoro-C １～３ - alkyl, R ２ But, -NHR ６ and R ３ is hydrogen, and R ４ is selected from the group consisting of hydrogen and methyl, or R ４ is hydrogen, and R ３ is selected from the group consisting of hydrogen, fluoro, and methyl; R ５ But C １～３ -Alkyl, C ３～６ -cycloalkyl, -NR ８ R ９ , pyrazolyl, and imidazolyl, １～６ -Alkyl and C ３～６ - cycloalkyl is optionally substituted with one or more substituents independently selected from fluoro and methoxy, and said pyrazolyl and imidazolyl is optionally substituted with one or more methyl; R ６ But C ２～６ -alkyl, and said C ２～６ - alkyl is substituted with hydroxy and fluoro, C ３～６ - optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and tetrahydrofuranyl; R ８ is hydrogen, R ９ But hydrogen, C １～３ -alkyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl, １～３ - alkyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl are optionally substituted with one or more substituents independently selected from halogen; R １０ But C １～３ -Alkyl, Fluoro-C １～３ -Alkyl, C ３～６ -cycloalkyl, C ３～６ - selected from the group consisting of cycloalkylmethyl, and tetrahydrofuranyl; R １１ is hydrogen and C １～３ - alkyl, R １２ But hydrogen, C １～３ -Alkyl and halo-C １～３ - alkyl, R １３ is hydrogen and C １～３ 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: - alkyl.

16. Where applicable, R １ But C １～３ -Alkyl and fluoro-C １～３ - alkyl, R ２ But, -NHR ６ and R ３ is selected from the group consisting of hydrogen and fluoro; R ４ is hydrogen, R ５ But C １～３ -Alkyl, cyclopropyl, -NR ８ R ９ , pyrazolyl, and imidazolyl, １～６ - alkyl and cyclopropyl are optionally substituted with one or more substituents independently selected from fluoro and methoxy, and said pyrazolyl and imidazolyl are optionally substituted with one or more methyl; R ６ But C ２～６ -alkyl, and said C ２～６ - alkyl is substituted with hydroxy and fluoro, C ３～６ - optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and tetrahydrofuranyl; R ８ is hydrogen, R ９ But hydrogen, C １～３ -alkyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl, １～３ - alkyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl are optionally substituted with one or more fluoro; R １０ is selected from the group consisting of methyl, ethyl, fluoroethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, and tetrahydrofuranyl; R １１ is selected from the group consisting of hydrogen and methyl; R １２ 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, methyl, and fluoromethyl.

17. Where applicable, R １ is selected from the group consisting of methyl, ethyl, isopropyl, fluoromethyl, and difluoromethyl; R ２ But, -NHR ６ and R ３ and R ４ is hydrogen, R ５ is methyl, fluoromethyl, trifluoromethyl, methoxyethyl, cyclopropyl, -NR ８ R ９ , imidazolyl, pyrazolyl, methylimidazolyl, and methylpyrazolyl; R ６ But C ２～６ -alkyl, and said C ２～６ - alkyl is substituted with hydroxy and fluoro, C ３～６ - optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and tetrahydrofuranyl; R ８ is hydrogen, R ９ is selected from the group consisting of hydrogen, methyl, ethyl, difluoroethyl, trifluoroethyl, tetrahydrofuranyl, and 1,4-dioxanylmethyl; R １０ is selected from the group consisting of methyl, ethyl, fluoroethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, and tetrahydrofuranyl; R １１ is selected from the group consisting of hydrogen and methyl; R １２ 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of hydrogen, methyl, and fluoromethyl.

18. The compound is (S)-3-((9-ethyl-2-(1-oxoisoindolin-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-((R)-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-((R ＊ )-1-hydroxy-1-methyl-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)-amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-sulfonamide, (S)—N-(2,2-difluoroethyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (S)—N-ethyl-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (S)—N-ethyl-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-pyrrolidine-1-sulfonamide, (S)—N-ethyl-3-((9-ethyl-2-(((2S,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)-amino)pyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (S)—N-ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)-amino)pyrrolidine-1-sulfonamide, (S)—N-ethyl-3-((9-ethyl-2-(((R)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (S)—N-ethyl-3-((9-ethyl-2-(((2R,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)-amino)-N-ethylpyrrolidine-1-sulfonamide, 2-cyclopentyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol, 2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-2-(tetrahydrofuran-2-yl)ethan-1-ol, (R)-2-((6-(((3R) ＊ , 4R ＊ )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-2-cyclopropylethan-1-ol, (S)-3-((2-(((2S,3R)-1,3-dihydroxybutan-2-yl)amino)-9-ethyl-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide, (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide, (R)-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)-amino)-3-methylbutan-1-ol, (S)-3-((9-ethyl-2-(((3S,4R)-1,1,1-trifluoro-4-hydroxypentan-3-yl-)-amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide, (S)—N-(((S)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (2R,3S)-3-((9-ethyl-6-(((S)-1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol, (S)—N-(((R)-1,4-dioxan-2-yl)methyl)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)-amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (3R ＊ , 4R ＊ )-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)-amino)-N-ethyl-4-fluoropyrrolidine-1-sulfonamide, (R)-2-(6-((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-ylamino)-3-methylbutan-1-ol, (R)-2-(9-ethyl-6-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (R)-2-(9-cyclopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (R)-2-cyclopropyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol, (2R,3S)-3-((9-isopropyl-6-(((S)-1-(1-methyl-1H-pyrazol-4-yl-sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol, (2R,3S)-3-((9-isopropyl-6-(((S)-1-(1-methyl-1H-imidazol-4-yl-sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol, (R)-2-((6-(((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (R)-2-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (R)-2-((9-isopropyl-6-(((3S,5S)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (R)-2-((9-isopropyl-6-(((3S,4R)-4-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (2R,3S)-3-((9-isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol, (R)-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol, (R)-2-cyclopropyl-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol, (R)-2-((9-ethyl-6-(((S)-1-(2,2,2-trifluoroethylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (R)-2-((9-ethyl-6-(((S)-1-((2-methoxyethyl)sulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (R)-2-((9-ethyl-6-(((S)-1-(fluoromethylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol, (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((S)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((2R ＊ , 3S ＊ )-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-ethyl-2-(((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (3R ＊ , 4R ＊ )-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-4-fluoro-N-methylpyrrolidine-1-sulfonamide, (S)—N-ethyl-3-((2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (S)-3-((9-(fluoromethyl)-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (S)-3-((9-(difluoromethyl)-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide, (2R,3S)-3-((6-(((3R ＊ , 4R ＊ )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)-amino)-9-methyl-9H-purin-2-yl)amino)pentan-2-ol, (2R,3S)-3-((6-(((3R ＊ , 4R ＊ )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoropyrrolidin-3-yl)-amino)-9-(difluoromethyl)-9H-purin-2-yl)amino)-1,1,1-trifluorobutan-2-ol, (S)-3-((2-(((R ＊ )-1-cyclopropyl-3-hydroxypropan-2-yl)amino)-9-ethyl-9H-purin-6-yl)-amino)-N-ethylpyrrolidine-1-sulfonamide, (S)-N-ethyl-3-((9-ethyl-2-(((R ＊ )-3-hydroxy-3-methylbutan-2-yl)-amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide, (S)—N-ethyl-3-((3-ethyl-5-(((2R,3S)-2-hydroxypentan-3-yl)amino)-3H-imidazo[4,5-b]pyridin-7-yl)amino)pyrrolidine-1-sulfonamide, (R)-2-((6-(((3R) ＊ , 4R ＊ )-1-((1H-imidazol-2-yl)sulfonyl)-4-fluoro-pyrrolidin-3-yl)amino)-9-(difluoromethyl)-9H-purin-2-yl)amino)-2-cyclopropylethan-1-ol, and 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (2R,3S)-3-((6-(((S)-1-((1H-pyrazol-5-yl)sulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)pentan-2-ol.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

20. 20. A method of treating cancer in a subject suffering from or susceptible to cancer, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

21. 21. The method of claim 20, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, cervical cancer, uterine cancer, gastric cancer, prostate cancer, bladder cancer, lung cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, pancreatic cancer, thyroid cancer, colorectal cancer, and skin cancer.

22. 23. The method of claim 21 or 22, wherein the method further comprises administering to the subject a therapeutically effective amount of a CDK4 / 6 inhibitor.

23. 20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer.

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