2, 6, 9-trisubstituted purines

Abstract

Compounds having the structure of Formula (I) and pharmaceutically acceptable salts thereof are provided, wherein R1, R2, R3, R4 and R5 are as defined in the specification; pharmaceutical compositions comprising such compounds and salts; the use of such compounds and salts for the treatment or prevention of cyclin dependent kinase 2 (CDK2) mediated disorders; kits comprising such compounds and salts; and processes for preparing such compounds and salts. # imgabs0 #

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 387,734, filed on December 16, 2022, which is hereby incorporated by reference in its entirety for all purposes. Technical Field

[0003] The present disclosure generally relates to 2,6,9 - trisubstituted purines and pharmaceutically acceptable salts thereof. This specification also relates to pharmaceutical compositions comprising such compounds and salts; the use of such compounds and salts for the treatment or prevention of cyclin - dependent kinase 2 (CDK2) - mediated disorders; kits comprising such compounds and salts; and methods for preparing such compounds and salts. Background Art

[0004] Cyclin - dependent kinases (CDKs), including CDK2, are serine / threonine protein kinases involved in cell cycle regulation. CDK2 drives cell progression into the S - phase and M - phase of the cell cycle. Overexpression of CDK2 is associated with abnormal regulation of the cell cycle and tumor growth in a variety of cancer types. The monomeric form of CDK2 is inactive but is activated when it forms a heterodimeric complex with one of its two regulatory partners, cyclin A or cyclin E. The binding of cyclin E to CDK2 in the late G1 - phase of the cell cycle is essential for the transition of the cell cycle from the G1 - phase to the S - phase. Then, cyclin A is required to bind to CDK2 to pass through the S - phase of the cell cycle. The activated CDK2 - cyclin A / E complex controls the phosphorylation of multiple transcription factors that regulate multiple oncogenic signaling pathways affecting cell cycle progression. CDK2 activation also leads to the hyperphosphorylation and inactivation of the retinoblastoma protein (pRB), a tumor suppressor protein that helps to maintain cells in a quiescent state (i.e., the G0 - phase of the cell cycle).

[0005] Overexpression of the CCNE1 gene, which produces cyclin E, occurs in many tumor cells, which causes those cells to become dependent on CDK2 and cyclin E. For example, abnormal cyclin E activity has been observed in solid - tumor cancers such as breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, endometrial cancer, and bone cancer, as well as in blood cancers such as leukemia and lymphoma. In addition, amplification and / or overexpression of cyclin E have been reported as a potential mechanism of resistance to CDK4 / 6 therapy in ER - positive HER2 - negative breast cancer. Similarly, abnormal expression of cyclin A is associated with chromosomal instability and tumor proliferation, and inhibition of cyclin A leads to a slowdown in tumor growth.

[0006] Inhibition of CDK2 activity is an underexplored therapeutic approach for treating cancer and other diseases associated with CDK2 activity. Despite significant efforts, there are currently no approved pharmacological agents that can generally inhibit CDK2 activity or specifically inhibit CDK2 activity. The efforts to identify such inhibitors have been challenging, partly due to two major obstacles. First, the mechanism of CDK2 degradation is still poorly understood. Second, the CDK2 inhibitors developed to date generally lack the necessary specificity or otherwise exhibit off-target CDK-driven toxicity. The sequence and structural similarity among various CDKs is generally high, and the similarity between CDK binding sites results in poor specificity and / or high toxicity for most CDK2 inhibitors. Accordingly, there is a need for CDK2 inhibitors, particularly those with pharmacologically appropriate properties, including selectivity, suitable for administration to a subject 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 treating cancer and other CDK2-mediated conditions. SUMMARY OF THE INVENTION

[0007] In one aspect, the present disclosure provides a compound having a structure of formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] R 1 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl, and cyclopropyl;

[0011] R 2 is selected from the group consisting of -NHR 6 ,

[0012] R 3 and R 4 one of which is hydrogen, and R 3 and R 4 the other of which is selected from the group consisting of hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy;

[0013] R 5 is selected from the group consisting of C 1-6 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; wherein the C1-6 -alkyl and C 3-6 -cycloalkyl is optionally substituted by one or more substituents independently selected from halogen and C 1-3 -alkoxy; and the pyrazolyl and imidazolyl are optionally substituted by one or more substituents independently selected from C 1-3 -alkyl;

[0014] R 6 is C 1-10 -alkyl or wherein the C 1-10 -alkyl is substituted by hydroxy or oxo, and is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl and tetrahydrofuranyl;

[0015] R 7 is hydrogen or C 1-3 -alkyl;

[0016] R 8 is hydrogen; and

[0017] R 9 is selected from the group consisting of: 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 the 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 by one or more substituents independently selected from halogen; or

[0018] 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, wherein the remaining ring atoms are carbon atoms, and wherein the monocyclic ring is optionally substituted by one or more substituents independently selected from halogen.

[0019] In another aspect, the present 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.

[0020] In another aspect, the present disclosure provides a method for treating or preventing a CDK2-mediated disorder in a subject suffering from or susceptible to a CDK2-mediated disorder 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 disorder is cancer. In another aspect, the disorder is cancer characterized by amplification or overexpression of the cyclin E1 (CCNE1) gene and / or the cyclin E2 (CCNE2) gene.

[0021] In another aspect, the present 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 CDK2-mediated disorder.

[0022] In another aspect, the present disclosure provides the use of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing a CDK2-mediated disorder.

[0023] In another aspect, the present disclosure provides a method for treating or preventing a CDK2-mediated disorder in a subject suffering from or susceptible to a CDK2-mediated disorder 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 agent. In one aspect, the second agent is a CDK4 / 6 inhibitor.

[0024] In another aspect, the present 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 agent.

[0025] In another aspect, the present disclosure provides a method for preparing a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1A and Figure 1B show the effect of treatment with a CDK2 inhibitor on the cell cycle phases in OVCAR3 cells. Figure 1A Corresponds to treatment with the compound of Example 6. Figure 1B Corresponds to treatment with the compound of Example 20.

[0027] Figure 2 shows a Western blot (pRB) of OVCAR3 cells after treatment with a CDK2 inhibitor. Figure 2A Corresponds to treatment with the compound of Example 6. Figure 2B Corresponds to treatment with the compound of Example 20.

[0028] Figure 3AShows the combined signal heatmap (inhibition % of growth signal) of 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).

[0029] Figure 3B Shows the combined signal heatmap (inhibition % of growth signal) of 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).

[0030] Figure 3C Shows the combined signal heatmap (inhibition % of growth signal) of 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).

[0031] Figure 4A Shows the combined signal heatmap (senescence induction %) of 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).

[0032] Figure 4B Shows the combined signal heatmap (senescence induction %) of 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).

[0033] Figure 5A Shows the combined signal heatmap (senescence induction %) of 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).

[0034] Figure 5BShows the combined signal heatmap (% senescence induction) of 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).

[0035] Figure 6 Shows the combined signal heatmap (% senescence induction) of 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).

[0036] Figure 7A and Figure 7B Collectively show 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 body weight in an OVCAR3 human ovarian cancer xenograft mouse model.

[0037] Figure 8 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.

[0038] Figure 9 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 the level of pRB in an OVCAR3 human ovarian cancer xenograft mouse model.

[0039] Figure 10 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 the level of pRB in an MCF7-PC1 human palbociclib-resistant ER+ breast cancer xenograft mouse model.

[0040] Figure 11 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.

[0041] Figure 12Shows 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 the pRB level in a CTG-3298 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model.

[0042] Figure 13 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 the pHH3 level in a CTG-3298 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model.

[0043] Figure 14 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 the pRB level in a T47D P1 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model.

[0044] Figure 15 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 the tumor volume in a CTG-3283 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model.

[0045] Figure 16 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 the pRB level in a CTG-3283 human CDK4 / 6-resistant ER+ breast cancer xenograft mouse model. Detailed Description

[0046] Numerous embodiments are described in detail throughout the specification, and these embodiments will be apparent to those skilled in the art. The specification should not be construed as limited to any particular embodiment described herein.

[0047] I. Definitions

[0048] With respect to the embodiments disclosed in this specification, the following terms have the meanings set forth below:

[0049] Reference to "a" or "an" means "one or more / one or more kinds". Throughout the text, except for indications of quantity, the plural and the singular should be considered interchangeable.

[0050] Unless the context otherwise requires, the words "comprise", "comprising", or "include" or "including" are used on the basis and with the clear understanding that they are to be interpreted inclusively and not exclusively, and the Applicant intends that each of these words be so interpreted when interpreting this patent (including the claims below).

[0051] The term "halogen" (alone or in combination with other terms) means a fluorine radical (which may be depicted as -F), a chlorine radical (which may be depicted as -Cl), a bromine radical (which may be depicted as -Br), or an iodine radical (which may be depicted as -I).

[0052] The term "hydroxy" (alone or in combination with other terms) means -OH.

[0053] The term "oxo" (alone or in combination with other terms) means an oxo group and may be depicted as =O.

[0054] The term "alkyl" (alone or in combination with other terms) means a straight-chain or branched-chain saturated hydrocarbon group substituent (i.e., a substituent containing only carbon and hydrogen). Alkyl typically contains from 1 to about 20 carbon atoms, more typically 1 to about 10 carbon atoms, even more typically 1 to about 8 carbon atoms, and still 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, isopentyl, and 2,2-dimethylpropyl), and hexyl.

[0055] The term "cycloalkyl" (alone or in combination with other terms) means a saturated carbocyclic group substituent containing from 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. Cycloalkyl includes a single carbocyclic ring, which typically contains 3 to 6 carbon ring atoms. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0056] The term "alkoxy" (alone or in combination with other terms) means an alkyl ether substituent, i.e., alkyl-O-. Examples of alkoxy include methoxy (CH3-O-), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Thus, for example, the term "alkoxyalkyl" (alone or in combination with other terms) means an alkyl substituted with an alkoxy, such as "methoxymethyl", which may be depicted as:

[0057]

[0058] The prefix "halo-" indicates that the substituent to which it is attached is substituted by one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced by a halogen radical. In cases where more than one hydrogen is replaced by a halogen, the halogens may be the same or different. Examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, 1,1,1-trifluoroethyl, pentafluoroethyl, difluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyl, difluorochloromethyl, dichlorofluoromethyl, and dichloropropyl. Similarly, "haloalkoxy" means an alkoxy substituent in which at least one hydrogen radical is replaced by a halogen radical. In cases where more than one hydrogen is replaced by a halogen, the halogens may be the same or different. Examples of haloalkoxy substituents include fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethoxy"), 1,1,1-trifluoroethoxy, and chloromethoxy.

[0059] 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 of carbon atoms. Thus, for example, "C 1-6 -alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Further illustration, C 3-6 -cycloalkyl refers to a cycloalkyl substituent containing from 3 to 6 carbon ring atoms.

[0060] If a substituent contains at least one carbon or nitrogen atom bonded to one or more hydrogen atoms, the substituent is "substitutable". Thus, for example, hydrogen, halogen, and cyano do not fall within this definition.

[0061] If a substituent is described as "substituted", a non-hydrogen radical replaces a hydrogen radical on a 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 replaces a hydrogen radical on the alkyl substituent. By way of example, a fluoroalkyl is an alkyl substituted by one fluorine radical, and a difluoroalkyl is an alkyl substituted by two fluorine radicals. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen radical may be the same or different (unless otherwise specified).

[0062] If a substituent is described as "optionally substituted", the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of a series of substituents, one or more hydrogens on the carbon (if any hydrogens are present) can be replaced individually and / or together with independently selected optional substituents. If a nitrogen of a substituent is described as optionally substituted with one or more of a series of substituents, one or more hydrogens on the nitrogen (if any hydrogens are present) can each be replaced with an independently selected optional substituent.

[0063] If a substituent is described as "independently selected from" a group, each substituent is selected independently of the others. Thus, each substituent can be the same as or different from the other substituents.

[0064] The term "pharmaceutically acceptable" is used in this specification as an adjective, meaning that the modified noun is suitable for use as a pharmaceutical product or as part of a pharmaceutical product. For example, "pharmaceutically acceptable salts" are salts that are suitable for mammals (especially humans) and include salts formed with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids that are suitable for mammals (especially humans).

[0065] A "therapeutically effective amount" means an amount of the administered compound that will, to some extent, alleviate one or more symptoms of the disorder being treated, or otherwise provide a beneficial or desired result with respect to the disorder. When an agent is administered to treat cancer, a therapeutically effective amount means, for example, an amount having one or more of the following effects: (1) reducing the size of a tumor, (2) inhibiting (i.e., slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting (i.e., slowing to some extent, preferably stopping) tumor growth or tumor invasion to some extent, (4) alleviating (or, preferably, eliminating) one or more signs or symptoms associated with cancer to some extent, (5) reducing the dosage of other drugs required to treat the disease, (6) enhancing the action of another drug, and / or (7) delaying the progression of the patient's disease.

[0066] The term "treat / treating / treatment" is readily understood by an ordinarily skilled physician and, with respect to the treatment of a particular disorder, can include (1) reducing the extent or cause of the disorder being treated, and / or (2) alleviating or ameliorating one or more symptoms associated with the disorder. Treatment of a subject having or diagnosed with cancer can include, for example, reducing the number of cancer cells, reducing the size of a tumor, decreasing the rate of cancer cell infiltration into peripheral organs, decreasing the rate of tumor metastasis or tumor growth, or otherwise reversing, alleviating, or inhibiting the progression of cancer.

[0067] II. Compounds

[0068] A. Compounds of Formula (I)

[0069] In one embodiment, the present disclosure provides a compound having a structure of formula (I):

[0070]

[0071] and pharmaceutically acceptable salts thereof, wherein:

[0072] R 1 is selected from the group consisting of: C 1-6 -alkyl, halo-C 1-6 -alkyl, and cyclopropyl;

[0073] R 2 is selected from the group consisting of: -NHR 6 ,

[0074] R 3 and R 4 one of which is hydrogen, and R 3 and R 4 the other of which is selected from the group consisting of: hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy;

[0075] R 5 is selected from the group consisting of: C 1-6 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; wherein the C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and C 1-3 -alkoxy; and the pyrazolyl and imidazolyl are optionally substituted with one or more substituents independently selected from C 1-3 -alkyl;

[0076] R 6 is C 1-10 -alkyl or wherein the C 1-10 -alkyl is substituted with a hydroxyl or oxo group, and is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl, and tetrahydrofuranyl;

[0077] R 7 is hydrogen or C 1-3 -alkyl;

[0078] R 8 is hydrogen; and

[0079] R 9 is selected from the group consisting of: 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

[0080] 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, wherein the remaining ring atoms are carbon atoms, and wherein said monocyclic ring is optionally substituted with one or more substituents independently selected from halogen.

[0081] In some embodiments, the present disclosure provides a compound of formula (I) having the structure of formula (I-A):

[0082]

[0083] and its pharmaceutically acceptable salts, wherein R 1 、R 2 、R 3 、R 4 and R 5 are as previously defined.

[0084] R 1 Substituent

[0085] In some embodiments, the present disclosure provides a compound having the structure of formula (I) or formula (I-A) and its pharmaceutically acceptable salts, wherein R 1 is selected from the group consisting of: C 1-3 -alkyl, halo-C 1-3 -alkyl, and cyclopropyl. In one aspect, R 1 is selected from the group consisting of: C 1-3 -alkyl and halo-C 1-3 -alkyl. In another aspect, R 1 is selected from the group consisting of: methyl, ethyl, isopropyl, fluoromethyl, and difluoromethyl. In another aspect, R 1Selected from the group consisting of: ethyl and isopropyl. In another aspect, R 1 is C 1-3 -alkyl. In another aspect, R 1 is methyl. In another aspect, R 1 is ethyl. In another aspect, R 1 is n-propyl. In another aspect, R 1 is isopropyl. In another aspect, R 1 is halo-C 1-3 -alkyl. In another aspect, R 1 is fluoro-C 1-3 -alkyl. In another aspect, R 1 is selected from the group consisting of: fluoromethyl and difluoromethyl. In another aspect, R 1 is fluoromethyl. In another aspect, R 1 is difluoromethyl. In another aspect, R 1 is cyclopropyl.

[0086] R 2 Substituent

[0087] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 .

[0088] In some embodiments, R 2 is -NHR 6 and R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl, and tetrahydrofuranyl. In one aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl, and tetrahydrofuranyl. In another aspect, R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, cyclopropyl, and tetrahydrofuranyl. In another aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6-The alkyl group is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of fluorine, cyclopropyl, and tetrahydrofuranyl. In another aspect, R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl group is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of fluorine and cyclopropyl. In another aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl group is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of fluorine and cyclopropyl.

[0089] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl group is substituted with a hydroxyl group. In one aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl group is substituted with a hydroxyl group. In another aspect, R 6 is C4-alkyl, wherein the C4-alkyl group is substituted with a hydroxyl group. In another aspect, R 6 is C5-alkyl, wherein the C5-alkyl group is substituted with a hydroxyl group. In another aspect, R 6 is C6-alkyl, wherein the C6-alkyl group is substituted with a hydroxyl group. In another aspect, R 6 is

[0090]

[0091] In another aspect, R 6 is selected from the group consisting of:

[0092]

[0093] In another aspect, R 6 is

[0094]

[0095] In another aspect, R 6 is selected from the group consisting of:

[0096]

[0097] In another aspect, R 6 is

[0098]

[0099] In another aspect, R 6 is selected from the group consisting of:

[0100]

[0101] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted with a hydroxyl group and one or more halogens. In one aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted with a hydroxyl group and one or more halogens. In another aspect, R 6 is C4-alkyl, wherein the C4-alkyl is substituted with a hydroxyl group and one or more halogens. In another aspect, R 6 is C5-alkyl, wherein the C5-alkyl is substituted with a hydroxyl group and one or more halogens. In another aspect, R 6 is C6-alkyl, wherein the C6-alkyl is substituted with a hydroxyl group and one or more halogens. In a further aspect, the halogen is fluorine.

[0102] In another aspect, R 6 is

[0103]

[0104] In another aspect, R 6 is

[0105]

[0106] In another aspect, R 6 is

[0107]

[0108] In another aspect, R 6 is

[0109]

[0110] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted by a hydroxyl group and a C 3-6 -cycloalkyl. In one aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted by a hydroxyl group and a C 3-6 -cycloalkyl. In another aspect, R 6 is C2-alkyl, wherein the C2-alkyl is substituted by a hydroxyl group and a C 3-6 -cycloalkyl. In another aspect, R 6 is C3-alkyl, wherein the C3-alkyl is substituted by a hydroxyl group and a C 3-6 -cycloalkyl.

[0111] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted by a hydroxyl group and a cyclopropyl group. In one aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted by a hydroxyl group and a cyclopropyl group. In another aspect, R 6 is C2-alkyl, wherein the C2-alkyl is substituted by a hydroxyl group and a cyclopropyl group. In another aspect, R 6 is C3-alkyl, wherein the C3-alkyl is substituted by a hydroxyl group and a cyclopropyl group. In another aspect, R 6 is

[0112]

[0113] In another aspect, R 6 is selected from the group consisting of:

[0114]

[0115] In another aspect, R 6 is

[0116]

[0117] In another aspect, R 6 is selected from the group consisting of:

[0118]

[0119] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted with a hydroxyl group and a cyclopentyl group. In one aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted with a hydroxyl group and a cyclopentyl group. In another aspect, R 6 is C2-alkyl, wherein the C2-alkyl is substituted with a hydroxyl group and a cyclopentyl group. In another aspect, R 6 is C3-alkyl, wherein the C3-alkyl is substituted with a hydroxyl group and a cyclopentyl group. In another aspect, R 6 is

[0120]

[0121] In another aspect, R 6 is

[0122]

[0123] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted with a hydroxyl group and a tetrahydrofuranyl group. In one aspect, R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted with a hydroxyl group and a tetrahydrofuranyl group. In another aspect, R 6 is C2-alkyl, wherein the C2-alkyl is substituted with a hydroxyl group and a tetrahydrofuranyl group. In another aspect, R 6 is C3-alkyl, wherein the C3-alkyl is substituted with a hydroxyl group and a tetrahydrofuranyl group. In another aspect, R 6 is

[0124]

[0125] In another aspect, R 6 is

[0126]

[0127] In some embodiments, the present disclosure provides compounds having a structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R 6 is

[0128]

[0129] wherein R 10 is selected from the group consisting of: 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 selected from the group consisting of: hydrogen and C 1-3 -alkyl; and R 12 is selected from the group consisting of: hydrogen, C 1-3 -alkyl and halo-C 1-3 -alkyl. For clarity, the initial definition of R 6 set forth for the broadest embodiment of the compounds having a structure of formula (I) further limits the combinations of R 10 , R 11 and R 12 substituents that can be selected. In one aspect, R 10 is selected from the group consisting of: C 1-3 -alkyl and halo-C 1-3 -alkyl; R 11 is selected from the group consisting of: hydrogen and C 1-3 -alkyl; and R 12 is selected from the group consisting of: hydrogen, C 1-3 -alkyl and halo-C 1-3 -alkyl. In another aspect, R 10 is selected from the group consisting of: C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl and tetrahydrofuranyl; R 11 is selected from the group consisting of: hydrogen and C 1-3 -alkyl; and R 12 is selected from the group consisting of: hydrogen, C 1-3 -alkyl and halo-C 1-3 -alkyl. In another aspect, 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; and R12 is selected from the group consisting of: hydrogen, methyl, and trifluoromethyl. In another aspect, R 10 is selected from the group consisting of: methyl, ethyl, and fluoroethyl; R 11 is selected from the group consisting of: hydrogen and methyl; and R 12 is selected from the group consisting of: hydrogen, methyl, and trifluoromethyl. In another aspect, R 10 is methyl; R 11 is selected from the group consisting of: hydrogen and methyl; and R 12 is selected from the group consisting of: hydrogen, methyl, and trifluoromethyl. In another aspect, R 10 is ethyl; R 11 is selected from the group consisting of: hydrogen and methyl; and R 12 is selected from the group consisting of: hydrogen, methyl, and trifluoromethyl. In another aspect, R 10 is fluoroethyl; R 11 is selected from the group consisting of: hydrogen and methyl; and R 12 is selected from the group consisting of: hydrogen, methyl, and trifluoromethyl. In another aspect, R 10 is selected from the group consisting of: cyclopropyl and cyclopropylmethyl; R 11 is selected from the group consisting of: hydrogen and methyl; and R 12 is selected from the group consisting of: hydrogen and methyl. In another aspect, R 10 is cyclohexyl; R 11 is selected from the group consisting of: hydrogen and methyl; and R 12 is selected from the group consisting of: hydrogen and methyl. In another aspect, R 10 is tetrahydrofuranyl; R 11 is selected from the group consisting of: hydrogen and methyl; and R 12 is selected from the group consisting of: hydrogen and methyl. In another aspect, R 6 is

[0130]

[0131] In another aspect, R 6 is selected from the group consisting of:

[0132]

[0133] In another aspect, R 6 is

[0134]

[0135] In another aspect, R 6 is selected from the group consisting of:

[0136]

[0137] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted with an oxo group and is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl, and tetrahydrofuranyl. In one aspect, R 6 is C 2-5 -alkyl, wherein the C 2--5 -alkyl is substituted with an oxo group and is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl, and tetrahydrofuranyl. In another aspect, R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted with an oxo group. In another aspect, R 6 is C 1-5 -alkyl, wherein the C 2-5 -alkyl is substituted with an oxo group. In another aspect, R 6 is

[0138]

[0139] In another aspect, R 6 is selected from the group consisting of:

[0140]

[0141] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is -NHR 6 and R 6 is

[0142]

[0143] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is

[0144]

[0145] wherein R 7 is hydrogen or C1-3 -alkyl. In another aspect, R 7 is hydrogen or methyl. In another aspect, R 7 is hydrogen. In another aspect, R 7 is methyl.

[0146] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 2 is

[0147]

[0148] R 3 and R 4 substituent

[0149] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 3 is selected from the group consisting of: hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy, and R 4 is hydrogen. In another aspect, R 3 is selected from the group consisting of: hydrogen, fluorine, methyl, and methoxy, and R 4 is hydrogen. In another aspect, R 3 is selected from the group consisting of: hydrogen, methyl, and fluorine, and R 4 is hydrogen. In another aspect, R 3 is fluorine and R 4 is hydrogen. In another aspect, R 3 is methyl and R 4 is hydrogen.

[0150] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 3 is hydrogen and R 4 is selected from the group consisting of: 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, fluorine, methyl, and methoxy. In another aspect, R 3 is hydrogen and R 4 is selected from the group consisting of: hydrogen and methyl. In another aspect, R 3 is hydrogen and R 4 is methyl.

[0151] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 3 and R 4 are each hydrogen.

[0152] R 5 Substituent

[0153] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is selected from the group consisting of: C 1-6 -alkyl, C 3-6 -cycloalkyl, and -NR 8 R 9 ; wherein the C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and C 1-3 -alkoxy. In one aspect, R 5 is selected from the group consisting of: C 1-3 -alkyl, C 3-6 -cycloalkyl, and -NR 8 R 9 ; wherein the C 1-3 -alkyl and C 3-6 -cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and C 1-3 -alkoxy.

[0154] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is selected from the group consisting of: C 1-6 -alkyl and C 3-6 -cycloalkyl; wherein the C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and C 1-3 -alkoxy.

[0155] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from halogen and C 1-3 -alkoxy. In one aspect, R 5 is C 1-3 -alkyl, wherein the C 1-3- The alkyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In another aspect, R 5 is methyl, wherein the methyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In another aspect, R 5 is ethyl, wherein the ethyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In another aspect, R 5 is propyl, wherein the propyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In a further aspect, the halogen is fluorine and C 1-3 - alkoxy is methoxy.

[0156] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is C 3-6 - cycloalkyl, wherein the C 3-6 - cycloalkyl is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In one aspect, R 5 is cyclopropyl, wherein the cyclopropyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In another aspect, R 5 is cyclobutyl, wherein the cyclobutyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In another aspect, R 5 is cyclopentyl, wherein the cyclopentyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In another aspect, R 5 is cyclohexyl, wherein the cyclohexyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 - alkoxy. In a further aspect, the halogen is fluorine. In a further aspect, C 1-3 - alkoxy is methoxy. In a further aspect, the halogen is fluorine and C 1-3 - alkoxy is methoxy.

[0157] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is selected from the group consisting of pyrazolyl and imidazolyl, wherein the pyrazolyl and imidazolyl are optionally substituted by one or more substituents independently selected from C 1-3 - alkyl. In one aspect, R5 is selected from the group consisting of: pyrazolyl and imidazolyl, wherein the pyrazolyl and imidazolyl are optionally substituted with one or more methyl groups. In another aspect, R 5 is pyrazolyl, wherein the pyrazolyl is optionally substituted with one or more substituents independently selected from C 1-3 -alkyl. In another aspect, R 5 is pyrazolyl, wherein the pyrazolyl is optionally substituted with one or more methyl groups. In another aspect, R 5 is imidazolyl, wherein the imidazolyl is optionally substituted with one or more substituents independently selected from C 1-3 -alkyl. In another aspect, R 5 is imidazolyl, wherein the imidazolyl is optionally substituted with one or more methyl groups.

[0158] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) 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.

[0159] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 ; R 8 is hydrogen; and R 9 is selected from the group consisting of: 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 the 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 are optionally substituted with one or more substituents independently selected from halogen. In one aspect, R 9 is selected from the group consisting of: hydrogen, 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; wherein the 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. In another aspect, R 9 is selected from the group consisting of: hydrogen, C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1-3 -alkyl; wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. In a further aspect, the halogen is fluorine.

[0160] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 ; R 8 is hydrogen; and R 9 is hydrogen.

[0161] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 ; R 8 is hydrogen; and R 9 is C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from halogen. In one aspect, R 9 is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is methyl, wherein the methyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is ethyl, wherein the ethyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is propyl, wherein the propyl is optionally substituted with one or more substituents independently selected from halogen. In a further aspect, the halogen is fluorine.

[0162] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 ; R 8 is hydrogen; and R9 is C 3-6 -cycloalkyl, wherein the C 3-6 -cycloalkyl is optionally substituted with one or more substituents independently selected from halogen. In one aspect, R 9 is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is cyclobutyl, wherein the cyclobutyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is cyclopentyl, wherein the cyclopentyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is cyclohexyl, wherein the cyclohexyl is optionally substituted with one or more substituents independently selected from halogen. In a further aspect, the halogen is fluorine.

[0163] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 ; R 8 is hydrogen; and R 9 is C 1-6 -alkoxy-C 1-6 -alkyl, wherein the C 1-6 -alkoxy-C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from halogen. In one aspect, R 9 is C 1-3 -alkoxy-C 1-3 -alkyl, wherein the C 1-3 -alkoxy-C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is methoxy-C 1-3 -alkyl, wherein the methoxy-C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is methoxymethyl, wherein the methoxymethyl is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 9 is methoxyethyl, wherein the methoxyethyl is optionally substituted with one or more substituents independently selected from halogen. In a further aspect, the halogen is fluorine.

[0164] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I-A) and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R9 ; R 8 is hydrogen; and R 9 is selected from the group consisting of tetrahydrofuranyl and 1,4 - dioxanyl-C 1-3 -alkyl; wherein the tetrahydrofuranyl and 1,4 - dioxanyl-C 1-3 -alkyl are optionally substituted with one or more substituents independently selected from halogen. In one aspect, R 9 is tetrahydrofuranyl. In another aspect, R 9 is 1,4 - dioxanyl-C 1-3 -alkyl. In another aspect, R 9 is 1,4 - dioxanylmethyl. In a further aspect, the halogen is fluorine.

[0165] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I - A) and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 ; and R 8 and R 9 together with the nitrogen atom to which they are attached form a 4 - membered, 5 - membered or 6 - membered saturated monocyclic ring, wherein the remaining ring atoms are carbon atoms, and wherein the monocyclic ring is optionally substituted with one or more substituents independently selected from halogen. In one aspect, R 8 and R 9 together with the nitrogen atom to which they are attached form a 4 - membered saturated monocyclic ring, wherein the remaining ring atoms are carbon atoms, and wherein the monocyclic ring is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 8 and R 9 together with the nitrogen atom to which they are attached form a 5 - membered saturated monocyclic ring, wherein the remaining ring atoms are carbon atoms, and wherein the monocyclic ring is optionally substituted with one or more substituents independently selected from halogen. In another aspect, R 8 and R 9 together with the nitrogen atom to which they are attached form a 6 - membered saturated monocyclic ring, wherein the remaining ring atoms are carbon atoms, and wherein the monocyclic ring is optionally substituted with one or more substituents independently selected from halogen. In a further aspect, the halogen is fluorine.

[0166] In some embodiments, the present disclosure provides compounds having the structure of formula (I) or formula (I - A) and pharmaceutically acceptable salts thereof, wherein R 5 is -NR 8 R 9 ; R 8 is hydrogen; and R 9 is selected from the group consisting of hydrogen, methyl, ethyl, difluoroethyl, trifluoroethyl, tetrahydrofuranyl and 1,4 - dioxanylmethyl; or R8 and R 9 together with the nitrogen atom to which they are attached form an azetidinyl ring, and wherein said azetidinyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen. In a further aspect, the halogen is fluorine. In another aspect, R 5 is -NR 8 R 9 ; R 8 is hydrogen; and R 9 is selected from the group consisting of methyl, ethyl, difluoroethyl, trifluoroethyl, tetrahydrofuranyl, and 1,4-dioxanyl methyl.

[0167] B. Additional Embodiments

[0168] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from the structures of formulae I-1 to I-117 listed in Table 1:

[0169] Table 1

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179] wherein, when applicable:

[0180] R 1 is selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl, and cyclopropyl;

[0181] R 2 is selected from the group consisting of -NHR 6 ,

[0182] R 3 and R4 One of them is hydrogen, and R 3 and R 4 The other one is selected from the group consisting of: hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy;

[0183] R 5 is selected from the group consisting of: C 1-6 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; wherein the C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted by one or more substituents independently selected from halogen and C 1-3 -alkoxy; and the pyrazolyl and imidazolyl are optionally substituted by one or more substituents independently selected from C 1-3 -alkyl;

[0184] R 6 is C 1-10 -alkyl or wherein the C 1-10 -alkyl is substituted by a hydroxyl group or an oxo group, and is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl, and tetrahydrofuranyl;

[0185] R 7 is hydrogen or C 1-3 -alkyl;

[0186] R 8 is hydrogen;

[0187] R 9 is selected from the group consisting of: 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 the 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 are optionally substituted by one or more substituents independently selected from halogen; or

[0188] R 8 and R 9form, together with the nitrogen atom to which they are attached, a 4-, 5- or 6-membered saturated monocyclic ring, wherein the remaining ring atoms are carbon atoms, and wherein said monocyclic ring is optionally substituted with one or more substituents independently selected from halogen;

[0189] R 10 is selected from the group consisting of: C 1-3 -alkyl, halo-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl and tetrahydrofuranyl;

[0190] R 11 is selected from the group consisting of hydrogen and C 1-3 -alkyl;

[0191] R 12 is selected from the group consisting of hydrogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; and

[0192] R 13 is selected from the group consisting of hydrogen and C 1-3 -alkyl.

[0193] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein, when applicable:

[0194] R 1 is selected from the group consisting of: C 1-3 -alkyl, halo-C 1-3 -alkyl and cyclopropyl;

[0195] R 2 is -NHR 6 ;

[0196] R 3 is hydrogen and R 4 is selected from the group consisting of hydrogen and C 1-3 -alkyl; or R 4 is hydrogen and R 3 is selected from the group consisting of hydrogen, halogen and C 1-3 -alkyl;

[0197] R 5 is selected from the group consisting of: C 1-6 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 、pyrazolyl and imidazolyl; wherein the C 1-6 -alkyl and C 3-6-The cycloalkyl group is optionally substituted by one or more substituents independently selected from halogen and C 1-3 -alkoxy; and the pyrazolyl and imidazolyl groups are optionally substituted by one or more substituents independently selected from C 1-3 -alkyl;

[0198] R 6 is C 1-10 -alkyl, wherein the C 1-10 -alkyl is substituted by a hydroxyl group and is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl, and tetrahydrofuranyl;

[0199] R 8 is hydrogen;

[0200] R 9 is selected from the group consisting of: hydrogen, C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1-3 -alkyl; wherein the C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl-C 1-3 -alkyl are optionally substituted by one or more substituents independently selected from halogen; or

[0201] R 8 and R 9 together with the nitrogen atom to which they are attached form an azetidinyl ring, and wherein the azetidinyl ring is optionally substituted by one or more substituents independently selected from halogen;

[0202] R 10 is selected from the group consisting of: C 1-3 -alkyl, halo-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl, and tetrahydrofuranyl;

[0203] R 11 is selected from the group consisting of: hydrogen and C 1-3 -alkyl;

[0204] R 12 is selected from the group consisting of: hydrogen, C 1-3 -alkyl, and halo-C 1-3 -alkyl; and

[0205] R 13 is selected from the group consisting of: hydrogen and C 1-3 -alkyl.

[0206] In one aspect, the compound has a structure selected from the structures of Formulas I-1 to I-117 listed in Table 1.

[0207] In some embodiments, the present disclosure provides a compound of Formula (I) and a pharmaceutically acceptable salt thereof, wherein, when applicable:

[0208] R 1 is selected from the group consisting of: C 1-3 -alkyl and fluoro-C 1-3 -alkyl;

[0209] R 2 is -NHR 6 ;

[0210] 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, fluorine and alkyl;

[0211] R 5 is selected from the group consisting of: C 1-3 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 , pyrazolyl and imidazolyl; wherein the C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted with one or more substituents independently selected from fluorine and methoxy; and the pyrazolyl and imidazolyl are optionally substituted with one or more methyl groups;

[0212] R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted with a hydroxyl group and is optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, C 3-6 -cycloalkyl and tetrahydrofuranyl;

[0213] R 8 is hydrogen;

[0214] R 9 is selected from the group consisting of hydrogen, C 1-3 -alkyl, tetrahydrofuranyl and 1,4-dioxanyl methyl; wherein the C 1-3 -alkyl, tetrahydrofuranyl and 1,4-dioxanyl methyl are optionally substituted with one or more substituents independently selected from halogens;

[0215] R 10 is selected from the group consisting of: C 1-3 -alkyl, fluoro-C1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkylmethyl, and tetrahydrofuranyl;

[0216] R 11 is selected from the group consisting of hydrogen and C 1-3 -alkyl;

[0217] R 12 is selected from the group consisting of hydrogen, C 1-3 -alkyl, and halo-C 1-3 -alkyl; and

[0218] R 13 is selected from the group consisting of hydrogen and C 1-3 -alkyl.

[0219] In one aspect, the compound has a structure selected from the structures of Formulas I-1 to I-117 listed in Table 1.

[0220] In some embodiments, the present disclosure provides a compound of Formula (I) and a pharmaceutically acceptable salt thereof, wherein, when applicable:

[0221] R 1 is selected from the group consisting of C 1-3 -alkyl and fluoro-C 1-3 -alkyl;

[0222] R 2 is -NHR 6 ;

[0223] R 3 is selected from the group consisting of hydrogen and fluorine;

[0224] R 4 is hydrogen;

[0225] R 5 is selected from the group consisting of C 1-3 -alkyl, cyclopropyl, -NR 8 R 9 , pyrazolyl, and imidazolyl; wherein the C 1-6 -alkyl and cyclopropyl are optionally substituted with one or more substituents independently selected from fluorine and methoxy; and the pyrazolyl and imidazolyl are optionally substituted with one or more methyl groups;

[0226] R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted with a hydroxyl group and is optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, C 3-6 -cycloalkyl, and tetrahydrofuranyl;

[0227] R 8 is hydrogen;

[0228] R 9 is selected from the group consisting of: hydrogen, C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl methyl; wherein said C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl methyl are optionally substituted with one or more fluorines;

[0229] R 10 is selected from the group consisting of: methyl, ethyl, fluoroethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, and tetrahydrofuranyl;

[0230] R 11 is selected from the group consisting of: hydrogen and methyl; and

[0231] R 12 is selected from the group consisting of: hydrogen, methyl, and fluoromethyl.

[0232] In one aspect, the compound has a structure selected from the structures of Formulas I-1 to I-117 listed in Table 1.

[0233] In some embodiments, the present disclosure provides a compound of Formula (I) and a pharmaceutically acceptable salt thereof, wherein, when applicable:

[0234] R 1 is selected from the group consisting of: methyl, ethyl, isopropyl, fluoromethyl, and difluoromethyl;

[0235] R 2 is -NHR 6 ;

[0236] R 3 and R 4 are hydrogen;

[0237] R 5 is selected from the group consisting of: methyl, fluoromethyl, trifluoromethyl, methoxyethyl, cyclopropyl, -NR 8 R 9 , imidazolyl, pyrazolyl, methylimidazolyl, and methylpyrazolyl;

[0238] R 6 is C 2-6 -alkyl, wherein said C 2-6 -alkyl is substituted with a hydroxyl group and is optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, C 3-6 -cycloalkyl, and tetrahydrofuranyl;

[0239] R 8is hydrogen;

[0240] R 9 is selected from the group consisting of hydrogen, methyl, ethyl, difluoroethyl, trifluoroethyl, tetrahydrofuryl, and 1,4-dioxanyl methyl;

[0241] R 10 is selected from the group consisting of methyl, ethyl, fluoroethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, and tetrahydrofuryl;

[0242] R 11 is selected from the group consisting of hydrogen and methyl; and

[0243] R 12 is selected from the group consisting of hydrogen, methyl, and fluoromethyl.

[0244] In one aspect, the compound has a structure selected from the structures of Formulas I-1 to I-117 listed in Table 1.

[0245] In some embodiments, the present disclosure provides a compound of Formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (I-61):

[0246]

[0247] and wherein R 5 is as defined in any of the embodiments disclosed in this specification.

[0248] In some embodiments, the present disclosure provides a compound of Formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (I-62):

[0249]

[0250] and wherein R 5 is as defined in any of the embodiments disclosed in this specification.

[0251] In some embodiments, the present disclosure provides a compound of Formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (I-63):

[0252]

[0253] and wherein R 5 is as defined in any of the embodiments disclosed in this specification.

[0254] In some embodiments, the present disclosure provides a compound of Formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (I-64):

[0255]

[0256] and wherein R 5 、R 10 、R 11 and R 12 is defined as in any of the embodiments disclosed in this specification.

[0257] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I-65):

[0258]

[0259] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0260] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I-66):

[0261]

[0262] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0263] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I-67):

[0264]

[0265] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0266] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I-68):

[0267]

[0268] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0269] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (I-69):

[0270]

[0271] and wherein R5 As defined in any of the embodiments disclosed in this specification.

[0272] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-70):

[0273]

[0274] and wherein R 5 As defined in any of the embodiments disclosed in this specification.

[0275] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-71):

[0276]

[0277] and wherein R 5 As defined in any of the embodiments disclosed in this specification.

[0278] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-72):

[0279]

[0280] and wherein R 5 As defined in any of the embodiments disclosed in this specification.

[0281] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-73):

[0282]

[0283] and wherein R 5 As defined in any of the embodiments disclosed in this specification.

[0284] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-74):

[0285]

[0286] and wherein R 5 As defined in any of the embodiments disclosed in this specification.

[0287] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-75):

[0288]

[0289] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0290] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-76):

[0291]

[0292] and wherein R 5 , R 10 , R 11 and R 12 are defined as in any of the embodiments disclosed in this specification.

[0293] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-77):

[0294]

[0295] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0296] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-78):

[0297]

[0298] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0299] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-79):

[0300]

[0301] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0302] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-80):

[0303]

[0304] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0305] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-81):

[0306]

[0307] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0308] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-82):

[0309]

[0310] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0311] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-83):

[0312]

[0313] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0314] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula (I-84):

[0315]

[0316] and wherein R 5 is defined as in any of the embodiments disclosed in this specification.

[0317] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compound has a structure selected from the structures of formulae I-1 to I-117 listed in Table 1, and wherein, when applicable, R 5is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more substituents independently selected from fluorine and C 1-3 -alkoxy.

[0318] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from the structures of formulae I-1 to I-117 listed in Table 1, and wherein, when applicable, R 5 is C 3-6 -cycloalkyl, wherein the C 3-6 -cycloalkyl is optionally substituted with one or more fluorine substituents. In one aspect, R 5 is cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more fluorine substituents. In another aspect, R 5 is cyclobutyl, wherein the cyclobutyl is optionally substituted with one or more fluorine substituents. In another aspect, R 5 is cyclopentyl, wherein the cyclopentyl is optionally substituted with one or more fluorine substituents. In another aspect, R 5 is cyclohexyl, wherein the cyclohexyl is optionally substituted with one or more fluorine substituents.

[0319] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from the structures of formulae I-1 to I-117 listed in Table 1, and wherein, when applicable, R 5 is pyrazolyl, wherein the pyrazolyl is optionally substituted with one or more substituents independently selected from C 1-3 -alkyl. In one aspect, R 5 is pyrazolyl, wherein the pyrazolyl is optionally substituted with one or more methyl groups.

[0320] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from the structures of formulae I-1 to I-117 listed in Table 1, and wherein, when applicable, R 5 is imidazolyl, wherein the imidazolyl is optionally substituted with one or more substituents independently selected from C 1-3 -alkyl. In one aspect, R 5 is imidazolyl, wherein the imidazolyl is optionally substituted with one or more methyl groups.

[0321] In some embodiments, the present disclosure provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from the structures of formulae I-1 to I-117 listed in Table 1, and wherein, when applicable, R 5 is -NR 8R 9 . In one aspect, R 9 is C 1-3 -alkyl, wherein the C 1-3 -alkyl is optionally substituted with one or more fluoro substituents. In another aspect, R 9 is tetrahydrofuranyl. In another aspect, R 9 is 1,4-dioxanyl-C 1-3 -alkyl. In another aspect, R 9 is 1,4-dioxanylmethyl.

[0322] In some embodiments, the present disclosure provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein the compounds are selected from the group consisting of:

[0323] (S)-3-((9-Ethyl-2-(1-oxoisoindolin-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 1];

[0324] (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];

[0325] (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];

[0326] (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];

[0327] (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];

[0328] (S)-N-Ethyl-3-((9-ethyl-2-((((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 6];

[0329] (S)-N-Ethyl-3-((9-ethyl-2-((((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-pyrrolidine-1-sulfonamide [Example 7];

[0330] (S)-N-Ethyl-3-((9-ethyl-2-(((2S,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)-amino)pyrrolidine-1-sulfonamide [Example 8];

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

[0332] (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 10];

[0333] (S)-N-Ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)-amino)pyrrolidine-1-sulfonamide [Example 11];

[0334] (S)-N-Ethyl-3-((9-ethyl-2-(((R)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 12];

[0335] (S)-N-Ethyl-3-((9-ethyl-2-(((2R,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 13];

[0336] (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)-amino)-N-ethylpyrrolidine-1-sulfonamide [Example 14];

[0337] 2-Cyclopentyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol [Example 15];

[0338] 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];

[0339] (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];

[0340] (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];

[0341] (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide [Example 19];

[0342] (R)-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-amino)-9H-purin-2-yl)-amino)-3-methylbutan-1-ol [Example 20];

[0343] (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];

[0344] (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];

[0345] (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];

[0346] (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];

[0347] (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];

[0348] (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];

[0349] (R)-2-(6-((S)-1-(Cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H-purin-2-ylamino)-3-methylbutan-1-ol [Example 27];

[0350] (R)-2-(9-Ethyl-6-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 28];

[0351] (R)-2-(9-Cyclopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl-amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 29];

[0352] (R)-2-Cyclopropyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol [Example 30];

[0353] (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];

[0354] (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];

[0355] (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];

[0356] (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];

[0357] (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];

[0358] (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];

[0359] (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];

[0360] (R)-2-((9-Ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)butan-1-ol [Example 38];

[0361] (R)-2-Cyclopropyl-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethanol [Example 39];

[0362] (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];

[0363] (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 41];

[0364] (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];

[0365] (R)-2-((9-Ethyl-6-(((S)-1-(fluoromethylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol [Example 43];

[0366] (S)-3-((9-Ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 44];

[0367] (S)-3-((9-Ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 45];

[0368] (S)-3-((9-Ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 46];

[0369] (S)-3-((9-Ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 47];

[0370] (S)-3-((9-Ethyl-2-(((S)-1-hydroxybutan-2-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 48];

[0371] (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];

[0372] (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];

[0373] (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];

[0374] (S)-N-Ethyl-3-((2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide [Example 53];

[0375] (S)-3-((9-(Fluoromethyl)-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 54];

[0376] (S)-3-((9-(Difluoromethyl)-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidine-1-sulfonamide [Example 55];

[0377] (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];

[0378] (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];

[0379] (S)-3-((2-(((R*)-1-cyclopropyl-3-hydroxypropan-2-yl)amino)-9-ethyl-9H-purin-6-yl)-amino)-N-ethylpyrrolidine-1-sulfonamide [Example 58];

[0380] (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];

[0381] (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];

[0382] (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

[0383] (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].

[0384] C. Combinations of Embodiments

[0385] Any embodiment of the compounds described in this disclosure can be combined with any other suitable embodiment described herein to provide additional embodiments. For example, in one embodiment, the possible groups of R 1 、R 2 、R 3 、R 4 and / or R 5 are described alone or together and one separate embodiment describes R5 In the case of possible groups, it should be understood that these embodiments can be combined to provide descriptions of the possible groups described for R 1 , R 3 , R 4 and / or R 5 along with additional embodiments of the possible groups described for R 5 . In other words, for any embodiment of the compounds described in this disclosure, the R 5 substituent can be defined as in any embodiment of R 5 described in this specification.

[0386] D. Other Embodiments

[0387] In some embodiments, the compounds of the present disclosure have an IC 50 value for CDK2 inhibition that is less than about 200 nM, as measured in the NanoBRET assay described in Example 63 below. In one aspect, the IC 50 value is less than about 150 nM. In another aspect, the IC 50 value is less than about 100 nM. In another aspect, the IC 50 value is less than about 50 nM. In another aspect, the IC 50 value is less than about 25 nM.

[0388] In some embodiments, the compounds of the present disclosure have an IC 50 value for NPM phosphorylation inhibition that is less than about 1 μM, as measured in the pNPM phosphorylation assay described in Example 64 below. In one aspect, the IC 50 value in the assay is less than about 750 nM. In another aspect, the IC 50 value in the assay is less than about 500 nM. In another aspect, the IC 50 value in the assay is less than about 250 nM. In another aspect, the IC 50 value in the assay is less than about 100 nM.

[0389] In some embodiments, the compounds of the present disclosure are selective inhibitors of CDK2, i.e., they have a lower inhibition constant (e.g., Ki or IC 50)。Relative to non-selective CDK2 inhibitors, compounds that are selective CDK2 inhibitors generally have an improved safety profile, an improved dosing regimen, and / or enhanced overall efficacy. In one aspect, the compound has an inhibition constant for CDK2 that is at least 10-fold lower than the corresponding inhibition constant for at least one of CDK1, CDK4, CDK6, and / or CDK9. In another aspect, the compound has an inhibition constant for CDK2 that is at least 10-fold lower than the corresponding inhibition constant for at least two of CDK1, CDK4, CDK6, and / or CDK9. In another aspect, the compound has an inhibition constant for CDK2 that is at least 10-fold lower than the corresponding inhibition constant for at least three of CDK1, CDK4, CDK6, and / or CDK9. In another aspect, the compound has an inhibition constant for CDK2 that is at least 10-fold lower than the corresponding inhibition constant for CDK1, CDK4, CDK6, and CDK9.

[0390] In some embodiments, the compounds of the present disclosure are at least about 5-fold more selective for CDK2 relative to CDK1, as measured in the NanoBRET assay described in Example 63 below. In one aspect, the compound is at least about 10-fold more selective for CDK2 relative to CDK1. In another aspect, the IC 50 value for inhibition of CDK1 by the compound is greater than about 0.1 μM. In another aspect, the IC 50 value for inhibition of CDK1 by the compound is greater than about 0.2 μM. In another aspect, the IC 50 value for the compound against CDK1 is greater than about 0.3 μM.

[0391] In some embodiments, the compounds of the present disclosure are at least about 30-fold more selective for CDK2 relative to CDK4, as measured in the NanoBRET assay described in Example 63 below. In one aspect, the compound is at least about 100-fold more selective for CDK2 relative to CDK4. In another aspect, the compound is at least about 500-fold more selective for CDK2 relative to CDK4. In another aspect, the IC 50 value for inhibition of CDK4 by the compound is greater than about 0.7 μM. In another aspect, the IC 50 value for inhibition of CDK4 by the compound is greater than about 1.0 μM. In another aspect, the IC 50 value for inhibition of CDK4 by the compound is greater than about 5.0 μM.

[0392] In some embodiments, the compounds of the present disclosure are at least about 100-fold more selective for CDK2 relative to CDK9, as measured in the POLR2A Ser2 phosphorylation assay as described in Example 65 below. In one aspect, the compounds are at least about 100-fold more selective for CDK2 relative to CDK9. In another aspect, the compounds are at least about 500-fold more selective for CDK2 relative to CDK9. In another aspect, the compounds are at least about 1000-fold more selective for CDK2 relative to CDK9. In another aspect, the compounds have an IC 50 value greater than about 1.0 μM in the assay. In another aspect, the compounds have an IC 50 value greater than about 5.0 μM in the assay. In another aspect, the compounds have an IC 50 value greater than about 10.0 μM in the assay.

[0393] In some embodiments, the compounds of the present disclosure inhibit MCF7 cell proliferation, as measured in the EdU assay as described in Example 66 below. In one aspect, the compounds have an IC 50 value below about 2.0 μM in the assay. In another aspect, the IC 50 value is below about 1.0 μM. In another aspect, the IC 50 value is below about 750 nM. In another aspect, the IC 50 value is below about 500 nM.

[0394] In some embodiments, the compounds of the present disclosure inhibit OVCAR3 cell proliferation, as measured in the EdU assay as described in Example 66 below. In one aspect, the compounds have an IC 50 value below about 1.0 μM in the assay. In another aspect, the IC 50 value is below about 750 nM. In another aspect, the IC 50 value is below about 500 nM. In another aspect, the IC 50 value is below about 250 nM.

[0395] In some embodiments, the compounds of the present disclosure have pharmaceutically acceptable metabolic stability, as measured in the human liver microsome (HLM) assay reported in Example 83 below. In one aspect, the compounds have an HLM CL int value less than about 300 μL / min / mg. In another aspect, the HLM CL int value is less than about 200 μL / min / mg. In another aspect, the HLM CL int value is less than about 100 μL / min / mg. In another aspect, the HLM CL intThe value is less than about 50 μL / min / mg.

[0396] E. Salts

[0397] The compounds of the present disclosure can exist in salt form or in non-salt form (i.e., as the free base), and the present disclosure encompasses both salt form and non-salt form. The compounds can form acid addition salts or base addition salts. Generally, acid addition salts can be prepared using various inorganic acids or organic acids. Such salts can typically be formed by, for example, mixing the compound with an acid (e.g., a stoichiometric amount of the acid) using various methods known in the art. This mixing can occur in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or an aqueous / organic mixture. In another aspect, the acid addition salt is, for example, a trifluoroacetate, formate, acetate, or hydrochloride salt. Generally, base addition salts can be prepared using various inorganic bases or organic bases, such as alkali metal or alkaline earth metal salts, such as sodium, calcium, or magnesium salts; or other metal salts, such as potassium or zinc; or ammonium salts; or salts formed with an organic base (such as methylamine, dimethylamine, trimethylamine, piperidine, or morpholine). Those skilled in the art will recognize the general principles and techniques for preparing pharmaceutically acceptable salts, such as those described, for example, in J. Pharm. Sci. 1977 66, 1. Examples of pharmaceutically acceptable salts are also described in Stahl and Wermuth's “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002).

[0398] F. Isomers

[0399] The compounds and salts of the present disclosure can exist in one or more geometric forms, optical forms, enantiomeric forms, and diastereomeric forms, including but not limited to cis and trans forms, E and Z forms, and R, S, and meso forms. Unless otherwise indicated, a reference to a particular compound includes all such isomeric forms, including their racemic and other mixtures. Where appropriate, such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g., chromatographic techniques and recrystallization techniques). Where appropriate, such isomers can be prepared by the application or adaptation of known methods. In some embodiments, a single stereoisomer is obtained by separating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by direct synthesis from, for example, chiral starting materials.

[0400] The specific enantiomers of the compounds 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 having an enantiomeric excess (% ee) of ≥90, ≥95%, ≥96%, ≥97, ≥98% or ≥99%. In one aspect, the single enantiomer is present with an enantiomeric excess (% ee) of ≥99%.

[0401] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients, wherein the compound or a pharmaceutically acceptable salt thereof is a single enantiomer having an enantiomeric excess (% ee) of ≥90, ≥95%, ≥96%, ≥97, ≥98% or ≥99%. In one aspect, the single enantiomer is present with an enantiomeric excess (% ee) of ≥99%.

[0402] G. Additional Forms

[0403] The compounds and salts of the present disclosure may exist in various tautomeric forms, and this specification encompasses all such tautomeric forms. A "tautomer" is a structural isomer in which equilibrium exists due to the migration of a hydrogen atom.

[0404] The compounds of the present disclosure and their pharmaceutically acceptable salts may exist as solvates (such as hydrates) as well as in non-solvated forms, and this specification encompasses all such solvates.

[0405] The compounds of the present disclosure and their pharmaceutically acceptable salts may exist in crystalline or amorphous forms, and this specification encompasses all such forms.

[0406] The compounds and salts of the present disclosure may be isotopically labeled (or "radioactively labeled"). In such cases, one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. This specification encompasses isotopically labeled forms of the compounds disclosed herein. Examples of isotopes that may be incorporated include 2 H (also written as "D", representing deuterium), 3 H (also written as "T", representing tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O and 36 Cl. The isotope used will depend on the specific application of the radiolabeled derivative. For example, for in vitro receptor labeling and competition assays, 3 H or14 C is generally useful. For radiological imaging applications, 11 C is generally useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C.

[0407] H. Intermediates

[0408] In some embodiments, the present disclosure provides additional compounds that can be used as intermediates for preparing the compounds of the present disclosure and their pharmaceutically acceptable salts.

[0409] III. Methods of Use

[0410] The compounds of the present disclosure and their pharmaceutically acceptable salts are inhibitors of cyclin-dependent kinase 2 (CDK2) activity.

[0411] Thus, in some embodiments, the present disclosure provides a method for treating or preventing a CDK2-mediated disorder in a subject by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject having or susceptible to the CDK2-mediated disorder.

[0412] In some embodiments, the present disclosure provides a method for inhibiting CDK2 activity in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject having or susceptible to a CDK2-mediated disorder.

[0413] In some embodiments, the present disclosure provides a method for treating cancer in a subject by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject having or susceptible to cancer. 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.

[0414] In some embodiments, the present disclosure provides a method for treating a subject having or at risk of developing cancer, which is characterized by amplification or overexpression of the cyclin E (CCNE) gene, by administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. 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 both 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.

[0415] In some embodiments, the present disclosure provides a method for treating or preventing cancer in a subject having or at risk of developing a solid tumor 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.

[0416] 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 having breast cancer has been previously treated with a CDK4 / 6 inhibitor.

[0417] 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 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 been previously treated with platinum-based chemotherapy.

[0418] In some embodiments, the cancer disorder 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.

[0419] In some embodiments, the present disclosure provides a method for treating or preventing cancer in a subject having or susceptible to a hematological cancer by administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to the subject, wherein the hematological cancer is selected from the group consisting of: non-Hodgkin lymphoma, leukemia, multiple myeloma (MM), and myelodysplastic syndrome (MDS). In one aspect, the hematological cancer is non-Hodgkin lymphoma (NHL). In another aspect, the non-Hodgkin 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 myeloid 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).

[0420] In some embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered as a first-line therapy.

[0421] In some embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered as a second-line (or later) therapy.

[0422] In some embodiments, a subject administered a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof exhibits a partial response (PR) to such treatment.

[0423] In some embodiments, a subject administered a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof shows a complete response (CR) to such treatment.

[0424] In some embodiments, a subject administered a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof shows an improved progression-free survival (PFS) to such treatment.

[0425] In some embodiments, a subject administered a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof shows an improved overall response (OR) to such treatment.

[0426] PR, CR, PFS, and OR can be evaluated, for example, according to the RECIST (Response Evaluation Criteria in Solid Tumors) guidelines (version 1.1).

[0427] The subjects to be treated are generally human or non-human mammals, especially humans. Suitable subjects can also include domestic or wild animals; companion animals (including dogs, cats, etc.); livestock (including horses, cattle and other ruminants, pigs, poultry, rabbits, etc.); primates (including monkeys such as rhesus monkeys, cynomolgus monkeys (also known as crab-eating monkeys or long-tailed monkeys), marmosets, tamarins, chimpanzees, macaques, etc.); and rodents (including rats, mice, gerbils, guinea pigs, etc.).

[0428] 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 cancer mediated in whole or in part by CDK2.

[0429] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating cancer mediated in whole or in part by CDK2.

[0430] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer mediated in whole or in part by CDK2.

[0431] IV. Combination Therapies and Fixed Dose Combinations

[0432] The compounds and pharmaceutically acceptable salts of the present disclosure can be used as a single pharmacological agent or in combination with other pharmacological agents or techniques in the methods described above. Such combination therapies can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately. These combination therapies (and corresponding combination products) use the compounds and pharmaceutically acceptable salts of the present disclosure within the dosage ranges described in this application and other pharmacological agents generally within their approved dosage ranges.

[0433] In some embodiments, the present disclosure provides a combination suitable for treating cancers mediated, in whole or in part, by CDK2, wherein the combination comprises 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, lero ciclib (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 aspect, the CDK4 / 6 inhibitor is ribociclib. In another aspect, the CDK4 / 6 inhibitor is dalpiciclib.

[0434] In some embodiments, the present disclosure provides a combination suitable for treating cancers mediated, in whole or in part, by CDK2, wherein the combination comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and an endocrine therapy. In one aspect, the cancer is breast cancer.

[0435] In some embodiments, the present disclosure provides a combination suitable for treating cancers mediated, in whole or in part, by CDK2, wherein the combination comprises 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.

[0436] In some embodiments, the present disclosure provides a combination suitable for treating cancer mediated, in whole or in part, by CDK2, wherein the combination comprises 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, giredestrant (GDC-9545), amcenestrant (SAR439859), camizestrant (AZD9833), rintodestrant (G1T48), imlunestrant (LY3484356), elacestrant (RAD-1901), taragarestrant (D-0502), OP1250 (Olema), LSZ102 (Novartis), ZN-c5 (Zentalis), and SHR9549 (Jiangsu Hengrui Medicine). In another aspect, the SERD is selected from the group consisting of: fulvestrant, giredestrant, camizestrant, imlunestrant, and elacestrant. In another aspect, the SERD is fulvestrant. In another aspect, the SERD is fulvestrant and the administered combination further comprises alpelisib. In another aspect, the SERD is camizestrant (AZD9833). In another aspect, the SERD is camizestrant and the administered combination further comprises alpelisib. In another aspect, the cancer is breast cancer.

[0437] In some embodiments, the present disclosure provides a combination suitable for treating cancers mediated in whole or in part by CDK2, wherein the combination comprises 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, gedatolisib (GDC-9545), amcenestrant (SAR439859), camizestrant (AZD9833), retatrutide (G1T48), elacestrant (LY3484356), elagolix (RAD-1901), talazoparib (D-0502), OP1250 (Olema), LSZ102 (Novartis), ZN-c5 (Zentalis), and SHR9549 (Jiangsu Hengrui Medicine); and the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, lerociclib (G1T38), trilaciclib (G1T28), dalpiciclib (SHR-6390), and BPI-16350. In another aspect, the SERD is selected from the group consisting of fulvestrant, gedatolisib, camizestrant, elacestrant, and elagolix; and the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, and dalpiciclib. In another aspect, 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 aspect, the SERD is camizestrant; and the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, and ribociclib. In another aspect, the cancer is breast cancer.

[0438] In some embodiments, the present disclosure provides a combination suitable for treating cancers mediated in whole or in part by CDK2, wherein the combination comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a PROTAC estrogen receptor degrader (PROTAC ER degrader). In one aspect, the PROTAC ER degrader is vepdegestrant. In another aspect, the cancer is breast cancer.

[0439] In some embodiments, the present disclosure provides a combination suitable for treating cancer mediated, in whole or in part, by CDK2, wherein the combination comprises 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, clomifene, cyclofenil, 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, enclomifene, endoxifen, and zuclomifene. In another aspect, the SERM is selected from the group consisting of arzoxifene, brilanestrant, clomifenoxide, droloxifene, etacstil, fispemifene, idoxifene, levormeloxifene, miproxifene, nafoxidine, nitromifene, panomifene, pipendoxifene, trioxifene, zindoxifene, GW-7604 (Glaxo Wellcome), and NNC 45-0095 (NovoNordisk). In another aspect, the cancer is breast cancer.

[0440] In some embodiments, the present disclosure provides a combination suitable for treating cancer mediated, in whole or in part, by CDK2, wherein the combination comprises 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.

[0441] In some embodiments, the present disclosure provides a combination suitable for treating cancer mediated, in whole or in part, by CDK2, wherein the combination comprises 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 No. 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.

[0442] In some embodiments, the present disclosure provides a combination suitable for treating cancer mediated, in whole or in part, by CDK2, wherein the combination comprises 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.

[0443] In some embodiments, the present disclosure provides a combination suitable for treating cancer mediated, in whole or in part, by CDK2, wherein the combination comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and radiotherapy.

[0444] In some embodiments, the present disclosure provides a combination suitable for treating cancer mediated, in whole or in part, by CDK2, wherein the combination comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and chemotherapy.

[0445] In some embodiments, the present disclosure provides a combination suitable for treating breast cancer, wherein the combination comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and chemotherapy. In one aspect, the chemotherapy comprises administering a combination of cyclophosphamide and doxorubicin (“AC”). In another aspect, the chemotherapy comprises administering a combination of cyclophosphamide, doxorubicin, and a taxane (such as paclitaxel or docetaxel) (“CAT”). In another aspect, the chemotherapy comprises administering a combination of cyclophosphamide, methotrexate, and fluorouracil (or “CMF”).

[0446] In some embodiments, the present disclosure provides a combination suitable for treating ovarian cancer, wherein the combination comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof and chemotherapy. In one aspect, the chemotherapy comprises administering 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 administering a combination of carboplatin and doxorubicin, gemcitabine, paclitaxel, or docetaxel. In another aspect, the chemotherapy comprises administering a combination of carboplatin and paclitaxel or docetaxel. In another aspect, the chemotherapy comprises administering topotecan. In another aspect, the chemotherapy comprises administering a combination of bleomycin, etoposide, and cisplatin (BEP). In another aspect, the chemotherapy comprises administering a combination of vincristine, dactinomycin, and cyclophosphamide (VAC). In another aspect, the chemotherapy comprises administering a combination of paclitaxel, gemcitabine, and oxaliplatin.

[0447] V. Pharmaceutical Compositions

[0448] The compounds of the present disclosure and their pharmaceutically acceptable salts can be administered as a pharmaceutical composition, which comprises one or more pharmaceutically acceptable excipients. Thus, in some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0449] The excipients selected to be included in a particular composition will depend on factors such as the mode of administration and the form of the composition being 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; Quinn, Marian. Pharmaceutically acceptable excipients can function, for example, as adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickening agents, and coating agents. As will be understood by those skilled in the art, certain pharmaceutically acceptable excipients can perform more than one function and can perform alternative functions, depending on how much excipient is present in the composition and what other excipients are present in the composition.

[0450] The composition may be in a form suitable for oral use (such as tablets, lozenges, hard or soft gelatin capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (such as creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (such as fine powders or liquid aerosols), in a form suitable for administration by insufflation (such as fine powders) or in a form suitable for parenteral administration (such as sterile aqueous or oily solutions for intravenous, subcutaneous or intramuscular injection) or in the form of suppositories suitable for rectal administration. The composition can be obtained by conventional processes using conventional pharmaceutical excipients well known in the art. Thus, a composition intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents and / or preservatives.

[0451] The total daily dose will have to vary according to the subject being treated, the particular route of administration, any therapy co-administered and the severity of the disease being treated, and may include a single dose or multiple doses. The specific dose can be adjusted, for example, according to the following factors: the condition being treated; the age, weight, general health, sex and diet of the subject; the route of administration; the dosing interval; the excretion rate; and other drugs co-administered to the subject. A person of ordinary skill in the art who understands the disclosure of this application will be able to determine the appropriate dose and regimen for administering a therapeutic agent to a subject according to methods well known in the art of therapy and adjust such dose and regimen as needed during the course of treatment. The compounds or pharmaceutically acceptable salts thereof of the present disclosure will generally be administered to warm-blooded animals in unit doses in the range of 2.5 mg / m 2 to 5000 mg / m 2 of body surface area of the animal or approximately 0.05 mg / kg to 100 mg / kg, and this generally provides a therapeutically effective dose.

[0452] In some embodiments, the present disclosure provides a pharmaceutical composition for use in therapy, the pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of the present disclosure and at least one pharmaceutically acceptable excipient.

[0453] In some embodiments, the present disclosure provides a pharmaceutical composition for use in the treatment of CDK2-mediated disorders, the pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of the present disclosure and at least one pharmaceutically acceptable excipient. In a further aspect, the CDK2-mediated disorders are selected from those disorders disclosed in this specification. In one aspect, the CDK2-mediated disorder is breast cancer. In another aspect, the CDK2-mediated disorder is ovarian cancer. In another aspect, the CDK2-mediated disorder is endometrial cancer. In another aspect, the CDK2-mediated disorder is lung cancer.

[0454] VI. Kits

[0455] The present disclosure also provides a kit, which comprises a unit dosage form and a label or package insert. The unit dosage form contains a compound of the present disclosure or a pharmaceutically acceptable salt thereof contained within a packaging material, and the label or package insert indicates that the unit dosage form can be used to treat one or more of the previously described conditions.

[0456] In some embodiments, the kit comprises a unit dosage form and a label or package insert. The unit dosage form contains a compound of the present disclosure or a pharmaceutically acceptable salt thereof contained within a packaging material, and the label or package insert indicates that the pharmaceutical composition can be used to treat CDK2-mediated conditions. In a further aspect, the CDK2-mediated conditions are selected from those disclosed in this specification. 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.

[0457] In some embodiments, the kit comprises: (a) a first unit dosage form that contains a compound of the present disclosure or a pharmaceutically acceptable salt thereof; (b) a second unit dosage form that contains an 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) a container device for containing the first dosage form and the second dosage form; and (d) a label or package insert that indicates that the first unit dosage form and the second unit dosage form can be used to treat CDK2-mediated conditions. In one aspect, the second unit dosage form contains a CDK4 / 6 inhibitor.

[0458] VII. Methods of Preparation

[0459] The present disclosure also provides methods for preparing the compounds of the present disclosure and their pharmaceutically acceptable salts. Reaction Schemes 1 to 8 illustrate the synthetic routes of these compounds, wherein unless otherwise specified, 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 R13 As defined in formula (I). Those skilled in the art will understand that these methods are representative and do not include all possible methods for preparing the compounds of the present disclosure.

[0460] Scheme 1

[0461]

[0462] Scheme 1 shows the synthetic routes of certain compounds of formula (I). The compound of formula A can be reacted with the compound of formula B (X is a leaving group such as I, Br, etc.) to obtain the compound of formula C. This reaction can be carried out in the presence of a base (usually an inorganic base such as K2CO3, NaH, etc.), using a solvent (such as DMSO), and at a temperature generally ranging from 0 °C to 60 °C.

[0463] The compound of formula C can be reacted with the amine of formula D to obtain the compound of formula E. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as ethanol), and at a temperature generally ranging from 0 °C to 80 °C.

[0464] The compound of formula E can be reacted with the amine of formula F to obtain the compound of formula G. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as n-butanol, DMF, DMSO, NMP, 3-ethyl-3-pentanol or a mixture thereof), and at a temperature generally ranging from 80 °C to 160 °C.

[0465] The compound of formula G can be converted to the compound of formula H by deprotecting Boc in a solvent (such as DCM) and at 23 °C using a suitable reagent (such as a 1,4-dioxane solution of 4M HCl).

[0466] The compound of formula H can be reacted with the compound of formula I to obtain the compound of formula (I). This reaction can be carried out in the presence of a base (usually an organic base such as TEA, DIPEA, etc.), using a solvent (such as DCM), and at a temperature generally ranging from -78 °C to 23 °C.

[0467] Scheme 2

[0468]

[0469] Scheme 2 shows the synthetic route of certain compounds of formula G. The compound of formula J can be reacted with the compound of formula B (where X is a leaving group such as I, Br, etc.) to obtain the compound of formula K. This reaction can be carried out in the presence of a base (usually an inorganic base such as K2CO3, NaH, etc.), using a solvent (such as DMSO), and at a temperature generally ranging from 0 °C to 60 °C.

[0470] The compound of formula K can be reacted with the amine of formula D to obtain the compound of formula L. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as ethanol), and at a temperature generally ranging from 0 °C to 80 °C.

[0471] The compound of formula L can be reacted with the amine of formula F to obtain the compound of formula G. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as n-butanol, DMF, DMSO, NMP, 3-ethyl-3-pentanol or a mixture thereof), and at a temperature generally ranging from 80 °C to 160 °C.

[0472] Scheme 3

[0473]

[0474] Scheme 3 shows the synthetic route of certain compounds of formula (I). The compound of formula K can be reacted with the amine of formula M to obtain the compound of formula N. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as ethanol), and at a temperature generally ranging from 0 °C to 80 °C.

[0475] The compound of formula N can be reacted with the amine of formula F to obtain the compound of formula (I). This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as n-butanol, DMF, DMSO, NMP, 3-ethyl-3-pentanol or a mixture thereof), and at a temperature generally ranging from 80 °C to 160 °C.

[0476] Scheme 4

[0477]

[0478] Scheme 4 shows the synthetic route of certain compounds of formula (I). The compound of formula C can be reacted with the amine of formula M to obtain the compound of formula O. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as ethanol), and at a temperature generally ranging from 0 °C to 80 °C.

[0479] The compound of formula O can be reacted with an amine of formula F to obtain a compound of formula (I). This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as n-butanol, DMF, DMSO, NMP, 3-ethyl-3-pentanol or a mixture thereof), and at a temperature generally ranging from 80 °C to 160 °C.

[0480] Scheme 5

[0481]

[0482] Scheme 5 shows the synthetic route of certain compounds of formula T. The compound of formula L can be converted to a compound of formula P by deprotecting Boc in a solvent (such as DCM) and at 23 °C using a suitable reagent (such as a 1,4-dioxane solution of 4M HCl).

[0483] 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 obtain a compound of formula Q. This reaction can be carried out using a solvent (such as acetonitrile, THF, etc.) and at 23 °C.

[0484] The compound of formula Q can be reacted with an amine of formula R to obtain a compound of formula S. This reaction can be carried out in the presence of methyl trifluoromethanesulfonate, using a solvent (such as DCM, acetonitrile, etc.), and at a temperature generally ranging from -20 °C to 70 °C.

[0485] The compound of formula S can be reacted with an amine of formula F to obtain a compound of formula T. This reaction can be catalyzed in the presence of a base (such as Cs2CO3), using a suitable solvent (such as t-BuOH), and at a temperature generally ranging from 80 °C to 100 °C with a suitable Pd-precatalyst (such as Pd(OAc)2) and a phosphine ligand (e.g., BrettPhos).

[0486] Scheme 6

[0487]

[0488] Scheme 6 shows the synthetic route of certain compounds of formula (I). The compound of formula P can be reacted with a compound of formula I to obtain a compound of formula U. This reaction can be carried out in the presence of a base (usually an organic base such as TEA, DIPEA, etc.), using a solvent (such as DCM), and at a temperature generally ranging from -78 °C to 23 °C.

[0489] The compound of formula U can be reacted with an amine of formula F to obtain a compound of formula (I). This reaction can be carried out in the presence of a base (such as NatBuO), using a suitable solvent (such as 1,4-dioxane), and catalyzed with a suitable Pd-catalyst (such as Pd-PEPPSI-IPentCl o-methylpyridine (2-methylpyridine)) at a temperature generally ranging from 80 °C to 120 °C.

[0490] Scheme 7

[0491]

[0492] Scheme 7 shows the synthetic route of certain compounds of formula (I). The compound of formula A can be reacted with an amine of formula D to obtain a compound of formula V. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as tert-amyl alcohol) and at 100 °C.

[0493] The compound of formula V can be reacted with a compound of formula B to obtain a compound of formula E. This reaction can be carried out in the presence of a base (usually an inorganic base such as K2CO3), using a solvent (such as DMSO), and at a temperature generally ranging from 0 °C to 60 °C.

[0494] The compound of formula E can be converted to a compound of formula W by deprotecting Boc in a solvent (such as DCM) and at 23 °C using a suitable reagent (such as a 1,4-dioxane solution of 4M HCl).

[0495] The compound of formula W can be converted to a compound of formula Y in the presence of a base (such as TEA), in a solvent (such as DCM) and at 23 °C using a suitable reagent (Ac2O).

[0496] The compound of formula Y can be reacted with an amine of formula F to obtain a compound of formula Z. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as 3-ethyl-3-pentanol) and at 160 °C.

[0497] The compound of formula Z can be converted to a compound of formula A1 using a suitable reagent (such as LiOH), in a solvent (such as an ethanol:water mixture) and at 80 °C.

[0498] The compound of formula A1 can be reacted with a compound of formula I to obtain a compound of formula (I). This reaction can be carried out in the presence of a base (usually an organic base such as TEA, DIPEA, etc.), using a solvent (such as DCM), and at a temperature generally ranging from -78 °C to 23 °C.

[0499] Scheme 8

[0500]

[0501] Scheme 8 shows the synthetic route of certain compounds of formula L. The compound of formula J can be reacted with the amine of formula D to obtain the compound of formula B1. This reaction can be carried out in the presence of a base (usually an organic base such as DIPEA), using a solvent (such as IPA), and at 100 °C.

[0502] The compound of formula B1 can be reacted with the compound of formula B to obtain the compound of formula L. This reaction can be carried out in the presence of a base (usually an inorganic base such as K2CO3), using a solvent (such as DMSO), and at a temperature generally ranging from 0 °C to 80 °C.

[0503] It should be understood that the organic reactions described herein are carried out according to laboratory practices known to those skilled in the art. It should be understood that some of the reactions described herein can optionally be carried out in a different order than that listed herein. It should be understood that the chiral isomers of the compounds herein can be resolved using chiral resolving agents described in the literature and known to those skilled in the art or chiral chromatography methods described in the literature and known to those skilled in the art or as further described in the examples.

[0504] It should also be understood that additional protecting groups may optionally be required in some of the steps described above, and it should also be understood that, accordingly, the deprotection steps can optionally be carried out using methods described in the literature and known to those skilled in the art. The protection and deprotection of functional groups are described in “Protective Groups in Organic Synthesis” 3rd Edition, T.W. Greene and P.G.M. Wutz, Wiley-Interscience (1999), the disclosure of which is incorporated herein by reference.

[0505] VIII Examples

[0506] The following descriptions of experiments, procedures, examples, and intermediates are intended to illustrate the embodiments of the present disclosure. They are in no way intended to be limiting. Other compounds of the present disclosure can be prepared using the methods shown in these examples alone or in combination with techniques generally known in the art.

[0507] A. General Conditions

[0508] Unless otherwise specified:

[0509] Unless otherwise specified, obtained using a Bruker 300 MHz, 400 MHz or 500 MHz spectrometer at 27 °C 11H NMR spectra. Chemical shifts are reported in parts per million (ppm) and referenced to the residual singlet of the solvent 1 1H isotopomer (CHCl3: 7.24 ppm; CHDCl2: 5.32 ppm; CD3S(=O)CD2H: 2.49 ppm). Coupling constants are given in Hertz (Hz). Splitting patterns describe the apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br s (broad singlet).

[0510] LC-MS was performed using Waters UPLC equipped with a Waters SQD mass spectrometer or Shimadzu LC-20AD LC-20XR LC-30AD equipped with a Shimadzu 2020 mass spectrometer. Unless otherwise stated, the reported molecular ion corresponds to [M+H] + . For molecules with multiple isotope patterns (Br, Cl, etc.), unless otherwise stated, the reported value is the one obtained for the lowest isotopic mass.

[0511] On a Biotage TM SP1 TM Purification system, an ISCO Rf or on a Gilson system from Thermo Fisher using normal-phase flash chromatography with normal-phase silica FLASH+ TM (40M, 25M or 12M) or SNAP TM KP-Sil columns (340, 100, 50 or 10), Agela's Flash Column Silica-CS column and C18-Flash column or standard flash chromatography for flash chromatography. Generally, all solvents used are commercially available and of analytical grade. Reactions are generally carried out using anhydrous solvents. The phase separator used in the examples is a 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 according to literature procedures.

[0512] Generally, the examples and intermediate compounds are named using ChemDraw Professional version 21.0.0.28 from PerkinElmer. ChemDraw Professional version 21.0.0.28 uses the Cahn-Ingold-Prelog (CIP) rules for stereochemistry to generate the names of chemical structures and adheres as strictly as possible to the IUPAC rules when generating chemical names. Stereoisomers are distinguished from each other by stereodescriptors cited in the name and are assigned according to the CIP rules:

[0513] (a) ChemDraw has optionally used markers such as “&” and

[0514] “or” in the illustration of a stereocenter to describe the configuration of the stereochemical centers present in the structure. Generally, for the chemical structures of examples and intermediates containing the marker “&” at a stereocenter, it means that the configuration of such an example or intermediate at that stereocenter is a mixture of both (R) and (S); and the marker “or” means that the configuration of such an example or intermediate at that stereocenter is (S) or (R). Absolute, unspecified, “&” and “or” stereocenters can all be present in a single structure.

[0515] (b) Generally, for the structures of examples and intermediates in which all stereocenters are designated as “&”, the structure is named with the prefix “racemic-”. For the structures of examples and intermediates in which all stereocenters are designated as “or”, the structure is named with the

[0516] prefix “rel-”.

[0517] (c) Generally, the examples and intermediate compounds are named using the descriptors (RS) and (SR) to represent the general “&” centers of chemical structures with multiple chiral centers, where

[0518] only some are designated as “&”. The descriptors (R*) and (S*) are used to represent the general “or” centers of chemical structures with multiple chiral centers, where only some are designated as

[0519] “or”.

[0520] (d) Generally, on a given chiral HPLC column and eluent, the marker “isomer 1”

[0521] corresponds to the first eluting isomer, and “isomer 2” corresponds to the second eluting isomer, and is used to distinguish between two isomers containing one or more stereocenters and having an absolutely unknown configuration at one or more stereocenters.

[0522] In addition to those mentioned above, the following abbreviations are also used:

[0523] ACN = acetonitrile;

[0524] Ac2O = acetic anhydride;

[0525] AcOH = acetic acid;

[0526] aq. = aqueous solution;

[0527] BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;

[0528] Boc = tert-butoxycarbonyl;

[0529] Boc2O = di-tert-butyl dicarbonate;

[0530] A Pd G3 = palladium(II) mesylate of [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)];

[0531] CDCl3 = deuterated chloroform;

[0532] CD3OD = deuterated methanol;

[0533] CH3NO2 = nitromethane;

[0534] CO2 = carbon dioxide;

[0535] Cs2CO3 = cesium carbonate;

[0536] DCE = 1,2-dichloroethane;

[0537] DCM = dichloromethane;

[0538] DEA = diethylamine;

[0539] DEAD = diethyl azodicarboxylate;

[0540] Dess-Martin periodinane = 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one;

[0541] DIEA = N,N-diisopropylethylamine;

[0542] DMAP = 2,6-dimethylaminopyridine;

[0543] DMF = N,N-dimethylformamide;

[0544] DMSO = dimethyl sulfoxide;

[0545] DMSO-d6 = deuterated dimethyl sulfoxide;

[0546] DIAD = Diisopropyl (E)-diazene-1,2-dicarboxylate;

[0547] DIBAL-H = Diisobutylaluminum hydride;

[0548] DSC = Differential scanning calorimetry;

[0549] DTAD = Di-tert-butyl (E)-diazene-1,2-dicarboxylate;

[0550] EDC = N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide;

[0551] ee = Enantiomeric excess;

[0552] eq = Equivalent;

[0553] ESI = Electrospray ionization;

[0554] Et2O = Diethyl ether;

[0555] EtOAc = Ethyl acetate;

[0556] E2O = Diethyl ether;

[0557] EtOH = Ethanol;

[0558] FA = Formic acid;

[0559] h = Hour;

[0560] HATU = (Dimethylamino)-N,N-dimethyl(3-oxo-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)methaniminium hexafluorophosphate;

[0561] HBr = Hydrobromic acid;

[0562] HCl = Hydrochloric acid;

[0563] H2O = Water;

[0564] H2O2 = Hydrogen peroxide;

[0565] HOBt = 1-Hydroxybenzotriazole;

[0566] HP = High pressure;

[0567] IPA or iPrOH = Isopropyl alcohol;

[0568] IPAmine = Isopropylamine;

[0569] KHSO4 = Potassium bisulfate;

[0570] LAH = Lithium aluminum hydride;

[0571] LC = Liquid Chromatography;

[0572] LC-MS / MS = Liquid Chromatography with Tandem Mass Spectrometry

[0573] LiClO4 = Lithium Perchlorate;

[0574] LiOH = Lithium Hydroxide;

[0575] mCPBA = meta-Chloroperoxybenzoic Acid;

[0576] MeCN or CH3CN = Acetonitrile;

[0577] MeMgBr = Methylmagnesium Bromide;

[0578] MeNO2 = Nitromethane;

[0579] MeOH = Methanol;

[0580] MgSO4 = Magnesium Sulfate;

[0581] min = Minute;

[0582] mmol = Millimole;

[0583] MP Carbonate = Polymer-Bound Tetraalkylammonium Carbonate, 2.5 mmol / g - 3.5 mmol / g Loading;

[0584] MS = Mass Spectrometry;

[0585] MTBE = Methyl Tert-Butyl Ether;

[0586] Na2CO3 = Sodium Carbonate;

[0587] NaCl = Sodium Chloride;

[0588] NaH = Sodium Hydride;

[0589] NaHCO3 = Sodium Bicarbonate;

[0590] Na2SO4 = Sodium Sulfate;

[0591] NH3 = Ammonia;

[0592] NH4Cl = Ammonium Chloride;

[0593] NH4HCO3 = Ammonium Bicarbonate;

[0594] NMP = N-Methyl-2-Pyrrolidone;

[0595] NMR = Nuclear Magnetic Resonance;

[0596] Pd / C = Palladium on Carbon;

[0597] PdCl2(dppf) = Dichloropalladium(II) complex with 1,1'-bis(di-tert-butylphosphino)ferrocene;

[0598] Pd2dba3 = Tris(dibenzylideneacetone)dipalladium(0);

[0599] Pd(OH)2 = Palladium(II) hydroxide;

[0600] Pd-PEPPSI-IPentCl o-Tolylpyridine (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;

[0601] PE = Petroleum ether;

[0602] PPh3 = Triphenylphosphine;

[0603] rt = Room temperature;

[0604] Rt or RT = Retention time;

[0605] Ruphos Pd G3 = Palladium(II) [2-(dicyclohexylphosphino)-2',6'-diisopropoxy-1,1'-biphenyl][2-(2'-amino-1,1'-biphenyl)]methanesulfonate;

[0606] sat = Saturated;

[0607] SFC = Supercritical fluid chromatography;

[0608] SOCl2 = Thionyl chloride;

[0609] TBAF = Tetrabutylammonium fluoride;

[0610] tBuBrettPhos = 2-(Di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl;

[0611] tBuBrettPhos Pd G3 = Palladium(II) [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate;

[0612] tBuOH = tert-Butanol;

[0613] TEA = Triethylamine;

[0614] TFA = Trifluoroacetic acid;

[0615] THF = Tetrahydrofuran;

[0616] TLC = Thin Layer Chromatography;

[0617] TMS = Trimethylsilyl;

[0618] T3P = 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide; and

[0619] UPLC = Ultra Performance Liquid Chromatography

[0620] ​

[0621] ​ ​

[0622]

[0623] ​

[0624] 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 mixture was stirred at room temperature over the weekend. The reaction mixture 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 silica gel chromatography, eluting with a hexane solution with an elution gradient of 0% to 100% EtOAc. 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 1H NMR (500 MHz, DMSO-d6) 1.43 (3H, t), 4.27 (2H, q), 8.75 (1H, s); m / z (ES + ) [M+H] + = 217.

[0625] ​

[0626] Under nitrogen, 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), cooled to 0 °C, and then N,N-diisopropylethylamine (13.74 ml, 78.64 mmol) was added dropwise. The reaction mixture was warmed 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 (Intermediate 3, 8.00 g, 83%) as a white solid. 1 H NMR (500 MHz, DMSO-d6) 1.32 - 1.47 (12H, m), 1.86 - 2.09 (1H, m), 2.08 - 2.25 (1H, 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 - ) [M - H] - = 365.

[0627] ​

[0628] 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 ppt was washed with DCM and dried in vacuo to give the white solid product (S)-2-chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 4, 0.850 g, 100%); m / z (ES + ) [M + H] + = 267.

[0629] ​

[0630] Weigh (S)-2-chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine·HCl (Intermediate 4, 0.850 g, 2.80 mmol) in a 40 mL scintillation vial, add dichloromethane (30 mL) and triethylamine (1.943 mL, 14.02 mmol). Cool the reactants to -40 °C. Add a solution of methylsulfamoyl chloride (0.454 g, 3.36 mmol) in dichloromethane (5 mL) to the reaction mixture, stir for 1 hour, and then warm to room temperature. Quench the reactants by adding an aqueous solution of NaHCO3. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo. Purify the resulting white solid by flash silica gel chromatography using a DCM solution of 0%-10% MeOH to obtain (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. 1 H 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.

[0631] ​ ​

[0632]

[0633] Weigh (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 A Pd G3 (10.12 mg, 0.01 mmol) was evacuated, filled with N2 and sealed. 1,4-Dioxane (2 mL) and water (0.500 mL) were added. The reaction vial was placed on a heating block preheated to 100 °C and stirred for 16 h. The reaction mixture was cooled, quenched with brine and extracted with DCM (a solid precipitated), and a DCM:MeOH mixture was added (a clear two-phase mixture was obtained). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo over silica gel. The resulting solid was purified by flash silica chromatography using a DCM solution of 0%-10% MeOH to give a light brown solid. The brown solid was further purified by flash C18 chromatography using an aqueous (0.1% NH4OH) solution of 0%-100% ACN 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 (500 MHz, 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.

[0634] ​ ​

[0635]

[0636] ​ ​

[0637] (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 Pd G3 (10.12 mg, 0.01 mmol) was evacuated, filled 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 extracted with DCM (solid precipitated) and a DCM:MeOH mixture was added. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo over silica gel. The resulting solid was purified by flash silica chromatography using a 0%-10% MeOH in DCM solution to give an off-white solid. The above solid was further purified by flash C18 chromatography using a 0%-100% ACN in water (0.1% NH4OH) solution to give (S)-3-((9-ethyl-2-(1-oxo-2,3-dihydro-1H-inden-4-yl)-9H-purin-6-yl)amino)-N-methylpyrrolidin-1-sulfonamide as a white solid (Intermediate 6, 0.050 g, 79%). 1 H NMR (500 MHz, DMSO-d6) 1.49 (3H, t), 2.15 - 2.37 (2H, m), 2.53 - 2.59 (3H, m), 2.61 - 2.72 (2H, 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.

[0638] ​ ​

[0639]

[0640] (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. At room temperature, sodium borohydride (7.31 mg, 0.19 mmol) was added to the reaction mixture 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 in vacuo. The crude product containing the diastereomeric mixture was purified by chiral SFC (Whelk-O 4.6 mm×100 mm 5 μm column) using MeOH containing 0.2% NH4OH 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%) 1 H NMR (500 MHz, 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 s), 5.09 (1H, br s), 5.21 (1H, br d), 7.02 (1H, br s), 7.32 (1H, t), 7.42 (1H, d), 7.93 (1H, br s), 8.15 (1H, br d), 8.22 (1H, s). 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%).

[0641] ​ 9H- ​ -6-yl) ​ )-N- ​ -1- ​

[0642]

[0643] Weigh (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) in a 20 mL scintillation vial, evacuate, fill with N2, seal, and add tetrahydrofuran (2 mL). Cool the reaction vial to 0 °C, and add methylmagnesium bromide (0.146 ml, 0.44 mmol, 1 M solution in Et2O) dropwise and stir for 1.5 hours. Add another 2 equivalents of MeMgBr and stir for 1.5 hours. Quench the reaction mixture with brine and extract with DCM. Separate the organic layer, dry over Na2SO4, and concentrate. Purify the crude product containing the diastereomeric mixture by chiral SFC (Whelk-O 4.6 mm × 100 mm 5 μm column) using MeOH containing 0.2% NH4OH to obtain (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 (500 MHz, 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%).

[0644] ​ ​

[0645]

[0646] ​

[0647] At 23 °C, 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). The resulting suspension was stirred at 23 °C for 20 h. The reaction mixture 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 flash silica gel chromatography eluting with a hexane solution with an elution gradient of 0% to 100% EtOAc. The product fractions were concentrated to give 6-chloro-9-ethyl-2-fluoro-9H-purine (Intermediate 8, 7.00 g, 60.2%). 1 1H 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.

[0648] ​

[0649] Under nitrogen, 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), cooled to 0 °C, and then N,N-diisopropylethylamine (4.01 mL, 22.93 mmol) was added dropwise. The reaction mixture was warmed to 80 °C and stirred for 1 h. The solvent was removed under reduced pressure and the white residue was purified by flash silica gel chromatography eluting with a hexane solution with an elution gradient of 50% to 100% EtOAc and then a DCM solution of 15% MeOH. The product fractions were concentrated under reduced pressure to give (S)-tert-butyl 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 1H NMR (300 MHz, 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.

[0650] ​ tert-Butyl (aminopyrrolidine-1-carboxylate)

[0651] (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 mixture was heated at 100 °C. The reaction mixture was stirred at 100 °C for 65 h and then continued to be stirred at 120 °C for 16 h. The reaction mixture was concentrated and purified by flash C18 chromatography, eluting with a gradient of 0% to 100% acetonitrile in water (containing 0.1% formic acid additive) to give (S)-tert-butyl 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.

[0652] Intermediate 11: (2R,3S)-3-((9-Ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol hydrochloride 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

[0653] (S)-tert-Butyl 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) were added to a scintillation vial. The vial was sealed and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo 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.

[0654] 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 Example 6: (S)-N-Ethyl-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0655]

[0656] Weigh (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) in a scintillation vial, add dichloromethane (5 mL) and triethylamine (195 μl, 1.40 mmol), and cool the reactants to 0 °C. Add (2,2,2-trifluoroethyl)sulfamoyl chloride (55.2 mg, 0.28 mmol) to the reaction mixture and stir for 30 minutes. Concentrate the reaction mixture and purify by flash C18 chromatography using a water (0.1% NH4OH) solution of 0%-100% ACN, followed by SFC purification to obtain (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 (500 MHz, 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), 3.37 - 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 (471 MHz, DMSO-d6) -71.28 (3F, s). m / z (ES + ) [M + H] + = 495.

[0657] Example 7: (S)-N-Ethyl-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide Example 8: (S)-N-Ethyl-3-((9-ethyl-2-(((2S,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide 9 Example 9: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0658]

[0659] (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 in a 20 mL scintillation vial, dichloromethane (5 mL) and triethylamine (165 μl, 1.19 mmol) were added, and the reaction mixture 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 flash C18 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 (500 MHz, 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 (471 MHz, DMSO-d6) -122.03 (2F, s). m / z (ES + ) [M + H] + = 477.

[0660] Intermediate 12: (((S)-3-((9-Ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamic acid tert-butyl ester Example 9: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0661]

[0662] (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 in a 40 mL scintillation vial, dichloromethane (20 mL) and triethylamine (0.903 mL, 6.52 mmol) were added, and the reaction mixture was cooled to -78 °C. Ethylsulfamoyl chloride (0.177 g, 1.17 mmol) was added to the reaction mixture and stirred for 2 h. Additional ethylsulfamoyl chloride (0.030 g, 0.20 mmol) was added and stirred for 1 h. The reaction was quenched with aqueous NaHCO3, warmed to 25 °C, stirred for 15 min, extracted with DCM, the organic layer was separated, dried over MgSO4 and concentrated to give a white foam. The solid was purified by flash silica chromatography using a DCM solution of 0%-20% MeOH 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%). 1 H NMR (400 MHz, 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.

[0663] Example 10: (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide Intermediate 13: (((S)-3-((9-Ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamic acid tert-butyl ester

[0664]

[0665] 3-Oxo-1l5-benzo[d][1,2]iodoxol-1,1,1(3H)-triyltriacetate (42.4 mg, 0.10 mmol) was added to a solution of (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 h. The reaction mixture was concentrated and purified by flash C18 chromatography using an H2O solution of 0%-100% ACN 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%). 1 H NMR (500 MHz, 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.

[0666] Example 10: (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide Example 11: (S)-N-Ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0667]

[0668] (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 borohydride (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 coated onto silica and purified by flash silica chromatography, eluting with a gradient of 0% to 10% MeOH in DCM. The product fractions were concentrated under reduced pressure to give the crude product as a white solid (0.152 g, 78%). The solid was purified by chiral SFC (IH 4.6×150 mm, 5 μm column), using a MeOH solution of 0.2% NH4OH to give (S)-N-ethyl-3-((9-ethyl-2-(((2S,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide as the minor positional isomer (Example 8, 0.016 g, 8.46%). 1 H NMR (500 MHz, 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 - 3.41 (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.

[0669] Intermediate 14: (S)-3-((9-Ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester, ​

[0670]

[0671] ​ ​

[0672] (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 in a 30 mL scintillation vial, dichloromethane (12.77 ml) and triethylamine (0.974 ml, 7.03 mmol) were added, and the reaction mixture was cooled to -40 °C. A solution of tert-butyl (chlorosulfonyl)carbamate (0.303 g, 1.41 mmol) in dichloromethane (12.77 ml) (poor solubility) was added to the reaction mixture and stirred for 1 hour. The reaction was quenched by adding an aqueous NaHCO3 solution. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The resulting white solid was purified by flash silica gel chromatography using a DCM solution of 0%-10% MeOH to give 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%). 1 H NMR (500 MHz, 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 - 4.76 (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.

[0673] ​ ​

[0674]

[0675] In a 20 mL scintillation vial, weigh ((S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)carbamic acid tert-butyl ester (Intermediate 12, 0.121 g, 0.24 mmol), add dichloromethane and hydrochloric acid (0.236 mL, 0.94 mmol) (4 M 1,4-dioxane solution) and stir at room temperature for 1.5 hours (LCMS shows no SM residue). Concentrate the reaction mixture to obtain a white foam, which is the HCl salt of the desired product. Dissolve a portion of the solid in ethyl acetate and add an aqueous solution of NaHCO3. Separate the organic layer, dry and concentrate to obtain (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide as the free base (Example 9, 33 mg, 33.9%). 1 H 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。

[0676] ​ ​

[0677]

[0678] ​ ​

[0679] 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) and 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 pyridine - sulfur trioxide (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 was 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 flash silica gel chromatography, eluting with a hexane solution with an elution gradient of 0% to 100% EtOAc, followed by an EtOAc solution of 2% MeOH. 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%). 1 HNMR(500MHz,DMSO-d6)δppm 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。

[0680] ​ ​

[0681]

[0682] Weigh 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) in a 20 mL scintillation vial, add dichloromethane (5 mL) and hydrochloric acid (0.374 mL, 1.50 mmol) (1,4-dioxane solution of 4 M) and stir at room temperature for 1.5 h. Concentrate the reaction mixture to obtain a white foam. Purify the solid by flash C18 chromatography using a solution of H2O (0.1% NH4OH additive) with 0%-100% ACN, and directly lyophilize the product fraction to obtain (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 (500 MHz, 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.

[0683] ​ ​

[0684]

[0685] ​ ​

[0686] (S)-tert-Butyl 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%) was obtained as a white solid by dissolving (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) in dimethyl sulfoxide (12.31 ml) and heating the reaction mixture at 140 °C. The reaction mixture was stirred at 140 °C for 65 h, cooled, concentrated in vacuo and purified by flash C18 column chromatography using a solution of water (0.1% formic acid) in 0%-100% acetonitrile. 1 HNMR (500 MHz, 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

[0687] - 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.

[0688] Intermediate 15: (2S,3R)-3-((9-Ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol hydrochloride Example 11: (S)-N-Ethyl-3-((9-ethyl-2-(((2S,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0689] (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%) was obtained as a white solid by adding (S)-tert-butyl 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 solution in 1,4-dioxane) to a reaction flask. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. m / z (ES + ) [M + H] + = 334.

[0690] Example 12: (S)-N-Ethyl-3-((9-ethyl-2-(((R)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide Example 13: (S)-N-Ethyl-3-((9-ethyl-2-(((2RS,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide

[0691]

[0692] (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 in a reaction flask, dichloromethane (50 mL) and triethylamine (3.00 mL, 21.63 mmol) were added, and the reaction mixture was cooled to -78 °C. Ethylsulfamoyl chloride (0.686 g, 4.54 mmol) was added to the reaction mixture as a solution in DCM and stirred for 2 hours. The reaction was quenched with aqueous NaHCO3, stirred for 15 minutes, extracted with DCM, the organic layer was separated, dried over MgSO4 and concentrated to give a white foam. The solid was purified by flash silica gel chromatography using a DCM solution of 0%-20% MeOH 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 (500 MHz, 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.

[0693] Example 14: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin amino

[0694]

[0695] (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 mixture was treated with pyridine-sulfur trioxide (1.262 g, 7.93 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 layers were 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 flash C18 chromatography using a solution of H2O (0.1% formic acid) in 0%-100% acetonitrile. 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 HNMR(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。

[0696] ethylpyrrolidine sulfonamide

[0697]

[0698] (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 borohydride (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 purified by SFC (IH 21×250 mm, 5 μm column), using a MeOH solution of 0.2% NH4OH for separation, to give (S)-N-ethyl-3-((9-ethyl-2-(((2R,3R)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide as the minor isomer (Example 13, 28 mg, 0.064 mmol, 13.94%). 1 H NMR (500 MHz, 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.

[0699] Intermediate 16: 2,6-Dichloro-9-(difluoromethyl)-9H-purine Intermediate 17: (S)-3-((2-Chloro-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester -6-yl) Intermediate 18: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester )-N- Intermediate 19: (R)-2-Cyclopropyl-2-((9-(difluoromethyl)-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol hydrochloride -1- Example 14: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide

[0700]

[0701] Example 15: 2-Cyclopentyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol

[0702] A solution of 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) was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction mixture was quenched with water, extracted with EtOAc, and the EtOAc layer was dried and concentrated. The colorless liquid was purified by flash silica gel chromatography 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.

[0703] Intermediate 20: 2,6-Dichloro-9-isopropyl-9H-purine Intermediate 21: (S)-2-Chloro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine

[0704] 2,6-Dichloro-9-(difluoromethyl)-9H-purine (Intermediate 16, 4.00 g, 4.18 mmol, 25 wt%) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.812 g, 4.18 mmol) were dissolved in acetonitrile (30 mL) under N2, N,N-diisopropylethylamine (2.192 mL, 12.55 mmol) was added, and the mixture was stirred at room temperature for 16 h. An additional 0.3 equiv of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate was added and stirred for 6 h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM and washed with aqueous NaHCO3 solution. The aqueous layer was re-extracted with DCM, the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil, which was purified by flash silica gel chromatography to give (S)-tert-butyl 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.

[0705] Example 15: 2-Cyclopentyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol Example 16: 2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin

[0706] (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'-triisopropyl-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 filled with nitrogen twice, then tBuOH (5.19 mL) was added, and the reaction mixture was sealed and heated at 90 °C for 16 h. The reaction mixture was concentrated, and the resulting residue was purified by flash silica gel chromatography, eluting with a hexane solution with an elution gradient of 0% to 100% EtOAc, followed by a DCM solution with 0% - 10% MeOH. The product fractions were concentrated under reduced pressure to give (3S)-tert-Butyl 3-((2-((1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 18, 0.361 g, 43.9%). 1 H NMR (500 MHz, 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.

[0707] amino tetrahydrofuran

[0708] (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-(difluoromethyl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 18, 0.3612 g, 0.80 mmol), dichloromethane (2 mL), and hydrogen chloride (0.996 mL, 3.98 mmol) (4 M 1,4-dioxane solution) were added to a 30 mL scintillation vial. 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%).

[0709] 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 ​

[0710]

[0711] (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 mixture was cooled to -78 °C. Ethylsulfamoyl chloride (0.039 g, 0.26 mmol) was added to the reaction mixture and stirred for 60 min. Additional ethylsulfamoyl chloride (5.34 mg, 0.04 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction was quenched with aqueous NaHCO3, extracted with DCM, the organic layer was dried and concentrated. The crude product was purified by flash silica chromatography using a DCM solution of 0%-20% MeOH 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%). 11H NMR (500 MHz, 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 19F NMR (471 MHz, dichloromethane-d2) -96.02 (2F, s). m / z (ES + ) [M+H] + = 461.

[0712] ​ ​

[0713]

[0714] ​

[0715] DIAD (20.57 mL, 105.82 mmol) was slowly added to a solution of 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 successively with saturated aqueous Na2CO3 solution (300 mL × 3) and brine aqueous solution (300 mL × 2). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography, eluting with a petroleum ether solution with an elution gradient of 0% to 50% EtOAc. The 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.

[0716] ​

[0717] DIEA (2.72 mL, 15.58 mmol) was added to a solution of 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), extracted with DCM (3 × 100 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash C18 chromatography, eluting with a gradient of 5% to 70% MeCN in water (0.1% NH4HCO3). The pure fractions were evaporated to dryness to give (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 (400 MHz, DMSO-d6) δ 1.50 (6H, d), 2.04 (1H, s), 2.23 (1H, s), 2.92 (3H, s), 3.24 (1H, s), 3.33–3.39 (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.

[0718] ​ ​

[0719]

[0720] 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. Then N-ethyl-N-isopropylpropan-2-amine (648 mg, 5.02 mmol) was added. The reaction mixture was heated at 140 °C for 16 h with stirring. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was purified by flash C18 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

[0721] ​ ​ -2-yl) ​ )-2-( ​ -2-yl)ethan-1-ol

[0722]

[0723] Place 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) in a vial, and dissolve the reaction mixture in 1 mL of anhydrous NMP. Then add N-ethyl-N-isopropylpropan-2-amine (648 mg, 5.02 mmol). Heat the reaction mixture with stirring at 140 °C for 16 h. After cooling to room temperature, evaporate the mixture in vacuo. Purify the residue by flash C18 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

[0724] ​ ​

[0725]

[0726] Intermediate 22: racemic-(3R,4R)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine tert-butyl 1-carboxylate

[0727] Under nitrogen, 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 and dissolved in acetonitrile (8.44 mL). The reaction mixture was treated with DIEA (0.772 ml, 4.42 mmol), sealed and heated at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography, eluting with a gradient of 0% to 100% hexane solution of EtOAc (EtOAc containing 6% MeOH). The product fractions were concentrated under reduced pressure to give racemic-(3R,4R)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 22, 0.529 g, 93%). 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.

[0728] Intermediate 23: (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine tert-butyl 1-carboxylate

[0729] Racemic-(3R,4R)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (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'-triisopropyl-1,1'-biphenyl (0.221 g, 0.41 mmol) and palladium(II) acetate (0.031 g, 0.14 mmol) were placed in a microwave vial dried in an oven and under nitrogen. The vial was evacuated and filled with nitrogen twice, then tBuOH (6.87 mL) was added, and the reaction mixture was sealed and heated overnight in an oil bath at 90 °C. LC / MS showed that the reaction was complete. The reaction mixture was diluted with EtOAc / H2O. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, eluting with a gradient of 0% to 100% EtOAc in hexane (EtOAc containing 7% MeOH). The product fractions were concentrated under reduced pressure to give (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (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.

[0730] 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 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

[0731] (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-ethyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 23, 0.308 g, 0.69 mmol) was dissolved in MeOH (2.57 mL) and treated with HCl (4.0 M solution in dioxane) (1.713 ml, 6.85 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture 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%); m / z (ES + ) [M+H] + = 350.

[0732] 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 Intermediate 26: 2,3-dimethyl-1-((2-methyl-1H-imidazol-1-yl)sulfonyl)-1H-imidazol-3-ium trifluoromethanesulfonate

[0733]

[0734] (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 mixture was cooled to -78 °C and treated with a suspension of 1H-imidazole-2-sulfonyl chloride (106 mg, 0.64 mmol) in 3 mL DCM. The reaction mixture was stirred at this temperature for 30 min and then allowed to warm slowly to room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash silica gel chromatography, eluting with a gradient of 0% to 15% MeOH in DCM, followed by preparative SFC (Chiralpak AD column, 5 μm, 21 mm diameter, 250 mm length), column temperature 40 °C, outlet pressure 100 bar, flow rate 70 mL / min), eluting with 15% MeOH / CO2 containing 0.2% NH4OH 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%), 11H 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; and isomer 2 as a dry film (106 mg, 34.8%).

[0735] Intermediate 3: (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-pyrrolidine-1-tert-butyl carboxylate Intermediate 4: (S)-2-chloro-9-ethyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine

[0736]

[0737] Intermediate 27: (S)-2-chloro-9-ethyl-N-(1-((2-methyl-1H-imidazol-1-yl)sulfonyl)-pyrrolidin-3-yl)-9H-purin-6-amine Intermediate 28: (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((R)-tetrahydrofuran-3-yl)pyrrolidine-1-sulfonamide

[0738] Dissolve 1,1'-sulfonylbis(2-methyl-1H-imidazole) (intermediate 25, 3.00 g, 13.26 mmol) in DCM (53.8 mL) and cool in a dry ice / MeOH bath (-20 °C) under nitrogen. Dissolve methyl trifluoromethanesulfonate (1.460 ml, 13.26 mmol) in DCM (17.95 mL) and add dropwise to the cold solution. Allow the reaction to warm to 20 °C and stir for 1.5 h. Allow the white precipitate to settle and decant the supernatant. Wash the solid with 30 mL of DCM and dry in vacuo 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 1H 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).

[0739] 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

[0740] 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 mixture was then treated with DIEA (3.26 ml, 18.65 mmol) and allowed to warm to room temperature and stirred for 48 h. The reaction mixture 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 coated onto silica and purified by flash silica chromatography, eluting with a gradient of 0% to 100% hexane solution of EtOAc, then 10% MeOH in EtOAc. The product fractions were concentrated under reduced pressure to give (S)-tert-butyl 3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 3, 3.56 g, 104%) as a white foam, which solidified on standing. NMR showed 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.

[0741] Example 19: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide

[0742] (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 solution in dioxane) (10.34 ml, 41.38 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with methanol and concentrated under reduced pressure. The residue was diluted with 20% i-PrOH in DCM solution 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 solution. 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. 11H NMR (DMSO-d6) δ 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 dd), 4.13 (2H, q), 4.62 (1H, br s), 6.40 - 6.78 (1H, m), 8.20 (1H, s), 8.33 (1H, br s); m / z (ES + ) [M + H] + = 267。

[0743] Intermediate 29: (S)-3-((2-chloro-9H-purin-6-yl)amino)pyrrolidine-1-tert-butyl carboxylate Intermediate 30: (S)-3-((2-chloro-9-methyl-9H-purin-6-yl)amino)-pyrrolidine-1-tert-butyl carboxylate

[0744] (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). When the reaction mixture became homogeneous, it was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography eluting with a hexane solution with an elution gradient of 0% to 100% EtOAc (EtOAc containing 15% MeOH). The product fractions were concentrated under reduced pressure to give (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 1H NMR (methanol-d4) δ 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); no N-H observed; m / z (ES + ) [M + H] + = 411。

[0745] Intermediate 31: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-tert-butyl carboxylate ​

[0746] (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 cold solution. The reaction mixture was warmed to 20 °C and stirred for 1 hour. 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 as a white foam (434 mg, 100%); 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 hours. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography, eluting with a gradient of 0% to 100% hexane solution of EtOAc (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 as a white solid (Intermediate 28, 0.115 g, 73.6%). 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, brs), 8.35 - 8.62 (1H, m); m / z (ES + ) [M + H] + = 416.

[0747] ​ ​

[0748]

[0749] (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'-triisopropyl-1,1'-biphenyl (44.1 mg, 0.08 mmol), and palladium(II) acetate (6.15 mg, 0.03 mmol) were placed in a microwave vial dried in an oven and under nitrogen. The vial was evacuated and filled with nitrogen twice, then tBuOH (1.371 mL) was added, and the reaction mixture was sealed and heated at 100 °C for 3 h. The reaction mixture was diluted with EtOAc / H2O. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography, eluting with a gradient of 0% to 20% MeOH in DCM. The product fractions were concentrated under reduced pressure to give (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%). 1 1H 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.

[0750] ​ ​

[0751]

[0752] ​

[0753] Under nitrogen, at room temperature, (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). 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 and the product was extracted with ethyl acetate (200 mL). 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 as a yellow solid (Intermediate 29, 17.20 g, 96%). 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 / z (ES + ) [M+H] + = 339.

[0754] ​

[0755] 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 coated onto silica and purified by flash silica chromatography, eluting with a hexane solution of ethyl acetate with a gradient of 0% to 100%. The product fractions were concentrated under reduced pressure to give (S)-tert-butyl 3-((2-chloro-9-methyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate as a white solid (Intermediate 30, 8.50 g, 47.5%). 11H 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。

[0756] ​ ​

[0757] tert-Butyl (S)-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'-triisopropyl-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 filled with nitrogen twice, then tBuOH (28 mL) was added, and the reaction mixture was heated in an oil bath at 100 °C for 3.5 h. The reaction mixture was diluted with EtOAc / H2O, and the layers were separated. The organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, eluting with a hexane solution of EtOAc with a gradient of 0% to 100% EtOAc (EtOAc containing 17% MeOH). The product fractions were concentrated under reduced pressure to give 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%). 1 1H 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。

[0758] Intermediate 32: (R)-2-Cyclopropyl-2-((9-methyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)ethan-1-ol hydrochloride Example 19: (S)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-N-ethylpyrrolidine-1-sulfonamide

[0759] Dissolve tert-butyl (S)-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) in MeOH (14.7 mL) and treat with HCl (4 M dioxane solution) (6.33 ml, 25.15 mmol). Stir the reaction mixture at room temperature for 3.5 h, then concentrate it 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。

[0760] Example 20: (R)-2-((9-Isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-3-methylbutan-1-ol Intermediate 34: (S)-(1-(Methylsulfonyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester

[0761]

[0762] Suspend (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) in DCM (59 mL) and treat with TEA (2.22 ml, 15.91 mmol). Cool the reaction mixture to -60 °C and treat dropwise over 20 min with a solution of ethylsulfamoyl chloride (0.381 g, 2.65 mmol) in 20 mL DCM. Allow the reaction mixture to warm to -35 °C over 3 h, then concentrate it under reduced pressure. Apply the resulting residue to silica and purify by flash silica chromatography, eluting with a hexane solution with an EtOAc gradient of 0% to 100% (EtOAc containing 20% MeOH). Concentrate the product fractions 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. 11H 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。

[0763] Intermediate 35: (S)-1-(Methylsulfonyl)pyrrolidin-3-amine Intermediate 36: 6-Chloro-2-fluoro-9-isopropyl-9H-purine

[0764]

[0765] Intermediate 37: (S)-2-Fluoro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine

[0766] Under nitrogen, (S)-tert-butyl pyrrolidin-3-ylcarbamate (Intermediate 33, 14.17 g, 76.08 mmol) was dissolved in DCM (200 mL). 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 about 5 minutes, and the reaction mixture was stirred while allowing the cooling bath to stop and the reaction mixture was slowly warmed to room temperature overnight. The reaction mixture was concentrated under reduced pressure and the mixture was diluted with EtOAc and stirred for 5 minutes. The mixture was filtered and the solid was washed thoroughly with EtOAc. The filtrate was washed with 1 M aqueous HCl (2 × 100 mL), water, and saturated aqueous NaCl. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (S)-(1-(methylsulfonyl)pyrrolidin-3-yl)carbamate (Intermediate 34, 15.91 g, 79%) as an off-white solid. 1 1H 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。

[0767] Example 20: (R)-2-((9-Isopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0768] HCl (4.0 M solution in dioxane) (100 mL, 400.00 mmol) was slowly added via a 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 mixture was stirred at room temperature for 18 h (the reaction mixture became a suspension). The solvent was removed under reduced pressure and the solid residue was washed with Et2O 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 1H 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).

[0769] 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

[0770] Under nitrogen, 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. The solution was treated with 2-propanol (14.29 mL, 185.46 mmol), followed by triphenylphosphine (24.32 g, 92.73 mmol) and DIAD (18.03 mL, 92.73 mmol) which was added dropwise over 20 min. After addition, the reaction mixture was stirred at room temperature for 17 h. The reaction mixture 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 silica gel chromatography eluting with a hexane solution with an elution gradient of 0% to 80% EtOAc. 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 1H NMR (DMSO-d6) 1.54 (6H, d), 4.73–4.84 (1H, m), 8.81 (1H, s); m / z (ES + ) [M + H] + = 215.

[0771] Intermediate 39: 2-((tert-Butoxycarbonyl)amino)-4,4,4-trifluorobutyric acid

[0772] Under nitrogen, 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), 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 mixture was warmed to room temperature and stirred for 4 days (usually 48 hours for convenience). 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 coated on silica and purified by flash silica chromatography, eluting with a gradient of 50% to 100% hexane solution of EtOAc, and then 8% MeOH solution 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 as a beige solid (Intermediate 37, 6.46 g, 63.3%). 1 HNMR (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.

[0773] Intermediate 40: (4,4,4-Trifluoro-1-(methoxyamino)-1-oxobutan-2-yl)carbamic acid tert-butyl ester Intermediate 41: (4,4,4-Trifluoro-1-oxobutan-2-yl)carbamic acid tert-butyl ester

[0774]

[0775] (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 mixture was placed in a preheated oil bath at 140 °C. The reaction mixture was heated for 64 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc, washed with water and brine, dried over sodium sulfate / magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography, eluting with a gradient of 40% to 100% hexane solution of EtOAc, then 5% MeOH in DCM solution. The product fractions were concentrated under reduced pressure to give an impure product. The residue was repurified by flash silica gel chromatography, eluting with a gradient of 0% to 10% MeOH in EtOAc solution. 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 white dry 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.

[0776] Intermediate 42: (1,1,1-Trifluoro-4-hydroxypentan-3-yl)carbamic acid tert-butyl ester Intermediate 43: 3-Amino-5,5,5-trifluoropentan-2-ol

[0777]

[0778] Intermediate 44: (3S)-3-((9-Ethyl-2-((1,1,1-trifluoro-4-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0779] 2-Amino-4,4,4-trifluorobutyric 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 mixture was warmed to room temperature and stirred overnight. The reaction mixture was extracted with water, the aqueous extract was acidified with 1 N HCl, and then 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-trifluorobutyric acid as a white foam (Intermediate 39, 3.19 g, 78%). 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).

[0780] Intermediate 45: 3-((9-Ethyl-6-(((S)-pyrrolidin-3-yl)amino)-9H-purin-2-yl)amino)-5,5,5-trifluoropentan-2-ol

[0781] 2-((tert-Butoxycarbonyl)amino)-4,4,4-trifluorobutyric 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 mixture 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 mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and a 5% aqueous KHSO4 solution (50 mL). The organic layer was then washed with 5% KHSO4 (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 flash silica gel chromatography, eluting with a hexane solution with an elution gradient of 0% to 100% EtOAc. 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 as a white solid (Intermediate 40, 2.80 g, 75%). 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。

[0782] 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

[0783] In an oven-dried flask under nitrogen, 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). The solution was cooled to 0 °C in an ice bath for 15 minutes, at which point it was treated with LAH (2.0 M solution in THF) (7.23 ml, 14.45 mmol). The reaction mixture was stirred at 0 °C for 1 hour. A solution of potassium bisulfate (2.54 g, 18.65 mmol) in 28 mL of water was added slowly at 0 °C and the mixture was stirred for 15 minutes. The organic solvent in the reaction mixture was concentrated under reduced pressure. An additional 28 mL of water was added to the aqueous residue and the mixture was extracted with DCM (3×). The combined extracts were then washed with 1N 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%). 1 1H 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).

[0784] 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

[0785] 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 solution in Et2O) (10.40 ml, 31.20 mmol) and stirred at this temperature for 20 minutes. The reaction mixture 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 were 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 flash silica gel chromatography, eluting with a hexane solution with an elution gradient of 0% to 80% EtOAc. 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. 11H 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).

[0786] ​

[0787] Dissolve tert-butyl (1,1,1-trifluoro-4-hydroxypentan-3-yl)carbamate (Intermediate 42, 1.51 g, 5.87 mmol) in 1,4-dioxane (22.01 mL) and treat with HCl (4.0 M solution in dioxane) (14.67 ml, 58.70 mmol). Stir the reaction mixture overnight at room temperature. Concentrate the reaction mixture 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 HCl salt, which solidifies upon standing in the refrigerator. 1 1H 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).

[0788] ​ ​

[0789] (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 (1,812 mg, 5.56 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-triisopropyl-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 filled with nitrogen, then tBuOH (2.009 mL) was added, and the reaction mixture was sealed and heated at 100 °C over the weekend. The reaction mixture was diluted with EtOAc / H2O. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in hexane (EtOAc containing 6% MeOH). The product fractions were concentrated under reduced pressure to give (3S)-tert-butyl 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%). m / z (ES + ) [M+H] + = 488.

[0790] ​ ​

[0791] (3S)-tert-Butyl 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 mixture was stirred at room temperature for 16 h to form a gel. The reaction mixture 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 h to give the free base product. The MP carbonate was filtered off 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%). m / z (ES + ) [M+H] + = 388.

[0792] ​ ​

[0793]

[0794] 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 mixture was cooled in a dry ice / MeOH bath and treated with methylsulfamoyl chloride (0.117 g, 0.91 mmol). The reaction mixture was stirred at this temperature for 2 h. The reaction mixture was concentrated under reduced pressure, coated onto silica, and the resulting residue was purified by flash silica chromatography, eluting with a gradient of 0% to 10% MeOH in DCM. The product fractions were concentrated under reduced pressure, and the sample was subjected to chiral separation. Four isomers were separated using two methods. Isomers 1 and 2 were purified by preparative SFC (Chiralpak IG column, 5 μm, 21 mm diameter, 250 mm length), column temperature 40 °C, outlet pressure 100 bar, flow rate 70 mL / min), eluting with 17% MeOH / CO2 containing 0.2% NH4OH. Isomers 3 and 4 were purified by preparative SFC (Chiralpak IC column, 5 μm, 21 mm diameter, 250 mm length), column temperature 40 °C, outlet pressure 100 bar, flow rate 70 mL / min), eluting with 20% IPA / CO2 containing 0.2% NH4OH 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) N-H not observed; m / z (ES + ) [M+H] += 481; and isomers 1, 2, and 3 as a colorless film.

[0795] ​ ​

[0796]

[0797] Intermediate 46: (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl) pyrrolidine-1-sulfonamide

[0798] Dissolve (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) in DCM (3.07 mL) and cool in a dry ice / MeOH bath (-20 °C) under nitrogen. Dissolve methyl trifluoromethanesulfonate (74.8 μl, 0.68 mmol) in DCM (1.023 mL) and add dropwise to the cold solution. Allow the reaction mixture to warm to 20 °C and stir for 1 hour. Remove the solvent 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 as a white foam (434 mg, 100%). Dissolve (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) in acetonitrile (6.26 mL) and heat at 70 °C for 16 hours. Concentrate the reaction mixture under reduced pressure and purify by flash silica gel chromatography, eluting with a hexane solution of EtOAc with a gradient of 0% to 100% EtOAc (EtOAc containing 15% MeOH). Concentrate the product fractions 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%). 11H NMR (DMSO-d6) δ 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。

[0799] 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

[0800]

[0801] (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'-triisopropyl-1,1'-biphenyl (49.9 mg, 0.09 mmol) and palladium(II) acetate (6.96 mg, 0.03 mmol) were placed in a microwave vial dried in an oven and under nitrogen. The vial was evacuated and filled with nitrogen twice, then tBuOH (1.551 mL) was added, and the reaction mixture was sealed and heated at 100 °C for 3 h. The reaction mixture was diluted with EtOAc / H2O. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, eluting with a gradient of 0% to 20% MeOH in DCM. The product fractions were concentrated under reduced pressure to give (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%). 11H 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, brd), 7.25 - 7.52 (2H, m), 7.72 (1H, s); m / z (ES + ) [M + H] + = 416。

[0802] 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

[0803]

[0804] Intermediate 47: (S)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)-N-((S)-tetrahydrofuran-3-yl) pyrrolidine-1-sulfonamide

[0805] (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 cold solution. The reaction mixture was warmed to 20 °C and stirred for 1 h. The solvent was removed under reduced pressure to afford (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate as a white foam (216 mg, 100%). (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 mixture was stirred for 10 min. Then the solution was 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). Then the reaction mixture was heated at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography, eluting with a hexane solution of EtOAc with a gradient of 0% to 100% EtOAc (EtOAc containing 15% MeOH). The product fractions were concentrated under reduced pressure to afford (S)-N-(((S)-1,4-dioxan-2-yl)methyl)-3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-sulfonamide as a pale yellow solid (Intermediate 47, 0.122 g, 72.8%). 1 H 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.

[0806] 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

[0807]

[0808] (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'-triisopropyl-1,1'-biphenyl (42.8 mg, 0.08 mmol) and palladium(II) acetate (5.97 mg, 0.03 mmol) were placed in a vial dried in an oven and under nitrogen. The vial was evacuated and filled with nitrogen, then tBuOH (1.329 mL) was added, and the reaction mixture was sealed and heated at 100 °C for 5.5 h. The reaction mixture was diluted with EtOAc / H2O. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography, eluting with a gradient of 0% to 15% MeOH in DCM. The product fractions were concentrated under reduced pressure to give (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%). 1 H NMR (DMSO-d6) 0.85 (3H, br t), 1.04 (3H, brd), 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, brs), 7.72 (1H, s); m / z (ES + ) [M+H] + = 513.

[0809] Example 24: (2R,3S)-3-((9-ethyl-6-(((S)-1-((3-fluoroazetidin-1-yl)sulfonyl)py rrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0810]

[0811] Intermediate 48: (S)-2-chloro-9-ethyl-N-(1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3- yl)-9H-purin-6-amine

[0812] Dissolve (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) in DCM (1.565 mL) and cool in a dry ice / MeOH bath (-20 °C) under nitrogen. Dissolve methyl trifluoromethanesulfonate (38.1 μl, 0.35 mmol) in DCM (0.522 mL) and add dropwise to the cold solution. Allow the reaction to warm to 20 °C and stir for 1 h. Remove the solvent under reduced pressure to afford (S)-1-((3-((2-chloro-9-ethyl-9H-purin-6-yl)amino)pyrrolidin-1-yl)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate as a white foam (221 mg, 100%). Dissolve 3-fluoroazetidine HCl (60.0 mg, 0.54 mmol) in acetonitrile (3.17 mL) and treat with TEA (75 μl, 0.54 mmol), and stir the reaction for 10 min. Then add 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), and then heat the reaction at 70 °C for 3 h. Concentrate the reaction under reduced pressure and purify by flash silica chromatography, eluting with a hexane solution of EtOAc with a gradient of 0% to 100% EtOAc (EtOAc containing 15% MeOH). Concentrate the product fractions under reduced pressure to afford (S)-2-chloro-9-ethyl-N-(1-((3-fluoroazetidin-1-yl)sulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine as a white solid (Intermediate 48, 0.114 g, 73.1%). 1 H 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.

[0813] Example 24: (2R,3S)-3-((9-ethyl-6-(((S)-1-((3-fluoroazetidin-1-yl)sulfonyl)py rrolidin-3-yl)amino)-9H-purin-2-yl)amino)pentan-2-ol

[0814]

[0815] (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'-triisopropyl-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 filled with nitrogen, then tBuOH (1.300 mL) was added, and the reaction mixture was sealed and heated at 100 °C for 5.5 h. The reaction mixture was diluted with EtOAc / H2O. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography, eluting with a gradient of 0% to 20% MeOH in DCM. The product fractions were concentrated under reduced pressure to give (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), 3.85 - 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.

[0816] 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

[0817]

[0818] Intermediate 49: (S)-N-(((R)-1,4-dioxan-2-yl)methyl)-3-((2-chloro-9-ethyl-9H-purin-6- yl)amino)pyrrolidine-1-sulfonamide

[0819] (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 cold solution. The reaction mixture was warmed 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 as a white foam (216 mg, 100%). (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 mixture was stirred for 10 min. Then the solution was 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). Then the reaction mixture was heated at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography, eluting with a hexane solution of EtOAc with a gradient of 0% to 100% EtOAc (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%). 1 H 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, brs); m / z (ES + ) [M + H] + = 446.

[0820] 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

[0821]

[0822] (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'-triisopropyl-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 filled with nitrogen, then tBuOH (0.940 mL) was added, and the reaction mixture was sealed and heated at 100 °C for 5.5 h. The reaction mixture was diluted with EtOAc / H2O. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography, eluting with a gradient of 0% to 15% MeOH in DCM. The product fractions were concentrated under reduced pressure to give (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%). 1 H NMR (500 MHz, 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.

[0823] Example 26: (3R*,4R*)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-pur in-6-yl)amino)-N-ethyl-4-fluoropyrrolidine-1-sulfonamide

[0824]

[0825] Intermediate 50: racemic-(3R,4R)-3-((2-chloro-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

[0826] 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 racemic-(3R,4R)-tert-butyl 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 flash silica gel chromatography, eluting with a gradient of 0% to 10% MeOH in DCM. The product fractions were concentrated under reduced pressure to give racemic-(3R,4R)-tert-butyl 3-((2-chloro-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 50, 2.260 g, 80%) as a pale yellow solid.

[0827] Intermediate 51: racemic-(3R,4R)-3-((2-chloro-9-methyl-9H-purin-6-yl)-amino)-4-fluoropyrrolidine tert-butyl 1-carboxylate

[0828] Methyl iodide (0.432 mL, 6.91 mmol) was added to a stirred solution of racemic-(3R,4R)-tert-butyl 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 h. 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 coated onto silica and purified by flash silica gel chromatography, eluting with a gradient of 0% to 100% ethyl acetate in hexane. The product fractions were concentrated under reduced pressure to give racemic-(3R,4R)-tert-butyl 3-((2-chloro-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate (Intermediate 51, 1.56 g, 67%). 1 1H 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 was not observed.

[0829] Intermediate 52: (3RS,4RS)-3-((2-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylate tert-butyl

[0830] Racemic - (3R,4R)-3-((2-chloro-9-methyl-9H-purin-6-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (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'-triisopropyl-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 filled with nitrogen twice, then tBuOH (6.16 mL) was added, and the reaction mixture was sealed and heated at 96 °C for 16 h. The reaction mixture was diluted with EtOAc / H2O. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography, eluting with a hexane solution of EtOAc with a gradient of 0% to 100% EtOAc (EtOAc containing 6% MeOH). The product fractions were concentrated under reduced pressure to give 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%).

[0831] 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 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

[0832] At 20 °C, HCl (4 M in 1,4-dioxane solution) (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). The resulting solution was stirred at room temperature for 1 h. The reaction mixture 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%).

[0833] Example 27: (R)-2-(6-((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl-9H- purin-2-ylamino)-3-methylbutan-1-ol

[0834]

[0835] Weigh (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) in a 40 mL scintillation vial, add dichloromethane (5 mL) and triethylamine (261 μl, 1.88 mmol), and cool the reaction mixture to -78 °C. Add ethylsulfamoyl chloride (51.2 mg, 0.34 mmol) to the reaction mixture and stir for 2 hours. Add additional ethylsulfamoyl chloride (17.08 mg, 0.12 mmol) to the reaction mixture and stir for 1 hour. Quench the reaction with aqueous NaHCO3, stir for 15 minutes, extract with DCM, separate the organic layer, dry over MgSO4 and concentrate to obtain a white foam. Purify the resulting residue by flash silica gel chromatography, eluting with a gradient of 0% to 20% MeOH in DCM. Concentrate the product fraction under reduced pressure to obtain the racemic product, and perform chiral separation on this racemic product. Purify the product by preparative SFC (AD column, 5 μm, 4.6 mm diameter, 100 mm length), column temperature 40 °C, outlet pressure 120 bar, flow rate 4.0 mL / min), eluting with 10%-60% methanol / CO2 to obtain (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%).

[0836] Intermediate 36: 6-chloro-2-fluoro-9-isopropyl-9H-purine Intermediate 54: (S)-N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-2-fluoro-9-isopropyl-9H-purin-6-

[0837]

[0838] amine

[0839] Under nitrogen, DIAD (22.54 mL, 115.91 mmol) was added to a solution of 6-chloro-2-fluoro-9H-purine (Intermediate 7, 10 g, 57.96 mmol), IPA (8.93 mL, 115.91 mmol) and PPh3 (30.4 g, 115.91 mmol) in THF (200 mL) over a 30-minute period at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 (200 mL), extracted with EtOAc (3 × 100 mL), the organic layer was dried over Na2SO4, filtered and evaporated to give a yellow solid. The crude product was purified by flash silica chromatography, eluting with a gradient of 0% to 90% petroleum ether solution of EtOAc. The 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 (containing triphenylphosphine oxide, difficult to separate). 1 H NMR (400 MHz, 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.

[0840] Example 27: (R)-2-(6-((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-isopropyl purin

[0841] DIEA (0.488 mL, 2.80 mmol) was added to a solution of 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 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed successively with saturated aqueous NH4Cl (20 mL × 1), saturated aqueous Na2CO3 (20 mL) and saturated aqueous brine (20 mL). The organic layer was dried over Na2SO4, 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 (containing triphenylphosphine oxide). 11H NMR (300 MHz, DMSO-d6) δ 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。

[0842] ylamino -9H- methylbut -2- Example 28: (R)-2-(9-ethyl-6-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin- )-3- 2-yl)amino)-3-methylbutan-1-ol -1-ol

[0843]

[0844] DIEA (0.474 mL, 2.71 mmol) was added to a solution of (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 μm silica, 50 mm diameter, 150 mm length) using a mixture of water (containing 0.01% NH4HCO3) and MeCN with decreasing polarity as the eluent. The fraction containing the desired compound was 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 1H NMR (400 MHz, DMSO-d6) δ 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.

[0845] Intermediate 8: 6-chloro-9-ethyl-2-fluoro-9H-purine Intermediate 55: (S)-9-ethyl-2-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine

[0846]

[0847] Example 28: (R)-2-(9-ethyl-6-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H-purin-

[0848] Under nitrogen, DIAD (0.845 mL, 4.35 mmol) was added dropwise to a solution of 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). The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography eluting with a petroleum ether solution with an elution gradient of 0% to 80% EtOAc. The pure fractions were evaporated to dryness to afford 6-chloro-9-ethyl-2-fluoro-9H-purine (Intermediate 8, 0.400 g, 68.8%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) 1.18 (3H, d), 4.72 - 4.84 (2H, m), 8.86 (1H, s); m / z (ES + )[M+H] + = 201.

[0849] purin TEA (1.042 mL, 7.48 mmol) was added to a solution of 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 Na2CO3 (100 mL), extracted with DCM (3 × 100 mL), and the organic layer was dried over Na2SO4. The crude product was purified by flash silica gel chromatography eluting with a petroleum ether solution with an elution gradient of 0% to 80% EtOAc. The pure fractions were evaporated to dryness to afford (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.

[0850] amino methylbut -2-yl)Example 29: (R)-2-(9-cyclopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl-amino)-9H- )-3- purin-2-yl)amino)-3-methylbutan-1-ol -1-ol

[0851]

[0852] A solution of (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) was stirred at 140 °C for 3 days. The crude product was purified by preparative HPLC, column: XBridgeShield 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: 18B to 38B in 7 minutes. The 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 (400 MHz, 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.

[0853] Intermediate 57: 6-chloro-N-cyclopropyl-2-(methylthio)-5-nitropyrimidin-4-amine Intermediate 59: 6-chloro-9-cyclopropyl-2-(methylthio)-9H-purine

[0854]

[0855] Intermediate 60: (S)-9-cyclopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-2-(methylthio)-9H-purin-

[0856] At 25 °C, 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (Intermediate 56, 5 g, 20.83 mmol) was added to a solution of cyclopropylamine (1.070 g, 18.75 mmol) and TEA (8.71 mL, 62.48 mmol) in THF (100 mL). The resulting mixture was stirred at 25 °C for 1 day. The crude product was purified by flash silica gel chromatography, eluting with a petroleum ether solution with an elution gradient of 0% to 60% EtOAc. The pure fractions were evaporated to dryness to give 6-chloro-N-cyclopropyl-2-(methylthio)-5-nitropyrimidin-4-amine as a yellow solid (Intermediate 57, 3.00 g, 55.3%). m / z (ES + ) [M+H] + = 261.

[0857] Intermediate 58: 6-Chloro-N 4 -cyclopropyl-2-(methylthio)pyrimidine-4,5-diamine

[0858] At 25 °C, 6-chloro-N-cyclopropyl-2-(methylthio)-5-nitropyrimidin-4-amine (Intermediate 57, 3 g, 11.51 mmol) was added to a solution of iron (3.21 g, 57.54 mmol) in iPrOH (100 mL) and saturated aqueous NH4Cl solution (100 mL). The resulting mixture was stirred at 50 °C for 1 day. The reaction mixture was filtered through diatomaceous earth. The reaction mixture was diluted with DCM (300 mL) and washed successively with saturated aqueous NH4Cl solution (200 mL × 3) and saturated brine solution (300 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by flash silica gel chromatography, eluting with a petroleum ether solution with an elution gradient of 0% to 50% EtOAc. The pure fractions were evaporated to dryness to give 6-chloro-N4-cyclopropyl-2-(methylthio)pyrimidine-4,5-diamine as an off-white solid (Intermediate 58, 2.000 g, 75%). 1 1H NMR (400 MHz, 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.

[0859] 6-amine

[0860] Methanesulfonic acid (1.250 g, 13.00 mmol) was added to a solution of triethyl orthoformate (15 mL, 4.33 mmol) of 6-chloro-N4-cyclopropyl-2-(methylthio)pyrimidine-4,5-diamine (Intermediate 58, 1 g, 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 flash C18 chromatography, eluting with a gradient of 5% to 60% MeCN in water (0.1% NH4HCO3) solution. The 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. 1 H NMR (400 MHz, 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.

[0861] Intermediate 61: (S)-9-cyclopropyl-2-(methylsulfonyl)-N-(1-(methylsulfonyl)-pyrrolidin-3-yl)- 9H-purin-6-amine

[0862] DIEA (4.35 mL, 24.93 mmol) was added to a solution of 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 h. The reaction mixture was poured into saturated aqueous Na2CO3 (100 mL), extracted with DCM (3 × 100 mL), the organic layer was dried over Na2SO4, filtered and evaporated to give a pale yellow solid. The crude product was purified by flash silica gel chromatography, eluting with a gradient of 0% to 60% EtOAc in petroleum ether solution. The pure fractions were evaporated to dryness to give (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. 11H NMR (400 MHz, methanol-d4) δ 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 is not shown; m / z (ES + ) [M + H] + = 369.

[0863] Example 29: (R)-2-(9-cyclopropyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)-9H- ​

[0864] mCPBA (562 mg, 3.26 mmol) was slowly added to a solution of (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 h. The crude product was purified by flash silica gel chromatography, eluting with a petroleum ether solution with an elution gradient of 0% to 60% EtOAc. The pure fractions were evaporated to dryness to give (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.

[0865] ​ (Purine-2-yl)amino)-3-methylbutan-1-ol

[0866]

[0867] (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, 30×150 mm, 5 μm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20B to 40B in 7 minutes. The fraction containing the desired compound was 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 (400 MHz, 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), 3.15 - 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.

[0868] Example 30: (R)-2-Cyclopropyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)-pyrrolidin-3- yl)amino)-9H-purin-2-yl)amino)ethanol

[0869]

[0870] Intermediate 37: (S)-2-Fluoro-9-isopropyl-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine

[0871] At 80 °C, 6-chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 500 mg, 2.33 mmol) was added to a solution of (S)-1-(methylsulfonyl)pyrrolidin-3-amine hydrochloride (468 mg, 2.33 mmol) and DIEA (2.034 mL, 11.65 mmol) in EtOH (5 mL) over a 2-hour period. 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 (300 MHz, DMSO-d6) 1.5 (6H, d), 2.1 (1H, br s), 2.2 (1H, br s), 2.9 (3H, s), 3.1 - 3.3 (2H, m), 3.3 - 3.4 (1H, m), 3.4 - 3.5 (1H, m), 3.6 (1H, s), 4.6 (1H, p), 8.3 (1H, s), 8.6 (1H, br s); m / z (ES + ) [M+H] + = 343.

[0872] Example 30: (R)-2-Cyclopropyl-2-((9-isopropyl-6-(((S)-1-(methylsulfonyl)-pyrrolidin-3- yl)amino)-9H-purin-2-yl)amino)ethanol

[0873]

[0874] N-Ethyl-N-isopropylpropan-2-amine (566 mg, 4.38 mmol) was added to a solution of (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 CSHOBD column 30×150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 14B to 24B in 7 minutes. The 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%). 1HNMR(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(1H, 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。

[0875] 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

[0876]

[0877] Intermediate 62: (S)-3-(2-Fluoro-9-isopropyl-9H-purin-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester

[0878] DIEA (1.221 mL, 6.99 mmol) was added to a solution of 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 h. The crude product was purified by flash silica gel chromatography, eluting with a petroleum ether solution with an elution gradient of 0% to 100% EtOAc. The pure fractions were evaporated to dryness to give (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。

[0879] Intermediate 63: (S)-2-Fluoro-9-isopropyl-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride

[0880] A solution of HCl in 1,4-dioxane (3 mL, 98.74 mmol, 4 M) was added dropwise to a solution of (S)-tert-butyl 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 h. The solvent was removed under reduced pressure to afford (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.

[0881] Intermediate 64: (S)-2-Fluoro-9-isopropyl-N-(1-(1-methyl-1H-pyrazol-4-yl-sulfonyl)pyrrolidin-3- yl)-9H-purin-6-amine

[0882] 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 h. 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 brine (20 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford (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.

[0883] 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

[0884]

[0885] DIEA (0.812 mL, 4.65 mmol) was added to a solution of (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 30×150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16B to 26B in 7 minutes. The 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, overlapping), 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.

[0886] 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

[0887]

[0888] Intermediate 65: (S)-2-Fluoro-9-isopropyl-N-(1-(1-methyl-1H-imidazol-4-yl-sulfonyl)pyrrolidin-3- yl)-9H-purin-6-amine

[0889] 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 h. 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 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 as a white solid (Intermediate 65, 600 mg, 90%). 1 H NMR (300 MHz, DMSO-d6) 1.50 (6H, d), 1.92 - 2.16 (2H, m), 3.26 - 3.47 (4H, m, overlapping), 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.

[0890] 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

[0891]

[0892] DIEA (0.641 mL, 3.67 mmol) was added dropwise to a solution of (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 the following: preparative column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase A: water (0.05% NH4OH), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23B to 63B in 7 minutes. The 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 (600 MHz, 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, brdd), 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.

[0893] 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

[0894]

[0895] Intermediate 66: (3R,4R)-3-Fluoro-4-(2-fluoro-9-isopropyl-9H-purin-6-yl-amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0896] At 25 °C, 6-chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 0.300 g, 1.40 mmol) was added to a solution of (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (0.314 g, 1.54 mmol) and DIEA (0.732 mL, 4.19 mmol) in MeCN (3 mL). The resulting mixture was stirred at 80 °C for 1 day. The reaction mixture was concentrated and the crude product was purified by flash silica gel chromatography eluting with a petroleum ether solution with an elution gradient of 0% to 60% EtOAc. The pure fractions were evaporated to dryness to give (3R,4R)-3-fluoro-4-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 66, 0.280 g, 52.4%) as a white solid. 1 H NMR (400 MHz, 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, brs); m / z (ES + ) [M+H] + = 383.

[0897] Intermediate 67: 2-Fluoro-N-((3R,4R)-4-fluoropyrrolidin-3-yl)-9-isopropyl-9H-purin-6-amine hydrochloride

[0898] At 25 °C, (3R,4R)-3-fluoro-4-((2-fluoro-9-isopropyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 66, 0.200 g, 0.52 mmol) was added to a 1,4-dioxane solution of HCl (18 mL, 4 M). 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.

[0899] Intermediate 68: 2-Fluoro-N-((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)-9-isopropyl-9H- purin-6-amine

[0900] At 25 °C, 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 a solution of methanesulfonic anhydride (0.081 g, 0.47 mmol) and triethylamine (0.118 g, 1.17 mmol) in DCM (20 mL). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture 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 as a white solid (Intermediate 68, 0.090 g, 72.3%). 1 HNMR (300 MHz, 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.

[0901] Example 33: (R)-2-((6-(((3R,4R)-4-fluoro-1-(methylsulfonyl)pyrrolidin-3-yl)amino)- 9- isopropyl -9H- purine -2-yl) amino )-3- methylbutane -1-ol

[0902]

[0903] At 25 °C, 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 a solution of (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). The resulting mixture was stirred at 140 °C for 1 day. The reaction mixture was concentrated and 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: MeOH; flow rate: 60 mL / min; gradient: 46B to 54B in 7 minutes. The 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 (400 MHz, 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 (376 MHz, DMSO-d6) -177.52; m / z (ES + ) [M+H] + = 444.

[0904] 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

[0905]

[0906] Intermediate 69: (2R,4S)-4-(2-Fluoro-9-isopropyl-9H-purin-6-ylamino)-2-methylpyrrolidine-1-carboxylic tert-butyl ester

[0907] At 25 °C, 6-chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 0.300 g, 1.40 mmol) was added to a solution of (2R,4S)-tert-butyl 4-amino-2-methylpyrrolidine-1-carboxylate (0.308 g, 1.54 mmol) and DIEA (0.732 mL, 4.19 mmol) in MeCN (5 mL). The resulting mixture was stirred at 100 °C for 1 day. The crude product was purified by flash silica gel chromatography, eluting with a petroleum ether solution with an elution gradient of 0% to 100% EtOAc. The pure fractions were evaporated to dryness to give (2R,4S)-tert-butyl 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.

[0908] Intermediate 70: 2-Fluoro-9-isopropyl-N-((3S,5R)-5-methylpyrrolidin-3-yl)-9H-purin-6-amine hydrochloride salt

[0909] At 25 °C, (2R,4S)-tert-butyl 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 a 1,4-dioxane solution of HCl (15 mL, 4 M). 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.

[0910] Intermediate 71: 2-Fluoro-9-isopropyl-N-((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)- 9H-purin-6-amine

[0911] At 20 °C, 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 a solution of TEA (0.195 mL, 1.40 mmol) and methanesulfonic anhydride (0.098 g, 0.56 mmol) in DCM (15 mL). 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 as a white solid (Intermediate 71, 0.130 g, 78%). 1 H NMR (300 MHz, 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。

[0912] 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

[0913]

[0914] At 20 °C, 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 a solution of DIEA (0.147 mL, 0.84 mmol) and (R)-2-amino-3-methylbutan-1-ol (87 mg, 0.84 mmol) in NMP (2 mL). 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, 30×150 mm, 5 μm; mobile phase A: water (0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35B to 35B in 6 minutes. The fraction containing the desired compound was 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 (400 MHz, 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 (3H, 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.

[0915] 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

[0916]

[0917] Intermediate 72: (2S,4S)-4-(2-Fluoro-9-isopropyl-9H-purin-6-ylamino)-2-methylpyrrolidine-1-carboxylic tert-butyl ester

[0918] At 25 °C, 6-chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 0.300 g, 1.40 mmol) was added to a solution of (2S,4S)-tert-butyl 4-amino-2-methylpyrrolidine-1-carboxylate (0.308 g, 1.54 mmol) and DIEA (0.732 mL, 4.19 mmol) in MeCN (5 mL). The resulting mixture was stirred at 100 °C for 1 day. The reaction mixture was concentrated and the crude product was purified by flash silica gel chromatography eluting with a petroleum ether solution with an elution gradient of 0% to 100% EtOAc. The pure fractions were evaporated to dryness to give (2S,4S)-tert-butyl 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.

[0919] Intermediate 73: 2-Fluoro-9-isopropyl-N-((3S,5S)-5-methylpyrrolidin-3-yl)-9H-purin-6-amine hydrochloride salt

[0920] At 25 °C, (2S,4S)-tert-butyl 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 a 1,4-dioxane solution of HCl (3 mL, 4 M). The resulting mixture was stirred at 25 °C for 1 day. The reaction mixture was filtered and evaporated to give the 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.

[0921] Intermediate 74: 2-Fluoro-9-isopropyl-N-((3S,5S)-5-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)- 9H-purin-6-amine

[0922] At 20 °C, 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 a solution of TEA (0.195 mL, 1.40 mmol) and methanesulfonic anhydride (0.098 g, 0.56 mmol) in DCM (15 mL). The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture 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 as a white solid (Intermediate 74, 0.130 g, 88.2%). 1 H NMR (300 MHz, 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.

[0923] Example 35: (R)-2-((9-Isopropyl-6-(((3S,5S)-5-methyl-1-(methylsulfonyl)-pyrrolidine -3-yl) amino )-9H- purine -2-yl) amino )-3- methylbutane -1-ol

[0924]

[0925] At 20 °C, 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 a solution of DIEA (0.147 mL, 0.84 mmol) and (R)-2-amino-3-methylbutan-1-ol (87 mg, 0.84 mmol) in NMP (2 mL). The resulting mixture was stirred at 140 °C for 2 days. The reaction mixture 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.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 34B to 39B in 7 minutes. The fraction containing the desired compound was 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 (400 MHz, 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.

[0926] 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

[0927]

[0928] Intermediate 75: (3S,4R)-3-(2-Fluoro-9-isopropyl-9H-purin-6-ylamino)-4-methylpyrrolidine-1-carboxylic tert-butyl ester

[0929] At 20 °C, 6-chloro-2-fluoro-9-isopropyl-9H-purine (Intermediate 36, 0.300 g, 1.40 mmol) was added to a solution of (3S,4R)-tert-butyl 3-amino-4-methylpyrrolidine-1-carboxylate (0.308 g, 1.54 mmol) and DIEA (0.732 mL, 4.19 mmol) in MeCN (5 mL). The resulting mixture was stirred at 80 °C for 1 day. The reaction mixture was concentrated and the residue was purified by preparative TLC (EtOAc:petroleum ether = 1:1) to give (3S,4R)-tert-butyl 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.

[0930] Intermediate 76: 2-Fluoro-9-isopropyl-N-((3S,4R)-4-methylpyrrolidin-3-yl)-9H-purin-6-amine hydrochloride salt

[0931] At 20 °C, (3S,4R)-tert-butyl 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 a 1,4-dioxane solution of HCl (15 mL, 4 M). 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.

[0932] Intermediate 77: 2-Fluoro-9-isopropyl-N-((3S,4R)-4-methyl-1-(methylsulfonyl)-pyrrolidin-3-yl)- 9H-Purin-6-amine

[0933] At 20 °C, 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 a solution of methanesulfonic anhydride (0.068 g, 0.39 mmol) and TEA (0.225 mL, 1.62 mmol) in DCM (2 mL). The resulting mixture was stirred at 20 °C for 1 day. The reaction mixture was concentrated to give a 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%). 1HNMR(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。

[0934] Example 36: (R)-2-((9-Isopropyl-6-(((3S,4R)-4-methyl-1-(methylsulfonyl)-pyrrolidin -3-yl) amino ) - 9H - purine -2-yl) amino ) - 3 - methylbut -1-ol

[0935]

[0936] At 25 °C, 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 a solution of (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). The resulting mixture was stirred at 120 °C for 1 day. The reaction mixture was concentrated and the residue 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: MeOH; flow rate: 60 mL / min; gradient: 48B to 50B in 7 minutes. The fraction containing the desired compound was 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%). 11H NMR (300 MHz, DMSO-d6) δ 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。

[0937] Example 37: (2R,3S)-3-((9-Isopropyl-6-(((3S,5R)-5-methyl-1-(methylsulfonyl)-pyrrol idine -3-yl) amino ) - 9H - purine -2-yl) amino ) pentan - 2 - ol

[0938]

[0939] At 20 °C, 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 a solution of DIEA (147 μl, 0.84 mmol) and (2R,3S) - 3 - aminopentan - 2 - ol hydrochloride (118 mg, 0.84 mmol) in NMP (2 mL). The resulting mixture was stirred at 140 °C for 2 days. The reaction mixture was purified as follows: preparative 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: 45B to 60B in 7 minutes. The fraction containing the desired compound was 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%). 11H NMR (400 MHz, DMSO-d6) δ 0.86 (3H, t), 1.06 (3H, d), 1.30 (3H, d), 1.37–1.50 (7H, m, overlapping), 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。

[0940] Example 38: (R)-2-((9-Ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)- 9H- pur ine -2-yl) amino )butan-1-ol

[0941]

[0942] Under nitrogen, DIEA (0.532 mL, 3.05 mmol) was added to a solution of (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). The resulting mixture was stirred at 140 °C for 4 days. The reaction mixture was concentrated and the crude product was purified by: preparative 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: 17B to 37B in 7 minutes. The 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%). 11H NMR (400 MHz, DMSO-d6) δ 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, overlapping), 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。

[0943] Example 39: (R)-2-Cyclopropyl-2-((9-ethyl-6-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)am ino)-9H-purin-2-yl)amino)ethanol

[0944]

[0945] (S)-9-Ethyl-2-fluoro-N-(1-(methylsulfonyl)pyrrolidin-3-yl)-9H-purin-6-amine (5.60 g, 17.05 mmol) was added to a solution of (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 mixture was concentrated and the crude product was purified by preparative SFC, column: GreenSep Basic, 30×150 mm 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.5% 2M NH3-MeOH); flow rate: 50 mL / min; gradient: 30% B. The 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%). 11H NMR (300 MHz, DMSO-d6) δ 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。

[0946] 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

[0947]

[0948] Intermediate 9: (S)-3-(9-Ethyl-2-fluoro-9H-purin-6-ylamino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0949] DIEA (5.75 ml, 32.90 mmol) was added to a solution of 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 h. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography, eluting with a petroleum ether solution with an elution gradient of 0% to 100% EtOAc. The pure fractions were evaporated to dryness to give (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 1H NMR (300 MHz, DMSO-d6) δ 1.40 - 1.33 (12H, m), 1.97 (1H, br s), 2.12 (1H, br s), 3.19–3.24 (2H, m, overlapping), 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。

[0950] Intermediate 78: (S)-3-(9-Ethyl-2-((R)-1-hydroxy-3-methylbutan-2-yl-amino)-9H-purin-6-yl amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0951] At 20 °C, (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 a solution of (R)-2-amino-3-methylbutan-1-ol (3.89 g, 37.67 mmol) in NMP (0.5 mL). The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with DCM (300 mL) and washed successively with water (200 mL × 3). The organic layer was dried over Na2SO4, filtered and evaporated to give the crude product. The product (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, 81%) was used directly in the next step without further purification. 1 H NMR (400 MHz, 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 - 3.28 (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.

[0952] Intermediate 79: (R)-2-(9-Ethyl-6-((S)-pyrrolidin-3-ylamino)-9H-purin-2-yl-amino)-3- methylbutan-1-ol hydrochloride

[0953] At 20 °C, (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 a dioxane solution of HCl (20 mL, 4 M). The resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was evaporated to give the crude product. The product as a solid, (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%) was used directly in the next step without further purification. m / z (ES + ) [M+H] + = 334.

[0954] 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

[0955]

[0956] At -20 °C, (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 a solution of 2,2,2-trifluoroethane-1-sulfonyl chloride (74 mg, 0.41 mmol) and TEA (170 μl, 1.22 mmol) in DCM (1 mL). The resulting mixture was stirred at -20 °C for 2 h. The reaction mixture was concentrated and the crude product was purified by preparative HPLC, column: Sunfire prep C18 column, 30×150, 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. The 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 (400 MHz, 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 (376 MHz, DMSO-d6) -60.04; m / z (ES + ) [M+H] + = 480.

[0957] Example 41: (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-ethyl-9H- purine-2-yl)amino)-3-methylbutan-1-ol

[0958]

[0959] Intermediate 80: (S)-N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-9-ethyl-2-fluoro-9H-purin-6-amine

[0960] DIEA (0.918 mL, 5.26 mmol) was added to a solution of 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 flash C18 chromatography, eluting with a gradient of 20% to 50% MeCN in water (0.1% NH4HCO3) solution. The 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.

[0961] Example 41: (R)-2-((6-(((S)-1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-9-ethyl- 9H- purine -2-yl) amino )-3- methylbut -1-ol

[0962]

[0963] (R)-2-Amino-3-methylbutan-1-ol (0.2 mL, 1.80 mmol) was added to a solution of (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 h. The reaction mixture was diluted with DCM (50 mL) and washed successively with saturated aqueous Na2CO3 (50 mL) and saturated brine (50 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: 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 purification by preparative chiral HPLC, column: CHIRALPAK IA, 2×25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (10 mM NH3-MeOH), mobile phase B: IPA-HPLC; flow rate: 20 mL / min; gradient: 10B to 10B in 12 min. The fractions containing the desired 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 HNMR(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。

[0964] 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

[0965]

[0966] (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 a solution of 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 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, column: XBridge Shield RP18 OBD column, 19×250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 43B to 48B in 7 min. The fraction containing the desired compound was 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 (400 MHz, 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.

[0967] Example 43: (R)-2-((9-Ethyl-6-(((S)-1-(fluoromethylsulfonyl)pyrrolidin-3-yl)-amino)- 9H-purin-2-yl)amino)-3-methylbutan-1-ol

[0968]

[0969] At 20 °C, fluoromethanesulfonyl chloride (31.8 mg, 0.24 mmol) was added dropwise to a solution of (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). The resulting mixture was stirred at -20 °C for 75 minutes. 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.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23B to 30B in 7 minutes. The fraction containing the desired compound was 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 HNMR(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,brs),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。

[0970] Example 44: (S)-3-((9-Ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl) amino)-N-methylpyrrolidine-1-sulfonamide

[0971]

[0972] Intermediate 81: (S)-tert-Butyl 3-(2-fluoro-9H-purin-6-ylamino)pyrrolidine-1-carboxylate

[0973] Under nitrogen, at room temperature, 6-chloro-2-fluoro-9H-purine (Intermediate 7, 50 g, 289.78 mmol) was dissolved in tert-amyl alcohol (1200 mL), and then heated to 100 °C (Solution 1). Under nitrogen, at room temperature, (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 in a separate container (Solution 2). Solution 2 was added dropwise to Solution 1, and the reaction mixture was heated at 100 °C for 90 minutes. After 1 hour, LCMS indicated completion of the reaction, with a Cl:F substitution ratio of 13:1. The mixture was poured into ice water (2 L), and the aqueous phase was extracted with EtOAc (2 × 1 L), and the organic phase was washed with Na2SO4, 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 (300 MHz, 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.

[0974] Intermediate 9: (S)-tert-Butyl 3-(9-ethyl-2-fluoro-9H-purin-6-ylamino)pyrrolidine-1-carboxylate

[0975] At room temperature, iodoethane (22.34 ml, 276.41 mmol) was added dropwise to a solution of (S)-tert-butyl 3-((2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 81, 100 g, 251.29 mmol, 81 wt%) in DMSO (1500 mL). 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 in vacuo to give the crude product. The crude product was triturated with MeCN to give (S)-tert-butyl 3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 60.0 g, 68%) as a pale yellow solid. 1HNMR(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。

[0976] Intermediate 82: (S)-9-Ethyl-2-fluoro-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride

[0977] Add (S)-tert-butyl 3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate (Intermediate 9, 54 g, 154.11 mmol) to a 1,4-dioxane solution of HCl (385 ml, 1540.76 mmol, 4 M). Stir the resulting mixture at 25 °C for 6 h. Collect the formed solid, wash with MTBE and air dry to obtain (S)-9-ethyl-2-fluoro-N-(pyrrolidin-3-yl)-9H-purin-6-amine hydrochloride as a white solid (Intermediate 82, 50.0 g, 100%).(ES + )[M + H] + = 251。

[0978] Intermediate 83: (S)-1-(3-(9-ethyl-2-fluoro-9H-purin-6-ylamino)pyrrolidin-1-yl)ethanone

[0979] At 0 °C, add Ac2O (19.70 ml, 208.85 mmol) dropwise to a solution of (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). Stir the resulting mixture at 25 °C for 12 h. Pour the mixture into saturated aqueous NH4Cl (2 L), and extract the aqueous phase with DCM (2 × 1 L). Wash the organic phase with saturated aqueous NaHCO3 and saturated brine, then dry over Na2SO4, filter and evaporate to obtain (S)-1-(3-((9-ethyl-2-fluoro-9H-purin-6-yl)amino)pyrrolidin-1-yl)ethan-1-one as a pale yellow solid (Intermediate 83, 39.0 g, 95%). 1H (300 MHz, 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.

[0980] Intermediate 84: 1-((S)-3-(9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl amino)pyrrolidin-1-yl)ethanone

[0981] Divide 28 g of Intermediate 83 into 4 equal portions. In each portion, add DIEA (25.09 ml, 143.68 mmol) to a solution of (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 stir at room temperature for 20 minutes. Stir the resulting mixture at 160 °C for 96 hours. Combine the 4 batches. Pour the reaction mixture into DCM / MeOH (10:1) (2.5 L), wash with saturated aqueous NH4Cl solution (300 mL × 1), dry the organic layer over Na2SO4, filter, and evaporate to obtain the crude product. Purify the crude product by flash silica gel chromatography with an elution gradient of 0% to 8% MeOH in DCM solution. Evaporate the pure fractions to dryness to obtain 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.

[0982] Intermediate 11: (2R,3S)-3-(9-ethyl-6-((S)-pyrrolidin-3-ylamino)-9H-purin-2-yl-amino) pentan-2-ol hydrochloride

[0983] 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 a solution of LiOH (22.97 g, 958.79 mmol) in EtOH:H2O = 1:1 (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 flash silica gel chromatography, eluting with a gradient of 0% to 10% MeOH(NH3) in DCM. The 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 (300 MHz, 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.

[0984] Example 44: (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6- yl)-amino)-N-methylpyrrolidine-1-sulfonamide

[0985]

[0986] Methylsulfamoyl chloride (0.474 g, 3.6 mmol) was added to a solution of (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 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl (75 mL), 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 flash silica chromatography eluting with a gradient of 0% to 10% MeOH in DCM. The pure fractions were evaporated and re-purified by flash C18 - flash chromatography eluting with a gradient of 2% to 50% MeCN in water (0.1% NH4HCO3). The 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 (400 Hz, DMSO-d6) 0.86 (3H, t), 1.06 (3H, d), 1.34 (3H, t), 1.38 - 1.46 (1H, 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.

[0987] Example 45: (S)-3-((9-ethyl-2-(((S)-2-oxopentan-3-yl)amino)-9H-purin-6-yl)-amino yl )-N- methylpyrrolidine -1- sulfonamide

[0988]

[0989] Dess-Martin periodinane (497 mg, 1.17 mmol) was added to a solution of (S)-3-((9-ethyl-2-(((2R,3S)-2-hydroxypentan-3-yl)amino)-9H-purin-6-yl)amino)-N-methylpyrrolidin-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 as follows: preparative column: Xselect CSH OBD column 30 × 150 mm 5 μm, mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, aqueous solution of 5%-35% ACN. The 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-methylpyrrolidin-1-sulfonamide (Example 45, 0.051 g, 10.25%). 1 H NMR (400 MHz, 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, brs), 6.82 (1H, br s), 7.01 (1H, q), 7.54 (1H, br s), 7.78 (1H, s); m / z (ES + ) [M+H] + = 425.

[0990] Example 46: (S)-3-((9-ethyl-2-(((S)-2-hydroxy-2-methylpentan-3-yl)amino)-9H-purin-6- yl)amino)-N-methylpyrrolidine-1-sulfonamide

[0991]

[0992] Methylmagnesium bromide (1.413 mL, 3.53 mmol) was added to a solution of (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 × 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 × 150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, aqueous solution of 12%-25% ACN. The 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%). 1 H NMR (300 MHz, DMSO-d6) 0.84 (3H, t), 1.08 (6H, d), 1.31–1.36 (4H, m, overlappi...

Claims

1. A compound having the structure of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 selected from the group consisting of: C 1-6 -alkyl, halo-C 1-6 -alkyl and cyclopropyl; R 2 selected from the group consisting of: -NHR 6 , and R 3 and R 4 one of which is hydrogen, and R 3 and R 4 the other of which is selected from the group consisting of: hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl and C 1-3 -alkoxy; R 5 selected from the group consisting of: C 1-6 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 , pyrazolyl and imidazolyl; wherein said C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted by one or more substituents independently selected from halogen and C 1-3 -alkoxy; and said pyrazolyl and imidazolyl are optionally substituted by one or more substituents independently selected from C 1-3 -alkyl; R 6 is C 1-10 -alkyl or wherein said C 1-10 -alkyl is substituted by a hydroxyl or oxo group and is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl and tetrahydrofuranyl; R 7 is hydrogen or a C 1-3 -alkyl; R 8 is hydrogen; and R 9 is selected from the group consisting of: 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, and wherein said monocyclic ring is optionally substituted by one or more substituents independently selected from halogen.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the structure of formula (I-A): and wherein R 1 、R 2 、R 3 、R 4 and R 5 are as defined in claim 1.

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

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

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1-10 -alkyl, wherein said C 1-10 -alkyl is substituted by a hydroxyl group and is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl, and tetrahydrofuranyl.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 6 is C 2-6 -alkyl, wherein the C 2-6 -alkyl is substituted with a hydroxyl group.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein R 6 is 8. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of:

9. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein R 6 is Wherein: R 10 selected from the group consisting of: 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 selected from the group consisting of hydrogen and C 1-3 -alkyl; and R 12 selected from the group consisting of: hydrogen, C 1-3 -alkyl and halo-C 1-3 -alkyl.

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

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R 5 is -NR 8 R 9 ; R 8 is hydrogen; and R 9 is selected from the group consisting of: 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 the 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.

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

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure selected from the group consisting of: Among them, When applicable: R 1 selected from the group consisting of: C 1-6 -alkyl, halo-C 1-6 -alkyl and cyclopropyl; R 2 selected from the group consisting of: -NHR 6 , R 3 and R 4 one of which is hydrogen, and R 3 and R 4 the other of which is selected from the group consisting of: hydrogen, halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, and C 1-3 -alkoxy; R 5 is selected from the group consisting of: C 1-6 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 , pyrazolyl and imidazolyl; wherein said C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted by one or more substituents independently selected from halogen and C 1-3 -alkoxy; and said pyrazolyl and imidazolyl are optionally substituted by one or more substituents independently selected from C 1-3 -alkyl; R 6 is C 1-10 -alkyl or wherein said C 1-10 -alkyl is substituted by a hydroxyl or oxo group and optionally substituted by one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl and tetrahydrofuranyl; R 7 is hydrogen or a C 1-3 -alkyl; R 8 is hydrogen; R 9 is selected from the group consisting of: 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, and wherein said monocyclic ring is optionally substituted by one or more substituents independently selected from halogen; R 10 selected from the group consisting of: 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 selected from the group consisting of hydrogen and C 1-3 -alkyl; R 12 is selected from the group consisting of hydrogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; and R 13 selected from the group consisting of hydrogen and C 1-3 -alkyl.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 13, wherein, When applicable: R 1 selected from the group consisting of: C 1-3 -alkyl, halo-C 1-3 -alkyl and cyclopropyl; R 2 is - NHR 6 ; R 3 is hydrogen and R 4 is selected from the group consisting of: hydrogen and C 1-3 -alkyl; or R 4 is hydrogen and R 3 is selected from the group consisting of: hydrogen, halogen, and C 1-3 -alkyl; R 5 selected from the group consisting of: C 1-6 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 , pyrazolyl and imidazolyl; wherein said C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted with one or more substituents independently selected from halogen and C 1-3 -alkoxy; and said 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, wherein said C 1-10 -alkyl is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 3-6 -cycloalkyl and tetrahydrofuranyl; R 8 is hydrogen; R 9 is selected from the group consisting of: 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, and wherein said azetidinyl ring is optionally substituted with one or more substituents independently selected from halogen; R 10 selected from the group consisting of: 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 selected from the group consisting of hydrogen and C 1-3 -alkyl; R 12 is selected from the group consisting of: hydrogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; and R 13 selected from the group consisting of hydrogen and C 1-3 -alkyl 15. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein, When applicable: R 1 selected from the group consisting of: C 1-3 -alkyl and fluoro-C 1-3 -alkyl; R 2 is - NHR 6 ; 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, fluorine and alkyl; R 5 selected from the group consisting of: C 1-3 -alkyl, C 3-6 -cycloalkyl, -NR 8 R 9 , pyrazolyl and imidazolyl; wherein said C 1-6 -alkyl and C 3-6 -cycloalkyl are optionally substituted with one or more substituents independently selected from fluorine and methoxy; and said pyrazolyl and imidazolyl are optionally substituted with one or more methyl groups; R 6 is C 2-6 -alkyl, wherein said C 2-6 -alkyl is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, C 3-6 -cycloalkyl and tetrahydrofuranyl; R 8 is hydrogen; R 9 is selected from the group consisting of hydrogen, C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl methyl; wherein said C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl methyl are optionally substituted with one or more substituents independently selected from halogen; R 10 selected from the group consisting of: C 1-3 -alkyl, fluoro-C 1-3 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkylmethyl and tetrahydrofuryl; R 11 selected from the group consisting of hydrogen and C 1-3 -alkyl; R 12 is selected from the group consisting of: hydrogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; and R 13 selected from the group consisting of hydrogen and C 1-3 -alkyl.

16. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein, When applicable: R 1 selected from the group consisting of: C 1-3 -alkyl and fluoro-C 1-3 -alkyl; R 2 is - NHR 6 ; R 3 selected from the group consisting of hydrogen and fluorine; R 4 is hydrogen; R 5 selected from the group consisting of: C 1-3 -alkyl, cyclopropyl, -NR 8 R 9 , pyrazolyl and imidazolyl; wherein said C 1-6 -alkyl and cyclopropyl are optionally substituted with one or more substituents independently selected from fluorine and methoxy; and said pyrazolyl and imidazolyl are optionally substituted with one or more methyl groups; R 6 is C 2-6 -alkyl, wherein said C 2-6 -alkyl is substituted with a hydroxyl group and optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, C 3-6 -cycloalkyl and tetrahydrofuranyl; R 8 is hydrogen; R 9 selected from the group consisting of hydrogen, C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl methyl; wherein said C 1-3 -alkyl, tetrahydrofuranyl, and 1,4-dioxanyl methyl are optionally substituted with one or more fluorines; R 10 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; and R 12 is selected from the group consisting of hydrogen, methyl and fluoromethyl.

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

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of: (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 (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. A method of treating cancer in a subject having or susceptible to cancer, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

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

23. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer.

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