Heterocyclic compounds or salts thereof as atr kinase inhibitors, pharmaceutical compositions comprising the same and uses thereof

Abstract

The present disclosure relates to compounds of structural formula (I) or salts thereof, which are useful as ATR kinase inhibitors, pharmaceutical compositions comprising the compounds or salts thereof, and uses in the treatment or prevention of ATR kinase-mediated diseases. The compounds of the present invention possess ATR inhibitor activity, and in vivo experiments have observed that the compounds of the present invention have a significant tumor growth inhibitory effect.

Description

[0001] This application is a divisional application of International Application No. PCT / US2018 / 042128, filed July 13, 2018, and National Application No. 201880051484.9, entitled "Heterocyclic Inhibitor of ATR Kinase". This application claims priority to U.S. Provisional Application No. 62 / 531,951, filed July 13, 2017, the disclosure of which is incorporated herein by reference as if it were written in its entirety. Technical Field

[0002] This article discloses novel heterocyclic compounds and compositions, as well as their applications as pharmaceuticals for treating diseases. Methods for inhibiting ATR kinase activity in human or animal subjects to treat diseases such as cancer are also provided. Background Technology

[0003] Ataxia-telangiectasia and Rad3-associated kinase (ATR) are members of the phosphatidylinositol 3-kinase-associated protein kinase (PIKK) family, which also includes ataxia-telangiectasia mutant (ATM) kinase, DNA-dependent protein kinase (DNA-PK), germ formation inhibitor gene-1 (SMG-1), mammalian target of rapamycin (mTOR), and transformation / transcription-associated protein (TRAPP). ATR and ATM are key regulators of the cellular DNA damage response (DDR) pathway and are involved in maintaining genome integrity in response to DNA damage. Various types of DNA damage can occur due to different damage events, including errors during normal replication, exposure to ionizing radiation (IR), and genotoxic agents, and different DNA repair mechanisms have evolved to address specific types of DNA damage.

[0004] ATM is primarily activated by double-stranded DNA breaks (DSBs), which may be caused by stalled replication fork folding or exposure to IR. ATM plays a crucial role in activating the G1 / S checkpoint, thereby preventing DNA-damaged cells from entering S phase and allowing DNA repair before replication begins. This effect is mainly mediated by phosphorylation of two major downstream targets of ATM: CHK2 kinase and the tumor suppressor p53.

[0005] Conversely, the ATR is primarily activated in response to single-strand DNA breaks (SSBs), which are found at stalled replication forks or originate from the excision of DNA ends after processing DNA DSBs. Replication protein A (RPA) binds to the single strand of DNA, and then the ATR interacting protein (ATRIP) binds to the RPA-coated DNA strand and recruits the ATR to the SSB damage site. Recruiting additional protein components to this complex activates ATR kinases, which subsequently phosphorylate and activate their downstream effectors (including CHK1 kinase). Activation of the ATR slows the initiation of replication, stabilizes stalled replication forks (preventing them from folding into DSBs), and resumes fork replication once the damage is repaired. The ATR / CHK1 pathway is a major regulator of the G2 / M checkpoint, which prevents cells from prematurely entering mitosis in the presence of incomplete DNA replication and / or DNA damage (reviewed in MJO'Connor, Molecular Cell, 2015, 60, Nov 19, pp. 547-560; AM Weber et al., Pharmacology and Therapeutics, 2015, 149, 124-138).

[0006] Because ATR plays a crucial role in DDR, pharmacological inhibition of ATR may be an effective cancer treatment in many specific situations. Indeed, many cancers (e.g., oncogene-driven tumors) are characterized by higher levels of replication stress compared to normal cells, and blocking ATR can increase their genomic instability and induce significant cell death (O. Gilad et al., Cancer Res., 70, 9693-9702, 2010). Furthermore, most cancers are characterized by the loss or dysregulation of one or more DDR pathways, leading to increased genomic instability and greater survival dependence on the remaining DDR pathways. For example, cancer cells with G1 checkpoint defects due to p53 mutations will rely more heavily on G2 / M checkpoints for DNA repair and cell survival. Inhibition of ATR (a key regulator of G2 / M checkpoints) can lead to complete loss of the DNA damage checkpoint, ultimately resulting in DNA damage accumulation and mitotic catastrophe. Normal cells with functional G1 checkpoints are less affected by pharmacological inhibition of ATR. Similarly, in cancer cells with ATM deficiency, ATR inhibition leads to comprehensive lethal dependence, resulting in increased sensitivity and preferential killing. Therefore, ATR inhibition could be used to treat tumors with ATM and / or p53 deficiency (PMReaper, MRGriffiths et al., Nature Chem. Bio., 7, 428-430, 2011).

[0007] Additional potential integrated lethal interactions between ATR and other components of the DDR pathway have been reported, which could potentially be exploited through treatment with ATR inhibitors, including in cancers characterized by loss / deficiency of XRCC1, ERCC1, MRE11, and other components (if part of the MRN complex) (reviewed in AM Weber et al., Pharmacology and Therapeutics, 2015, 149, 124-138). Recently, an integrated lethal dependence of ATR inhibition in ARID1A-deficient tumors, a member of the SWI / SNF chromatin remodeling complex, which is frequently mutated in human cancers, has been reported (CT Williamson et al., Nature Communications, 2016, 7, 13837).

[0008] DNA damage therapies (such as radiotherapy and chemotherapy) can also be combined to treat cancer by utilizing ATR inhibition. Widely used chemotherapy includes antimetabolites (e.g., gemcitabine), DNA cross-linking agents (e.g., platinum salts), alkylating agents (e.g., temozolomide), and topoisomerase inhibitors (e.g., camptothecin, topotecan, irinotecan). Administration of these agents and / or ionizing radiation induces various forms of DNA damage, ultimately leading to mitotic catastrophe and cell death in cancer cells. In cancer cells treated with these agents, inhibition of ATR signaling can prevent DNA damage repair, thereby further reducing the already compromised ability of cancer cells to respond to induced replication stress, and thus enhancing the effectiveness of the aforementioned treatments.

[0009] Another opportunity to utilize ATR inhibition in combination therapy is in use with other DDR agents, such as in combination with poly-ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors prevent the repair of single-strand DNA breaks, leading to the formation of DNA double-strand breaks. PARP inhibition has demonstrated clinical efficacy in cancers lacking homologous recombination (HR) DNA repair pathways, such as BRCA1 / 2-mutant cancers. Recent reports highlight that simultaneous targeting of key cell cycle checkpoints (e.g., through combination of PARP inhibitors and ATR inhibitors) leads to increased sensitivity to PARP inhibition and produces significant efficacy in several preclinical cancer models, including patient-derived models resistant to PARP inhibitors. These findings highlight the potential clinical applications of ATR inhibitors in combination with other DDR inhibitors, and the field may expand to include several other combination opportunities beyond PARP inhibitors (H. Kim et al., Clinical Cancer Research, April 2017, DOI:10.1158 / 1078-0432.CCR-16-2273; AYKLau et al., AACR National Meeting 2017, Abstract 2494 / 25, ATR inhibitor AZD6738 as monotherapy and incombination with olaparib or chemotherapy:defining pre-clinical dose-schedules and efficacy modelling). Summary of the Invention

[0010] Therefore, this paper discloses methods for treating cancer using ATR inhibitors, particularly cancers characterized by elevated replication stress levels, cell cycle checkpoint defects, or defects in cellular DNA damage repair pathways (such as ATM / p53 pathway defects or other combined lethal-dependent defects with other DDR components). This paper also discloses methods for treating cancers with ARID1A mutations / defects or mutations / defects in cellular pathways that are combined with the ATR pathway and are lethally dependent on it. Furthermore, this paper discloses methods for treating cancer using ATR inhibitors in combination with radiation, DNA damage chemotherapy agents, and other DDR inhibitors (including PARP inhibitors).

[0011] Furthermore, inhibiting ATR offers an opportunity to treat certain cancers associated with regulation of telomere length. Telomeres are nucleoprotein complexes containing hexnucleotide repeating sequences of DNA and telomere-associated proteins that play a role in stabilizing the ends of chromosomes. In normal somatic cells, telomere shortening over time leads to senescence or apoptosis, and this role may play a role in the aging of cells. In most advanced cancers, telomerase is activated, which adds a repeating sequence to the 3' end of DNA, thereby reversing the telomere shortening process and extending cell lifespan. Thus, telomerase activation has been induced in cancer cell immortalization. A second mechanism for maintaining telomeres, independent of telomerase, is called telomere elongation replacement (ALT), which is involved in approximately 5% of human cancers and is prevalent in certain types of cancer, including osteosarcoma and glioblastoma. ALT is enriched in tumors originating from mesenchyme and is often associated with reduced survival. Studies have shown that ALT functionally requires ATR kinase, and that ALT cells are more sensitive to ATR inhibition (RLFlynn, KECox, Science, 2015, 347(6219), 273-277).

[0012] Effective therapies for ALT-positive cancers are needed. Little is known about the ALT pathway, and ALT-characterized cancers are resistant to telomerase inhibitors. Therefore, this article describes a method for treating cancers, particularly ALT-positive types, using ATR inhibitors.

[0013] This article discloses novel compounds and pharmaceutical compositions (some of which have been found to inhibit ATR kinases), as well as methods for synthesizing and using these compounds, including methods for treating patients with ATR kinase-mediated diseases by administering these compounds.

[0014] This document provides Example 1: A compound having structural formula (I):

[0015]

[0016] Or its salt, wherein:

[0017] R 1 and R 2 Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which is optionally bound by one or more R 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted heterocyclic alkyl rings;

[0018] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0019] R 4 Selected from C 5-10 aryl and heteroaryl, either of which may optionally be influenced by one or more R 6 Group substitution;

[0020] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0021] Each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0022] Each R 7 R 8 and R 9 Independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl groups, either of which may optionally be converted by a halogen group, a hydroxyl group, or a C-group. 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0023] Each R 10 R 11 and R 12 Independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl groups, any one of which may be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0024] Certain compounds disclosed herein may have useful ATR kinase inhibitory activity and may be used to treat or prevent diseases or conditions in which ATR kinases play an active role. Therefore, in a broad sense, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, and methods for preparing and using these compounds and compositions. Certain embodiments provide methods for inhibiting ATR kinases. Other embodiments provide methods for treating ATR kinase-mediated disorders in patients requiring treatment, including administering a therapeutically effective amount of a compound or composition according to this disclosure to a patient requiring such treatment. Use of certain compounds disclosed herein in the manufacture of medicaments for treating diseases or conditions improved by inhibiting ATR kinases is also provided.

[0025] In some embodiments, R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Heterocyclic alkyl rings substituted with functional groups.

[0026] In some embodiments, R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Heterocyclic alkyl rings substituted with functional groups.

[0027] In some embodiments, R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 A 4, 5, 6 or 7-membered heterocyclic alkyl ring substituted with a functional group.

[0028] In some embodiments, R 4 Selected from C 5-10 Aryl and C 5-10 Heteroaryl groups, any one of which may be optionally bound by one or more R 6 Group substitution.

[0029] In some embodiments, R 4 Selected from C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 6 Group substitution.

[0030] In some embodiments, R 4 Selected from

[0031] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0032] In some embodiments, each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0033] In some embodiments, each R 5 Independently selected from C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0034] In some embodiments, each R 5 Independently selected from C(O)R 8 and C(O)OR 8 .

[0035] In some embodiments, each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo group, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 .

[0036] In some embodiments, each R 6Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl and oxo groups.

[0037] In some embodiments, each R 6 It is independently selected from halogens and cyano groups.

[0038] In some embodiments, each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0039] In some embodiments, each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0040] This disclosure provides additional embodiments:

[0041] Example 2: A compound or a salt thereof as described in Example 1, wherein R 3 It is selected from methyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0042] Example 3: A compound or a salt thereof as described in Example 1, wherein R 3 It is C 1-6 alkyl.

[0043] Example 4: A compound or a salt thereof as described in Example 3, wherein R 3 It is a methyl group.

[0044] This document provides Example 5: A compound having structural formula (II):

[0045]

[0046] Or its salt, wherein:

[0047] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0048] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0049] R 4 Selected from C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 6 Group substitution;

[0050] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0051] Each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0052] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0053] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0054] This disclosure provides additional embodiments:

[0055] Example 6: A compound or a salt thereof as described in Example 5, wherein R 3 It is C 1-6 alkyl.

[0056] Example 7: A compound or a salt thereof as described in Example 6, wherein R 3 It is selected from methyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0057] Example 8: A compound or a salt thereof as described in Example 6, wherein R 3 It is a methyl group.

[0058] Example 9: A compound or a salt thereof as described in any one of Examples 5-7, wherein R 4 It is a 5-10 aryl group and optionally surrounded by one or more R groups. 6 Group substitution.

[0059] Example 10: A compound or a salt thereof as described in Example 9, wherein R 4 Selected from indole, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrazine, pyrazolopyrazine, pyrrolopyrimidine, pyrazolopyrimidine, imidazopyrimidine, pyrrolopyridazine, pyrazolopyridazine, and imidazopyridazine, any one of which is optionally precipitated by one or more R 6 Group substitution.

[0060] Example 11: The compound as described in Example 9, wherein R 4 It is pyridine and optionally contains one or more R 6 Group substitution.

[0061] Example 12: The compound as described in Example 11, wherein R 4 It is unsubstituted pyridine.

[0062] Example 13: The compound as described in Example 11, wherein R 4 It is pyridine and is controlled by an R 6 Group substitution.

[0063] Example 14: The compound as described in Example 11, wherein R 4 It is pyridine and is affected by two Rs. 6 Group substitution.

[0064] Example 15: A compound or a salt thereof as described in Example 10, wherein R 4 Selected from 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-c]pyridazine, 7H-pyrrolo[2,3-d]pyrimidine, and 5H-pyrrolo[2,3-b]pyrazine, any one of which is optionally subjected to one, two, or three R 6 Group substitution.

[0065] Example 16: A compound or a salt thereof as described in Example 15, wherein R 4 It is 1H-pyrrolo[2,3-b]pyridine and optionally is separated by one or two R 6 Group substitution.

[0066] Example 17: A compound or a salt thereof as described in any one of Examples 5-16, wherein each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo group, OR11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 .

[0067] Example 18: A compound or a salt thereof as described in Example 17, wherein each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl and oxo groups.

[0068] Example 19: A compound or a salt thereof as described in Examples 5-18, wherein R 4 Selected from

[0069]

[0070] Example 20: A compound or a salt thereof as described in Example 19, wherein

[0071] R 1 and R 2 Independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 Aryl and 5-10 heteroaryl groups, and optionally surrounded by one or two R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional structure with one or two R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0072] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0073] Example 21: A compound or a salt thereof as described in Example 20, wherein each R 5 Independently selected from alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0074] Example 22: A compound or a salt thereof as described in Example 21, wherein each R 5 Independently selected from C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0075] Example 23: A compound or a salt thereof as described in Example 22, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-10 Aryl and 5-10 heteroaryl groups, and optionally surrounded by one or two R groups. 5 Group substitution.

[0076] Example 24: A compound or a salt thereof as described in Example 23, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups, and optionally with one or two R groups. 5 Group substitution.

[0077] Example 25: A compound or a salt thereof as described in Example 23, wherein R 1 and R2 Selected independently from C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0078] Example 26: A compound or a salt thereof as described in Example 23, wherein R 1 and R 2 Together with sulfur attached to both of them, they form a heterocyclic alkyl ring and are optionally bounded by one or two R... 5 Group substitution.

[0079] Example 27: A compound or a salt thereof as described in Example 10, wherein R 4 Selected from 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl, 1H-indazole-1-yl, 1H-indazole-4-yl, 1H-benzo[d]imidazol-1-yl, 1H-benzo[d]imidazol-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2 [3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-3-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-1-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 3H-imidazo[4,5-b]pyridin-7-yl, and 1H-benzo[d][1,2,3]triazol-1-yl, any of which may be optionally separated by one or two R 6 Group substitution.

[0080] Example 28: The compound as described in Example 27, wherein R 4 The R group is selected from 1H-benzo[d]imidazol-1-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino, 1H-indol-4-yl, pyridin-4-yl, any one of which is optionally separated by one or two R groups selected from amino, fluorine, methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxymethyl, 1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl)imino. 6 Group substitution.

[0081] Example 29: A compound or a salt thereof as described in Example 27, wherein each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo group, OR 11 NR 10 C(O)R11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 .

[0082] Example 30: A compound or a salt thereof as described in Example 29, wherein each R 5 Independently selected from C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0083] Example 31: A compound or a salt thereof as described in Example 30, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bounded by one or two R groups. 5 Group substitution.

[0084] Example 32: The compound as described in Example 31, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups, and optionally with one or two R groups. 5 Group substitution.

[0085] Example 33: A compound or a salt thereof as described in Example 32, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0086] Example 34: A compound or a salt thereof as described in Example 32, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0087] Example 35: A compound or a salt thereof as described in any one of Examples 33 or 34, wherein R 4 Selected from pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[2,3-c]pyridin-4-yl, and benzo[d]imidazol-1-yl.

[0088] Example 36: A compound or a salt thereof as described in Example 36, wherein R 4 Selected from 1H-benzo[d]imidazol-1-yl and pyrrolo[2,3-b]pyridin-4-yl, either of which is optionally separated by one or two R 6 Group substitution.

[0089] Example 37: A compound or a salt thereof as described in Example 36, wherein R 3 It is a methyl group.

[0090] Example 38: A compound or a salt thereof as described in Example 37, wherein R 1 and R 2 It is independently selected from methyl, cyclopropyl and oxetane-3-yl.

[0091] Example 39: A compound or a salt thereof as described in Example 30, wherein R 1 and R 2 Together with the sulfur attached to both of them, they form an optional structure with one or two R 5 Thiomorpholine rings substituted with functional groups.

[0092] Example 40: A compound or a salt thereof as described in Example 39, wherein R 1 and R 2 Together with sulfur attached to both of them, they form on nitrogen and are selected from C(O)R 8 and C(O)OR 8 R 5 Thiomorpholine rings substituted with functional groups.

[0093] This document provides Example 41: A compound having structural formula (III):

[0094]

[0095] Or its salt, wherein:

[0096] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0097] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0098] R 4 Selected from C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 6 Group substitution;

[0099] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0100] Each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0101] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0102] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0103] This disclosure provides additional embodiments:

[0104] Example 42: A compound or a salt thereof as described in Example 1, wherein R 4 It is a 5-10 aryl group and optionally surrounded by one or more R groups. 6 Group substitution.

[0105] Example 43: A compound or a salt thereof as described in Example 42, wherein R 4 Selected from monocyclic 5-10-membered heteroaryl and bicyclic 5-10-membered heteroaryl, either of which is optionally constituting one or more R 6 Group substitution.

[0106] Example 44: A compound or a salt thereof as described in Example 43, wherein R 4 The group is selected from pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indoleyl, indazole, benzimidazolyl, benzotriazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, pyrrolopyrimidinyl, pyrrolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, pyrrolopyridazinyl, and imidazopyridazinyl, any one of which is optionally divided by one or more R 6 Group substitution.

[0107] Example 45: A compound or a salt thereof as described in Example 44, wherein R 4 Selected from pyrazolyl, imidazoleyl, pyridinyl, pyrimidinyl, indoleyl, indazoleyl, benzo[d]imidazolyl, imidazo[1,2-a]pyridinyl, pyrazol[1,5-a]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, benzo[d][1,2,3]triazolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazol[3,4-b]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl, any of which may be optionally converted by one or more R 6 Group substitution.

[0108] Example 46: A compound or a salt thereof as described in Example 44, wherein R 4 Selected from 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl, 1H-indazole-1-yl, 1H-indazole-4-yl, 1H-benzo[d]imidazol-1-yl, 1H-benzo[d]imidazol-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2 [3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-3-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-1-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl, 3H-imidazo[4,5-b]pyridin-7-yl, and 1H-benzo[d][1,2,3]triazol-1-yl, any of which may be optionally separated by one or two R 6 Group substitution.

[0109] Example 47: A compound or a salt thereof as described in Example 45, wherein R 4 The group is selected from imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridazinyl, and imidazo[4,5-b]pyrazinyl, any one of which is optionally surrounded by one, two, or three R... 6 Group substitution.

[0110] Example 48: A compound or a salt thereof as described in Example 47, wherein R 4 The group is selected from pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridazinyl, pyrrolo[2,3-d]pyrimidinyl, and pyrrolo[2,3-b]pyrazine, any one of which is optionally bounded by one, two, or three R... 6 Group substitution.

[0111] Example 49: A compound or a salt thereof as described in Example 48, wherein R 4 It is pyrrolo[2,3-b]pyridyl and optionally surrounded by one or two R 6 Group substitution.

[0112] This document provides Example 50: A compound having structural formula (IV):

[0113]

[0114] Or its salt, wherein:

[0115] X is selected from N and CR. 6c ;

[0116] Y is selected from N and CR. 6d ;

[0117] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0118] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0119] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR8 R 9 ;

[0120] R 6a and R 6b Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ,

[0121] Or R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6 heteroaryl rings with substituent groups;

[0122] Each R 6c and R 6d Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0123] R 6 Selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0124] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0125] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0126] This document provides Example 51: A compound having structural formula (IVa):

[0127]

[0128] Or its salt, wherein:

[0129] X is selected from N and CR. 6c ;

[0130] Y is selected from N and CR. 6d ;

[0131] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0132] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0133] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0134] R 6a and R 6b Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ,

[0135] Or R 6a and R6b Combined with intercalation atoms, they form optionally formed by one or more R 6 heteroaryl rings with substituent groups;

[0136] Each R 6c and R 6d Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0137] R 6 Selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0138] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0139] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0140] This disclosure provides additional embodiments:

[0141] Example 52: A compound or a salt thereof as described in any one of Examples 50 or 51, wherein R3 is C 1-6 alkyl.

[0142] Example 53: A compound or a salt thereof as described in any one of Examples 50 or 51, wherein R3 is selected from methyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0143] Example 54: A compound or a salt thereof as described in any one of Examples 50 or 51, wherein R3 is a methyl group.

[0144] Example 55: A compound or a salt thereof as described in any one of Examples 50-54, wherein R 6a and R 6b Together with intercalation atoms, they form a five-membered heteroaryl ring selected from pyrrole, pyrazole, and imidazole, any of which is optionally bonded by one or more R atoms. 6 Group substitution.

[0145] Example 56: A compound or a salt thereof as described in any one of Examples 50-55, wherein R 6 It is selected from alkyl, haloalkyl and cycloalkyl.

[0146] Example 57: A compound or a salt thereof as described in any one of Examples 50-56, wherein:

[0147] X is CR 6c ;and

[0148] Y is N.

[0149] Example 58: A compound or a salt thereof as described in any one of Examples 50-54, wherein R 6a and R 6b Independently selected from H and NR11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 .

[0150] Example 59: A compound or a salt thereof as described in Example 58, wherein R 6b It is H.

[0151] Example 60: A compound or a salt thereof as described in any one of Examples 58 or 59, wherein R 6a Selected from H, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl and OR 11 .

[0152] Example 61: A compound or a salt thereof as described in any one of Examples 58-60, wherein

[0153] X is CR 6c ;and

[0154] Y is N.

[0155] Example 62: A compound or a salt thereof as described in any one of Examples 58-61, wherein R 6c It is NH2.

[0156] Example 63: A compound or a salt thereof as described in any one of Examples 58-62, wherein R 6a Selected from H and OR 11 .

[0157] Example 64: A compound or a salt thereof as described in any one of Examples 58-63, wherein R 11 It is C 1-4 alkyl.

[0158] Example 65: A compound or a salt thereof as described in any one of Examples 58-64, wherein R 1 and R 2 It is independently selected from cyclopropyl, oxetane-3-yl and methyl.

[0159] Example 66: A compound or a salt thereof as described in any one of Examples 58-65, wherein R1 and R 2 At least one of them is methyl.

[0160] Example 67: A compound or a salt thereof as described in any one of Examples 58-66, wherein R 1 and R 2 One of them is methyl.

[0161] Example 68: A compound or a salt thereof as described in Example 66, wherein R 1 and R 2 It is a methyl group.

[0162] Example 69: A compound or a salt thereof as described in Example 66, wherein R 1 It is methyl and R 2 It is cyclopropyl.

[0163] Example 70: A compound or a salt thereof as described in Example 66, wherein R 1 It is cyclopropyl and R 2 It is a methyl group.

[0164] This document provides Example 71: A compound having structural formula (V):

[0165]

[0166] Or its salt, wherein:

[0167] X is selected from N and CR. 6c ;

[0168] Y is selected from N and CR. 6d ;

[0169] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 aryl and heteroaryl, either of which may optionally be influenced by one or more R 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0170] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0171] Each R5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0172] R 6a and R 6b Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ,

[0173] Or R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6 heteroaryl rings with substituent groups;

[0174] Each R 6c and R 6d Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0175] R 6 Selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0176] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0177] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0178] This document provides Example 72: A compound having the structural formula (Va):

[0179]

[0180] Or its salt, wherein:

[0181] X is selected from N and CR. 6c ;

[0182] Y is selected from N and CR. 6d ;

[0183] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0184] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0185] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0186] R 6a and R 6b Independently selected from H and NR 11 R 12Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ,

[0187] Or R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6 heteroaryl rings with substituent groups;

[0188] Each R 6c and R 6d Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0189] R 6 Selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR11 and C(O)NR 11 R 12 ;

[0190] Each R 7 R 8 and R 9 Independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0191] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0192] This disclosure provides additional embodiments:

[0193] Example 73: A compound or a salt thereof as described in any one of Examples 71 or 72, wherein R 6a and R 6b Together with intercalated atoms, they form a pyridine ring.

[0194] Example 74: A compound or a salt thereof as described in any one of Examples 71-73, wherein:

[0195] R 6a and R 6b Independently selected from H, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl and hydroxyalkyl; and

[0196] Each R 6c and R 6d Independently selected from H, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl and hydroxyalkyl.

[0197] Example 75: A compound as described in Example 71, wherein the compound is Or its salt.

[0198] This document provides Example 76: A compound having structural formula (VI):

[0199]

[0200] Or its salt, wherein:

[0201] X is selected from N and CR. 6c ;

[0202] Y is selected from N and CR. 6d ;

[0203] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0204] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0205] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0206] R 6a and R6b Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ,

[0207] Or R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6 heteroaryl rings with substituent groups;

[0208] Each R 6c and R 6d Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0209] R 6 Selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0210] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0211] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0212] This document provides Example 77: A compound having structural formula (VIa):

[0213]

[0214] Or its salt, wherein:

[0215] X is selected from N and CR. 6c ;

[0216] Y is selected from N and CR. 6d ;

[0217] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0218] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0219] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0220] R 6a and R 6b Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ,

[0221] Or R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6heteroaryl rings with substituent groups;

[0222] Each R 6c and R 6d Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0223] R 6 Selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0224] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0225] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0226] This disclosure provides additional embodiments:

[0227] Example 78: A compound or a salt thereof as described in any one of Examples 76 or 77, wherein R 6a and R 6b Together with intercalated atoms, they form a pyridine ring.

[0228] Example 79: A compound or a salt thereof as described in any one of Examples 76-78, wherein each R 6c and R 6d Independently selected from H, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl and hydroxyalkyl.

[0229] Example 80: A compound as described in Example 76, wherein the compound is selected from...

[0230] Or its salt.

[0231] This document provides Example 81: A compound having structural formula (VII):

[0232]

[0233] Or its salt, wherein:

[0234] X is selected from N and CR. 6c ;

[0235] Y is selected from N and CR. 6d ;

[0236] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0237] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0238] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0239] R 6a and R 6b Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ,

[0240] Or R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6 A aryl or heteroaryl ring with a substituent group;

[0241] Each R 6c and R6d Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0242] R 6 Selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0243] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0244] Each R 10 R 11 and R 12 Independently selected from hydrogen and C1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0245] This document provides Example 82: A compound having structural formula (VIIa):

[0246]

[0247] Or its salt, wherein:

[0248] X is selected from N and CR. 6c ;

[0249] Y is selected from N and CR. 6d ;

[0250] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Group-substituted 4-, 5-, 6-, or 7-membered heterocyclic alkyl rings;

[0251] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0252] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0253] R 6a and R 6b Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ,

[0254] Or R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6 A aryl or heteroaryl ring with a substituent group;

[0255] Each R 6c and R 6d Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0256] R 6 Selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0257] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any one of which may be converted by a halogen group, hydroxyl group, C-group, etc. 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0258] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0259] This disclosure provides additional embodiments:

[0260] Example 83: A compound or a salt thereof as described in any one of Examples 81 or 82, wherein R 6a and R 6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 A benzene ring substituted with a group.

[0261] Example 84: A compound or a salt thereof as described in any one of Examples 81-83, wherein X is a CR 6c And Y is N.

[0262] Example 85: A compound or a salt thereof as described in any one of Examples 81-84, wherein R 6c Selected from H, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl and hydroxyalkyl.

[0263] Example 86: A compound or a salt thereof as described in Example 85, wherein R 6c Selected from H and alkyl groups.

[0264] Example 87: A compound or a salt thereof as described in Example 86, wherein R 6c Selected from H and methyl.

[0265] Example 88: A compound or a salt thereof as described in Example 86, wherein R 6c It is a methyl group.

[0266] Example 89: A compound or a salt thereof as described in any one of Examples 81-88, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl.

[0267] Example 90: A compound or a salt thereof as described in any one of Examples 81-88, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0268] Example 91: A compound or a salt thereof as described in Example 89, wherein R 1 and R 2 At least one of them is methyl.

[0269] Example 92: A compound or a salt thereof as described in Example 89, wherein R 1 and R 2 Only one of them is selected from cyclopropyl and oxetane-3-yl.

[0270] Example 93: A compound or a salt thereof as described in Example 91, wherein R 1 and R 2 Only one of them is cyclopropyl.

[0271] Example 94: A compound or a salt thereof as described in Example 91, wherein R 1 and R 2 It is a methyl group.

[0272] Example 95: A compound or a salt thereof as described in any one of Examples 81-93, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0273] Example 96: A compound or a salt thereof as described in Example 81, wherein the compound is selected from:

[0274]

[0275]

[0276]

[0277] Or its salt.

[0278] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6a and R 6b Combined with intercalation atoms, they form optionally one or more R 6 A heteroaryl ring with a substituent group.

[0279] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6a and R 6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 Five-membered heteroaryl rings substituted with functional groups.

[0280] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6a and R 6b Together with intercalating atoms, they form a five-membered heteroaryl ring selected from pyrrole, pyrazole, and imidazole, any one of which is optionally separated by one or two R atoms. 6 Group substitution.

[0281] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6a and R 6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 A six-membered heteroaryl ring with a substituent group.

[0282] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6a and R 6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 A pyridine ring with a substituent group.

[0283] In some embodiments of compounds having formulas selected from (IV) and (IVa), R 6a and R 6b Combined with intercalation atoms, they form optionally one or more R 6 A aryl ring with a substituent group.

[0284] In some embodiments of compounds having formulas selected from (IV) and (IVa), R 6a and R 6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 A benzene ring substituted with a group.

[0285] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6 It is selected from halogen, cyano, alkyl, haloalkyl and cycloalkyl.

[0286] In some embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), X is N and Y is CR. 6c .

[0287] In some embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), X is CR 6c And Y is N.

[0288] In some embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), X and Y are both CR 6c .

[0289] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6a and R 6b Independently selected from H and NR 11 R12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 .

[0290] In certain embodiments of compounds having the formulas (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6a and R 6b Independently selected from H and NR 11 R 12 , halogen, alkyl, haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0291] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6b It is H.

[0292] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6a It is H.

[0293] In certain embodiments of compounds having formulas selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), each R 6c and R 6d Independently selected from H, NH2, halogen, cyano, alkyl, OR 11 and C(O)NR 11 R 12 .

[0294] In some embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), at most one R 6c Not H.

[0295] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 6c It is H.

[0296] In certain embodiments of compounds having the formulas (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution.

[0297] In certain embodiments of compounds having the formulas (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, any of which may optionally be bound by one or more R 5 Group substitution.

[0298] In certain embodiments of compounds having the formulas (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 Selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, any of which may optionally be composed of one or two R 5 Group substitution.

[0299] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 At least one of them is C 1-4 alkyl.

[0300] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2At least one of them is methyl.

[0301] In certain embodiments of compounds having the formulas (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0302] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 At least one of them is C 1-4 alkyl.

[0303] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 At least one of them is methyl.

[0304] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 One of them is selected from C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0305] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 One of them is selected from cyclopropyl and oxetane-3-yl.

[0306] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 It is a methyl group.

[0307] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 A 4, 5, 6 or 7-membered heterocyclic alkyl ring substituted with a functional group.

[0308] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 Together with the sulfur attached to both of them, they form an optional structure with one or two R 5 5-7 membered heterocyclic alkyl rings substituted with functional groups.

[0309] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 Together with sulfur attached to both, they form a 5-7 membered heterocyclic alkyl ring selected from cyclopentane sulfide and thiomorpholine, either of which is optionally bounded by one or two R... 5 Group substitution.

[0310] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 1 and R 2 Together with sulfur attached to both of them, they form 4, 5, 6 or 7-membered heterocyclic alkyl rings.

[0311] In certain embodiments of compounds having formulas selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), each R 5 Independently selected from halogen, cyano, hydroxyl, OR 8 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0312] In certain embodiments of compounds having formulas selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), each R 5 Independently selected from C(O)R 8 and C(O)OR 8 .

[0313] In certain embodiments of compounds having formulas selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), each R 8 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be converted by a halogen group, a hydroxyl group, and a C-group. 1-3 Alkyl-substituted.

[0314] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 3 It is H.

[0315] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 3 Selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0316] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 3 Selected from C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[0317] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 3 It is selected from methyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0318] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 3 It is C 1-6 alkyl.

[0319] In certain embodiments of compounds having the formula selected from (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R 3 It is a methyl group.

[0320] In certain embodiments of compounds having the formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), any of the listed alkoxy groups is C 1-3 Alkyl group.

[0321] In some embodiments, the compound is selected from:

[0322]

[0323] Or any of the above-mentioned salts.

[0324] In some embodiments, the compound is selected from:

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] Or any of the above-mentioned salts.

[0337] This disclosure provides additional embodiments:

[0338] Example 97: A compound or a salt thereof as described in any one of Examples 50, 51, 71, 72, 76, 77, 81 or 82, wherein R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6 A heteroaryl ring with a substituent group.

[0339] Example 98: A compound or a salt thereof as described in Example 97, wherein R 6a and R6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 Five-membered heteroaryl rings substituted with functional groups.

[0340] Example 99: A compound or a salt thereof as described in Example 98, wherein R 6a and R 6b Together with intercalating atoms, they form a five-membered heteroaryl ring selected from pyrrole, pyrazole, and imidazole, any one of which is optionally separated by one or two R atoms. 6 Group substitution.

[0341] Example 100: A compound or a salt thereof as described in Example 97, wherein R 6a and R 6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 A six-membered heteroaryl ring with a substituent group.

[0342] Example 101: A compound or a salt thereof as described in Example 100, wherein R 6a and R 6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 A pyridine ring with a substituent group.

[0343] Example 102: A compound or a salt thereof as described in Example 81, wherein R 6a and R 6b Combined with intercalation atoms, they form optionally formed by one or more R 6 A aryl ring with a substituent group.

[0344] Example 103: A compound or a salt thereof as described in Example 102, wherein R 6a and R 6b Combined with intercalation atoms, they form a group that is optionally bounded by one or two R atoms. 6 A benzene ring substituted with a group.

[0345] Example 104: A compound or a salt thereof as described in any one of Examples 97-103, wherein R 6 It is selected from halogen, cyano, alkyl, haloalkyl and cycloalkyl.

[0346] Example 105: A compound or a salt thereof as described in any one of Examples 50-104, wherein X is N and Y is CR. 6c .

[0347] Example 106: A compound or a salt thereof as described in any one of Examples 50-104, wherein X is a CR 6c And Y is N.

[0348] Example 107: A compound or a salt thereof as described in any one of Examples 50-104, wherein X and Y are both CR 6c .

[0349] Example 108: A compound or a salt thereof as described in any one of Examples 50-81, wherein R 6a and R 6b Independently selected from H and NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 .

[0350] Example 109: The compound as described in Example 108, wherein R 6a and R 6b Independently selected from H and NR 11 R 12 , halogen, alkyl, haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0351] Example 110: A compound or salt thereof as described in any one of Examples 108 or 109, wherein R 6b It is H.

[0352] Example 111: A compound or salt thereof as described in any one of Examples 108, 109 or 110, wherein R 6a It is H.

[0353] Example 112: A compound or a salt thereof as described in any one of Examples 50-111, wherein each R 6c and R 6d Independently selected from H, NH2, halogen, cyano, alkyl, OR 11 and C(O)NR 11 R 12 .

[0354] Example 113: A compound or a salt thereof as described in Example 112, wherein at most one R 6c Not H.

[0355] Example 114: A compound or a salt thereof as described in Example 112, wherein R 6c It is H.

[0356] Example 115: A compound or a salt thereof as described in any one of Examples 1-114, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-10 aryl and 5-10 heteroaryl groups, any one of which may be selectively bound by one or more R groups. 5 Group substitution.

[0357] Example 116: A compound or a salt thereof as described in Example 115, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, any of which may optionally be bound by one or more R 5 Group substitution.

[0358] Example 117: A compound or a salt thereof as described in Example 116, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, any of which may optionally be composed of one or two R 5 Group substitution.

[0359] Example 118: A compound or a salt thereof as described in any one of Examples 115-117, wherein R 1 and R 2 At least one of them is C 1-4 alkyl.

[0360] Example 119: A compound or a salt thereof as described in Example 118, wherein R 1 and R 2 At least one of them is methyl.

[0361] Example 120: A compound or a salt thereof as described in Example 116, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0362] Example 121: A compound or a salt thereof as described in Example 120, wherein R 1 and R 2 At least one of them is C 1-4 alkyl.

[0363] Example 122: A compound or a salt thereof as described in Example 121, wherein R 1 and R 2 At least one of them is methyl.

[0364] Example 123: A compound or salt thereof as described in any one of Examples 121 or 122, wherein R 1 and R 2 One of them is selected from C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups.

[0365] Example 124: A compound or a salt thereof as described in Example 123, wherein R 1 and R 2 One of them is selected from cyclopropyl and oxetane-3-yl.

[0366] Example 125: A compound or a salt thereof as described in Example 122, wherein R 1 and R 2 It is a methyl group.

[0367] Example 126: A compound or a salt thereof as described in any one of Examples 1-111, wherein R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 A 4, 5, 6 or 7-membered heterocyclic alkyl ring substituted with a functional group.

[0368] Example 127: A compound or a salt thereof as described in Example 126, wherein R 1 and R 2 Together with the sulfur attached to both of them, they form an optional structure with one or two R 5 5-7 membered heterocyclic alkyl rings substituted with functional groups.

[0369] Example 128: A compound or a salt thereof as described in Example 127, wherein R 1 and R 2 Together with sulfur attached to both, they form a 5-7 membered heterocyclic alkyl ring selected from cyclopentane sulfide and thiomorpholine, either of which is optionally bounded by one or two R... 5 Group substitution.

[0370] Example 129: A compound or a salt thereof as described in Example 126, wherein R 1 and R 2Together with sulfur attached to both of them, they form 4, 5, 6 or 7-membered heterocyclic alkyl rings.

[0371] Example 130: A compound or a salt thereof as described in any one of Examples 115, 116, 117, 118, 119, 126, 127 or 128, wherein each R 5 Independently selected from halogen, cyano, hydroxyl, OR 8 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0372] Example 131: A compound or a salt thereof as described in Example 130, wherein each R 5 Independently selected from C(O)R 8 and C(O)OR 8 .

[0373] Example 132: A compound or salt thereof as described in any one of Examples 130 or 131, wherein each R 8 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups, any of which may optionally be converted by a halogen group, a hydroxyl group, and a C-group. 1-3 Alkyl-substituted.

[0374] Example 133: A compound or a salt thereof as described in any one of Examples 1-132, wherein R 3 It is H.

[0375] Example 134: A compound or a salt thereof as described in any one of Examples 1-132, wherein R 3 Selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0376] Example 135: A compound or a salt thereof as described in Example 134, wherein R 3 Selected from C 1-6 Alkyl and C 1-6 Fluoroalkyl groups.

[0377] Example 136: A compound or a salt thereof as described in Example 135, wherein R 3 It is selected from methyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0378] Example 137: A compound or a salt thereof as described in Example 134, wherein R 3 It is C 1-6 alkyl.

[0379] Example 138: A compound or a salt thereof as described in Example 137, wherein R 3 It is a methyl group.

[0380] Pharmaceutical compositions comprising the compounds disclosed herein or salts thereof, together with a pharmaceutically acceptable carrier, are also provided. In some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138).

[0381] In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0382] In some embodiments, the oral pharmaceutical composition is selected from tablets and capsules.

[0383] In some embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0384] This disclosure also relates to a method for inhibiting the function of at least one ATR kinase, the method comprising contacting the ATR kinase with a compound described herein or a salt thereof. Changes in cell phenotype, cell proliferation, ATR kinase activity, biochemical outputs produced by active ATR kinase, ATR kinase expression, or binding of ATR kinase to a natural binding partner can be monitored. Such methods can be used as disease treatment modalities, bioassays, cellular assays, biochemical assays, etc.

[0385] This document also provides a method for treating ATR kinase-mediated diseases, comprising administering to a patient in need a therapeutically effective amount of a compound as disclosed herein or a salt thereof. In some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138).

[0386] In some embodiments, ATR kinase-mediated diseases are proliferative disorders.

[0387] In some embodiments, the proliferative disorder is myeloproliferative disorder.

[0388] In some embodiments, proliferative diseases are cancers.

[0389] In some embodiments, the cancer is lymphoma.

[0390] In some embodiments, the cancer is B-cell lymphoma.

[0391] In some embodiments, the cancer is pancreatic cancer.

[0392] This document also provides for use as a medicament of the disclosed compounds or salts thereof; or for use as a medicament of the disclosed pharmaceutical compositions. In either case, in some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138).

[0393] This document also provides the disclosed compounds or salts thereof for use as medicaments for treating ATR kinase-mediated diseases. In any instance, in some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138). In some embodiments, the ATR kinase-mediated disease is a proliferative disease. In some embodiments, the proliferative disease is myeloproliferative disorder. In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is pancreatic cancer.

[0394] The use of the compounds disclosed herein or their salts as pharmaceuticals is also provided; or the use of the pharmaceutical compositions disclosed herein as pharmaceuticals. In some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138).

[0395] Also provided are the use of the compounds disclosed herein or salts thereof as medicaments for treating ATR kinase-mediated diseases; or the use of the pharmaceutical compositions disclosed herein as medicaments for treating ATR kinase-mediated diseases; the use of the compounds disclosed herein or salts thereof in the manufacture of medicaments for treating ATR kinase-mediated diseases; or the use of the pharmaceutical compositions disclosed herein in the manufacture of medicaments for treating ATR kinase-mediated diseases; or the use of the compounds disclosed herein or salts thereof in the treatment of ATR kinase-mediated diseases; or the use of the pharmaceutical compositions disclosed herein in the treatment of ATR kinase-mediated diseases. In some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138). In any of these cases, in some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138). In some embodiments, the ATR kinase-mediated disease is a proliferative disease. In some embodiments, the proliferative disease is a myeloproliferative disorder. In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma. In some embodiments, the cancer is pancreatic cancer.

[0396] This document also provides a method for inhibiting ATR kinase, the method comprising contacting the ATR kinase with a compound disclosed herein or a salt thereof. In some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138).

[0397] This document also provides a method for achieving an effect in a patient, the method comprising administering a therapeutically effective amount of the compound disclosed herein or a salt thereof to the patient, wherein the effect is selected from cognitive enhancement. In some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138).

[0398] Methods for modulating ATR kinase-mediated function in subjects are also provided, comprising administering a therapeutically effective amount of the compound disclosed herein or a salt thereof. In some embodiments, the compound is the compound disclosed in any of the foregoing embodiments (including any of Examples 1-138). Detailed Implementation

[0399] the term

[0400] As used herein, the following terms have indicative meanings.

[0401] When numerical ranges are disclosed and notation such as “n1…to n2” or “between n1…and n2” is used, where n1 and n2 are numbers, this notation is intended to include the numbers themselves as well as the range between them, unless otherwise specified. The range can be a complete or continuous range between these endpoints and includes those endpoints. For example, the range “2 to 6 carbons” is intended to include two, three, four, five, and six carbons because carbon appears in integer units. For example, the range “1 μM to 3 μM (micromolars)” (intended to include 1 μM, 3 μM, and all numbers in between) is compared to many significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0402] As used in this article, the term “approximately” is intended to define the numerical value it modifies, indicating that the value is a variable within the error limits. When no specific error limits are listed (such as the standard deviation of the mean given in a chart or data table), the term “approximately” should be understood to mean the range that covers the listed values, and the range that is included considering significant figures through rounding.

[0403] As used alone or in combination herein, the term "acyl" refers to a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclic, or any other moiety, wherein the atom attached to the carbonyl group is carbon. An "acetyl" group refers to a -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to a portion of the parent molecule via a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aromatic acyl groups.

[0404] As used herein, alone or in combination, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In some embodiments, the alkenyl group will contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached to two or more sites, such as vinylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl groups include vinyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, etc. Unless otherwise specified, the term "alkenyl" may include "alkenylene" groups.

[0405] As used alone or in combination herein, the term "alkoxy" refers to an alkyl ether group, wherein the term alkyl is defined as follows. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0406] As used herein, the term "alkyl" alone or in combination means a straight-chain or branched alkyl group containing 1 to 20 carbon atoms. In some embodiments, the alkyl group will contain 1 to 10 carbon atoms. In other embodiments, the alkyl group will contain 1 to 8 carbon atoms. The alkyl group may optionally be substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, nonyl, etc. As used herein, the term "alkylene" alone or in combination means a saturated aliphatic group derived from a straight-chain or branched saturated hydrocarbon attached to two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.

[0407] As used alone or in combination herein, the term "alkylamino" refers to an alkyl group attached to a portion of the parent molecule via an amino group. Suitable alkylamino groups can be monoalkylated or dialkylated forming groups, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, etc.

[0408] The term “pseudoalkyl” as used alone or in combination herein refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond is part of the alkenyl group to which it is attached.

[0409] As used alone or in combination herein, the term "alkylthio" refers to an alkyl thioether (RS-) group, wherein the term alkyl is as defined above, and wherein sulfur may be mono- or di-oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfonyl, etc.

[0410] As used herein, the term "alkynyl" alone or in combination refers to a straight-chain or branched hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In some embodiments, the alkynyl group contains 2 to 6 carbon atoms. In other embodiments, the alkynyl group contains 2 to 4 carbon atoms. The term "ynynyl" refers to a carbon-carbon triple bond attached to two positions, such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, etc. Unless otherwise specified, the term "alkynyl" may include an "ynynyl" group.

[0411] As used individually or in combination herein, the terms “amide group” and “carbamoyl group” refer to an amino group attached to a parent molecule via a carbonyl group, as described below, and vice versa. The term “C-amide group” as used individually or in combination herein refers to a -C(O)N(RR') group, where R and R' are as defined herein or as defined by the specific enumeration of “R” groups specified herein. The term “N-amide group” as used individually or in combination herein refers to an RC(O)N(R')- group, where R and R' are as defined herein or as defined by the specific enumeration of “R” groups specified herein. The term “acylamino” as used individually or in combination herein includes an acyl group attached to a parent molecule via an amino group. An example of an “acylamino” group is acetylamino (CH3C(O)NH-).

[0412] The term "amino" as used alone or in combination in this article refers to -NRR ’ , where R and R ’ The groups are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any one of which may be optionally substituted. Furthermore, R and R' may combine to form heterocycloalkyl groups, either of which may be optionally substituted.

[0413] As used alone or in combination herein, the term "aryl" refers to a carbocyclic aromatic system containing one, two, or three rings, wherein such polycyclic rings are fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthracene, and phenanthrene.

[0414] As used alone or in combination in this article, the terms "aryl-alkenyl" or "aryl-alkenyl" refer to an aryl group attached to a portion of the parent molecule via an alkenyl group.

[0415] As used alone or in combination in this article, the terms "arylalkoxy" or "arylalkoxy" refer to an aryl group attached to a portion of the parent molecule via an alkoxy group.

[0416] As used alone or in combination in this article, the terms "arylalkyl" or "aryl" refer to an aryl group attached to a portion of the parent molecule via an alkyl group.

[0417] As used alone or in combination in this article, the terms "arylynyl" or "aryynyl" refer to an aryl group attached to a portion of the parent molecule via an ynyl group.

[0418] As used alone or in combination in this article, the terms “arylalkylacyl” or “aryl acyl” or “aryl” refer to the acyl group derived from an aryl-substituted alkyl carboxylic acid, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, etc.

[0419] As used alone or in combination in this article, the term aryloxy group refers to an aryl group attached to a portion of the parent molecule via an oxygen group.

[0420] As used alone or in combination herein, the term "benzo[]" refers to the divalent group C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.

[0421] As used alone or in combination herein, the term "carbamate" refers to an ester (-NHCOO-) of carbamic acid that may be attached from the nitrogen or acid end to the parent molecule and may optionally be substituted as defined herein.

[0422] As used alone or in combination herein, the term “O-carbamoyl” refers to the -OC(O)NRR’ group, where R and R’ are as defined herein.

[0423] As used alone or in combination herein, the term “N-carbamoyl” refers to the ROC(O)NR'- group, where R and R' are as defined herein.

[0424] The term “carbonyl” in this article includes formyl [-C(O)H] when used alone, and is a -C(O)- group when used in combination.

[0425] As used herein, the term "carboxyl group" refers to -C(O)OH or the corresponding "carboxylate" anion, such as in carboxylate salts. "O-carboxyl" group refers to the RC(O)O- group, where R is as defined herein. "C-carboxyl" group refers to the -C(O)OR group, where R is as defined herein.

[0426] The term "cyano" as used alone or in combination in this article refers to -CN.

[0427] As used herein, the term “cycloalkyl” alone or in combination refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, wherein each ring moiety contains 3 to 12 carbon atom ring members, and optionally is a benzo-fused ring system optionally substituted as defined herein. In some embodiments, the cycloalkyl group will contain 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indanyl, adamantyl, etc. As used herein, “bicyclic” and “tricyclic” are intended to include two fused ring systems, such as decahydronaphthyl, octahydronaphthyl, and polycyclic (multicentric) saturated or partially unsaturated types. Isomers of the latter type are generally exemplified by bicyclic [1.1.1]pentane, camphor, adamantane, and bicyclic [3.2.1]octane. As used individually or in combination, “cycloalkyl” in this article encompasses “bicycloalkyl”, “bridged cycloalkyl” and “spirocycloalkyl” as defined below.

[0428] As used alone or in combination herein, the term "bicycloalkyl" refers to a cyclic alkyl system characterized by the presence of two atoms, referred to as "bridgehead atoms," which are interconnected by three bonds. Thus, for example, "bicycloalkyl" encompasses bicyclo[2.2.1]heptane (also known as norbornane), bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, and bicyclo[3.3.0]octane.

[0429] As used alone or in combination herein, the term "bridged cycloalkyl" refers to a dibridged alkyl system in which all three bond pathways between the bridgehead atoms contain at least one atom. Thus, for example, "bridged cycloalkyl" encompasses bicyclo[2.2.1]heptane (also known as norbornane) and bicyclo[2.2.2]octane. Therefore, "bridged cycloalkyl" does not encompass bicyclo[2.2.0]hexane or bicyclo[3.3.0]octane.

[0430] As used alone or in combination in this article, the term "ester" refers to a carboxyl group that bridges two parts connected at a carbon atom.

[0431] As used alone or in combination in this article, the term "ether" refers to an oxygen group that bridges two parts connected at a carbon atom.

[0432] As used alone or in combination in this article, the terms “halogen” or “halogen” refer to fluorine, chlorine, bromine, or iodine.

[0433] As used alone or in combination in this article, the term "haloalkoxy" refers to a haloalkyl group that is attached to a portion of the parent molecule via an oxygen atom.

[0434] As used alone or in combination herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, having the meaning as defined above. This includes monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups. For example, a monohaloalkyl group may have an iodine, bromine, chlorine, or fluorine atom within the group. Dihaloalkyl and polyhaloalkyl groups may have two or more identical halogen atoms or combinations of different halogen groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached to two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), etc.

[0435] As used alone or in combination herein, the term "heteroalkyl" refers to a stable straight-chain or branched hydrocarbon group or combination thereof that is fully saturated or contains one to three degrees of unsaturation and consists of the stated number of carbon atoms and one to three heteroatoms selected from N, O, and S, wherein the N and S atoms may optionally be oxidized and the N heteroatoms may optionally be quaternized. One or more heteroatoms may be placed at any internal position within the heteroalkyl group. The maximum number of heteroatoms may be consecutive, such as -CH2-NH-OCH3.

[0436] As used individually or in combination herein, the term "heteroaryl" refers to a 3- to 15-membered unsaturated heterocyclic monocyclic or fused monocyclic, bicyclic, or tricyclic ring system, wherein at least one fused ring is aromatic, and the heteroaryl contains at least one atom selected from N, O, and S. In some embodiments, the heteroaryl will contain 1 to 4 heteroatoms as ring members. In some embodiments, the heteroaryl will contain 1 to 3 heteroatoms as ring members. In other embodiments, the heteroaryl will contain 1 to 2 heteroatoms as ring members. In some embodiments, the heteroaryl will contain 5 to 7 atoms. The term also includes fused polycyclic groups, wherein the heterocycle is fused to an aryl ring, wherein the heteroaryl ring is fused to other heteroaryl rings, wherein the heteroaryl ring is fused to a heterocyclic alkyl ring, or wherein the heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrroloyl, pyrrolinyl, imidazoyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furanyl, thiophene, oxazolyl, isoxazolyl, oxadiazolyl, thiazoyl, thiazoyl, isothiazolyl, indoleyl, isoindoleyl, indazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxolinyl, quinazolinyl, indoleyl, benzotriazolyl, benzodioxacyclopentenyl, benzopyranyl, benzooxazolyl, benzooxadiazolyl, benzothiazoyl, benzothiazoyl, benzofuranyl, benzothiophene, crononeyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazopyridazinyl, tetrahydroisoquinolinyl, thiophene-pyridinyl, furan-pyridinyl, pyrrolopyridinyl, etc. Exemplary tricyclic heterocyclic groups include carbazole, benzoindolyl, phenanthrolinyl, dibenzofuranyl, acridineyl, phenanthridineyl, gurtolyl, etc.

[0437] Some heteroaryl groups are shown below:

[0438]

[0439]

[0440] As used individually or in combination herein, the terms "heterocyclic alkyl" and the interchangeable term "heterocyclic" refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group will contain 1, 2, 3, or 4 heteroatoms as ring members. In some embodiments, the heterocyclic alkyl group will contain 1, 2, or 3 heteroatoms as ring members. In other embodiments, the heterocyclic alkyl group will contain 1 or 2 heteroatoms as ring members. In some embodiments, the heterocyclic alkyl group will contain 3 to 6 ring members in each ring. In some embodiments, the heterocyclic alkyl group will contain 3 to 8 ring members in each ring. In other embodiments, the heterocyclic alkyl group will contain 3 to 7 ring members in each ring. In other embodiments, the heterocyclic alkyl group will contain 5 to 6 ring members in each ring. "Heterocyclic alkyl" and "heterocyclic" are intended to include sulfones, sulfoxides, sulfinimides, sulfonylimides, N-oxides having tertiary nitrogen ring members, and carbocyclic fused ring systems and benzo-fused ring systems; furthermore, both terms also include systems in which the heterocycle is fused with an aryl group or other heterocyclic group as defined herein. Examples of heterocyclic groups include acridinel, azacyclic butyl, 1,3-benzodioxane, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocenolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridyl, benzothiazolyl, dihydroindolyl, dihydropyridyl, 1,3-dioxalkyl, 1,4-dioxalkyl, 1,3-dioxopentyl, isodihydroindolyl, morpholinyl, piperazine, pyrrolidinyl, tetrahydropyridyl, piperidinyl, thiomorpholinyl, etc. Unless expressly prohibited, heterocyclic groups may optionally be substituted. The term “heterocyclic alkyl” as used alone or in combination herein shall be understood to encompass “heterocyclic bicyclic alkyl” and “bridged heterocyclic alkyl” as defined below.

[0441] As used alone or in combination herein, the term "heterocyclic alkyl" refers to a heterocyclic alkyl system characterized by the presence of two atoms, referred to as "bridgehead atoms," which are interconnected by three bonds. Thus, for example, "bicyclic alkyl" encompasses bicyclo[2.2.1]heptane (also known as norbornane), bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane, and bicyclo[3.3.0]octane.

[0442] As used alone or in combination herein, the term “bridged heterocycloalkyl” refers to a heterodibridged alkyl system in which all three bond pathways between the bridgehead atoms contain at least one atom. Thus, for example, “bridged heterocycloalkyl” encompasses 1,4-diazabicyclo[2.2.2]octane (also known as DABCO) and 7-diazabicyclo[2.2.1]heptane.

[0443] Bicyclic systems can be described using terminology that will be recognized by those skilled in the art. A bicyclic compound can be referred to as a fusion of two ring systems. For example, “benzo[a]benzene” should be understood to refer to naphthalene. Unless specifically limited, any ring-fused isomers will be included by this term. For example, “benzo[a]naphthalene” should be understood to include both anthracene and phenanthrene. As another example, pyrrolopyridine should be understood to include any compound having pyrrole fused with pyridine, and therefore includes 4-azaindole, 5-azaindole, 6-azaindole, and 7-azaindole.

[0444] As used alone or in combination herein, the term "heterocyclic alkyl" refers to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic) cyclic alkyl system characterized by the presence of two atoms, referred to as "bridgehead atoms," which are interconnected by three bonds. Thus, for example, "heterocyclic alkyl" includes 7-azabicyclo[2.2.1]heptane, 1,4-diazabicyclo[2.2.2]octane (also known as "DABCO"), 1-azabicyclo[2.2.0]hexane, and 3-azabicyclo[3.3.0]octane.

[0445] As used alone or in combination herein, the term “bridged heterocycloalkyl” refers to a heterodibridged alkyl system in which all three bond pathways between the bridgehead atoms contain at least one atom. Thus, for example, “bridged heterocycloalkyl” includes 7-azabicyclo[2.2.1]heptane and 1,4-diazabicyclo[2.2.2]octane (also known as “DABCO”), but excludes 1-azabicyclo[2.2.0]hexane or 3-azabicyclo[3.3.0]octane.

[0446] The term "hydrazine" as used alone or in combination in this article refers to two amino groups bonded by a single bond, namely -NN-.

[0447] The term "hydroxyl group" as used alone or in combination in this article refers to -OH.

[0448] As used alone or in combination herein, the term "hydroxyalkyl" refers to a hydroxyl group attached to a portion of a parent molecule via an alkyl group. Examples of hydroxyalkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 2-hydroxy-2-propyl.

[0449] The term "imino" as used alone or in combination in this article refers to =N-.

[0450] As used alone or in combination in this article, the term "iminohydroxyl" refers to =N(OH) and =NO-.

[0451] The phrase “in the main chain” refers to the longest continuous chain or adjacent chain from the group to the attachment point of a compound having any of the formulas disclosed herein.

[0452] The term "isocyanate group" refers to the -NCO group.

[0453] The term "isothiocyanate group" refers to the -NCS group.

[0454] The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0455] The term “lower” as used alone or in combination herein means, unless otherwise explicitly defined, that which contains 1 to 6 carbon atoms, including 6 carbon atoms (i.e., C1-C6 alkyl).

[0456] The term “lower aryl” as used alone or in combination herein means phenyl or naphthyl, either of which may optionally be substituted as provided.

[0457] As used alone or in combination herein, the term “lower heteroaryl” means 1) a monocyclic heteroaryl containing five or six ring members, wherein one to four members may be heteroatoms selected from N, O and S, or 2) a bicyclic heteroaryl, wherein each fused ring contains five or six ring members, wherein one to four ring members contain heteroatoms selected from N, O and S.

[0458] As used alone or in combination herein, the term "lower cycloalkyl" means a monocyclic cycloalkyl group (i.e., C3-C6 cycloalkyl) having three to six ring members. Lower cycloalkyl groups may be unsaturated. Examples of lower cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0459] As used alone or in combination herein, the term "lower heterocyclic alkyl" means a monocyclic heterocyclic alkyl group having three to six ring members, wherein one to four ring members may be heteroatoms selected from N, O, and S (i.e., C3-C6 heterocyclic alkyl). Examples of lower heterocyclic alkyl groups include pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocyclic alkyl groups may be unsaturated.

[0460] As used alone or in combination herein, the term "lower amino" refers to -NRR', where R and R' are independently selected from hydrogen and lower alkyl groups, either of which may optionally be substituted.

[0461] As used alone or in combination in this document, the term "thiol" refers to the RS- group, where R is as defined herein.

[0462] The term "nitro" as used alone or in combination in this article refers to -NO2.

[0463] As used alone or in combination in this article, the terms “oxygen group” or “oxo-” refer to -O-.

[0464] The term "oxo" as used alone or in combination in this article refers to =O.

[0465] The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0466] As used alone or in combination in this article, the term "fully halogenated alkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0467] As used alone or in combination herein, the term "spirocycloalkyl" refers to an alkyl group having two rings and a single atom common to both rings. Examples of spirocycloalkyl systems include spiro[3.3]heptane and spiro[4.4]nonane.

[0468] As used alone or in combination herein, the term "spirocycloalkyl" refers to a heteroalkyl group having two rings and a single atom common to both rings. Examples of spirocycloalkyl systems include 2-azaspiro[3.3]heptane and 3-azaspiro[4.4]nonane.

[0469] The term "sulfonic acid" as used alone or in combination herein refers to the -SO3H group and its anion as a sulfonic acid used in salt formation.

[0470] The term "hydrothio-" as used alone or in combination in this article refers to -S-.

[0471] The term "sulfinyl" as used alone or in combination in this article refers to -S(O)-.

[0472] The term "sulfonyl" as used alone or in combination in this article refers to -S(O)2-.

[0473] The term “N-sulfonamide” refers to the RS(=O)2NR'- group, where R and R' are as defined herein.

[0474] The term “S-sulfonamide” refers to the -S(=O)2NRR' group, where R and R' are as defined herein.

[0475] The term "sulfonamide" refers to the RS(=NR')R” group, where R, R', and R” are as defined herein.

[0476] The term "sulfinimide" refers to the RS(=O)(=NR')R” group, where R, R', and R” are as defined herein.

[0477] As used individually or in combination herein, the terms “thia” and “thio” refer to an ether with an -S- group or in which oxygen is replaced by sulfur. Oxidized derivatives of the thio group (i.e., sulfinyl and sulfonyl groups) are included in the definitions of thia and thio.

[0478] The term "thiol" as used alone or in combination in this article refers to the -SH group.

[0479] The term “thiocarbonyl” in this article includes thioformyl-C(S)H when used alone, and is a -C(S)- group when used in combination.

[0480] The term “N-thiocarbamoyl” refers to the ROC(S)NR'- group, where R and R' are as defined herein.

[0481] The term “O-thiocarbamoyl” refers to the -OC(S)NRR' group, where R and R' are as defined herein.

[0482] The term "thiocyanate" refers to the -CNS group.

[0483] The term “trihalomethanesulfonamide” refers to the X3CS(O)2NR- group, where X is a halogen and R is as defined herein.

[0484] The term "trihalomethanesulfonyl" refers to the X3CS(O)2- group, where X is a halogen.

[0485] The term "trihalomethaneoxy" refers to the X3CO- group, where X is a halogen.

[0486] As used alone or in combination herein, the term "trisubstituted silyl" refers to a silane group whose three free valences are replaced by groups listed herein under the definition of substituted amino groups. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, etc.

[0487] Any definition in this document may be used in conjunction with any other definition to describe complex structural groups. By convention, the trailing element in any such definition is the element attached to the parent part. For example, the complex group alkylamide group indicates an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl indicates an alkoxy group attached to the parent molecule via an alkyl group.

[0488] When a group is defined as "none", it means that the group does not exist.

[0489] The term "optionally substituted" means that the aforementioned group may or may not be substituted. When substituted, the substituents of the "optionally substituted" group may include, but are not limited to, one or more substituents independently selected from the following groups or a specifically designated group of groups (alone or in combination): lower alkyl, lower alkenyl, lower alkynyl, lower acyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo. The following groups are included: lower acyloxy groups, carbonyl groups, carboxyl groups, lower alkyl carbonyl groups, lower carboxylic acid esters, lower formamido groups, cyano groups, hydrogen, halogens, hydroxyl groups, amino groups, lower alkylamino groups, arylamino groups, amide groups, nitro groups, thiols, lower alkylthio groups, lower haloalkylthio groups, lower perhaloalkylthio groups, arylthio groups, sulfonates, sulfonic acids, trisubstituted silyl groups, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridyl, thiophene, furanyl, lower carbamates, and lower ureas. Where structurally feasible, two substituents can be joined together to form fused five-, six-, or seven-membered carbon rings or heterocycles consisting of zero to three heteroatoms, such as methylenedioxy or ethylenedioxy. Optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at a level between full and monosubstituted (e.g., -CH2CF3). In cases where substituents are listed but not definitively identified as substituted, both substituted and unsubstituted forms are included. When a substituent is definitively identified as "substituted," the substituted form is explicitly indicated. Furthermore, optional substituents for different groups of specific moieties can be defined as needed; in these cases, optional substitution will be, as defined, typically followed by the phrase "optionally substituted by...".

[0490] Unless otherwise defined, the term R or R' or R" (when appearing alone and without a numerical designation) refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may optionally be substituted. Such R, R', and R" groups should be understood as optionally substituted as defined herein. Regardless of whether the R group is numerically designated, each R group (including R, R', and R") nWhere n = (1, 2, 3, ... n)), each substituent, and each term should be understood to be independent of all other terms in selection from the group. If any variable, substituent, or term (e.g., aryl, heterocyclic, R, etc.) appears more than once in the formula or general structure, then its definition should be independent of its definition in each occurrence. Those skilled in the art will further recognize that certain groups may be attached to the parent molecule or may occupy a position in a chain of elements from either end as written. For example, asymmetric groups such as -C(O)N(R)- may be attached to the parent moiety at carbon or nitrogen.

[0491] As used alone or in combination in this article, the term "enantiomer" refers to one of a pair of compounds that are distinct in absolute stereochemistry at each stereocenter. Thus, each enantiomer in a pair of compounds is a mirror image of the other enantiomer.

[0492] The term “diamer” as used alone or in combination in this article refers to one of a pair of compounds that are absolutely stereochemically different in a single stereocenter.

[0493] As used alone or in combination in this article, the term “diastereomer” refers to one of a pair of compounds that are neither identical in stereochemistry nor enantiomers of each other.

[0494] Asymmetric centers are present in the compounds disclosed herein. These centers are designated by the symbols “R” or “S”, depending on the configuration of the substituents surrounding the chiral carbon atom. It should be understood that this disclosure covers all stereochemical isomers, including diastereomers, enantiomers, and epiomers, as well as D-isomers and L-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing mixtures of enantiomeric products followed by separation (e.g., conversion to a mixture of diastereomers), followed by separation or recrystallization, chromatography, direct separation of enantiomers on a chiral column, or any other suitable method known in the art. Starting compounds of a particular stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. Furthermore, the compounds disclosed herein can exist as geometric isomers. This disclosure includes all cis, trans, synonymous, antisense, isolateral (E), and homolateral (Z) isomers and suitable mixtures thereof. Furthermore, the compounds may exist as tautomers; this disclosure provides all tautomer isomers. Additionally, the compounds disclosed herein may exist in nonsolvent form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. Generally, the solvated form is considered equivalent to the nonsolvent form.

[0495] Some of the compounds disclosed herein can exist as a mixture of two diastereomers. In some embodiments, the two diastereomers are present in equal amounts. In some embodiments, the compound contains 60% or more of the major diastereomer. In some embodiments, the compound contains 70% or more of the major diastereomer. In some embodiments, the compound contains 80% or more of the major diastereomer. In some embodiments, the compound contains 90% or more of the major diastereomer. In some embodiments, the compound contains 95% or more of the major diastereomer. In some embodiments, the compound contains 98% or more of the major diastereomer.

[0496] The term "bond" refers to the covalent connection between two atoms or two parts when the atoms bound by the bond are considered part of a larger molecular structure. Unless otherwise specified, a bond can be a single, double, or triple bond. The dashed line between two atoms in a molecular diagram indicates the location where another bond may or may not be present.

[0497] As used herein, the term “disease” is intended to be generally synonymous and may be used interchangeably with the terms “disorder,” “symptom,” and “illness” (as in medical conditions), since all of these reflect an abnormality in a human or animal body or in one of the parts that impairs its normal function, typically manifested as distinct signs and symptoms, and resulting in a reduced lifespan or quality of life for the human or animal.

[0498] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic condition or disorder described in this disclosure. Such administration includes co-administering these therapeutic agents in a substantially simultaneous manner (such as in a single capsule having a fixed proportion of the active ingredients or in multiple separate capsules for each active ingredient). Furthermore, such administration also includes the sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effects of the combination of drugs in treating the condition or disorder described herein.

[0499] The term "ATR inhibitor" as used in this article refers to an IC50 concentration of no more than approximately 100 μM, and more typically no more than approximately 50 μM, relative to ATR kinase activity. 50 Compounds, such as those measured in the ATR / ATRIP biochemical assay or in the ATR kinase pCHK1 cell assay described herein. "IC 50 "This refers to the inhibitor concentration that reduces the activity of an enzyme (e.g., ATR kinase) or ATR-induced CHK1 phosphorylation at serine 345 in cells to half its maximum level. Certain compounds disclosed herein have been found to exhibit inhibition of ATR kinase. In some embodiments, the compounds will exhibit an IC50 concentration of no more than about 10 μM relative to ATR kinase." 50In another embodiment, the compound will exhibit an IC50 of no more than about 2 μM relative to ATR kinase. 50 In another embodiment, the compound will exhibit an IC50 of no more than about 1 μM relative to ATR kinase; in another embodiment, the compound will exhibit an IC50 of no more than about 500 nM relative to ATR kinase. 50 In another embodiment, the compound will exhibit an IC50 of no more than about 200 nM relative to ATR kinase. 50 In another embodiment, the compound will exhibit an IC50 of no more than about 100 nM relative to ATR kinase. 50 As measured in the ATR kinase assay described herein.

[0500] The phrase “therapeuticly effective” is intended to define the amount of active ingredient used in the treatment of a disease or disorder or in relation to a clinical endpoint.

[0501] The term “therapeutically acceptable” refers to compounds (or salts, prodrugs, tautomers, zwitterions, etc.) that are suitable for contact with patient tissues without causing excessive toxicity, irritation, or allergic reactions, and that are commensurate with a reasonable benefit / risk ratio and effective for their intended use.

[0502] As used herein, references to “treating” a patient are intended to include prevention. Treatment can also be preemptive in nature, meaning it can include disease prevention. Disease prevention can involve complete protection from disease, such as in the case of preventing infection by a pathogen, or it can involve prevention of disease progression. For example, disease prevention may not mean completely delineating any level of disease-related effects, but rather preventing the symptoms of the disease to a clinically significant or detectable level. Disease prevention can also mean preventing the progression of the disease to a later stage. In some embodiments, treatment is not preventative. For example, treatment is administered after the disease is diagnosed or after the onset of disease symptoms.

[0503] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock (such as cattle, goats, sheep, pigs, and rabbits), and pets (such as dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0504] The term "prodrug" refers to a compound that becomes more active in vivo. Some of the compounds disclosed herein can also exist as prodrugs, as described in *Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology* (Testa, Bernard, and Mayer, Joachim M. Wiley-VHCA, Zurich, 2003). The prodrugs of the compounds described herein are structurally modified versions of compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, in an in vitro environment, prodrugs can be converted into the compounds by chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, it can be slowly converted into the compound. Prodrugs are often useful because, in some cases, they are easier to administer than the compound or the parent drug. For example, they may be bioavailable through oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. A wide variety of prodrug derivatives are known in the art, such as prodrug derivatives that depend on the hydrolytic cleavage or oxidative activation of the prodrug. Examples of prodrugs (but not limited to) are compounds that are administered as esters (“prodrugs”) but subsequently metabolized and hydrolyzed to carboxylic acids (the active entity). Other examples include peptide derivatives of compounds.

[0505] Salt

[0506] The compounds disclosed herein can exist as salts, including pharmaceutically acceptable salts. This disclosure includes the compounds listed above in salt form, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will generally be pharmaceutically acceptable. However, pharmaceutically unacceptable salts may be useful in the preparation and purification of the compounds under consideration. Base addition salts may also be formed, and these are also pharmaceutically acceptable.

[0507] As used herein, the term "therapeuticly acceptable salt" refers to the salt or zwitterionic form of the compounds disclosed herein, which are water-soluble, oil-soluble, or dispersible, and are therapeutically acceptable as defined herein. These salts can be prepared during the final separation and purification of the compound, or individually by reacting a suitable compound in its free base form with a suitable acid. Representative acid addition salts include acetates, adipates, alginates, L-ascorbic acid salts, aspartates, benzoates, benzenesulfonates (benzenesulfonates), bisulfates, butyrates, camphorates, camphorsulfonates, citrates, digluconates, formates, fumarates, gentianates, glutarate, glycerophosphates, glycolates, hemisulfates, heptanates, hexanoates, hippurates, hydrochlorides, hydrobromide, hydroiodates, and 2-hydroxyethanesulfonates (hydroxyethylsulfonates). ( ), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, dihydroxynaphthalate, pectin salt, persulfate, 3-phenylpropionate, phosphate, picrate, pitavaate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetic acid, trifluoroacetic acid, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. Additionally, the basic groups in the compounds disclosed herein can be quaternized with the following: chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl; sulfates of dimethyl, diethyl, dibutyl, and dipentyl; chlorides, bromides, and iodides of decyl, lauryl, cardamyl, and sterol groups; and bromides of benzyl and phenethyl. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid) and organic acids (such as oxalic acid, maleic acid, succinic acid, and citric acid). Salts can also be formed by coordination of these compounds with alkali metal or alkaline earth metal ions. Therefore, this disclosure considers sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein.

[0508] Base addition salts can be prepared during the final separation and purification of compounds by reacting the carboxyl group with a suitable base (such as a hydroxide, carbonate, or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable cations for these salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, and N,N'-dibenzylethylenediamine. Other representative organic amines that can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0509] Preparations

[0510] While the compounds disclosed herein, or salts thereof, may be administered as raw chemical substances, they may also be provided as pharmaceutical formulations. Therefore, pharmaceutical formulations are provided herein that comprise one or more of the compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, and one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. Such carriers or carriers must be “acceptable” in the sense of compatibility with the other components of the formulation and harmlessness to the recipient. A suitable formulation depends on the chosen route of administration. Any well-known techniques, carriers, and excipients may be suitably used and are known in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, such as by conventional methods of mixing, dissolving, granulating, forming sugar-coated pellets, grinding, emulsifying, encapsulating, embedding, or tableting.

[0511] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including skin, buccal, sublingual, and intraocular) administration, but the most suitable route may depend, for example, on the recipient's condition and impairment. Formulations may be conveniently presented in unit dosage forms and may be prepared by any method known in the field of pharmaceutical formulation. Typically, these methods involve the step of associating the disclosed compound or its pharmaceutically acceptable salt, ester, amide, prodrug, or solvate (“active ingredient”) with a carrier constituting one or more excipients. Generally, formulations are prepared by uniformly and closely associating the active ingredient with a liquid carrier or a finely pulverized solid carrier, or both, and then, if desired, shaping the product into the desired formulation.

[0512] Formulations of the compounds disclosed herein suitable for oral administration may be presented in discrete units, such as capsules, tablets, or pellets each containing a predetermined amount of the active ingredient; in powder or granule form; in solutions or suspensions in aqueous or non-aqueous liquids; or in oil-in-water or water-in-oil emulsions. The active ingredient may also be presented as granules, sugar tablets, or pastes.

[0513] Pharmaceutical formulations that can be administered orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compression of an active ingredient in a free-flowing form (such as powder or granules), optionally mixed with a binder, an inert diluent or lubricant, a surfactant, or a dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and may be formulated to provide a slow or controlled release of the active ingredient therein. All formulations intended for oral administration should be at a dose suitable for such administration. Push-fit capsules may contain an active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Stabilizers may also be added. The core of the sugar-coated pill is fitted with a suitable coating. For this purpose, concentrated sugar solutions may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbomer, polyethylene glycol and / or titanium dioxide, lacquer solutions, and a variety of suitable organic solvents or solvent mixtures. Dyes or colorants may be added to the tablet or sugar-coated pill coating to identify or characterize different combinations of active compound dosages.

[0514] Compounds can be formulated for parenteral administration via injection (e.g., by bolus or continuous infusion). Formulations for injection may be presented in unit dosage forms (e.g., in ampoules or multi-dose containers) along with added preservatives. Compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous carriers and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. These formulations may be presented in unit or multi-dose containers (e.g., sealed ampoules and vials) and may be stored in powder form or under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier (e.g., saline or sterile pyrogen-free water) before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the aforementioned types.

[0515] Formulations intended for parenteral administration include: aqueous and non-aqueous (oil-based) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or carriers include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or reagents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0516] In addition to the formulations previously described, these compounds can also be formulated as reservoir preparations. Such long-acting formulations can be administered via implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, these compounds can be formulated with suitable polymers or hydrophobic substances (e.g., as emulsions in acceptable oils) or ion exchange resins, or formulated as slightly soluble derivatives, such as slightly soluble salts.

[0517] For oral or sublingual application, these compositions can be taken in the conventional form of tablets, lozenges, soft lozenges, or gels. Such compositions may contain active ingredients in flavoring matrices such as sucrose and gum arabic or astragalus gum.

[0518] These compounds can also be formulated into rectal compositions (such as suppositories or retention enemas), for example, containing conventional suppository bases (such as cocoa butter, polyethylene glycol, or other glycerides).

[0519] Some of the compounds disclosed herein (including the compositional forms described herein) can be administered topically, i.e., by non-systemic administration. This includes applying the compounds disclosed herein to the epidermis or external oral cavity and instilling such compounds into the ear, eye, and nose, such that the compounds do not enter the bloodstream in large quantities. Conversely, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0520] Formulations suitable for topical application include liquid or semi-liquid preparations (such as gels, liniments, lotions, creams, ointments, or pastes) suitable for penetration through the skin to the site of inflammation, and drops suitable for application to the eyes, ears, or nose. The active ingredient for topical application may constitute, for example, 0.001% to 10% w / w (by weight) of the formulation. In some embodiments, the active ingredient may constitute up to 10% w / w. In other embodiments, it may constitute less than 5% w / w. In some embodiments, the active ingredient may constitute 2% w / w to 5% w / w. In other embodiments, it may constitute 0.1% to 1% w / w of the formulation.

[0521] For inhalation administration, the compound (including the compositional forms described herein) can be conveniently delivered from an inhaler, a pressurized nebulizer pack, or other convenient device for delivering aerosol sprays. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve for delivering a measured amount. Alternatively, for inhalation or inhalation administration, the compounds according to this disclosure may be in the form of dry powder compositions, such as a mixture of the compound and a suitable powder matrix (such as lactose or starch). The powder compositions may be presented in unit dosage forms, such as capsules, cartridges, gelatin, or blister packs, from which the powder can be administered by means of an inhaler or inhaler.

[0522] Preferred unit-dose formulations are those containing an effective dose of the active ingredient or an appropriate fraction thereof, as listed below.

[0523] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations discussed may also include other pharmaceutical agents conventional in the art, such as flavoring agents, for example, formulations suitable for oral administration.

[0524] The compounds (including the compositional forms described herein) may be administered orally or by injection at doses ranging from 0.1 to 500 mg / kg / day. The adult dose range is typically 5 mg to 2 g / day. Tablets or other forms of presentation, available in separate units, conveniently contain an amount of one or more compounds effective at that dose or multiples thereof (e.g., units containing 5 mg to 500 mg (typically about 10 mg to 200 mg)).

[0525] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific method of administration.

[0526] Compounds (including the compositional forms described herein) can be administered in various ways, such as orally, topically, or by injection. The precise amount of compound administered to a patient is the responsibility of the attending physician. The specific dosage level for any particular patient will depend on a number of factors, including the activity of the specific compound used, age, weight, overall health condition, sex, diet, time of administration, route of administration, excretion rate, drug combination, the exact disorder being treated, and the severity of the indication or condition being treated. Furthermore, the route of administration may vary depending on the condition and its severity.

[0527] Combination and combination therapy

[0528] In some cases, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug, or a combination thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects a patient experiences while receiving one of the compounds described herein is hypertension, it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Alternatively, by way of example only, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., an adjuvant alone may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein together with another therapeutic agent (which also includes treatment regimens) that also has a therapeutic benefit. By way of example only, in the treatment of diabetes involving the administration of one of the compounds described herein, the increased therapeutic benefit may also be obtained by providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be a simple summation of the therapeutic agents, or the patient may experience a synergistic benefit.

[0529] The compounds disclosed herein can be used alone or in combination with other pharmaceutically active compounds to treat conditions such as those previously described above. One or more compounds disclosed herein may be administered simultaneously (in the same dosage form or in different dosage forms) or sequentially with one or more other pharmaceutically active compounds. Accordingly, in one embodiment, this disclosure includes a method of treating a condition by administering to a subject a therapeutically effective amount of one or more compounds of this disclosure and one or more other pharmaceutically active compounds.

[0530] In another embodiment, a pharmaceutical composition is provided comprising one or more compounds disclosed herein, one or more other pharmaceutically active compounds, and a pharmaceutically acceptable carrier.

[0531] In another embodiment, one or more other pharmaceutically active compounds are selected from anticancer drugs, antiproliferative drugs, and anti-inflammatory drugs.

[0532] The ATR inhibitor compositions described herein may also be used in combination with other therapeutic agents selected based on their therapeutic value for the condition to be treated. Typically, the compounds described herein and other agents in the examples employing combination therapy need not be administered in the same pharmaceutical composition, and may be administered via different routes due to their different physical and chemical properties. Typically, the initial administration is performed according to an established regimen, and then the dosage, method of administration, and timing of administration are subsequently modified based on observed effects. In some cases, it is appropriate to administer the ATR inhibitor compounds described herein in combination with other therapeutic agents. By way of example only, the therapeutic efficacy of an ATR inhibitor may be enhanced by administering another therapeutic agent (which also includes treatment regimens) that also has a therapeutic benefit. Regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is either a simple sum of the two therapeutic agents or an enhanced (i.e., synergistic) benefit experienced by the patient. Alternatively, if the compounds disclosed herein have side effects, it may be appropriate to administer an agent that reduces those side effects; or the therapeutic efficacy of the compounds described herein may be enhanced by administering an adjuvant.

[0533] When medications are used in combination therapy, the effective therapeutic dose is altered. Methods for determining the effective therapeutic dose of medications and other agents used in combination therapy regimens using experimental methods are documented. Combination therapy also includes periodic treatments that are started and stopped at different times to aid in the clinical management of patients. In any case, multiple therapeutic agents (one of which is an ATR inhibitor as described herein) may be administered in any order or simultaneously. If administered simultaneously, multiple therapeutic agents may optionally be provided in a single, uniform form or in multiple forms (by way of example only, as a single pill or as two separate pills).

[0534] In another embodiment, the ATR inhibitor is optionally used in combination with a procedure that provides additional benefit to the patient. The ATR inhibitor and any other therapy are optionally administered before, during, or after the onset of the disease or condition, and the timing of administration of the composition containing the ATR inhibitor varies in some embodiments. Thus, for example, the ATR inhibitor is used as a preventative agent and is administered continuously to a subject with a predisposition to develop the condition or disease in order to prevent its occurrence. The ATR inhibitor and composition are optionally administered to the subject as soon as possible during or after the onset of symptoms. While embodiments of this disclosure have been shown and described herein, such embodiments are provided by way of example only and will be apparent to those skilled in the art. Many variations, alterations, and substitutions will now occur to those skilled in the art without departing from this disclosure. It should be understood that various alternatives to the embodiments described herein are used to practice this disclosure in some embodiments of this disclosure.

[0535] ATR inhibitors can be used in combination with anticancer drugs, including but not limited to the following: alkylating agents, antimetabolites, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, angiogenesis inhibitors, and tyrosine kinase inhibitors.

[0536] For use in cancer and neoplastic diseases, ATR inhibitors may be optimally used in conjunction with one or more of the following non-limiting examples of anticancer agents:

[0537] 1) Inhibitors or regulators of proteins involved in one or more DNA damage repair (DDR) pathways, such as:

[0538] a.PARP1 / 2, including but not limited to: Olapani, Nirapani, Lucapani;

[0539] b. Checkpoint kinase 1 (CHK1), including but not limited to: UCN-01, AZD7762,

[0540] PF477736, SCH900776, MK-8776, LY2603618, V158411 and EXEL-9844;

[0541] c. Checkpoint kinase 2 (CHK2), including but not limited to: PV1019, NSC 109555 and VRX0466617;

[0542] d. Dual CHK1 / CHK2, including but not limited to: XL-844, AZD7762 and PF-473336;

[0543] e.WEE1, including but not limited to: MK-1775 and PD0166285;

[0544] f.ATM, including but not limited to KU-55933,

[0545] g. DNA-dependent protein kinases, including but not limited to NU7441 and M3814; and

[0546] Other proteins involved in h.DDR;

[0547] 2) Inhibitors or modulators of one or more immune checkpoints, including but not limited to:

[0548] a. PD-1 inhibitors, such as nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidizumab (CT-011), and AMP-224 (AMPLIMMUNE);

[0549] b. PD-L1 inhibitors, such as atezolizumab (TECENTRIQ), avermab (Bavencio), durvalumab (Imfinzi), MPDL3280A (Tecentriq), BMS-936559, and MEDI4736;

[0550] c. Anti-CTLA-4 antibodies, such as ipilimumab (YERVOY) and CP-675,206

[0551] (TREMELIMUMAB);

[0552] Inhibitors of dT cell immunoglobulin and mucin domain 3 (Tim-3);

[0553] Inhibitor of the V domain Ig repressor gene for eT cell activation (Vista);

[0554] Inhibitors of fB / T lymphocyte weakening factor (BTLA);

[0555] g. Inhibitors of lymphocyte activation gene 3 (LAG3); and

[0556] Inhibitors of hT cell immunoglobulins and inhibitory motif domains based on tyrosine receptors (TIGIT);

[0557] 3) Telomerase inhibitors or telomere DNA-binding compounds;

[0558] 4) Alkylating agents, including but not limited to: chlorambucil (LEUKERAN), oxaliplatin (ELOXATIN), streptozotocin (ZANOSAR), dacarbazine, ifosfamide, lomustine (CCNU), mebenzylhydrazine (MATULAN), temozolomide (TEMODAR), and thiotepa.

[0559] 5) DNA cross-linking agents, including but not limited to: carmustine, chlorambucil, carboplatin, cisplatin, busulfan, melphalan, mitomycin, and cyclophosphamide;

[0560] 6) Antimetabolites, including but not limited to: cladribine (LEUSTATIN), cytarabine (ARA-C), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and raltitrexed;

[0561] 7) Antimitotic agents, usually plant alkaloids and terpenoids or their derivatives, including but not limited to: taxanes (such as docetaxel, paclitaxel, abraxane, and vinblastine) and vinblastine alkaloids (such as vinblastine, vincristine, vinorelbine, and vinorelbine).

[0562] 8) Topoisomerase inhibitors, including but not limited to: acridine, camptothecin (CTP), genisten, irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), ICRF-193, teniposide (VUMON), mitoxantrone (NOVANTRONE), and etoposide (EPOSIN);

[0563] 9) DNA replication inhibitors, including but not limited to: fludarabine, afedipine, ganciclovir, and cidofovir;

[0564] 10) Ribonucleotide diphosphate reductase inhibitors, including but not limited to: hydroxyurea;

[0565] 11) Transcription inhibitors, including but not limited to: actinomycin D (Comomycin, COSMEGEN) and pravamycin (Comomycin);

[0566] 12) DNA lysis agents, including but not limited to: bleomycin (BLENOXANE), idarubicin,

[0567] 13) Cytotoxic antibiotics, including but not limited to: actinomycin D (Comomycin, Cosmegen),

[0568] 14) Aromatase inhibitors, including but not limited to: ammoniaglutide, anastrozole (ARIMIDEX), letrozole (FEMARA), vortexazole (RIVIZOR), and exemestane (AROMASIN);

[0569] 15) Angiogenesis inhibitors, including but not limited to: genistein, sunitinib, and bevacizumab.

[0570] 16) Antisteroids and antiandrogens, including but not limited to: aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone acetate, flutamethasone (EULEXIN), and nilandron;

[0571] 17) Tyrosine kinase inhibitors, including but not limited to: imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA);

[0572] 18) mTOR inhibitors, including but not limited to: everolimus, tesimolimus (TORISEL), and sirolimus;

[0573] 19) Monoclonal antibodies, including but not limited to: trastuzumab (HERCEPTIN) and rituximab (RITUXAN);

[0574] 20) Apoptosis inducers, such as cordycepin;

[0575] 21) Protein synthesis inhibitors, including but not limited to: clindamycin, chloramphenicol, streptomycin, anisin, and cyclohexylimide;

[0576] 22) Antidiabetic drugs, including but not limited to: metformin and phenformin;

[0577] 23) Antibiotics, including but not limited to:

[0578] a. Tetracyclines, including but not limited to: doxycycline

[0579] b. Erythromycin, including but not limited to: azithromycin;

[0580] c. Diglycine peptides, including but not limited to: tigecycline;

[0581] d. Antiparasitic agents, including but not limited to: embropivirium;

[0582] e. β-lactams, including but not limited to penicillins and cephalosporins;

[0583] f. Anthracycline antibiotics, including but not limited to: daunorubicin and doxorubicin;

[0584] g. Other antibiotics, including but not limited to: chloramphenicol, mitomycin C, and actinomycin;

[0585] 24) Antibody therapeutics, including but not limited to: moromumab-CD3, infliximab (REMICADE), adalimumab (HUMIRA), omalizumab (XOLAIR), dacrolimus (ZENAPAX), rituximab (RITUXAN), teimomab (ZEVALIN), tosimomab (BEXXAR), cetuximab (ERBITUX), trastuzumab (HERCEPTIN), bentuximab (ADCETRIS), alemtuzumab (CAMPATH-1H), Lym-1 (ONCOLYM), ipilimumab (YERVOY), vitaxin, bevacizumab (AVASTIN), and abciximab (REOPRO); and

[0586] 25) Other medications, such as BCG vaccine; ETILAMIDE; chloroquine; clodronate, pamidronate and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estradiol; neuprozepine; fludrocortisone; zoladex; interferon; leucovorin; leuprozepine; levamisole; chlordamine. Mesna; metformin; mitotane (o,p'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifoxine; porphyrin sodium (especially in combination with phototherapy and radiotherapy); suramin; tamoxifen; dichlorodicyclopentadiene; retinoic acid; anabolic steroids such as halotestin; estrogens such as estradiol, diethylstilbestrol (DES), and diethylstilbestrol; progestins such as medroxyprogesterone acetate (MPA) and medroxyprogesterone acetate; and testosterone.

[0587] In any case, multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a single, uniform form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents may be administered in multiple doses, or two may be administered in multiple doses. If not administered simultaneously, the time between multiple doses may be any duration ranging from several minutes to four weeks.

[0588] Therefore, in another aspect, certain embodiments provide methods for treating ATR kinase-mediated disorders in human or animal subjects requiring such treatment, methods comprising administering to the subject, in combination with at least one additional agent known in the art for treating the disorder, an amount of the compound disclosed herein or a salt thereof capable of effectively reducing or preventing the subject's disorder. In a related aspect, certain embodiments provide therapeutic compositions comprising a combination of at least one compound disclosed herein with one or more additional agents for treating ATR kinase-mediated disorders.

[0589] The specific diseases treated by the compounds, compositions and methods disclosed herein include proliferative and hyperproliferative diseases, including cancer.

[0590] In addition to their use in human treatment, some of the compounds and formulations disclosed herein can also be used in veterinary treatment of companion animals, exotic animals, and livestock, including mammals and rodents. More preferred animals include horses, dogs, and cats.

[0591] Exemplary embodiments of this disclosure are provided below.

[0592] Example I-1: A compound with structural formula (I):

[0593]

[0594] Or its salt, wherein:

[0595] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, aryl, and heteroaryl, each of which is optionally bound by one or more R 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Heterocyclic alkyl rings substituted with groups;

[0596] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0597] R 4 Selected from C 5-10 Aryl and C 5-10 Heteroaryl groups, each of which is optionally bounded by one or more R groups 6 Group substitution;

[0598] Each R5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0599] Each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0600] Each R 7 R 8 and R 9 Independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl groups, and optionally with halogen, hydroxyl, C 1-3 Alkyl, C 1-3

[0601] Halogenated alkyl and C 1-3 Alkoxy substitution; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0602] Each R 10 R 11 and R 12 Independently selected from hydrogen, C 1-4 Alkyl, C3-6 Cycloalkyl and heterocycloalkyl groups, and optionally substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0603] Example I-2: The compound as described in Example I-1, wherein R 3 It is C 1-6 alkyl.

[0604] Example I-3: The compound as described in Example I-2, wherein R 3 It is a methyl group.

[0605] Example II-4: A compound of structural formula (II):

[0606]

[0607] Or its salt, wherein:

[0608] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, aryl, and heteroaryl, each of which is optionally bound by one or more R 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional mixture of one or more R 5 Heterocyclic alkyl rings substituted with groups;

[0609] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups;

[0610] R 4 Selected from C 5-10 Aryl or C 5-10 Heteroaryl and optionally with one or more R 6 Group substitution;

[0611] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 ;

[0612] Each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclic alkyl, hydroxyalkyl, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12 ;

[0613] Each R 7 R 8 and R 9 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl groups, and optionally with halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl and C 1-3 alkoxy; or R 7 R 8 and R 9 Any two of them, together with the atoms to which both are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings; and

[0614] Each R 10 R 11 and R 12 Independently selected from hydrogen and C 1-4 Alkyl, C 3-6 Cycloalkyl and heterocycloalkyl groups, and optionally substituted with one or more groups selected from halogen, hydroxyl, and alkoxy groups; or R 10 R 11 and R 12 Any two of them, together with the atoms to which they are attached, can form 3-7 membered alkyl or heterocyclic alkyl rings.

[0615] Example II-5: The compound as described in Example II-4, wherein R 3 It is C 1-6 alkyl.

[0616] Example II-6: Compounds as described in Example II-5, wherein R 3 It is a methyl group.

[0617] Example II-7: The compound as described in Example II-6, wherein R 4 It is C 5-10 Heteroaryl and optionally with one or more R 6 Group substitution.

[0618] Example II-8: The compound as described in Example II-7, wherein R 4 Selected from indole, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrazine, pyrazolopyrazine, pyrrolopyrimidine, pyrazolopyrimidine, imidazopyrimidine, pyrrolopyridazine, pyrazolopyridazine, and imidazopyridazine, and optionally by one or more R 6 Group substitution.

[0619] Example II-9: Compounds as described in Example II-8, wherein R 4 Selected from 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-c]pyridazine, 7H-pyrrolo[2,3-d]pyrimidine and 5H-pyrrolo[2,3-b]pyrazine and optionally by one, two or three R 6 Group substitution.

[0620] Example II-10: The compound as described in Example II-9, wherein R 4 It is 1H-pyrrolo[2,3-b]pyridine and optionally is separated by one or two R 6 Group substitution.

[0621] Example II-11: The compound as described in Example II-10, wherein each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl, oxo group, OR 11 NR 10 C(O)R 11 NR 10 C(O)OR 11 NR 10 C(O)NR 11 R 12 C(O)R 11 C(O)OR 11 and C(O)NR 11 R 12.

[0622] Example II-12: The compound as described in Example II-11, wherein each R 6 Independently selected from NR 11 R 12 Halogen, cyano, hydroxyl and oxo groups.

[0623] Example II-13: The compound as described in Example II-12, wherein R 4 Selected from

[0624] Example II-14: The compound as described in Example II-13, wherein

[0625] R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, aryl, and heteroaryl groups, and optionally with one or two R groups. 5 Group substitution, or R 1 and R 2 Together with the sulfur attached to both of them, they form an optional structure with one or two R 5 Heterocyclic alkyl rings substituted with groups;

[0626] Each R 5 Independently selected from NR 8 R 9 Halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclic alkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR 8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0627] Example II-15: The compound as described in Example II-14, wherein each R 5 Independently selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxyalkyl, OR 8 NR 7 C(O)R 8 NR 7 C(O)OR8 NR 7 C(O)NR 8 R 9 C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0628] Example II-16: Compounds as described in Example II-15, wherein each R 5 Independently selected from C(O)R 8 C(O)OR 8 and C(O)NR 8 R 9 .

[0629] Example II-17: The compound as described in Example II-16, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, aryl, and heteroaryl groups, and optionally with one or two R groups. 5 Group substitution.

[0630] Example II-18: The compound as described in Example II-17, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl and C 3-6 Heterocyclic alkyl groups and optionally with one or two R groups 5 Group substitution.

[0631] Example II-19: The compound as described in Example II-17, wherein R 1 and R 2 Selected independently from C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0632] Example II-20: The compound as described in Example II-17, wherein R 1 and R 2 Together with sulfur attached to both of them, they form a heterocyclic alkyl ring and are optionally bounded by one or two R... 5 Group substitution.

[0633] Example C-21: A compound as described in Example I-1, wherein the structure is selected from...

[0634] Example C-22: The compound as described in Example I-1, which is used as a drug.

[0635] Example C-23: The compound as described in Example I-1, used to manufacture a medicament for the prevention or treatment of a disease or condition that is improved by inhibiting ATR kinase.

[0636] Example C-24: The compound as described in Example C-23, wherein the disease is cancer.

[0637] Example C-25: The compound as described in Example C-24, wherein the cancer is a chemotherapy-resistant cancer.

[0638] Example C-26: The compound as described in Example C-24, wherein the cancer is a radiotherapy-resistant cancer.

[0639] Example C-27: The compound as described in Example C-24, wherein the cancer is an ALT-positive cancer.

[0640] Example C-28: The compound as described in Example C-24, wherein the cancer is a sarcoma.

[0641] Example C-29: The compound as described in Example C-24, wherein the cancer is selected from osteosarcoma and glioblastoma.

[0642] Example C-30: The compound as described in Example C-24, wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.

[0643] Example C-31: The compound as described in Example C-24, wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.

[0644] Example C-32: The compound as described in Example C-24, wherein the cancer has a deficiency in base excision repair protein.

[0645] Example C-33: A pharmaceutical composition comprising the compound described in Example I-1 together with a pharmaceutically acceptable carrier.

[0646] Example M-34: A method for sensitizing cells to a DNA damaging agent, the method comprising administering to a patient the compound described in Example I-1.

[0647] Example M-35: A method for preventing cell repair of DNA damage, the method comprising administering to a patient the compound described in Example I-1.

[0648] Example M-36: A method for inhibiting ATR kinase, the method comprising contacting the ATR kinase with the compound described in Example I-1.

[0649] Example M-37: A method for treating an ATR kinase-mediated disease, the method comprising administering a therapeutically effective amount of the compound described in Example I-1 to a patient in need of it.

[0650] Example M-38: The method as described in Example M-37, wherein the disease is cancer.

[0651] Example M-39: The method as described in Example M-38, wherein the cancer is a chemotherapy-resistant cancer.

[0652] Example M-40: The method as described in Example M-38, wherein the cancer is a radiation-resistant cancer.

[0653] Example M-41: The method as described in Example M-38, wherein the cancer is an ALT-positive cancer.

[0654] Example M-42: The method is as described in Example M-38, wherein the cancer is a sarcoma.

[0655] Example M-43: The method as described in Example M-38, wherein the cancer is selected from osteosarcoma and glioblastoma.

[0656] Example M-44: The method as described in Example M-38, wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.

[0657] Example M-45: The method as described in Example M-38, wherein the cancer is selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.

[0658] Example M-46: The method as described in Example M-38, wherein the cancer has a deficiency of base excision repair protein.

[0659] Example M-47: The method as described in Example M-38, wherein the cancer has an ATM signal cascade defect.

[0660] Example M-48: The method as described in Example M-47, wherein the deficiency is an alteration in the expression or activity of one or more of the following: TM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1 / BRIT1, CTIP, or SMC1.

[0661] Example M-49: The method as described in Example M-38 further includes administering another therapeutic agent to the patient, wherein the other therapeutic agent inhibits or modulates base excision repair proteins.

[0662] Example M-50: A method for treating ATR kinase-mediated diseases, the method comprising administering:

[0663] a. A therapeutically effective amount of the compound described in Examples I-1; and

[0664] b. Another treatment.

[0665] Example M-51: The method as described in Example M-50, wherein the other therapeutic agent is a CHK1 inhibitor.

[0666] Example M-52: The method as described in Example M-50, wherein the CHK1 inhibitor is selected from MK-8776, LY2603618, V158411, PF-477736, UCN-01 and AZD7762.

[0667] Example M-53: The method as described in Example M-50, wherein the other therapeutic agent is a DNA damaging agent.

[0668] Example M-54: The method as described in Example M-53, wherein the DNA damaging agent is selected from ionizing radiation, radioactive neoplasms, platinum-based agents, Topo I inhibitors, Topo II inhibitors, antimetabolites, alkylating agents, alkyl sulfonates, and antibiotics.

[0669] Example M-55: The method as described in Example M-54, wherein the platinumizing agent is selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, triplatinium tetranitrate, pyridine, saxaplatin, ProLindac, and aroplatin.

[0670] Example M-56: The method as described in Example M-54, wherein the Topo I inhibitor is selected from camptothecin, topotecan, irinotecan / SN38, rubitecan, and belotetane.

[0671] Example M-57: The method as described in Example M-54, wherein the Topo II inhibitor is selected from etoposide, daunorubicin, doxorubicin, clarubicin, epirubicin, idarubicin, amorubicin, pirarubicin, pentorubicin, zorubicin, and teniposide.

[0672] Example M-58: The method as described in Example M-54, wherein the antimetabolite is selected from aminopterin, methotrexate, pemetrexed, raltitrexed, pentostatin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur, carmoflu, fluorouracil, cytarabine, gemcitabine, azacitidine, and hydroxyurea.

[0673] Example M-59: The method as described in Example M-54, wherein the alkylating agent is selected from dichloromethyldiethylamine, cyclophosphamide, ifosfamide, trefophosphamide, chlorambucil, melphalan, prenimustine, bendamustine, uramustine, estrustine, carmustine, lomustine, semustine, formustine, nimustine, ramustine, streptozotocin, busulfan, trooxanthan, carboquinone, thiotepa, triamidoquinone, tratamido, mebenzylhydrazine, dacarbazine, temozolomide, hexamethylmelamine, dibromomannitol, actinomycin, bleomycin, mitomycin, and procainoxam.

[0674] Example M-60: The method as described in Example M-38, wherein the method further includes a non-chemical method for administering cancer treatment.

[0675] Example M-61: The method as described in Example M-60, wherein the method further includes administering radiotherapy.

[0676] Example M-62: The method as described in Example M-60, wherein the method further comprises applying surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0677] Example M-63: A method for increasing the sensitivity of cancer cells to cancer therapies selected from chemotherapy or radiotherapy by administering to a patient a compound as described in Example I-1.

[0678] Example M-64: The method is as described in Example M-63, wherein the cancer cell is a pancreatic cancer cell.

[0679] Example M-65: A method for achieving an effect in a patient, the method comprising administering a therapeutically effective amount of the compound of claim 1 to the patient, wherein the effect is increased sensitivity to a chemotherapeutic agent.

[0680] List of abbreviations

[0681] Boc = tert-Butoxycarbonyl; BPi = 4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl; Br2 = Bromine; Bu = n-Butyl; t-Bu = tert-Butyl = 2,2-Dimethylethyl; ℃ = Celsius; CBz = Carboxybenzyl; CDCl3 = Deuterated chloroform; CD3CN = Deuterated acetonitrile; DBN = 1,5-diazabicyclo(4.3.0)non-5-ene; DBU = 1,8-diazabicyclo(5.4.0)non-5-ene. Undec-7-ene; DCM = CH2Cl2 = dichloromethane; DDTT = 3-((dimethylaminomethylene)amino)-3H-1,2,4-dithiazolyl-5-thione; DIPEA = iPr2NEt = diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; DMF-d7 = dimethylformamide-d7; DMSO = dimethyl sulfoxide; DMSO-d6 = dimethyl sulfoxide-d6; DMT r = dimethoxytriphenylmethyl = (4-methoxyphenyl)2(phenyl)methyl; D2O = deuterated water; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EA = EtOAc = ethyl acetate; ES+ = electrospray ionization; ES- = electrospray ionization; Et = ethyl; EtOH = ethanol; h = hour; H = hydrogen; HCl = hydrogen chloride; HCO2NH4 = ammonium formate; H2O = water; HPLC = high-performance liquid chromatography Also known as preparative high performance liquid chromatography; int. = intermediate; iPr = isopropyl = 2-propyl; M = mole; mCPBA = m-chloroperoxybenzoic acid; MeCN = CH3CN = acetonitrile; MeOH = methanol; MHz = megahertz; mL = milliliters; min = minutes; MS = mass spectrometry; MsCl = methanesulfonyl chloride; μW = microwave; N2 = nitrogen; NH3 = ammonia; NH4OH = ammonium hydroxide; NMP = N-methyl-2-pyrrolidone; 1 H-NMR = Proton Nuclear Magnetic Resonance; 31P-NMR = Phosphorus nuclear magnetic resonance; PBS = Phosphate-buffered saline; PE = Petroleum ether; Pin = Pinarol = 2,3-dimethylbutane-2,3-diol; Pin2B2 = 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborane); Piv = Neopentanoyl = (CH3)3C-C(=O)-; PPA = Polyphosphate; Preparative HPLC = Preparative high-performance liquid chromatography, also known as preparative high-performance liquid chromatography; RT = Room temperature; NaOH = Sodium hydroxide; Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; RuPhos = dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine; THF = tetrahydrofuran; Py = pyridine; SFC = supercritical fluid chromatography; TBSCl = tert-butyldimethylsilyl chloride; TEA = triethylamine; TEAB = tetraethylammonium bicarbonate; TMSCl = trimethylsilyl chloride; TFA = trifluoroacetic acid; K2CO3 = potassium carbonate; μL = ul = microliter.

[0682] General synthetic methods for preparing compounds

[0683] The following approaches can be used to implement this disclosure.

[0684] Option I

[0685]

[0686] The substituted pyrimidine compound 102 was obtained by Buchwald coupling reaction of chloropyrimidine 101 and sulfinimide.

[0687] Option II

[0688]

[0689] Scheme II describes one route for preparing the compounds disclosed herein. Buchwald coupling of intermediate 201 with sulfinimide yields chloropyrimidine 202. Subsequent Suzuki coupling with a borate ester or Stille coupling with a tinane yields pyrimidine compound 203.

[0690] Option III

[0691]

[0692] Scheme III describes one route for preparing the disclosed compounds. A Buchwald coupling of chloropyrimidine 301 and an arylamine is followed by iron-mediated reduction or palladium-catalyzed hydrogenation to yield an amino intermediate 303. This is then cyclized with an orthoester or carboxylic acid to give the pyrimidine compound 304.

[0693] Option IV

[0694]

[0695] One route for preparing the disclosed compounds is described in Scheme IV. Chloropyrimidine 401 is converted to tinane 402, followed by Stille coupling with an aryl bromide to give pyrimidine compound 403.

[0696] Option V

[0697]

[0698] Scheme V describes one route for preparing the compounds disclosed herein. This involves Buchwald coupling or S-coupling using chloropyrimidine 501 and an amino heterocycle. N Ar addition yields pyrimidine compound 402.

[0699] Intermediate A

[0700]

[0701] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine

[0702]

[0703] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine

[0704] A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 51.0 mmol), Pin2B2 (15.5 g, 61.0 mmol), PdCl2(dppf) (2.0 g, 2.5 mmol), and KOAc (10.0 g, 102 mmol) in 1,4-dioxane (200 mL) was degassed with Ar for 5 min. The reaction mixture was heated to 80 °C and stirred for 16 h. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-25% EtOAc in hexane solution) to give the title compound (3.8 g, 31% yield) as a white solid.

[0705] MS(ES + C 13 H 17 BN2O2 requirement: 244, actual measurement: 245 [M+H] + .

[0706] Intermediate B

[0707]

[0708] (R)-4-(6-chloro-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine

[0709]

[0710] 6(R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine was added to a solution of 2,4,6-trichloropyrimidine (12.3 g, 67.3 mmol) and Et3N (14.2 mL, 101 mmol) in EtOH (80 mL). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (200 mL), partitioned with H2O (150 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–5% EtOAc in hexane solution) to give the title compound (11.8 g, 71% yield) as a white solid.

[0711] MS(ES + C9H 11 Cl2N3O requirement: 241, actual measurement: 248 [M+H] + .

[0712]

[0713] (R)-4-(6-chloro-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine

[0714] A mixture of the product from the previous step (3.0 g, 12 mmol), intermediate A (2.8 g, 12 mmol), PdCl2 (dppf) (0.44 g, 0.60 mmol), and Na2CO3 (2.6 g, 24 mmol) in 1,4-dioxane (60 mL) and water (15 mL) was degassed with Ar for 5 min. The reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc in hexane solution) to give the title compound (1.84 g, 46% yield) as a yellow solid.

[0715] MS(ES + C 16 H 16 ClN5O requirement: 329, actual measurement: 330 [M+H] + .

[0716] Intermediate C

[0717]

[0718] Iminodimethyl-λ 6 -sulfanone

[0719]

[0720] (dimethyl(oxo)-λ) 6 PhI(OAc)2 (4.8 g, 15 mmol) was added to a suspension of DMSO (780 mg, 10.0 mmol), benzyl carbamate (2.3 g, 15 mmol), Rh2(OAc)4 (110 mg, 0.25 mmol), and MgO (1.6 g, 40 mmol) in CH2Cl2 (100 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography (0-90% EtOAc in petroleum ether solution) to give the title compound (900 mg, 40% yield) as a white solid.

[0721] MS(ES + C 10 H 13 NO3S requirement: 227, actual measurement: 228 [M+H] + .

[0722]

[0723] Iminodimethyl-λ 6- The sulfinyl group was prepared by suspending the product from the previous step (600 mg, 2.6 mmol) and Pd / C (243 mg, 2.6 mmol) in MeOH (20 mL). The mixture was stirred at 1 atm under a H2 atmosphere for 16 h. The reaction mixture was then purged with N2. The mixture was filtered, and the filter pad was washed with MeOH (10 mL). The mixture was concentrated under reduced pressure to give the title compound (205 mg, 85% yield) as a colorless oil.

[0724] MS(ES + C2H7NOS requirement: 93, actual measured 94 [M+H] + .

[0725] Intermediate D

[0726]

[0727] (R)-((2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[0728]

[0729] (R)-((2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulphinate: (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described in step 1 for intermediate B) (500 mg, 2.02 mmol), intermediate C (225 mg, 2.42 mmol), and dioxane (10 mL) were added to a reaction flask, and the mixture was degassed with N2 for 30 seconds. Cs2CO3 (1.97 g, 6.05 mmol), Pd2dba3 (185 mg, 0.202 mmol), and Xantphos (233 mg, 0.403 mmol) were added, and the mixture was degassed with N2 for 30 seconds. The flask was sealed and heated at 85 °C for 16 h. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% MeOH in EtOAc solution) to give (R)-((2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -Sulphinate (362 mg, 59% yield), as a pale yellow solid, and (R)-((4-chloro-6-(3-methylmorpholino)pyrimidin-2-yl)imino)dimethyl-λ 6 - Sulfinyl ester (222 mg, 36% yield) is a pale yellow solid.

[0730] 1 H NMR(600MHz, CDCl3) δ5.73(s,1H),4.21-4.15(m,1H),3.96(dd,J=11.5,3.7Hz,1H),3.91(d,J=13.0Hz,1H),3.74(d,J=11.5Hz,1H),3.67 (dd,J=11.5,3.2Hz,1H),3.52(td,J=11.9,3.1Hz,1H),3.37(d,J=3.1Hz,6H),3.19(td,J=12.8,3.9Hz,1H),1.26(d,J=6.8Hz,3H); MS(ES + C 11 H 17 ClN4O2S requirement: 304, actual measurement: 305 [M+H] + .

[0731] Intermediate E

[0732]

[0733] Cyclopropyl(imino)(methyl)-λ 6 -sulfinyl compounds

[0734] Step 1

[0735]

[0736] (Methylsulfinyl)cyclopropane: Cyclopropylmagnesium bromide (1M, 72mL, 72mmol) was slowly added to a solution of 1-bromo-4-(methylsulfinyl)benzene (10.5g, 48.0mmol) in THF (100mL). The mixture was stirred at 0°C for 1.5h. A saturated aqueous solution of NH4Cl (200mL) was added to separate the layers, and the aqueous layer was extracted with CH2Cl2 (5×150mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (50-100% EtOAc in petroleum ether solution) to give the title compound (3.2g, 64% yield) as a yellow oil.

[0737] MS(ES + C4H8OS requirement: 104, actual measured 105 [M+H] + .

[0738] Step 2

[0739]

[0740] Cyclopropyl(imino)(methyl)-λ6 - Sulphinate: NH3 (120 mL, 0.84 mol, 7 N MeOH solution) was added dropwise to a solution of the product from the previous step (22 g, 0.21 mol) and PhI(OAc)2 (204 g, 0.64 mol) in MeOH (100 mL). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid chromatography (15% EtOAc in petroleum ether solution followed by 2% MeOH in CH2Cl2 solution) to give the title compound (20 g, 79%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ3.06 (s, 3H), 2.58 (tt, J = 7.9, 4.8Hz, 1H), 1.26-1.19 (m, 1H), 1.19-1.12 (m, 1H), 1.05 (dt, J = 11.1, 4.5Hz, 2H).

[0741] intermediate F

[0742]

[0743] Imino(methyl)(oxetane-3-yl)-λ 6 -sulfinyl compounds

[0744] Step 1

[0745]

[0746] 3-(Methylsulfinyl)oxetane: Under N2, CH3SNa (2.28 g, 32.6 mmol) was added to a solution of 3-iodooxetane (6.0 g, 32.6 mmol) in DMF (60 mL). The reaction mixture was stirred at room temperature for 1 h. EtOAc (120 mL) and water (80 mL) were added, the layers were separated, and the organic layer was washed with brine (80 mL), dried over MgSO4, and filtered. MeOH (60 mL), water (60 mL), and NaIO4 (6.2 g, 29.3 mmol) were added to the EtOAc solution, and the reaction mixture was stirred at room temperature for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography (50% EtOAc in petroleum ether to 10% MeOH in CH2Cl2 solution) to give the title compound (3.5 g, 90% yield) as a pale yellow oil.

[0747] MS(ES + C4H8O2S requirement: 120, actual measured 121 [M+H] + .

[0748] Step 2

[0749]

[0750] (methyl(oxetane-3-yl)(oxo)-λ) 6 β-thionyl)carbamate: Benzyl carbamate (6.58 g, 43.6 mmol), Rh2(OAc)4 (383 mg, 0.873 mmol), PhI(OAc)2 (14.0 g, 43.6 mmol), and MgO (4.7 g, 116 mmol) were added to a solution of the product from the previous step (3.5 g, 29 mmol) in CH2Cl2 (260 mL), and the mixture was stirred for 16 h at room temperature under a N2 atmosphere. The reaction mixture was then passed through… The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography (20-50% EtOAc in petroleum ether solution) to give the title compound (4.1 g, 52% yield) as a pale yellow oil.

[0751] MS(ES + C 12 H 15 NO4S requirement: 269, actual measurement 270 [M+H] + .

[0752] Step 3

[0753]

[0754] Imino(methyl)(oxetane-3-yl)-λ 6 - Sulphinate: Under N2, the product of the previous step (4.1 g, 15 mmol) was added to a solution of Pd / C (4.1 g) in MeOH (60 mL). The atmosphere was removed and the mixture was purged with H2 (3×). The mixture was heated to 50 °C and stirred for 3 h under H2 atmosphere. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure to give the title compound (1.7 g, 83% yield) as a pale yellow oil.

[0755] MS(ES + C4H9NO2S requires a temperature of 135°C; actual measured temperature is 136°C [M+H]. + .

[0756] intermediate G

[0757]

[0758] 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

[0759] Step 1

[0760]

[0761] 4-Bromo-2-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: LDA (2.9 mL, 2 M THF solution) was added to a solution of 4-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.9 mmol) in THF (30 mL) at -78 °C, and the mixture was stirred at -78 °C for 1 h under an Ar atmosphere. MeI (4.0 g, 29 mmol) was added, and the mixture was warmed to RT and stirred for 3 h. A saturated aqueous solution of NH4Cl (50 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 65-95%; 18 min; column: Welch XB-C18, 10 μm, 21.2 × 250 mm) to give the title compound (420 mg, 40% yield) as a white solid.

[0762] MS(ES + C 15 H 13 BrN2O2S requirement: 364, actual measured 365 [M+H] + .

[0763] Step 2

[0764]

[0765] 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: A solution of the product of the previous reaction (410 mg, 1.13 mmol), Pin2B2 (345 mg, 1.3 mmol), KOAc (277 mg, 2.8 mmol), and Pd(dppf)Cl2 (82 mg, 0.11 mmol) in dioxane (5 mL) was added to the reaction flask. The mixture was degassed by bubbling Ar for 1 minute. The mixture was heated at 80 °C and stirred for 5 h. The mixture was cooled to room temperature and then... The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography (20% EtOAc in petroleum ether solution) to give the title compound (350 mg, 75% yield) as a white solid.

[0766] MS(ES + C 21 H 25 BN2O4S requires a strength of 412, but the actual measured value is 331 [M-81]. + .

[0767] intermediate H

[0768]

[0769] 4-Bromo-6-ethoxy-1H-pyrrolo[2,3-b]pyridine

[0770] Step 1

[0771]

[0772] 4-Bromo-6-ethoxy-1H-pyrrolo[2,3-b]pyridine: A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (426 mg, 2.0 mmol) and dimethyl sulfate (303 mg, 2.4 mmol) in CH3CN (10 mL) was heated to 70 °C and maintained for 24 h. The reaction mixture was cooled to room temperature, sodium ethoxide (40 mg, 6.0 mmol) was added, and the mixture was heated to 70 °C and maintained for 24 h. The reaction mixture was cooled to room temperature, neutralized to pH 7 with AcOH, and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3 solution (20 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether solution) to give the title compound (151 mg, 31% yield) as a white solid.

[0773] MS(ES + C9H9BrN2O requirement: 240°C, actual measurement: 241°C [M+H] + .

[0774] Intermediate I

[0775]

[0776] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine

[0777] Step 1

[0778]

[0779] 4-Bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine: NaH (92 mg, 2.25 mmol, 60%) was added to a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine (300 mg, 1.5 mmol) in DMF (10 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was warmed to room temperature, TsCl (429 mg, 2.25 mmol) was added, and the mixture was heated to 60 °C and stirred for another 2 h. H2O (10 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (0-20% EtOAc in petroleum ether solution) to give the title compound (300 mg, 57% yield) as a white solid.

[0780] MS(ES + C 14 H 11 BrN2O2S requires a temperature of 350°C, but the actual measured temperature was 351°C [M-81]. + .

[0781] Step 2

[0782]

[0783] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-c]pyridine: A mixture of the product from the previous step (300 mg, 0.86 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2-bis(1,3,2-dioxaboran) (254 mg, 1.0 mmol), Pd(dppf)Cl2 (63 mg, 0.086 mmol), and KOAc (169 mg, 1.72 mmol) in dioxane (10 mL) was degassed with Ar, and the reaction mixture was heated at 120 °C for 4 h. The reaction mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography (10-60% EtOAc in petroleum ether solution) to give the title compound (100 mg, 29% yield) as a white solid.

[0784] MS(ES + C 20 H 23 BN2O4S requires a value of 398, but the actual measured value is 399 [M+H]. + .

[0785] Intermediate J

[0786]

[0787] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)pyridine-2,3-diamine

[0788]

[0789] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)pyridine-2,3-diamine: Pd(dppf)Cl2 (63 mg, 0.086 mmol) was added to a solution of 4-bromopyridine-2,3-diamine (200 mg, 1.07 mmol), KOAc (262 mg, 2.67 mmol), and Pin2B2 (544 mg, 2.14 mmol) in dioxane (10 mL), and the mixture was stirred at 80 °C for 16 h under an Ar atmosphere. The reaction mixture was cooled to room temperature and then... Filter and concentrate under reduced pressure. Dissolve the residue in petroleum ether (20 mL) and stir for 10 minutes, filter and concentrate to give the title compound (>250 mg, assumed quantification) as a brown solid.

[0790] MS(ES + C 11 H 18 BN3O2 requirement: 235℃, actual measured 154℃ [M-81] + .

[0791] intermediate K

[0792]

[0793] 6-Chloro-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine

[0794]

[0795] 6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine: A suspension of 4-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.432 mmol), Pin2B2 (121 mg, 0.475 mmol), and KOAc (127 mg, 1.30 mmol) in dioxane (2160 μL) was degassed with N2 for 1 min. PdCl2(dppf)-CH2Cl2 (17 mg, 0.022 mmol) was added, and the mixture was degassed again with N2 for 1 min. The reaction mixture was heated to 100 °C and stirred for 12 h. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure to obtain the title compound (assuming quantitative determination), which was a brown solid.

[0796] MS(ES+)C 13 H 16 BClN2O2 requirement: 278, actual measurement: 279 [M+H] + .

[0797] intermediate L

[0798]

[0799] N-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine-2-amine

[0800]

[0801] N-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine-2-amine: Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added to a solution of 4-bromo-N-methylpyridine-2-amine (85 mg, 0.45 mmol), KOAc (132 mg, 1.35 mmol), and Pin2B2 (220 mg, 0.9 mmol) in dioxane (15 mL), and the mixture was heated at 90 °C and stirred under N2 atmosphere for 16 h. The reaction mixture was cooled to room temperature, EtOAc (50 mL) was added, and the mixture was stirred for 5 min. The mixture was then passed through... The mixture was filtered and concentrated under reduced pressure to obtain the title compound (100 mg) as a brown solid, which was ready for use without further purification.

[0802] MS(ES + C 12 H 19 BN2O2 requirement: 234, actual measurement: 153 [M-81] + .

[0803] intermediate M

[0804]

[0805] 7-Iodo-3-triphenylmethyl-3H-imidazo[4,5-b]pyridine

[0806] Step 1

[0807]

[0808] 7-Iodo-3H-imidazo[4,5-b]pyridine hydroiodide: A mixture of 7-chloro-3H-imidazo[4,5-b]pyridine (735 mg, 4.80 mmol) in an aqueous HI solution (12 mL) was heated and stirred at 80 °C for 16 h. The mixture was cooled to room temperature, the solid was collected by vacuum filtration, and dried under vacuum to give the title compound (1.5 g, 84% yield) as a yellow solid.

[0809] MS(ES + C6H4IN3 requirement: 245, actual measurement: 246 [M+H] + .

[0810] Step 2

[0811]

[0812] 7-Iodo-3-triphenylmethyl-3H-imidazo[4,5-b]pyridine: NaH (158 mg, 3.94 mmol, 60% mineral oil solution) was added to a solution of the product from the previous step (735 mg, 1.97 mmol) in DMF (8 mL) at 5 °C, and the resulting mixture was stirred at this temperature for 2 h. Triphenylmethyl chloride (822 mg, 2.96 mmol) in DMF (2 mL) was added dropwise to the reaction mixture, and the resulting mixture was stirred again for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10–25% EtOAc in hexane solution) to give the title compound (620 mg, 65% yield) as a white solid.

[0813] 1 H NMR (500MHz, DMSO-d6) δ8.23 (s, 1H), 7.71 (d, J = 5.0Hz, 1H), 7.64 (d, J = 5.0Hz, 1H), 7.39-7.25 (m, 9H), 7.20 (d, J = 7.2Hz, 6H).

[0814] intermediate N

[0815]

[0816] (R)-(4-benzylmorpholin-3-yl)methanol

[0817] Step 1

[0818]

[0819] Benzoyl-D-serine: The mixture was added to a stirred solution of (R)-2-amino-3-hydroxypropionic acid (50 g, 476 mmol), benzoyl chloride (66.64 g, 476 mmol), and K₂CO₃ (131.6 g, 952 mmol) in H₂O (500 mL), and stirred at 25 °C for 16 h. The reaction mixture was adjusted to pH 3–4 with 1 N HCl, and the aqueous layer was extracted with EtOAc (800 mL). The organic layer was washed with brine (2 × 500 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (35.8 g, 40% yield) as a white solid.

[0820] MS(ES + C 10 H 11 NO4 requirement: 209, actual measurement: 210 [M+H] + .

[0821] Step 2

[0822]

[0823] N-Benzoyl-O-Benzyl-D-Serine: Under a N2 atmosphere, a solution of the product from the previous step (96 g, 459 mmol) in DMF (300 mL) was added to a suspension of NaH (33.06 g, 1378 mmol) in DMF (300 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 1 h. Benzyl bromide (54.54 mL, 459.2 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The reaction mixture was poured into ice water, the layers were separated, and the aqueous phase was extracted with Et2O (1200 mL). The aqueous phase was acidified with 4N HCl and extracted with CH2Cl2 (1200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (126 g, 69% yield), which was ready for use without further purification.

[0824] MS(ES + C 17 H 17 NO4 Requirement: 299, Actual Measurement: 300 [M+H] + .

[0825] Step 3

[0826]

[0827] (S)-2-(benzylamino)-3-(benzyloxy)prop-1-ol: Under N2 atmosphere, the product of the previous step (50 g, 167 mmol) in a solution of THF (500 mL) was mixed with BH3-THF (1 M THF solution, 1.8 L, 1672 mmol) at 0 °C, and the resulting mixture was heated to room temperature and stirred for 16 h. MeOH (1 L) was added dropwise, and the mixture was concentrated under reduced pressure. MeOH (1.5 L) and 1 N NaOH aqueous solution (2.225 L) were added to the residue, and the mixture was refluxed and heated for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between H2O (2 L) and EtOAc (2 L), and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (40 g, 88% yield) as a colorless oil that could be used without further purification.

[0828] MS(ES + C 17 H 21 NO2 requirement: 271, actual measurement: 272 [M+H] + .

[0829] Step 4

[0830]

[0831] (R)-4-Benzyl-5-((benzyloxy)methyl)morpholin-3-one: Triethylamine (5.91 mL, 42.4 mmol) and chloroacetyl chloride (3.35 mL, 42.4 mmol) were added to a solution of the product from the previous step (10 g, 37 mmol) in CH2Cl2 (100 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between 1N HCl (100 mL) and CH2Cl2 (100 mL), and the layers were separated. The organic layer was washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 2-propanol (150 mL), KOH (4.14 g, 73.8 mmol) was added, and the mixture was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between water (100 mL) and EtOAc (100 mL), and the layers were separated. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc in hexane solution) to give the title compound (7.46 g, 65% yield) as a pale yellow oil.

[0832] MS(ES + C 19 H 21 NO3 requirement: 311, actual measurement: 312 [M+H] + .

[0833] Step 5

[0834]

[0835] (R)-4-Benzyl-5-(hydroxymethyl)morpholin-3-one: The product from the previous step (25 g, 80 mmol) and 10% palladium / activated carbon (13 g, 8 mmol) were stirred for 16 h at 1 atm in a suspension of EtOH (150 mL) and acetic acid (50 mL) under H2 pressure and at 40 °C. The mixture was cooled to room temperature, purged with N2, and subjected to... Filter and concentrate under reduced pressure. Concentrate the residue from toluene (2 × 100 mL) to give the title compound (32 g, assumed quantification), which can be used without further purification.

[0836] MS(ES + C 12 H 15 NO3 requirement: 221, actual measurement: 222 [M+H] + .

[0837] Step 6

[0838]

[0839] (R)-(4-Benzylmorpholino-3-yl)methanol: Under N2 atmosphere, the product of the previous step (24 g, 108.55 mmol) in a solution of THF (50 mL) was added to a borane-methyl sulfide complex (1.0 M THF solution, 40 mL), and the result was heated at 80 °C for 16 h. The mixture was cooled to room temperature, and MeOH (60 mL) was added dropwise and concentrated under reduced pressure. The residue was partitioned between MeOH (40 mL) and 1 N NaOH aqueous solution (40 mL), and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-10% EtOAc in hexane solution) to give the title compound (21.8 g, 97% yield) as a white solid.

[0840] 1H NMR (400MHz, DMSO-d6) δ7.37-7.18(m,5H),4.59(t,J=5.3Hz,1H),4.04(d,J=13.6Hz,1H),3.79-3.64(m,2H),3.58(dt,J= 11.0,3.4Hz,1H),3.45-3.35(m,3H),3.27(d,J=13.6Hz,1H),2.56-2.44(m,2H),2.11(ddd,J=12.1,9.1,3.2Hz,1H); MS(ES + C 12 H 17 NO2 requirement: 207, actual measurement: 208 [M+H] + .

[0841] Intermediate O

[0842]

[0843] (S)-3-(fluoromethyl)morpholine

[0844] Step 1

[0845]

[0846] (S)-4-Benzyl-3-(fluoromethyl)morpholine: Diethylaminosulfonium trifluoride (6.26 mL, 4.9 mmol) was added dropwise to a solution of intermediate N (6.81 g, 3.28 mmol) in CH2Cl2 (50 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was added dropwise to ice water, and a saturated aqueous solution of NaHCO3 was added to adjust the pH to 8. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (90% EtOAc in hexane solution) to give the title compound (5.18 g, 70% yield) as a yellow liquid.

[0847] MS(ES + C 12 H 16 FNO requirement: 209, Actual measurement: 210 [M+H] + .

[0848] Step 2

[0849]

[0850] (S)-3-(fluoromethyl)morpholine: The product from the previous step (5.18 g, 24.7 mmol) was added to a solution of DCE (50 mL) with ethyl 1-chloroformate (26.7 mL, 247 mmol), and the resulting mixture was heated and stirred at 80 °C for 16 h. The mixture was cooled to room temperature, MeOH was added until no bubbles were observed, DCE was removed under reduced pressure, and the residue was refluxed and heated for 1 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and n-heptane was added, and the mixture was concentrated under reduced pressure (2 × 50 mL). The residue was ground with EtOAc to give the title compound (25 g, 60% yield) as a white solid.

[0851] MS(ES + C5H 10 FNO requirement: 119, Actual measurement: 120 [M+H] + .

[0852] intermediate P

[0853]

[0854] 5-Fluoro-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine

[0855] Step 1

[0856]

[0857] 5-Fluoro-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrrolo[2,3-b]pyridine: 4-Bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.465 mmol), KOAc (137 mg, 1.40 mmol), Pin2B2 (142 mg, 0.558 mmol), PdCl2(dppf)-CH2Cl2 (19 mg, 0.023 mmol), and then dioxane (3.1 mL) were added to a sealed tube. The mixture was degassed by bubbling out a stream of N2 for 1 minute. The tube was sealed, and the reaction mixture was heated at 90 °C for 18 h. The reaction mixture was cooled to room temperature and then... The mixture was filtered, washed with EtOAc (5 mL), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–10% MeOH in CH2Cl2 solution) to give the title compound (112 mg, 46% yield) as a pale yellow solid.

[0858] MS(ES + C 13 H 16BFN2O2 requirement: 262, actual measurement: 181 [M-81] + .

[0859] intermediate Q

[0860]

[0861] ((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[0862]

[0863] ((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 - Sulphinate: Pd2(dba)3 (8.6 g, 9.4 mmol), XantPhos (5.5 g, 9.4 mmol), and Cs2CO3 (184 g, 0.57 mol) were added to a mixture of intermediate E (47 g, 0.19 mol), (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described in step 1 for intermediate B) (22 g, 0.19 mol) in dioxane (750 mL). The reaction mixture was degassed with N2 for 1 min and heated to 80 °C, and stirred for 6 h under N2 atmosphere. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% hexane solution of EtOAc) to give the title compound (26 g, 41% yield) as a grayish-white solid.

[0864] 1 H NMR (400MHz, DMSO-d6) δ5.86 (s, 1H), 4.22 (d, J = 5.3Hz, 1H), 3.92-3.80 (m, 2H), 3.66 (d, J = 11.4Hz, 1H), 3.54 (dd, J = 1 1.5, 2.9Hz, 1H), 3.45 (s, 3H), 3.39 (td, J = 11.9, 3.0Hz, 1H), 3.12-2.93 (m, 2H), 1.26-1.19 (m, 1H), 1.17-1.04 (m, 6H). MS(ES + C 13 H 19 ClN4O2S requirement: 330°C, actual measurement: 331°C [M+H] + .

[0865] intermediate R

[0866]

[0867] 1-Imine-1λ 6 1-Oxide of thiomorpholine-4-carboxylic acid tert-butyl ester

[0868] Step 1

[0869]

[0870] 1-(((benzyloxy)carbonyl)imino)-1λ 6 1-Thiomorpholine-4-carboxylic acid tert-butyl ester 1-oxide: PhI(OAc)2 (4.40 g, 13.7 mmol) was added to a suspension of 1-thiomorpholine-4-carboxylic acid tert-butyl ester 1-oxide (2.0 g, 9.1 mmol), benzyl carbamate (2.10 g, 13.7 mmol), MgO (1.5 g, 36 mmol), and Rh2(OAc)4 (0.1 g, 0.23 mmol) in CH2Cl2 (20 mL), and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was then subjected to… The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% EtOAc in petroleum ether solution) to give the title compound (2.4 g, 36% yield) as a white solid.

[0871] MS(ES + C 17 H 24 N2O5S requirement: 368, actual measurement: 369 [M+H] + .

[0872] Step 2

[0873]

[0874] 1-Imine-1λ 6 1-Oxide of thiomorpholine-4-carboxylic acid tert-butyl ester: A suspension of the product from the previous step (1.0 g, 2.7 mmol) and 10% Pd / C (250 mg, 0.235 mmol) in MeOH (20 mL) was stirred under H2 for 16 h. The reaction mixture was then passed through... The mixture was filtered and concentrated under reduced pressure to give the title compound (500 mg, 79% yield) as a colorless oil. The crude product was ready for use in subsequent steps without further purification.

[0875] MS(ES + C9H 18 N₂O₃S requirement: 234, actual measurement: 235 [M+H] + .

[0876] intermediate S

[0877]

[0878] 6-Methoxy-N-(4-Methoxybenzyl)-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-pyridine-2-amine

[0879] Step 1

[0880]

[0881] 6-Chloro-4-iodo-N-(4-methoxybenzyl)pyridine-2-amine: 2,6-Dichloro-4-iodopyridine (10 g, 36 mmol), 4-methoxybenzylamine (23.4 mL, 179 mmol), and ethanol (20 mL) were charged into a microwave-safe flask. The flask was sealed, and the reaction mixture was heated to 150 °C in a microwave reactor and maintained for 4 h. The mixture was cooled to room temperature, poured into water (20 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic fractions were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–20% EtOAc in hexane) to give the title compound (9.24 g, 69% yield) as a white solid.

[0882] MS(ES + C 13 H 12 ClIN2O requirement: 374, actual measurement: 375 [M+H] + .

[0883] Step 2

[0884]

[0885] 4-Iodo-6-methoxy-N-(4-methoxybenzyl)pyridine-2-amine: Sodium methoxide (1.8 mL, 8.0 mmol, 25% MeOH solution) was added to a suspension of the product from the previous step (1.0 g, 2.67 mmol) in dioxane (5.3 mL) at 0 °C, and the resulting mixture was stirred at 100 °C for 16 h. 1N HCl (5 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and subjected to… The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in hexane solution) to give the title compound (844 mg, 85% yield) as a colorless liquid.

[0886] MS(ES + C14 H 15 IN₂O₂ requirement: 370°C, actual measurement: 371°C [M+H] + .

[0887] Step 3

[0888]

[0889] 6-Methoxy-N-(4-Methoxybenzyl)-4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-pyridine-2-amine: The suspension of the product from the previous step (900 mg, 2.43 mmol), Pin2B2 (741 mg, 2.92 mmol), and KOAc (716 mg, 7.29 mmol) in dioxane (12.2 mL) was degassed with N2 for 1 min. PdCl2(dppf)-CH2Cl2 (99 mg, 0.12 mmol) was added, and the mixture was degassed again with N2 for 1 min. The reaction mixture was heated in a microwave reactor at 120 °C for 10 h. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% EtOAc in hexane solution) to give the title compound (860 mg, 72% yield) as a pale yellow liquid.

[0890] MS(ES + C 20 H 27 BN2O4 requirement: 370, actual measurement: 289 [M-81] + .

[0891] intermediate T

[0892]

[0893] (R)-4-(6-chloro-2-(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine

[0894]

[0895] (R)-4-(6-chloro-2-(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine: synthesized to (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (as described in step 1 for intermediate B) (467 mg, 1.88 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)- 1-Toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (900 mg, 2.26 mmol) was added to a solution of dioxane (7.1 mL) and water (2.4 μL) with Na₂CO₃ (439 mg, 4.14 mmol) and PdCl₂(dppf)-CH₂Cl₂ (77 mg, 0.094 mmol). The resulting mixture was degassed with N₂ for 1 min and stirred at 110 °C for 4 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (5 mL) and H₂O (2 mL) to separate the layers. The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–60% EtOAc in hexane solution) to give the title compound (300 mg, 33% yield) as a grayish-white solid.

[0896] 1 H NMR (600MHz, CDCl3) δ8.52(d,J=5.3Hz,1H),8.06(t,J=7.1Hz,3H),7.83(d,J=4.0Hz,1 H),7.48(d,J=3.9Hz,1H),7.26(d,J=1.5Hz,2H),6.46(s,1H),4.40(s,1H),4.07(dd,J= 11.4,3.5Hz,2H),3.85(d,J=11.6Hz,1H),3.75(dd,J=11.7,3.1Hz,1H),3.60(td,J=11 .9,2.8Hz,1H),3.37(td,J=12.8,4.0Hz,1H),2.36(s,3H),1.37(d,J=6.9Hz,3H); MS(ES + C 23 H 22 ClN5O3S: 483, Actual measurement: 484 [M+H] + .

[0897] intermediate U

[0898]

[0899] 4-Bromo-2-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

[0900]

[0901] 4-Bromo-2-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine: A mixture of 4-bromo-2-iodo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.3 g, 0.63 mmol), cyclopropylboronic acid (0.054 g, 0.63 mmol), Pd(PPh3)4 (73 mg, 0.063 mmol), Na2CO3 (134 mg, 1.26 mmol), dioxane (10 mL), and H2O (2 mL) was purged with Ar2, sealed, and heated in a microwave reactor at 130 °C for 3 h. The reaction mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc in hexane solution) to give the title compound (30 mg, 12% yield) as a white solid.

[0902] MS(ES + C 17 H 15 BrN2O2S requirement: 390°C, actual measurement: 391°C [M+H] + .

[0903] intermediate V

[0904]

[0905] (R)-Dimethyl((6-(3-methylmorpholino)-2-(tributyltinyl)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[0906]

[0907] (R)-Dimethyl((6-(3-methylmorpholino)-2-(tributyltinyl)pyrimidin-4-yl)imino)-λ 6-Synesinide, Intermediate 5: Under an Ar atmosphere, anhydrous THF (2 mL) and diisopropylamine (310 μL, 2.2 mmol) were added to a flame-dried round-bottom flask. The solution was cooled to -10 °C, and n-BuLi (2.5 M hexane solution, 0.84 mL, 2.1 mmol) was added dropwise, followed by warming the resulting mixture to 0 °C over 5 minutes. A solution of Bu3SnH (538 μL, 2.0 mmol) in THF (2.0 mL) was added dropwise, and the resulting mixture was stirred at 0 °C for 20 minutes, then cooled to -78 °C. A solution of intermediate D (610 mg, 2.0 mmol) in THF (2.0 mL) was added to the mixture at -78 °C, and the resulting mixture was stirred at -78 °C for 1 h. Water (10 mL) was added to the mixture, the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20-100% hexane solution of EtOAc) to give the title compound (350 mg, 31% yield) as a colorless oil.

[0908] MS(ES + C 23 H 44 N4O2SSn requirement: 560, actual measurement: 561 [M+H] + .

[0909] intermediate W

[0910]

[0911] (S)-3-(difluoromethyl)morpholine hydrochloride

[0912] Step 1

[0913]

[0914] (S)-4-Benzylmorpholine-3-carboxaldehyde: Oxaloyl chloride (12.2 mL, 145 mmol) in CH2Cl2 (50 mL) was added dropwise to a solution of DMSO (20.6 mL, 290 mmol) in CH2Cl2 (100 mL) at -78 °C, and the mixture was stirred at -78 °C for 15 min. Intermediate N (10 g, 48 mmol) in CH2Cl2 (50 mL) was added over 30 min, and the resulting mixture was warmed to room temperature and stirred for 30 min. A saturated aqueous solution of NaHCO3 (200 mL) was added to the reaction mixture, and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (9.9 g, 99% yield), which was ready for immediate use without further purification.

[0915] MS(ES + C 12 H 15 NO2 requirement: 205, actual measurement: 206 [M+H] + .

[0916] Step 2

[0917]

[0918] (S)-4-Benzyl-3-(difluoromethyl)morpholine: DAST (19.14 mL, 44.8 mmol) was added dropwise to a solution of the product from the previous step (9.9 g, 48.267 mmol) in CH2Cl2 (100 mL) at 0 °C while maintaining the temperature at 0–5 °C. The resulting reaction mixture was then warmed to room temperature and stirred for 16 h. A saturated aqueous solution of NaHCO3 (50 mL) was added to the reaction mixture, and the layers were separated. The organic layer was washed with water (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane) to give the title compound (5 g, 45.45% yield) as a pale yellow oil.

[0919] MS(ES + C 12 H 15 F2NO requirement: 227, actual measurement: 228 [M+H] + .

[0920] Step 3

[0921]

[0922] (S)-3-(difluoromethyl)morpholine hydrochloride: The product from the previous step (2.0 g, 8.806 mmol) was added to a solution of DCE (10 mL) with ethyl 1-chloroformate (9.44 mL, 88.1 mmol), and the resulting mixture was heated and stirred at 80 °C for 16 h. The mixture was cooled to room temperature, MeOH was added until no bubbles were observed, DCE was removed under reduced pressure, and the residue was refluxed and heated for 1 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and 2-propanol was added, and the mixture was concentrated under reduced pressure (2 × 10 mL). The residue was ground with EtOAc to give the title compound (1.9 g, quantitative yield) as a white solid.

[0923] 1H NMR(400MHz, DMSO-d6)δ6.42(td,J=53.7,3.9Hz,1H),4.04(dd,J=12.3,3.5Hz,1H),4.00 -3.83(m,2H),3.82-3.60(m,2H),3.25(dt,J=12.9,2.7Hz,1H),3.20-3.06(m,1H); MS(ES + C5H9F2NO requirement: 137, actual measurement: 138 [M+H] + .

[0924] Intermediate X

[0925]

[0926] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-benzo[d]imidazole

[0927]

[0928] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1H-benzo[d]imidazole: A mixture of 4-bromo-1H-benzo[d]imidazole (0.5 g, 2.5 mmol), Pin2B2 (0.77 g, 3.1 mmol), PdCl2 (dppf) (93 mg, 0.13 mmol), and KOAc (0.5 g, 5.1 mmol) in dioxane (20 mL) was degassed with N2 for 1 min, and the resulting mixture was heated at 90 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure to obtain the title compound (0.6 g, assumed quantification), which was a black solid and could be used directly in the next step without further purification.

[0929] MS(ES + C 13 H 17 BN2O2 requirement: 244, actual measurement: 163 [M-81] + .

[0930] intermediate Y

[0931]

[0932] 6-Chloro-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-pyridine-2-amine

[0933]

[0934] 6-Chloro-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-pyridine-2-amine: 6-chloro-4-iodo-N-(4-methoxybenzyl)pyridine-2-amine (synthesized as described in step 1 for intermediate S) (500 mg, 1.24 mmol), KOAc (365 mg, 3.72 mmol), Pin2B2 (378 mg, 1.49 mmol), PdCl2(dppf)-CH2Cl2 (0.051 g, 0.062 mmol), and dioxane (8.28 mL) were charged into a sealed tube, and the resulting mixture was degassed with N2 for 1 min. The reaction tube was sealed, and the reaction mixture was heated at 90 °C for 18 h. The reaction mixture was cooled to room temperature and subjected to… The mixture was filtered, washed with EtOAc, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc in hexane solution) to give the title compound (525 mg, 56% yield) as an orange liquid.

[0935] MS(ES + C 19 H 24 BClN2O3 requirement: 374, actual measurement: 293 [M-81] + .

[0936] Intermediate Z

[0937]

[0938] 4-Bromo-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[2,3-b]pyridine

[0939]

[0940] 4-Bromo-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[2,3-b]pyridine: A solution of 7-oxide of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.73 g, 8.13 mmol) and dimethyl sulfate (1.23 g, 9.75 mmol) in CH3CN (50 mL) was heated to 70 °C and maintained for 24 h. The reaction mixture was cooled to room temperature. 2,2,2-trifluoroethanol (5.2 g, 52 mmol) was added to a suspension of NaH (6.24 g, 156 mmol, 60% mineral oil solution) in CH3CN (50 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was then added to the mixture prepared above, and the resulting mixture was stirred at 70 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-67% EtOAc in petroleum ether solution; then 0-40% acetone in petroleum ether solution) to give the title compound (450 mg, 19% yield) as a white solid.

[0941] MS(ES + C9H6BrF3N2O required: 294, 296; actual measured: 295, 297 [M+H] + .

[0942] Intermediate AA

[0943]

[0944] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxynitrile

[0945] Step 1

[0946]

[0947] 4-Bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylonitrile: 4-Bromo-2-iodo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.42 mmol), Zn(CN)₂ (24 mg, 0.21 mmol), Pd(PPh₃)₄ (24 mg, 0.021 mmol), and DMF (5 mL) were charged into a microwave-safe bottle. The bottle was sealed, and the reaction mixture was heated in a microwave reactor at 150 °C for 30 minutes. The reaction mixture was cooled to room temperature and then subjected to... The residue was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 50-80%; 18 min; column: Welch XB-C18, 10 μm, 21.2 × 250 mm) to give the title compound (20 mg, 12% yield) as a white solid.

[0948] MS(ES + C 15 H 10 BrN3O2S requirement: 375℃, actual measurement: 376℃ [M+H] + .

[0949] Step 2

[0950]

[0951] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylonitrile: 4-bromo-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylonitrile (25 mg, 0.066 mmol), KOAc (19.6 mg, 0.199 mmol), bis(pinacol)diboron (20.3 mg, 0.0800 mmol), PdCl2(dppf)-CH2Cl2 (2.7 mg, 3.3 μmol), and dioxane (443 μL) were charged into a sealed tube. The reaction mixture was degassed with N2 for 30 seconds, sealed, and heated at 90 °C for 18 h. The reaction mixture was cooled to room temperature and then subjected to… The mixture was filtered, washed with EtOAc, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% EtOAc in hexane solution) to give the title compound (11 mg, 20% yield) as a pale yellow liquid.

[0952] MS(ES + C 21 H 22 BN3O4S requirement: 423, actual measurement: 342 [M-81] + .

[0953] intermediate BB

[0954]

[0955] (R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ) 6 methyl 6-(3-methylmorpholino)pyrimidin-2-yl)pyridinecarboxylate

[0956] Step 1

[0957]

[0958] Methyl 6-(tert-butylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridinecarboxylate: A suspension of methyl 4-bromo-6-(tert-butylamino)pyridinecarboxylate (222 mg, 0.773 mmol), Pin2B2 (216 mg, 0.850 mmol), and KOAc (228 mg, 2.32 mmol) in dioxane (3.87 mL) was degassed with N2 for 1 min. PdCl2(dppf)-CH2Cl2 (31.6 mg, 0.039 mmol) was added, and the mixture was degassed again with N2 for 1 min. The reaction mixture was heated to 100 °C and stirred for 12 h. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in CH2Cl2 solution) to give the title compound (226 mg, 87% yield) as a brown liquid.

[0959] MS(ES + C 17 H 27 BN2O4 requirement: 334, actual measurement: 253 [M-81] + .

[0960] Step 2

[0961]

[0962] (R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ) 6 Methyl pyrimidin-2-yl)pyridinecarboxylate (-thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)pyridinecarboxylate: A suspension of intermediate D (81 mg, 0.264 mmol), the product from the previous step (200 mg, 0.599 mmol), and K₂CO₃ (73 mg, 0.53 mmol) in THF (1.2 mL) and water (120 μL) was degassed with N₂ for 1 min. PdCl₂(dppf)-CH₂Cl₂ (11 mg, 0.013 mmol) was added, and the mixture was degassed again with N₂ for 1 min. The reaction mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to room temperature, and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 1 mL). The combined organic layers were washed with brine (1 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% EtOAc in hexane solution) to give the title compound (150 mg, quantitative yield) as a pale yellow liquid.

[0963] MS(ES + C 22 H 32 N6O4S requirement: 476, actual measurement: 477 [M+H] + .

[0964] intermediate CC

[0965]

[0966] (R)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[0967] as well as

[0968]

[0969] (S)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[0970]

[0971] (R)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -Syrinyl ester and (S)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 - Sulphinate: Pd2(dba)3 (8.6 g, 9.4 mmol), XantPhos (5.5 g, 9.4 mmol), and Cs2CO3 (184 g, 0.57 mol) were added to a solution of intermediate E (47 g, 0.19 mol) and (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described in step 1 for intermediate B) in dioxane (750 mL), and the resulting mixture was purged with N2 (3×), heated to 80 °C, and stirred for 6 h under N2 atmosphere. The reaction mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% hexane solution of EtOAc) to give the title compound as a mixture of two diastereomers of absolutely stereochemically unknown origin at the sulfur atom (26 g, 41% yield), as a grayish-white solid.

[0972] Separation of a mixture of diastereomers (35 g, 0.11 mol) in CH2Cl2 (300 mL) by chiral SFC (mobile phase: CO2 / EtOH = 75 / 25; flow rate: 70 g / min; 4 min; column temperature: 35 °C; back pressure: 100 bar; column: Daicel) (AD, 10μm, 20mm×250mm) Two diastereomers with absolutely unknown stereochemistry at the sulfur atom were obtained: isomer 1a (15.0g, 86%), a pale yellow solid, and isomer 1b (14.2g, 81%), a pale yellow solid.

[0973] Isomer 1a((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1 H NMR (400MHz, CDCl3) δ5.69(s,1H),4.15-4.05(m,1H),3.93-3.79(m,2H),3.67(d,J=11.5Hz,1H),3.59(app.d,J=11.5Hz,1H),3.51-3.39(m,1H),3 .36(s,3H),3.12(td,J=12.8,3.4Hz,1H),2.87-2.76(m,1H),1.51-1.40( m,1H),1.28-1.21(m,1H),1.19(d,J=6.7Hz,3H),1.14-0.99(m,2H); MS(ES + C 13 H 19 ClN4O2S requirement: 330°C, actual measurement: 331°C [M+H] + ;R t =3.19min.

[0974] Isomer 1b((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1H NMR (400MHz, CDCl3) δ5.68 (s, 1H), 4.14-4.05 (m, 1H), 3.88 (dd, J = 11.5, 3.9Hz, 1H), 3.83 (d,J=13.6Hz,1H),3.67(d,J=11.5Hz,1H),3.59(dd,J=11.5,3.2Hz,1H),3.45(td,J=11.9 ,3.1Hz,1H),3.37(s,3H),3.12(td,J=12.8,3.9Hz,1H),2.81(ddd,J=12.8,8.0,4.8Hz,1 H),1.49-1.41(m,1H),1.27-1.20(m,1H),1.18(d,J=6.8Hz,3H),1.14-1.01(m,2H); MS(ES + C 13 H 19 ClN4O2S requirement: 330°C, actual measurement: 331°C [M+H] + ;R t =5.62min.

[0975] intermediate DD

[0976]

[0977] Imino(methyl)(pyridin-3-yl)-λ 6 -sulfinyl compounds

[0978]

[0979] Imino(methyl)(pyridin-3-yl)-λ 6 - Sulphinate: NH₂COONH₄ (1.7 g, 21.8 mmol) and PhI(OAc)₂ (7.02 g, 21.8 mmol) were added to a solution of 3-(methylthio)pyridine (1.09 g, 8.72 mmol) in MeOH (10 mL), and the resulting mixture was stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH₄HCO₃ in H₂O aqueous solution, B = MeCN; gradient: B = 95%; 13 min; 30 mL / min; column: Ultimate Prep C18 OBD 21.2 × 250 mm, 10 μm) to give the title compound (760 mg, 55%) as a grayish-white solid.

[0980] (ES + C6H8N2OS requirement: 156, actual measurement: 157 [M+H] + .

[0981] Intermediate EE

[0982]

[0983] Imino(methyl)(1-methyl-1H-pyrazole-4-yl)-λ 6 -sulfinyl compounds

[0984] Step 1

[0985]

[0986] 1-Methyl-4-(methylthio)-1H-pyrazole: Under a nitrogen atmosphere, isopropyl magnesium chloride (5.2 mL, 10.4 mmol) was added to a solution of 4-iodo-1-methyl-1H-pyrazole (0.5 mL, 5.2 mmol) in THF (2 mL) at -78 °C, and the resulting mixture was stirred for 30 minutes. Dimethyl disulfide (1 mL, 11 mmol) was added to the reaction mixture. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (25 mL), the layers were separated, and the aqueous layer was extracted with Et2O (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 in H2O aqueous solution, B = MeCN; gradient: B = 95%; 13 min; 30 mL / min; column: Ultimate Prep C18 OBD 21.2 × 250 mm, 10 μm) to give the title compound (740 mg, 29%) as a grayish-white solid.

[0987] (ES + C5H8N2S requirement: 128, actual measurement: 129 [M+H] + .

[0988] Step 2

[0989]

[0990] Imino(methyl)(1-methyl-1H-pyrazole-4-yl)-λ 6- Sulphinate: The product from the previous step (1.09 g, 8.72 mmol) was added to a solution of MeOH (10 mL) with NH₂COONH₄ (1.7 g, 21.8 mmol) and PhI(OAc)₂ (7.02 g, 21.8 mmol), and the resulting mixture was stirred for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH₄HCO₃ in H₂O aqueous solution, B = MeCN; gradient: B = 95%; 13 min; 30 mL / min; column: Ultimate Prep C18 OBD 21.2 × 250 mm, 10 μm) to give the title compound (730 mg, 53%) as a grayish-white solid.

[0991] (ES + C5H9N3OS Requirements: 159, Actual Measurement: 160 [M+H] + .

[0992] intermediate FF

[0993]

[0994] 2-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazole

[0995]

[0996] 2-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazole: Pure TIPSCl (2.87 mL, 13.4 mmol) was added to a solution of (1H-benzo[d]imidazole-2-yl)methanol (1.66 g, 11.2 mmol), imidazole (0.92 g, 13 mmol), and DMAP (0.068 g, 0.56 mmol) in DMF (10 mL), and the resulting mixture was stirred at room temperature for 48 h. The reaction mixture was poured into water (100 mL), the layers were separated, and the aqueous layer was extracted with Et2O (2 × 100 mL). The combined organic layers were washed successively with water (2 × 100 mL) and brine (100 mL), stirred on MgSO4, filtered, and concentrated under reduced pressure to give the title compound (3.40 g, 99% yield) as a white solid.

[0997] MS(ES + C 17 H 28 N2OSi requirement: 304, actual measured value: 305 [M+H] + .

[0998] Example 1

[0999]

[1000] (R)-Dimethyl((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1001]

[1002] (R)-Dimethyl((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 - Sulfonate: Intermediate B (100 mg, 0.30 mmol), intermediate C (34 mg, 0.36 mmol), RuPhos Pd G4 (26 mg, 0.030 mmol), RuPhos (14 mg, 0.030 mmol), Cs₂CO₃ (293 mg, 0.90 mmol), and 1,4-dioxane (2 mL) were charged into a reaction flask. The flask was purged with N₂ and sealed. The reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was cooled to room temperature and analyzed by... Filter and concentrate under reduced pressure. Pass the residue through reversed-phase preparative HPLC (mobile phase: A = 10M NH4HCO3 / H2O, B = MeCN; gradient: B = 20-50%; 10 min; column: Venusil ASBC18, 10 μm). Purified by a 21.2 mm × 250 mm tube, the title compound (33.0 mg, 28% yield) was obtained as a white solid.

[1003] 1 H NMR(500MHz,DMSO)δ11.72(s,1H),8.31(d,J=5.0Hz,1H),7.89(d,J=5.0Hz,1H),7.59-7 .49(m,1H),7.41(dd,J=3.3,1.9Hz,1H),5.92(s,1H),4.45(s,1H),4.06(d,J=12.8Hz,1H ),3.96(dd,J=11.3,3.4Hz,1H),3.75(d,J=11.3Hz,1H),3.64(dd,J=11.3,2.9Hz,1H),3. 53-3.47(m,1H),3.45(s,6H),3.15(td,J=12.8,3.8Hz,1H),1.20(d,J=6.7Hz,3H); MS(ES + C 18 H 22N6O2S requirement: 386, actual measurement: 387 [M+H] + .

[1004] The compounds reported in Table 2 were synthesized using the methods described for the previously disclosed examples. Suitable sulfinylimides were prepared as described for intermediate C.

[1005] Table 1. Examples of compounds 2-9

[1006]

[1007]

[1008]

[1009] Example 10

[1010]

[1011] (R)-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1012] Step 1

[1013]

[1014] (R)-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -Sulfinylation: A solution of intermediate D (45 mg, 0.148 mmol), intermediate P (101 mg, 0.192 mmol), and K₂CO₃ (51 mg, 0.37 mmol) in dioxane (671 μL) and water (67 μL) was degassed with N₂ for 1 min. PdCl₂(dppf)-CH₂Cl₂ (6.0 mg, 7.9 μmol) was added, and the mixture was degassed again with N₂ for 1 min. The reaction mixture was then heated at 85 °C for 3 h. The reaction mixture was cooled to room temperature and subjected to... The sample was filtered, washed with CH2Cl2 (2 mL), and concentrated under reduced pressure. The residue was purified by preparative HPLC triggered by mass spectrometry (mobile phase: A = 0.1% TFA / H2O, B = 0.1% TFA / MeCN; gradient: B = 10-40%; 20 min; column: XBridge C18, 5 μm, 19 mm × 150 mm) to give the title compound (32 mg, 34% yield) as a pale yellow solid.

[1015] 1 H NMR (600MHz, methanol-d4) δ8.31(d,J=3.0Hz,1H),7.66(d,J=3.4Hz,1H),6.71(d,J=3 .5Hz,1H),6.31(s,1H),4.63(s,1H),4.19(s,1H),4.04(dd,J=11.9,3.8Hz,1H), 3.83(d,J=11.8Hz,1H),3.75(dd,J=11.9,3.2Hz,1H),3.61(td,J=11.9,2.9Hz, 1H), 3.57 (d, J = 5.4Hz, 6H), 3.51 (t, J = 13.5Hz, 1H), 1.42 (d, J = 6.8Hz, 3H); MS (ES + C 18 H 21 FN6O2S requirement: 404, actual test result: 405 [M+H] + .

[1016] Example 11

[1017]

[1018] (R)-Dimethyl((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1019] Step 1

[1020]

[1021] (R)-Dimethyl((2-(2-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 - Sulphinate: Intermediate D (103 mg, 0.5 mmol), intermediate G (280 mg, 0.68 mmol), Na₂CO₃ (216 mg, 2.04 mmol), PdCl₂ (dppf) (25 mg, 0.034 mmol), dioxane (3 mL), and H₂O (1 mL) were charged into a reaction flask. The flask was purged with N₂ and sealed. The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and analyzed by... The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc in hexane solution) to give the title compound (50 mg, 26% yield) as a white solid.

[1022] MS(ES+ C 26 H 30 N6O4S2 requirement: 554, actual measurement: 555 [M+H] + .

[1023] Step 2

[1024]

[1025] (R)-Dimethyl((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 - Sulphinate: A mixture of the product from the previous step (50 mg, 0.09 mmol), NaOH (72 mg, 1.8 mmol), H₂O (1 mL), and MeOH (2 mL) was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. MeOH (30 mL) was added, the mixture was stirred for 5 min, filtered, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (mobile phase: A = 10 mM NH₄HCO₃ / H₂O, B = MeCN; gradient: B = 30-60%; 18 min; column: Welch XB-C18, 10 μm). Purified by a 21.2 mm × 250 mm tube, the title compound (15 mg, 41% yield) was obtained as a white solid.

[1026] 1 H NMR (500MHz, DMSO-d6) δ11.53(s,1H),8.16(d,J=5.2Hz,1H),7.81(d,J=4.8Hz1H),7.11(s,1H),5.89(s,1H),4.44(s,1H),4.04(s,1 H),3.95(s,1H),3.75(d,J=12.6Hz,1H),3.65(s,1H),3.47(d,J=19.4Hz,7H),3.14(s,1H),2.42(s,3H),1.20(d,J=6.7Hz,3H); MS(ES + C 19 H 24 N6O2S requirement: 400, actual measurement: 401 [M+H] + .

[1027] Example 12

[1028]

[1029] (R)-1-(1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1-oxo-1λ 6 -Thiomorpholine)Ethyl-1-one

[1030] Step 1

[1031]

[1032] (R)-1-((6-(3-methylmorpholino)-2-(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1λ 6 1-Oxide of thiomorpholine-4-carboxylic acid tert-butyl ester was degassed with Ar for 5 minutes in a mixture of intermediate R (145 mg, 0.62 mmol), intermediate T (300 mg, 0.62 mmol), Pd2(dba)3 (57 mg, 0.062 mmol), X-phos (30 mg, 0.062 mmol), and Cs2CO3 (407 mg, 1.24 mmol) in dioxane (10 mL). The reaction mixture was heated to 100 °C and stirred for 3 h. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc in hexane solution) to give the title compound (310 mg, 73% yield) as a yellow solid.

[1033] MS(ES + C 32 H 39 N7O6S2 requirement: 681, actual measurement: 682 [M+H] + .

[1034] Step 2

[1035]

[1036] (R)-1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1λ 6-Thiomorpholine 1-oxide: A mixture of the product from the previous step (300 mg, 0.44 mmol), TFA (1 mL), and CH₂Cl₂ (5 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give a yellow oil. MeOH (5 mL) and NaOH (18 mg, 0.88 mmol) were added, and the mixture was stirred at 60 °C for 1 h. The mixture was cooled to room temperature, H₂O (10 mL) was added, and the aqueous layer was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (150 mg, 80% yield) as a white solid.

[1037] 1 H NMR(500MHz,DMSO-d6)δ1 1.78(s,1H),9.03(s,1H),8.31(d,J=5.1Hz,1H),7.86(d,J=5.0Hz,1H),7.57(s,1H),7.33(s,1H),6.07(s,1H), 4.50(s,1H),3.98(d,J=11.4Hz,6H),3.87-3.82(m,3H),3.52(s,4H),3.19(s,1H),1.23(d,J=6.7Hz,3H); MS(ES + C 20 H 25 N7O2S requirement: 427, actual measurement: 428 [M+H] + .

[1038] Step 3

[1039]

[1040] (R)-1-(1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1-oxo-1λ 6 (-Thiomorpholine) ethane-1-one: Acetyl chloride (18 mg, 0.23 mmol) was added to a solution of the product from the previous step (100 mg, 0.23 mmol) and Et3N (0.5 mL, 0.5 mmol) in CH2Cl2 (5 mL) at 0 °C, and the resulting mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 25-55%; 15 min; column: Welch XB-C18, 10 μm, 21.2 × 250 mm) to give the title compound (36 mg, 33% yield) as a white solid.

[1041] 1 H NMR (500MHz, DMSO-d6) δ11.72(s,1H),8.30(d,J=5.0Hz,1H),7.86(d,J=5.0Hz,1H),7.59-7.50(m,1H),7.37(dd,J=3.2,2.0Hz,1H),6.02(s,1H),4 .49(s,1H),4.18(s,1H),4.11-3.82(m,4H),3.79-3.56(m,6H),3.53-3.3 9(m,2H),3.17(s,1H),2.07(d,J=2.0Hz,3H),1.22(d,J=6.6Hz,3H);MS(ES + C 22 H 27 N7O3S requirement: 469, actual measurement: 470 [M+H] + .

[1042] Example 13

[1043]

[1044] (R)-((2-(2-amino-6-chloropyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1045] Step 1

[1046]

[1047] (R)-((2-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -Sulfinylation: A solution of intermediate D (150 mg, 0.492 mmol), intermediate Y (516 mg, 0.689 mmol), and K₂CO₃ (170 mg, 1.23 mmol) in dioxane (2.2 mL) and water (224 μL) was degassed with N₂ for 1 min. PdCl₂(dppf)-CH₂Cl₂A (20.1 mg, 0.025 mmol) was added, and the mixture was degassed again with N₂ for 1 min. The reaction mixture was heated at 85 °C for 3 h. The reaction mixture was cooled to room temperature and subjected to... The sample was filtered, washed with CH2Cl2, and concentrated under reduced pressure. The residue was purified by preparative HPLC triggered by mass spectrometry (mobile phase: A = 0.1% TFA / H2O, B = 0.1% TFA / MeCN; gradient: B = 40-80%; 16 min; column: XBridge C18, 5 μm, 19 mm × 150 mm) to give the title compound (166 mg, 23% yield) as a pale yellow solid.

[1048] MS(ES + C 24 H 29 ClN6O3S requirement: 516, actual measurement: 517 [M+H] + .

[1049] Step 2

[1050]

[1051] (R)-((2-(2-amino-6-chloropyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulphinate: The product from the previous step (32 mg, 0.021 mmol) was added to a solution of CH2Cl2 (215 μL) with TFA (33 μL, 0.43 mmol), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC triggered by mass spectrometry (mobile phase: A = 0.1% TFA / H2O, B = 0.1% TFA / MeCN; gradient: B = 20-60%; 20 min; column: XBridge C18, 5 μm, 19 mm × 150 mm) to give the title compound (12.2 mg, 91% yield) as a grayish-white solid.

[1052] 1 H NMR (600MHz, methanol-d4) δ7.15(d,J=1.0Hz,1H),7.10(s,1H),6.20(s,1H),4.58(s,1H),4.19(s,1H),4.03(dd,J=11.6,3.9Hz,1H),3.83(d,J=11.7Hz, 1H), 3.73 (dd, J = 11.7, 3.2Hz, 1H), 3.59 (td, J = 12.0, 3.1Hz, 1H), 3.53 (d, J = 4.1Hz, 6H), 3.42 (td, J = 13.1, 3.8Hz, 1H), 1.37 (d, J = 6.8Hz, 3H); MS (ES + C 16 H 21ClN6O2S requirement: 396 / 398, actual measured 397 / 399 [M+H] + .

[1053] Example 14

[1054]

[1055] (R)-((2-(2-amino-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1056] Step 1

[1057]

[1058] (R)-((2-(2-((4-methoxybenzyl)amino)-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -Sulfinylide: (R)-((2-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 A solution of sulfinyl ester (synthesized as described in step 1 of Example 13) (50 mg, 0.034 mmol), methylboronic acid (2.410 mg, 0.040 mmol), and K₂CO₃ (11.6 mg, 0.084 mmol) in dioxane (153 μL) and water (15 μL) was degassed with N₂ for 30 seconds, PdCl₂(dppf)-CH₂Cl₂ (1.4 mg, 1.7 μmol) was added, and the mixture was degassed again with N₂ for 30 seconds. The resulting mixture was then heated in a microwave reactor at 120 °C for 6 h. The reaction mixture was cooled to room temperature and subjected to... The sample was filtered, washed with CH2Cl2, and concentrated under reduced pressure. The residue was purified by preparative HPLC triggered by mass spectrometry (mobile phase: A = 0.1% TFA / H2O, B = 0.1% TFA / MeCN; gradient: B = 10-40%; 26 min; column: XBridge C18, 5 μm, 19 mm × 150 mm) to give the title compound (13.5 mg, 56% yield) as a pale yellow solid.

[1059] MS(ES + C 25 H 32 N6O3S requirement: 496, actual measurement: 497 [M+H] + .

[1060] Step 2

[1061]

[1062] (R)-((2-(2-amino-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulphinate: The product from the previous step (13.5 mg, 0.019 mmol) was dissolved in CH2Cl2 (186 μL) and TFA (29 μL, 0.37 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC triggered by mass spectrometry (mobile phase: A = 0.1% TFA / H2O, B = 0.1% TFA / MeCN; gradient: B = 10-40%; 20 min; column: XBridge C18, 5 μm, 19 mm × 150 mm) to give the title compound (8.6 mg, 76% yield) as a grayish-white solid.

[1063] 1 ¹H NMR (600MHz, methanol-d⁴) δ 7.69 (s, 1H), 7.47 (s, 1H), 6.04 (s, 1H), 4.51–4.45 (m, 1H), 4.09 (d, J = 12.9 Hz, 1H), 4.00 (dd, J = 11.5, 3.9 Hz, 1H), 3.80 (d, J = 11.5 Hz, 1H), 3.72 (dd, J = 11.6, 3.2 Hz, 1H), 3.57 (td, J = 11.9, 3.2 Hz, 1H), 3.49 (s, 6H), 3.32–3.24 (m, overlapping with MeOH, 1H), 2.55 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H); MS (ES) + C 17 H 24 N6O2S requirement: 376, actual measured 377 [M+H] + .

[1064] Example 15

[1065]

[1066] (R)-6-amino-4-(4-((dimethyl(oxo)-λ) 6 -thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)cyanopyridine

[1067]

[1068] (R)-6-amino-4-(4-((dimethyl(oxo)-λ)6 (-Thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)cyanopyridine: Example 13 (95 mg, 0.076 mmol), Pd2(dba)3 (7.0 mg, 7.6 μmol), DPPF (2.1 mg, 3.8 μmol), zinc (0.75 mg, 0.011 mmol), zinc dicyandicyanate (8.9 mg, 0.076 mmol), and DMA (380 μL) were charged into a microwave-safe bottle. The bottle was sealed, and the reaction mixture was heated to 150 °C in a microwave reactor and maintained for 3 h. The reaction mixture was cooled to room temperature and directly purified by preparative HPLC triggered by mass spectrometry (mobile phase: A = 0.1% TFA / H2O, B = 0.1% TFA / MeCN; gradient: B = 10-50%; 26 min; column: XBridge C18, 5 μm, 19 mm × 150 mm) to obtain the title compound (23.3 mg, 50% yield) as a pale yellow solid.

[1069] 1 H NMR (600MHz, methanol-d4) δ7.58(s,1H),7.44(s,1H),6.19(s,1H),4.58(s,1H),4.28-4.10(m,1H),4.03(dd,J=11.7,3.9Hz,1H),3.83(d,J=11.7Hz,1 H),3.73(dd,J=11.7,3.2Hz,1H),3.59(td,J=12.0,3.1Hz,1H),3.54(d,J=4.4Hz,6H),3.41(td,J=13.0,4.0Hz,1H),1.37(d,J=6.9Hz,3H); MS(ES + C 17 H 21 N7O2S requirement: 387, actual measurement: 388 [M+H] + .

[1070] Example 16

[1071]

[1072] Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1073] Step 1

[1074]

[1075] Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ6-sulfinyl compound: Intermediate T (300 mg, 0.60 mmol), intermediate E (80 mg, 0.67 mmol), Cs₂CO₃ (655 mg, 2.01 mmol), RuPhos Pd G₃ (56 mg, 0.067 mmol), RuPhos (31 mg, 0.067 mmol), and dioxane (4 mL) were charged into a reaction flask. The reaction mixture was purged with N₂, sealed, and heated at 80 °C for 3 h. The reaction mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% acetone in hexane solution) to give the title compound (130 mg, 37% yield) as a white solid.

[1076] MS(ES + C 27 H 30 N6O4S2 requirement: 566, actual measurement: 567 [M+H] + .

[1077] Step 2

[1078]

[1079] Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 - Sulphinate: The product from the previous step (130 mg, 0.23 mmol), NaOH (184 mg, 4.6 mmol), H2O (1 mL), and MeOH (2 mL) were charged into a reaction flask, and the mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. MeOH (30 mL) was added to the residue, and the resulting mixture was stirred for 5 min, filtered, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 30-60%; 18 min; column: Welch XB-C18, 10 μm, Purified by a 21.2 mm × 250 mm tube, the title compound (20 mg, 21% yield) was obtained as a white solid.

[1080] 1H NMR (500MHz, DMSO-d6) δ11.71(s,1H),8.30(d,J=5.0Hz,1H),7.90(dd,J=5.0,1. 8Hz,1H),7.53(d,J=2.9Hz,1H),7.40(s,1H),5.95(s,1H),4.47(s,1H),4.05(s,1 H),3.96(d,J=8.5Hz,1H),3.75(d,J=11.2Hz,1H),3.64(d,J=11.4Hz,1H),3.52( t,J=13.9Hz,4H),3.16(s,1H),3.00(s,1H),1.18(dd,J=34.3,27.3Hz,7H); MS(ES + C 20 H 24 N6O2S requirement: 412, actual measurement: 413 [M+H] + .

[1081] Examples 17a and 17b

[1082]

[1083] (S)-Ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1084] as well as

[1085]

[1086] (R)-Ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1087] Step 1

[1088]

[1089] S)-Ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 -Sulfinylide and (R)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6-Sulfinyl derivative: ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 - A sulfinyl compound (synthesized similarly to that described for Example 16) (350 mg, 0.63 mmol) was added to a solution of MeOH (6 mL) and THF (2 mL) with NaOH (1.5 mL, 4N aqueous solution), and the reaction mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2 solution) to give a mixture of the title compounds. The mixture of diastereomers was separated by chiral SFC (mobile phase: CO2 / ethanol (1% MeOH in ammonia solution) = 45 / 55; flow rate: 80 g / min; 6.5 min; column temperature: 35 °C; back pressure: 100 bar; column: Daicel). (AD, 10 μm, 20 mm × 250 mm) Two diastereomers with absolutely unknown stereochemistry at the sulfur atom were obtained: title compound 17a (43 mg, 18% yield, >99% ee), a white solid, and title compound 17b (47 mg, 20% yield, >94% ee), a white solid.

[1090] 17a((R)-ethyl(methyl)-λ 6 -Syrinyl or (S)-ethyl(methyl)-λ 6 -Sulinate): 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.30(d,J=5.0Hz,1H),7.88(d,J=5.0Hz,1H),7.63-7.48(m,1H ),7.42(d,J=2.0Hz,1H),5.93(s,1H),4.44(s,1H),4.07(d,J=12.7Hz,1H),3.96(dd,J=11.3,3.2Hz,1 H),3.75(d,J=11.3Hz,1H),3.63(dd,J=9.1,5.7Hz,2H),3.61(d,J=7.5Hz,1H),3.49(td,J=11.8,2.8H z,1H),3.38(s,3H),3.15(td,J=12.8,3.6Hz,1H),1.31(t,J=7.4Hz,3H),1.21(t,J=7.3Hz,3H); MS(ES + C 19 H 24 N6O2S requirement: 400, actual measurement: 401 [M+H] +;R t =2.72min.

[1091] 17b((R)-ethyl(methyl)-λ 6 -Syrinyl or (S)-ethyl(methyl)-λ 6 -Sulinate): 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),8.30(d,J=5.0Hz,1H),7.88(d,J=5.0Hz,1H),7.54(d,J =3.4Hz,1H),7.42(d,J=3.3Hz,1H),5.93(s,1H),4.47(s,1H),4.05(d,J=13.2Hz,1H),3.96(dd ,J=11.1,3.4Hz,1H),3.75(d,J=11.4Hz,1H),3.70-3.53(m,3H),3.54-3.44(m,1H),3.36(d,J= 13.0Hz, 3H), 3.15 (td, J=12.7, 3.6Hz, 1H), 1.32 (q, J=7.7Hz, 3H), 1.21 (d, J=6.7Hz, 3H); MS (ES + C 19 H 24 N6O2S requirement: 400, actual measurement: 401 [M+H] + ;R t =3.28min.

[1092] Example 18 (18a and 18b)

[1093]

[1094] (R)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[1095]

[1096] (S)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[1097] Step 1

[1098]

[1099] Cyclopropyl((2-(2-methoxy-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)-λ 6 -Sulfinylide: A suspension of intermediate Q (590 mg, 1.79 mmol), intermediate S (790 mg, 2.14 mmol), and K₂CO₃ (741 mg, 5.37 mmol) in dioxane (15 mL) and water (3 mL) was degassed with N₂ for 1 min. PdCl₂(dppf)-CH₂Cl₂ (73 mg, 0.090 mmol) was added, and the mixture was degassed again with N₂ for 1 min. The reaction mixture was heated to 130 °C in a microwave reactor and maintained for 4 h. The mixture was cooled to room temperature, the layers were separated, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-2% MeOH in CH₂Cl₂ solution) to give the title compound (910 mg, 95% yield) as a yellow solid.

[1100] MS(ES + C 27 H 34 N6O4S requirement: 538, actual measurement: 539 [M+H] + .

[1101] Step 2

[1102]

[1103] (S)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -Sulfinylide and (R)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6-Sulphinate: The product from the previous step (910 mg, 1.69 mmol) was added to a solution of CH2Cl2 (7 mL) with TFA (2.5 mL, 34 mmol), and the resulting mixture was stirred at 45 °C for 16 h. The mixture was cooled to room temperature and neutralized to pH 7 with 6N NaOH, then a saturated aqueous solution of NaHCO3 (30 mL) was added, and the mixture was stirred vigorously for 5 min. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–3% MeOH in CH2Cl2 solution) to give a mixture of the title compounds (650 mg, 92% yield). Separation of diastereomer mixtures by chiral SFC (mobile phase: CO2 / MeOH (0.2% MeOH ammonia solution) = 45 / 55; flow rate: 80 g / min; 7 min; column temperature: 35 °C; back pressure: 100 bar; column: Daicel) (AD, 10 μm, 20 mm × 250 mm) yielded two diastereomers of absolutely stereochemically unknown origin at the sulfur atom: compound 18a (167 mg, 26% yield, 98.6% ee), a white solid, and compound 18b (230 mg, 35% yield, >99% ee), a white solid; (R)-cyclopropyl(methyl)-λ 6 -Syrinyl amide and (S)-cyclopropyl(methyl)-λ 6 -sulfinyl compounds

[1104] 18a: 1 H NMR(400MHz,DMSO-d6)δ6.87(s,1H),6.67(s,1H),6.00(s,2H),5.90(s,1H),4.44-4.34(m,1H), 4.02(d,J=13.2Hz,1H),3.92(dd,J=11.3,3.2Hz,1H),3.77(s,3H),3.72(d,J=11.4Hz,1H),3.60 (dd, J = 11.3, 3.1 Hz, 1H), 3.55 (s, 3H), 3.45 (td, J = 11.6, 2.6 Hz, 1H), 3.09 (td, J = 12.7, 3.8 Hz, 1H), 3.06-2.94 (m, 1H), 1.25-1.19 (m, 1H), 1.16 (app.d, overlap, J = 6.6 Hz, 3H), 1.14-1.02 (m, 3H); MS(ES) + C 19 H 26 N6O3S requirement: 418, actual measurement: 419 [M+H] + ;R t=3.03min.

[1105] 18b: 1 H NMR(500MHz,DMSO-d6)δ6.88(d,J=1.2Hz,1H),6.68(d,J=1.1Hz,1H),5.99(s,2H),5.90(s,1H),4.43-4 .34(m,1H),4.03(d,J=13.3Hz,1H),3.92(dd,J=11.3,3.6Hz,1H),3.77(s,3H),3.71(d,J=11.3Hz,1H), 3.60(dd, J = 11.4, 3.1 Hz, 1H), 3.55(s, 3H), 3.45(td, J = 11.8, 3.1 Hz, 1H), 3.09(td, J = 12.8, 3.8 Hz, 1H), 3.01(tt, J = 7.9, 4.9 Hz, 1H), 1.25-1.19(m, 1H), 1.16(app.d, overlap, J = 6.7 Hz, 3H), 1.14-1.05(m, 2H); MS(ES) + C 19 H 26 N6O3S requirement: 418, actual measurement: 419 [M+H] + ;R t =3.71min.

[1106] Alternatively, Example 18b can also be prepared from intermediate CC, i.e., isomer 1b.

[1107] Example 19

[1108]

[1109] (R)-((2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1110] Step 1

[1111]

[1112] (R)-((2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6-Sulphinate: A suspension of intermediate K (278 mg, 1.00 mmol), intermediate D (304 mg, 1.00 mmol), Na₂CO₃ (212 mg, 2.00 mmol), and PdCl₂ (dppf) (75 mg, 0.1 mmol) in dioxane (20 mL) and H₂O (4 mL) was degassed with Ar (3×). The reaction mixture was heated to 80 °C and stirred for 16 h under an Ar atmosphere. The mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (66% EtOAc in petroleum ether solution) to give the title compound (130 mg, 31% yield) as a white solid.

[1113] 1 H NMR (500MHz, DMSO-d6) δ11.98(s,1H),7.86(s,1H),7.59(s,1H),7.45(s,1H),5.95(s,1H),4.42(s,1H),4.01(dd,J=43.8,11.0Hz ,2H),3.75(d,J=11.2Hz,1H),3.63(d,J=9.8Hz,1H),3.46(d,J=22.0Hz,7H),3.16(d,J=12.4Hz,1H),1.20(d,J=6.6Hz,3H); MS(ES + C 18 H 21 ClN6O2S requirement: 420, actual measurement: 421 [M+H] + .

[1114] Example 20

[1115]

[1116] (R)-4-(4-((dimethyl(oxo)-λ) 6 -thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile

[1117] Step 1

[1118]

[1119] (R)-4-(4-((dimethyl(oxo)-λ) 6(-thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxynitrile: A mixture of Example 19 (40 mg, 0.096 mmol), ZnCN2 (113 mg, 0.96 mmol), and Pd(PPh3)4 (110 mg, 0.096 mmol) in DMF (3 mL) was degassed with Ar. The reaction mixture was heated in a microwave reactor at 150 °C for 2 h. The mixture was cooled to room temperature and subjected to... The residue was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 in H2O aqueous solution, B = MeCN; gradient: B = 35-65%; 18 min; 30 mL / min; column: Welch XB-C182 1.2 × 250 mm, 10 μm) to give the title compound (13 mg, 33% yield) as a white solid.

[1120] 1 H NMR (500MHz, DMSO-d6) δ12.38(s,1H),8.32(s,1H),7.94(s,1H),7.61(d,J=3.0Hz,1H),5.96(s,1H),4.44(s,1H),4.09(d,J=12.5Hz,1H),3 .97(d,J=8.5Hz,1H),3.75(d,J=11.5Hz,1H),3.64(d,J=8.7Hz,1H),3.53-3.41(m,7H),3.16(t,J=10.9Hz,1H),1.20(d,J=6.7Hz,3H); MS(ES + C 19 H 21 N7O2S requirement: 411, actual measurement: 412 [M+H] + .

[1121] Example 21

[1122]

[1123] (R)-Dimethyl((2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)

[1124] Pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1125] Step 1

[1126]

[1127] (R)-Dimethyl((2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 -Sulphinate: A mixture of Example 19 (30 mg, 0.07 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (9 mg, 0.07 mmol), PdCl2(dppf) (5 mg, 0.007 mmol), and Cs2CO3 (70 mg, 0.21 mmol) in dioxane (6 mL) and H2O (1 mL) was degassed with Ar and heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and subjected to... The residue was filtered and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM aqueous solution of NH4HCO3, B = MeCN; gradient: B = 30-60%; 18 min; 30 mL / min; column: Welch XB-C182 1.2 × 250 mm, 10 μm) to give the title compound (4 mg, 14% yield) as a white solid.

[1128] 1 H NMR (500MHz, DMSO-d6) δ11.50(s,1H),7.75(s,1H),7.41(d,J=2.7Hz,1H),7.33(s,1H),5.91(s,1H),4.44(s,1H),4.07(d,J=13.4Hz,1H),3.96 (d,J=7.7Hz,1H),3.75(d,J=11.4Hz,1H),3.64(d,J=8.5Hz,1H),3.50(d,J=9.0Hz,1H),3.44(s,6H),2.59(s,3H),1.20(d,J=6.7Hz,3H); MS(ES + C 19 H 24 N6O2S requirement: 400, actual measurement: 401 [M+H] + .

[1129] Example 22

[1130]

[1131] (R)-Dimethyl((6-(3-methylmorpholino)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1132] Step 1

[1133]

[1134] (R)-Dimethyl((6-(3-methylmorpholino)-2-(1-triphenylmethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino)-16-sulfinyl: A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-triphenylmethyl-1H-pyrazolo[3,4-b]pyridine (60 mg, 0.12 mmol), intermediate D (37 mg, 0.12 mmol), Na2CO3 (25 mg, 0.24 mmol), and PdCl2 (dppf) (9.0 mg, 0.012 mmol) in dioxane (6 mL) and H2O (1 mL) was degassed with Ar (3×). The reaction mixture was heated to 80 °C and stirred for 16 h under an Ar atmosphere. The reaction mixture was cooled to room temperature and subjected to Ar (3×) saturation. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (66% EtOAc in petroleum ether solution) to give the title compound (45 mg, 60% yield) as a yellow oil.

[1135] MS(ES + C 36 H 35 N7O2S requirement: 629, actual measurement: 630 [M+H] + .

[1136] Step 2

[1137]

[1138] (R)-Dimethyl((6-(3-methylmorpholino)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 - Sulphinate: The product from the previous step was stirred at room temperature for 4 h in a solution of TFA (1 mL) and CH2Cl2 (4 mL). The solvent was removed under reduced pressure, and the residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 aqueous solution, B = MeCN; gradient: B = 25-65%; 18 min; 30 mL / min; column: Welch XB-C18 21.2 × 250 mm, 10 μm) to give the title compound (14 mg, 52% yield) as a pale yellow solid.

[1139] 1H NMR (500MHz, DMSO-d6) δ13.72(s,1H),8.93(s,1H),8.64(d,J=4.7Hz,1H),7.99(d,J=4.8Hz,1H),5.98(s,1H),4.46(s,1H),4.08(d,J=12.9Hz ,1H),3.97(d,J=8.0Hz,1H),3.76(d,J=11.4Hz,1H),3.64(d,J=8.4Hz,1H),3.53-3.43(m,7H),3.22-3.07(m,1H),1.21(d,J=6.7Hz,3H); MS(ES + C 17 H 21 N7O2S requirement: 387, actual measurement: 388 [M+H] + .

[1140] Example 23

[1141]

[1142] (R)-((2-(1H-indazol-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1143]

[1144] (R)-((2-(1H-indazol-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6- Sulphinate: A mixture of intermediate D (0.21 g, 0.69 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indazole (0.27 g, 0.83 mmol), K3PO4 (0.44 g, 2.1 mmol), and PdCl2(dppf)-CH2Cl2 (40 mg, 0.055 mmol) in dioxane (9 mL) and water (2 mL) was degassed with N2 for ten minutes, then heated to 85 °C and held for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and H2O (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (8 mL) and THF (2 mL) at room temperature, and concentrated HCl solution (approximately 12 N, 0.1 mL) was added to the solution. The reaction mixture was heated to 60 °C and maintained for 20 min, then stirred at room temperature for 18 h. A saturated aqueous solution of NaHCO3 (3 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (25 mL) and H2O (25 mL) to separate the layers, and the aqueous layer was extracted with CH2Cl2 (2 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10–30% CH3CN in CH2Cl2 solution) to give the title compound (0.26 g, quantitative yield) as a yellow solid.

[1145] 1 H NMR (400MHz, CDCl3) δppm 9.08(d,J=0.75Hz,1H),8.20(dd,J=7.28,1.00Hz,1H),7.61(d,J=8.28Hz,1H),7.46(dd,J=8.28,7.28Hz,1H),5.91(s,1H),4.39-4.51(m ,1H),3.97-4.19(m,2H),3.74-3.90(m,2H),3.56-3.73(m,2H),3.45(d,J=1.51Hz,6H),3.26-3.39(m,1H),1.36(d,J=6.78Hz,3H); MS(ES + C 18 H 22 N6O2S requirement: 386, actual measurement: 387 [M+H] + .

[1146] Example 24

[1147]

[1148] (R)-Dimethyl((2-(2-(methylamino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1149]

[1150] (R)-Dimethyl((2-(2-(methylamino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 - Sulphinate: Intermediate L (100 mg, 0.42 mmol), intermediate D (65 mg, 0.21 mmol), Na₂CO₃ (133 mg, 1.26 mmol), Pd(dppf)Cl₂ (24 mg, 0.03 mmol), dioxane (3 mL), and H₂O (1 mL) were charged into a microwave-safe flask. The flask was purged with N₂ and sealed. The reaction mixture was heated at 80 °C for 3 h. The reaction mixture was cooled to room temperature and analyzed by... Filter and concentrate under reduced pressure. Pass the residue through a reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 25-55%; 18 min; column: Welch XB-C18, 10 μm). Purified by a 21.2 mm × 250 mm tube, the title compound (8 mg, 10% yield) was obtained as a white solid.

[1151] 1 H NMR(500MHz,DMSO-d6)δ8.06(d,J=5.2Hz,1H),7.29(s,1H),7.24(d,J=5.3Hz,1 H),6.67(s,1H),5.87(s,1H),4.42-4.36(m,1H),4.07-4.01(m,1H),3.92(d,J=1 2.1Hz,1H),3.72(d,J=11.3Hz,1H),3.61(d,J=8.5Hz,1H),3.45(d,J=2.5Hz,6H ),3.31(s,1H),3.09(s,1H),2.80(d,J=4.8Hz,3H),1.16(d,J=6.8Hz,3H); MS(ES + C 17 H 24 N6O2S requirement: 376, actual measurement: 377 [M+H] + .

[1152] Example 25

[1153]

[1154] (R)-((2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1155]

[1156] (R)-((2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulfinylation: Intermediate V (34 mg, 0.06 mmol), 4-bromo-6-methoxy-1H-pyrrolo[2,3-b]pyridine (14 mg, 0.06 mmol), CuI (1.2 mg, 0.006 mmol), LiCl (5 mg, 0.12 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and DMF (5 mL) were charged into a microwave-safe flask. The flask was purged with Ar, sealed, and heated in a microwave reactor at 120 °C for 2 h. The reaction mixture was cooled to room temperature, saturated KF aqueous solution (10 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 40-70%; 18 min; column: Welch XB-C18, 10 μm, 21.2 × 250 mm) to give the title compound (5 mg, 20% yield) as a white solid.

[1157] 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),7.35(s,1H),7.26(d,J=11.3Hz,2H),5.92(s,1H),4.43(s,1H),4.03(d,J=12.7Hz,1H),3.95(d,J=7.6Hz ,1H),3.91(s,3H),3.75(d,J=11.2Hz,1H),3.63(d,J=8.8Hz,1H),3.46(d,J=21.0Hz,7H),3.14(t,J=11.0Hz,1H),1.20(d,J=6.7Hz,3H); MS(ES + C 19 H 24N6O3S requirement: 416, actual measurement: 417 [M+H] + .

[1158] Example 26

[1159]

[1160] (R)-((2-(3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1161]

[1162] (R)-((2-(3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulphinate: Intermediate V (150 mg, 0.268 mmol), intermediate M (170 mg, 0.35 mmol), LiCl (23 mg, 0.54 mmol), CuI (5 mg, 0.027 mmol), Pd(PPh3)4 (31 mg, 0.027 mmol), and DMF (2 mL) were charged into a microwave flask. The flask was degassed by bubbling Ar into the solution, sealed, and heated to 120 °C in a microwave reactor for 90 minutes. The reaction was then re-entered into microwave circulation until completion was determined by LCMS using the newly added palladium catalyst, and the flask was degassed with Ar before each cycle. The reaction mixture was diluted with EtOAc (20 mL) and then... The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in 1N HCl (10 mL) and washed with Et₂O (5 mL) and hexane (5 mL). The aqueous layer was then adjusted to pH > 12 with 2M NaOH aqueous solution and extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (mobile phase: A = 0.1% HCO₂H / H₂O, B = 0.1% HCO₂H / MeCN; gradient: B = 0-30%; 15 min; column: Biotage SNAP Ultra C18 30 g, HP-Sphere C18 25 μm). The combined fractions were treated with 0.1M HCl aqueous solution, concentrated under reduced pressure, and lyophilized to give the title compound (33.2 mg, 32% yield) as a white solid.

[1163] 1H NMR (400MHz, CDCl3) δppm 8.71 (d, J = 5.27Hz, 1H) 8.52 (s, 1H) 8.16 (d, J = 5.02Hz, 1H) 5.91 (s, 1H) 4.36-4.52 (m, 1H) 4.13-4.25 (m, 1H) 4.08 (br dd,J=11.54,3.76Hz,1H)3.82-3.91(m,1H)3.79(br d,J=2.76Hz,1H)3.64(br d,J=3.01Hz,1H)3.46-3.52(m,1H)3.43(s,6H)3.29-3.39(m,1H)1.37(d,J=6.78Hz,3H); MS(ES + C 17 H 21 N7O2S requirement: 387, actual measurement: 388 [M+H] + .

[1164] Example 27

[1165]

[1166] (R)-((2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidine

[1167] -4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1168] Step 1

[1169]

[1170] (R)-((2-(2-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6- Sulfinyl ester: Intermediate U (50 mg, 0.13 mmol), intermediate V (72 mg, 0.13 mmol), CuI (2 mg, 0.013 mmol), LiCl (3 mg, 0.26 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol), and DMF (5 mL) were degassed with Ar (3×) and then heated in a microwave reactor at 120 °C for 2 h. The mixture was cooled to room temperature, and saturated Na2S2O3 aqueous solution (10 mL) was added to separate the layers. The aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc in hexane solution) to give the title compound (30 mg, 40% yield) as a yellow solid.

[1171] MS(ES + C 28 H 32 N6O4S2 requirement: 580, actual measurement: 581 [M+H] + .

[1172] Step 2

[1173]

[1174] (R)-((2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulphinate: A mixture of the product from the previous step (30 mg, 0.05 mmol), NaOH (4 mg, 0.1 mmol), H₂O (1 mL), and MeOH (3 mL) was heated and stirred at 60 °C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC (mobile phase: A = 10 mM NH₄HCO₃ / H₂O, B = MeCN; gradient: B = 45-75; 15 min; column: Welch XB-C18, 10 μm, 21.2 × 250 mm) to give the title compound (2 mg, 10% yield) as a white solid.

[1175] 1H NMR (500MHz, DMSO-d6) δ11.58(s,1H),8.14(d,J=5.0Hz,1H),7.80(d,J=5.0Hz,1H ),7.11(s,1H),5.88(s,1H),4.44(s,1H),4.04(d,J=12.9Hz,1H),3.95(d,J=10.9 Hz,1H),3.74(d,J=11.4Hz,1H),3.63(d,J=8.2Hz,1H),3.46(d,J=25.8Hz,7H),2. 03(s,1H),1.20(d,J=6.7Hz,3H),1.06-0.97(m,2H),0.86(d,J=3.0Hz,2H);MS(ES + C 21 H 26 N6O2S requirement: 426, actual measurement: 427 [M+H] + .

[1176] Example 28

[1177]

[1178] (R)-Dimethyl((2-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1179] Step 1

[1180]

[1181] (R)-((2-(2,3-diaminopyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulphinate: Intermediate J (450 mg crude, assumed 1.07 mmol), intermediate D (250 mg, 0.82 mmol), Na₂CO₃ (260 mg, 2.46 mmol), Pd(dppf)Cl₂ (48 mg, 0.06 mmol), dioxane (12 mL), and H₂O (4 mL) were charged into a microwave-safe flask. The flask was purged with N₂ and sealed. The reaction mixture was heated at 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and analyzed by... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-15% MeOH in CH2Cl2 solution) to give the title compound (350 mg, 100% yield) as a brown solid.

[1182] MS(ES + C16 H 23 N7O2S requirement: 377, actual measurement: 378 [M+H] + .

[1183] Step 2

[1184]

[1185] (R)-Dimethyl((2-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 - Sulphinate: A mixture of the product from the previous step (150 mg, 0.4 mmol), HOAc (0.2 mL), and PPA (1 g) was placed in a 20 mL microwave-safe bottle and purged with N2 for 1 min. The bottle was sealed and heated at 150 °C for 1.5 h. The reaction mixture was cooled to room temperature, and saturated K2CO3 aqueous solution (30 mL) was added. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 25-55%; 18 min; column: Welch XB-C18, 10 μm). Purified by a 21.2 mm × 250 mm tube, the title compound (20 mg, 12% yield) was obtained as a white solid.

[1186] 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.42(d,J=5.1Hz,1H),7.89(d,J=5.1Hz,1H),5.97(s,1H),4.47(s,1H),4.14(s,1H),3.95(d,J= 11.1Hz,1H),3.74(d,J=11.5Hz,1H),3.63(d,J=8.3Hz,1H),3.47(s,7H),3.19-3.11(m,1H),2.58(s,3H),1.20(d,J=6.7Hz,3H); MS(ES) + C 18 H 23 N7O2S requirement: 401, actual test result: 402 [M+H] + .

[1187] Example 29

[1188]

[1189] (R)-((2-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1190]

[1191] (R)-((2-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulphinate: Intermediate D (120 mg, 0.39 mmol), 2-cyclopropyl-1H-benzo[d]imidazole (94 mg, 0.59 mmol), Pd2dba3 (18 mg, 0.02 mmol), XPhos (16 mg, 0.04 mmol), Cs2CO3 (380 mg, 1.17 mmol), and dioxane (6 mL) were charged into a reaction flask. The flask was purged with N2 for 2 minutes, sealed, and heated to 150 °C in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and subjected to... Filter and concentrate under reduced pressure. Pass the residue through reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 40-70%; 15 min; column: Agela C18, 10 μm). Purification was performed using a 21.2 mm × 250 mm filter to obtain the title compound (83.0 mg, 50% yield) as a white solid.

[1192] 1 H NMR (500MHz, DMSO-d6) δ8.10 (dd, J=6.8, 2.3Hz, 1H), 7.53 (dd, J=6.5, 2.2Hz, 1H), 7.24-7. 14(m,2H),5.93(s,1H),4.36(s,1H),3.94(dd,J=16.4,8.5Hz,2H),3.72(d,J=11.4Hz,1H) ,3.61(dd,J=11.4,2.9Hz,1H),3.50-3.44(m,1H),3.42(s,6H),3.17(td,J=13.0,3.9Hz,1 H),3.09-3.01(m,1H),1.21(d,J=6.7Hz,3H),1.17-1.11(m,2H),1.09-1.02(m,2H);MS(ES + C 18 H 22 N6O2S requirement: 426, actual measurement: 427 [M+H] + .

[1193] Example 30

[1194]

[1195] (R)-Dimethyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1196]

[1197] (R)-Dimethyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 - Sulphinate: Intermediate D (50 mg, 0.165 mmol), 2-methylbenzimidazole (44 mg, 0.329 mmol), XPhos Pd G2 (6.5 mg, 0.008 mmol), and K3PO4 (70 mg, 0.329 mmol) were charged into a microwave-safe flask. The flask was sealed, purged with Ar, and dioxane (2 mL) was added. The solution was degassed by purging Ar, and the resulting mixture was heated in a microwave reactor at 150 °C for 1 h. The reaction mixture was cooled to room temperature and then... The mixture was filtered, washed with CH2Cl2, and concentrated under reduced pressure. The residue was purified by rapid chromatography (1-5% MeOH in CH2Cl2 solution) to give the title compound (62 mg, 94% yield) as a white solid.

[1198] 1 H NMR (400MHz, CDCl3) δppm 8.22-8.39(m,1H)7.63-7.89(m,1H)7.30-7.54(m,2H)5.86(s,1H)4.25-4.41(m,1H)4.05(dd,J=11.54,3.76Hz,1H)3.90-3.98(m, 1H)3.70-3.89(m,2H)3.53-3.68(m,1H)3.26-3.51(m,7H)3.06(s,3H)1.36(d,J=6.78Hz,3H)1.10-1.32(m,1H)0.91(s,1H); MS(ES) + C 19 H 24 N6O2S requirement: 400, actual measurement: 401 [M+H] + .

[1199] Example 31

[1200]

[1201] Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1202] The synthesis using intermediate I is similar to the synthesis described for Example 11.

[1203] 1 H NMR(500MHz,DMSO-d6)δ11.72(s,1H),9.02(d,J=2.3Hz,1H),8.79(s,1H),7.67(t,J =2.7Hz,1H),7.45(s,1H),5.90(s,1H),4.46(s,1H),4.04(s,1H),3.96(d,J=7.8Hz,1 H),3.75(d,J=11.4Hz,1H),3.64(d,J=10.5Hz,1H),3.51(dd,J=32.0,6.9Hz,4H),3. 14(s,1H),3.01(d,J=7.6Hz,1H),1.21(t,J=7.1Hz,5H),1.09(d,J=7.8Hz,2H); MS(ES + C 20 H 24 N6O2S requirement: 412, actual measurement: 413 [M+H] + .

[1204] Example 32

[1205]

[1206] (S)-((6-(3-(fluoromethyl)morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1207] The synthesis using intermediate O and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine is similar to the synthesis described for Example 11.

[1208] 1H NMR (400MHz, CDCl3) δ10.35(s,1H),8.41(d,J=5.1Hz,1H),8.01(d,J=5.1Hz,1H),7.61-7.41(m,2H),5.94( s,1H),5.26-5.02(m,1H),4.53(s,1H),4.31-3.96(m,3H),3.83-3.61(m,4H),3.44(d,J=4.8Hz,6H); MS(ES + C 18 H 21 FN6O2S requirement: 404, actual test result: 405 [M+H] + .

[1209] Example 33

[1210]

[1211] (S)-((6-(3-(difluoromethyl)morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1212] The synthesis using intermediate W and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine is similar to the synthesis described for Example 11.

[1213] 1 ¹H NMR (400MHz, methanol-d⁴) δ 8.28 (d, J = 5.1 Hz, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.51 (dd, J = 21.8, 3.5 Hz, 2H), 6.34 (td, J = 56.1, 5.7 Hz, 1H), 6.06 (s, 1H), 4.25 (d, J = 12.3 Hz, 1H), 4.06 (dd,J=11.4,3.6Hz,2H),3.78(dd,J=12.3,3.2Hz,1H),3.67(td,J=11.8,3.1Hz,1H), 3.49(t,J=7.2Hz,7H),3.43(dd,J=12.7,3.8Hz,1H),3.34(s,2H),3.32(s,2H); MS(ES + C 18 H 20 Required value for F2N6O2S: 422; Actual value: 423 [M+H] + .

[1214] Example 34

[1215]

[1216] (R)-((2-(4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 -sulfinyl compounds

[1217] Step 1

[1218]

[1219] (R)-((2-((3-fluoro-2-nitrophenyl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulfonate was added to a reaction flask by charging intermediate D (250 mg, 0.82 mmol), 3-fluoro-2-nitroaniline (192 mg, 1.23 mmol), Pd2dba3 (38 mg, 0.041 mmol), XPhos (35 mg, 0.082 mmol), Cs2CO3 (800 mg, 2.47 mmol), and dioxane (10 mL). The flask was purged with N2 for 2 minutes, and the reaction mixture was heated at 100 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and analyzed by... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50-75% EtOAc in hexane solution) to give the title compound (290 mg, 74% yield) as an orange solid.

[1220] MS(ES + C 17 H 21 FN6O4S requirement: 424, actual measurement: 425 [M+H] + .

[1221] Step 2

[1222]

[1223] (R)-((2-((2-amino-3-fluorophenyl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - Sulphinate: Under a N2 atmosphere, the product from the previous step (280 mg, 0.66 mmol), 10% Pd / C (50 mg, 0.047 mmol), and EtOH (40 mL) were charged into a reaction vessel. The suspension was degassed with N2 for 1 minute and purged with H2 for 1 minute. The reaction mixture was stirred at 1 atm under a H2 atmosphere for 2 hours. The reaction mixture was then purged with N2. The mixture was filtered and concentrated under reduced pressure to give the title compound (260 mg, quantitative yield) as a red solid.

[1224] MS(ES + C 17 H 23 FN6O2S requirement: 394, actual measurement: 395 [M+H] + .

[1225] Step 3

[1226]

[1227] (R)-((2-(4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 - The sulfinyl group was heated at 150°C for 3 h with a mixture of the product from the previous step (260 mg, 0.66 mmol) and acetic acid (132 mg, 2.21 mmol) in PPA (5 g). The reaction was cooled to room temperature, diluted with water (50 mL), and 5 N NaOH aqueous solution was added to adjust the pH to 14. The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layers were concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 aqueous solution, B = MeCN; gradient: B = 35-65%; 15 min; column: Agela C18, 10 μm, Purified by a 21.2 mm × 250 mm tube, the title compound (146 mg, 53% yield) was obtained as a yellow solid.

[1228] 1 H NMR(500MHz,DMSO-d6)δ8.10(d,J=8.2Hz,1H),7.19(td,J=8.2,5.1Hz,1H),7.06( dd,J=10.6,8.1Hz,1H),5.92(s,1H),4.35(s,1H),4.03-3.85(m,2H),3.72(d,J=11 .4Hz,1H),3.61(dd,J=11.4,2.9Hz,1H),3.47(td,J=11.9,3.0Hz,1H),3.40(d,J=2 .1Hz, 6H), 3.17 (td, J=12.9, 3.8Hz, 1H), 2.85 (s, 3H), 1.21 (d, J=6.7Hz, 3H); MS (ES + C 19 H 23 FN6O2S requirement: 418, actual measurement: 419 [M+H] + .

[1229] Example 35

[1230]

[1231] (R)-1-(4-((dimethyl(oxo)-λ) 6 -thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-benzo[d]imidazol-6-carboxynitrile

[1232] Step 1

[1233]

[1234] (R)-4-amino-3-((4-((dimethyl(oxo)-λ) 6 -thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)amino)benzyl nitrile: to (R)-3-((4-((dimethyl(oxo)-λ) 6 (-Thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)amino)-4-nitrobenzyl nitrile (synthesis similar to that described in step 1 of Example 34) (110 mg, 0.255 mmol) was added to a solution of EtOH (1.3 mL) with ammonium chloride (54.5 mg, 1.02 mmol), water (425 μL) and iron (56.9 mg, 1.02 mmol), and the resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-20% MeOH in CH2Cl2 solution) to give the title compound (83 mg, 81% yield) as a yellow solid.

[1235] MS(ES + C 18 H 23 N7O2S requirement: 401, actual test result: 402 [M+H] + .

[1236] Step 2

[1237]

[1238] (R)-1-(4-((dimethyl(oxo)-λ) 6(-thionyl)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-benzo[d]imidazol-6-carboxynitrile: The product from the previous step (30 mg, 0.037 mmol) was added to a solution of toluene (75 μL) with triethyl orthoformate (12 μL, 0.075 mmol) and Ts-OH hydrate (0.71 mg, 3.7 μmol), and the resulting mixture was heated to 110 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC triggered by mass spectrometry (mobile phase: A = 0.1% TFA / H2O, B = 0.1% TFA / MeCN; gradient: B = 10-40%; 16 min; column: XBridge C18, 5 μm, 19 mm × 150 mm) to give the title compound (7.9 mg, 33% yield) as a white solid.

[1239] 1 ¹H NMR (600MHz, methanol-d⁴) δ 9.36 (s, 1H), 9.25–9.22 (m, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.4, 1.6 Hz, 1H), 5.91 (s, 1H), 4.47–4.39 (m, 1H), 4.08–3.98 (m, 2H), 3.82 (d, J = 11.5 Hz, 1H), 3.75 (dd, J = 11.5, 3.2 Hz, 1H), 3.60 (td, J = 12.0, 3.2 Hz, 1H), 3.46 (s, 6H), 3.33–3.27 (m, overlapping with MeOH, 1H), 1.33 (d, J = 6.8 Hz, 3H); MS (ES) + C 19 H 21 N7O2S requirement: 411, actual measurement: 412 [M+H] + .

[1240] Example 36

[1241]

[1242] (R)-Dimethyl((2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1243]

[1244] (R)-Dimethyl((2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ6 -Sulphinate: (R)-((2-((2-aminopyridin-3-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ 6 A suspension of the sulfinyl compound (synthesized similarly to step 2 of Example 34) (38 mg, 0.10 mmol) was added to a solution of triethyl orthoacetate (4 mL) with p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol), and the resulting mixture was heated to 50 °C and maintained for 16 h. The reaction mixture was cooled to room temperature and purified directly by rapid chromatography (0-10% MeOH in CH2Cl2 solution containing 0.5% NH4OH aqueous solution) to give the title compound (20 mg, 0.05 mmol) as a solid.

[1245] 1 H NMR (400MHz, CDCl3) δppm 8.63-8.83(m,1H)8.52(dd,J=4.77,1.25Hz,1H)7.20-7.34(m,2H)5.82(s,1H)4.17-4.39(m,1H)4.04(dd,J=11.54,3.51Hz,1H)3.91(br d,J=12.30Hz,1H)3.82(d,J=11.54Hz,1H)3.73(dd,J=11.54,3.01Hz,1H)3.59(td ,J=11.86,3.14Hz,1H)3.27-3.45(m,7H)3.04(s,3H)1.34(d,J=7.03Hz,3H); MS(ES + C 18 H 23 N7O2S requirement: 401, actual test result: 402 [M+H] + .

[1246] Example 37

[1247]

[1248] ((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6 -sulfinyl compounds

[1249] Step 1

[1250]

[1251] ((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6 -Sulfinylation: Under a N2 atmosphere, Pd2(dba)3 (850 mg, 0.925 mmol), XantPhos (2.14 g, 3.7 mmol), and K2CO3 (6.4 g, 46 mmol) were added to a solution of (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized as described in step 1 of intermediate B) (4.6 g, 18.5 mmol) and intermediate F (2.5 g, 18.5 mmol) in dioxane (80 mL), and the resulting mixture was heated at 90 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and subjected to... The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25–70% hexane solution of EtOAc) to give the title compound (1.8 g, 28% yield) as a white solid.

[1252] 1 H NMR(500MHz,DMSO-d6)δ5.86(s,1H),5.07-4.74(m,5H),4.23(s,1H),3.87(dd,J=11.3,3.5Hz,2H),3.65(d,J=1 1.5Hz, 1H), 3.53 (dd, J=11.5, 2.9Hz, 1H), 3.43-3.31 (m, 4H), 3.05 (d, J=3.6Hz, 1H), 1.12 (d, J=6.7Hz, 3H); MS (ES + C 13 H 19 ClN4O3S requirement: 346, actual measurement: 347 [M+H] + .

[1253] Step 2

[1254]

[1255] ((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6-Sulfinylide: Under a N2 atmosphere, the product of the previous step (120 mg, 0.34 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)pyridin-2-amine (61 mg, 0.51 mmol) in a solution of dioxane (4 mL) and H2O (1 mL) were mixed with Pd(dppf)Cl2 (25 mg, 0.034 mmol) and K2CO3 (141 mg, 1.02 mmol), and the resulting mixture was heated at 90 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and subjected to... Filter and concentrate under reduced pressure. Pass the residue through reversed-phase preparative HPLC (mobile phase: A = 10 mM NH4HCO3 / H2O, B = MeCN; gradient: B = 20-50%; 18 min; column: Agela C18, 10 μm). Purified by a 21.2 mm × 250 mm tube, the title compound (42 mg, 31% yield) was obtained as a white solid.

[1256] 1 H NMR(500MHz,DMSO-d6)δ7.99(d,J=5.2Hz,1H),7.50-7.03(m,2H),5.97(d,J= 58.0Hz,3H),5.10-4.75(m,5H),4.49-4.26(m,1H),4.15-3.97(m,1H),3.95- 3.88(m,1H),3.71(d,J=11.3Hz,1H),3.60(dd,J=11.4,2.8Hz,1H),3.52(d,J =2.0Hz, 3H), 3.45 (s, 1H), 3.10 (d, J = 3.5Hz, 1H), 1.16 (d, J = 6.7Hz, 3H); MS (ES + C 18 H 24 N6O3S requirement: 404, actual test result: 405 [M+H] + .

[1257] Examples 38a and 38b

[1258]

[1259] (R)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6 -sulfinyl compounds

[1260] as well as

[1261]

[1262] (S)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6 -sulfinyl compounds

[1263] The synthesis of the intermediates using the first step of the procedure in Example 37 is similar to the synthesis described for Example 29. The mixture of diastereomers (56 mg, 0.13 mmol) was separated by chiral SFC (mobile phase: CO2 / MeOH (0.2% ammonia solution of MeOH) = 55 / 45; flow rate: 80 g / min; 6.3 min; column temperature: 35 °C; back pressure: 100 bar; column: Daicel). OJ (10 μm, 20 mm × 250 mm) yielded two diastereomers of absolutely stereochemical unknown at the sulfur atom: title compound 38a (14 mg, 25% yield, >99% ee), a white solid, and title compound 38b (15 mg, 27% yield, >99% ee), a white solid.

[1264] 38a((R)-methyl(oxecyclobutane-3-yl)-λ 6 -Sulfinylide or (S)-methyl(oxetane-3-yl)-λ 6 -Sulinate): 1 H NMR(500MHz,DMSO-d6)δ9.09-8.93(m,1H),8.68-8.50(m,1H),7.81-7.66(m,1H),7.4 4-7.25(m,2H),5.96-5.86(m,1H),5.06(dd,J=7.0,1.1Hz,1H),5.00-4.84(m,4H),4. 53-4.36(m,1H),4.12-4.00(m,1H),3.99-3.90(m,1H),3.76-3.70(m,1H),3.68-3.58 (m,1H),3.50(dd,J=19.4,1.5Hz,4H),3.18(d,J=3.6Hz,1H),1.24-1.18(m,3H); MS(ES + C 20 H 24 N6O3S requirement: 428, actual measurement: 429 [M+H] + ;R t =0.95min.

[1265] 38b((R)-methyl(oxecyclobutane-3-yl)-λ 6-Sulfinylide or (S)-methyl(oxetane-3-yl)-λ 6 -Sulinate): 1 H NMR(500MHz,DMSO-d6)δ9.02(s,1H),8.60(d,J=8.0Hz,1H),7.76(d,J=7.9H z,1H),7.49-7.20(m,2H),5.92(s,1H),5.11-5.01(m,1H),4.99-4.85(m,4H) ,4.47-4.39(m,1H),4.15-4.02(m,1H),3.99-3.91(m,1H),3.72(s,1H),3.6 6-3.59(m,1H),3.51(s,4H),3.23-3.11(m,1H),1.22(d,J=6.7Hz,3H); MS(ES + C 20 H 24 N6O3S requirement: 428, actual measurement: 429 [M+H] + ;R t =1.31min.

[1266] Examples 39a and 39b

[1267]

[1268] (R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[1269] as well as

[1270]

[1271] (S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[1272] The synthesis was similar to that described for Example 24. A mixture of diastereomers (26.8 mg, 0.069 mmol) was separated by chiral SFC (mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA) = 70:30; flow rate: 80 g / min; 20 min; column temperature: 35 °C; back pressure: 100 bar; column: Gilson-281, AY 20 × 250 mm, 10 μm) to give two diastereomers at the sulfur atom with absolutely unknown stereochemistry: title compound 39a (6.6 mg, 25% yield, >99% ee), a white solid, and title compound 39b (7.1 mg, 27% yield, >99% ee), a white solid.

[1273] 39a((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1 HNMR(500MHz,CD3OD)δ8.03-7.91(m,1H),7.53(s,1H),7.49(dd,J=5.5,1.4Hz,1H),5.97(s,1H),4. 48(d,J=4.6Hz,1H),4.11(d,J=12.0Hz,1H),4.02(dd,J=11.3,3.6Hz,1H),3.82(d,J=11.4Hz,1H),3. 75(dd,J=11.5,3.0Hz,1H),3.65-3.56(m,4H),3.25(td,J=12.8,3.8Hz,1H),3.01(td,J=7.9,4.0Hz, 1H), 1.42 (dd, J=10.2, 5.4Hz, 1H), 1.31 (dd, J=11.1, 6.2Hz, 4H), 1.20 (dt, J=11.3, 5.7Hz, 2H); MS (ES + C 18 H 24 N6O2S requirement: 388, actual measurement: 389 [M+H] + ;R t = 11.35min.

[1274] 39b((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1HNMR(500MHz,CD3OD)δ7.97(d,J=5.4Hz,1H),7.53(s,1H),7.49(dd,J=5.5,1.3Hz,1H),5.97(s, 1H),4.50(s,1H),4.08(d,J=12.7Hz,1H),4.02(dd,J=11.4,3.7Hz,1H),3.82(d,J=11.3Hz,1H),3 .75(dd,J=11.4,3.0Hz,1H),3.66-3.55(m,4H),3.25(td,J=12.9,3.9Hz,1H),3.05-2.97(m,1H) ,1.41(dd,J=10.6,5.2Hz,1H),1.31(dd,J=11.8,5.8Hz,4H),1.20(dt,J=11.1,5.6Hz,2H); MS(ES + C 18 H 24 N6O2S requirement: 388, actual measurement: 389 [M+H] + ;R t =15.22min.

[1275] Alternatively, Example 39a can also be prepared from intermediate CC, i.e., isomer 1b.

[1276] Examples 40a and 40b

[1277]

[1278] (R)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[1279] as well as

[1280]

[1281] (S)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[1282] The synthesis was similar to that described for Example 29. A mixture of diastereomers (31 mg, 0.075 mmol) was separated by chiral SFC (mobile phase: CO2 / MeOH (0.2% ammonia solution of MeOH) = 50 / 50; flow rate: 80 g / min; 10 min; column temperature: 35 °C; back pressure: 100 bar; column: OD (10 μm, 20 mm × 250 mm), yielded two diastereomers of absolutely stereochemical unknown at the sulfur atom: title compound 40a (6.0 mg, 19% yield, >99% ee), a white solid, and title compound 40b (5.0 mg, 16% yield, >98% ee), a white solid.

[1283] 40a((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1 HNMR(500MHz,DMSO-d6)δ9.01(s,1H),8.60(d,J=7.7Hz,1H),7.74(d,J=7.4Hz, 1H),7.33(dd,J=13.5,7.5Hz,2H),5.90(s,1H),4.53-4.29(m,1H),3.95(d,J=7. 7Hz,2H),3.74(d,J=11.2Hz,1H),3.63(d,J=11.3Hz,1H),3.50(d,J=19.7Hz,4H) ,3.17(s,1H),3.04(s,1H),1.22(d,J=6.7Hz,5H),1.13(d,J=19.3Hz,2H); MS(ES + C 20 H 24 N6O2S requirement: 412, actual measurement: 413 [M+H] + ;R t = 3.50min.

[1284] 40b((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1 HNMR(500MHz,DMSO-d6)δ9.01(s,1H),8.60(d,J=7.7Hz,1H),7.74(d,J=7.6Hz,1H),7. 33(ddd,J=15.1,13.9,6.7Hz,2H),5.90(s,1H),4.42(s,1H),4.04(s,1H),3.95(dd,J= 11.3,3.4Hz,1H),3.74(d,J=11.4Hz,1H),3.63(dd,J=11.5,2.9Hz,1H),3.55-3.45(m, 4H),3.22-3.14(m,1H),3.10-3.01(m,1H),1.28-1.18(m,5H),1.17-1.07(m,2H); MS(ES+ C 20 H 24 N6O2S requirement: 412, actual measurement: 413 [M+H] + ;R t = 4.44 min.

[1285] Alternatively, Example 40b can also be prepared from intermediate CC, i.e., isomer 1b.

[1286] Examples 41a and 41b

[1287]

[1288] (R)-Methyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6)-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(oxetane-3-yl)-λ 6 -sulfinyl compounds and

[1289]

[1290] (S)-Methyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6)-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(oxetane-3-yl)-λ 6 -sulfinyl compounds

[1291] The synthesis was similar to that described for Example 29. A mixture of diastereomers (45 mg, 0.1 mmol) was separated by chiral SFC (mobile phase: n-hexane (0.1% DEA): IPA (0.1% DEA) = 35:65; flow rate: 80 g / min; 20 min; column temperature: 35 °C; back pressure: 100 bar; column: Gilson-281, sc 20 × 250 mm, 10 μm) to give two diastereomers at the sulfur atom with absolutely unknown stereochemistry: title compound 41a (7.0 mg, 16% yield, 99% ee), a white solid, and title compound 41b (4.0 mg, 9.0% yield, >93% ee), a white solid.

[1292] 41a((R)-methyl(oxecyclobutane-3-yl)-λ 6 -Sulfinylide or (S)-methyl(oxetane-3-yl)-λ 6 -Sulinate): 1H NMR(500MHz,DMSO-d6)δ8.24(dd,J=6.1,3.1Hz,1H),7.58(dd,J=6.0,3.0Hz,1H),7. 29-7.15(m,2H),6.02-5.86(m,1H),4.89(dddd,J=17.8,15.5,7.8,6.8Hz,5H),4.40 (s,1H),3.92(d,J=11.3Hz,2H),3.72(d,J=11.4Hz,1H),3.65-3.55(m,1H),3.44(dd ,J=15.6,5.9Hz,4H),3.22-3.12(m,1H),2.88-2.77(m,3H),1.29-1.12(m,3H); MS(ES + C 21 H 26 N6O3S requirement: 442, actual measurement: 443 [M+H] + ;R t =13.15min.

[1293] 41b((R)-methyl(oxecyclobutane-3-yl)-λ 6 -Sulfinylide or (S)-methyl(oxetane-3-yl)-λ 6 -Sulinate): 1 H NMR (500MHz, DMSO-d6) δ8.30-8.15(m,1H),7.66-7.51(m,1H),7.23(dd,J=6.0,3.2Hz,2H),5.95(s,1H),4.84(s,5H),4.41-4.30(m,1H ),4.03-3.88(m,2H),3.75-3.67(m,1H),3.64-3.58(m,1H),3.42(s,4H),3.23-3.12(m,1H),2.83(s,3H),1.20(d,J=6.7Hz,3H); MS(ES) + C 21 H 26 N6O3S requirement: 442, actual measurement: 443 [M+H] + ;R t =17.06min.

[1294] Examples 42a and 42b

[1295]

[1296] (R)-((2-(2-amino-6-chloropyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[1297] as well as

[1298]

[1299] (S)-((2-(2-amino-6-chloropyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ 6 -sulfinyl compounds

[1300] The synthesis was similar to that described for Example 24. A mixture of diastereomers (100 mg, 0.18 mmol) was separated by chiral SFC (mobile phase: CO2 / ethanol (1% MeOH ammonia solution) = 40 / 60; flow rate: 80 g / min; 12 min; column temperature: 35 °C; back pressure: 100 bar; column: OJ (10 μm, 20 mm × 250 mm) yielded two diastereomers of absolutely stereochemical unknown at the sulfur atom: title compound 42a (13 mg, 20% yield, >99% ee), a white solid, and title compound 42b (20 mg, 31% yield, 96.7% ee), a yellow solid.

[1301] 42a((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1 HNMR(400MHz,MeOD-d4)δ7.41(s,2H),5.97(s,1H),4.45(s,1H),4.05(dd,J=29.3,11.7Hz,2H),3.82(d,J=11.6Hz,1H),3.74(d,J=8.8H z,1H),3.63-3.55(m,4H),3.26-3.21(m,1H),3.02-2.95(m,1H),1.41(s,1H),1.31(dd,J=11.6,5.8Hz,4H),1.20(d,J=7.5Hz,2H); MS(ES + C 18 H 23 ClN6O2S requirement: 422, actual measurement: 423 [M+H] + ;R t =4.27min.

[1302] 42b((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1 HNMR(400MHz,MeOD-d4)δ7.25(d,J=1.7Hz,,2H),5.88(s,1H),4.36(d,J=4.8Hz,,1H),4.00-3.86(m,2H),3.70(d,J=11.5Hz,1H),3.62(dd,J=11.5,2. 8Hz,1H),3.52-3.43(m,4H),3.18-3.10(m,1H),2.92-2.83(m,1H),1.31(dd ,J=11.3,5.6Hz,1H),1.22-1.17(m,4H),1.09(dd,J=9.5,5.3Hz,2H); MS(ES + C 18 H 23 ClN6O2S requirement: 422, actual measurement: 423 [M+H] + ;R t =5.48min.

[1303] Alternatively, Example 42a can also be prepared from intermediate CC, i.e., isomer 1b.

[1304] Examples 43a and 43b

[1305]

[1306] (R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6 -sulfinyl compounds

[1307] as well as

[1308]

[1309] (S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6 -sulfinyl compounds

[1310] The synthesis was similar to that described for Example 24. A mixture of diastereomers (36 mg, 0.089 mmol) was separated by chiral SFC (mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA) = 60:40; flow rate: 80 g / min; 17 min; column temperature: 35 °C; back pressure: 100 bar; column: Gilson-281, AY 20*250 mm, 10 μm) to give two diastereomers at the sulfur atom with absolutely unknown stereochemistry: title compound 43a (9.0 mg, 23% yield, >99% ee), a white solid, and title compound 43b (7.0 mg, 19% yield, >98% ee), a white solid.

[1311] 43a((R)-methyl(oxecyclobutane-3-yl)-λ 6 -Sulfinylide or (S)-methyl(oxetane-3-yl)-λ 6 -Sulinate): 1 H NMR(500MHz,CD3OD)δ7.98(d,J=5.7Hz,1H),7.59-7.37(m,2H),5.99(s,1H),5 .12(d,J=2.4Hz,1H),5.07-4.96(m,4H),4.52-4.41(m,1H),4.16-4.06(m,1H), 4.00(d,J=3.7Hz,1H),3.82(d,J=11.4Hz,1H),3.75(d,J=3.0Hz,1H),3.60(d, J=2.9Hz,1H),3.52(s,3H),3.25(d,J=4.1Hz,1H),1.29(d,J=6.8Hz,3H); MS(ES + C 18 H 24 N6O3S requirement: 404, actual test result: 405 [M+H] + ;R t = 9.34 min.

[1312] 43b((R)-methyl(oxecyclobutane-3-yl)-λ 6 -Sulfinylide or (S)-methyl(oxetane-3-yl)-λ 6 -Sulinate): 1H NMR (500MHz, CD3OD) δ7.86 (d, J=5.6Hz, 1H), 7.44-7.29 (m, 2H), 5.87 (s, 1H), 4.99 (d, J=2.5Hz, 1H), 4.89 (ddd, J=10.3, 7.5, 4.5Hz, 4H), 4.40-4. 32(m,1H),4.02-3.85(m,2H),3.64(dt,J=11.4,7.2Hz,2H),3.47(d,J=2.9Hz,1H),3.39(s,3H),3.16-3.07(m,1H),1.17(d,J=6.8Hz,3H); MS(ES + C 18 H 24 N6O3S requirement: 404, actual test result: 405 [M+H] + ;R t =12.75min.

[1313] Examples 44a and 44b

[1314]

[1315] (R)-Cyclopropyl(methyl)((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1316] as well as

[1317]

[1318] (S)-Cyclopropyl(methyl)((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-λ 6 -sulfinyl compounds

[1319] The synthesis was similar to that described for Example 30. A mixture of diastereomers (33.8 mg, 0.08 mmol) was separated by chiral SFC (mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA) = 75:25; flow rate: 80 g / min; 17 min; column temperature: 35 °C; back pressure: 100 bar; column: Gilson-281, sc 20 × 250 mm, 10 μm) to give two diastereomers at the sulfur atom with absolutely unknown stereochemistry: title compound 44a (5.0 mg, 15% yield, >99% ee), a white solid, and title compound 44b (5.0 mg, 15% yield, >93% ee), a white solid.

[1320] 44a((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1 HNMR(500MHz,CD3OD)δ8.32(dd,J=6.4,2.9Hz,1H),7.69-7.54(m,1H),7.38-7.20(m,2H),5.97(s,1H),4.45(s,1H),4.07-3.91(m,2H),3.85-3 .72(m,2H),3.67-3.56(m,1H),3.49(s,3H),2.97-2.86(m,4H),1.40(dd,J=12.6,10.1Hz,1H),1.35-1.25(m,5H),1.18(q,J=7.2Hz,2H); MS(ES + C 21 H 26 N6O2S requirement: 426, actual measurement: 427 [M+H] + ;R t =12.98min.

[1321] 44b((R)-cyclopropyl(methyl)-λ 6 -Syrinyl or (S)-cyclopropyl(methyl)-λ 6 -Sulinate): 1 HNMR (400MHz, CD3OD) δ8.31(dd,J=6.5,2.9Hz,1H),7.67-7.51(m,1H),7.29(dd,J=6.1,3.2Hz,2H),5.97(s,1H),4.44-4.34(m,1H),4.02( d,J=11.4Hz,2H),3.80(dd,J=22.8,7.2Hz,2H),3.60(s,1H),3.49(s,3H),2.95-2.87(m,4H),1.43-1.29(m,6H),1.21-1.12(m,2H); MS(ES) + C 21 H 26 N6O2S requirement: 426, actual measurement: 427 [M+H] + ;R t =16.31min.

[1322] Alternatively, Example 44b can also be prepared from intermediate CC, i.e., isomer 1b.

[1323] Examples 45a and 45b

[1324]

[1325] (R)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6 -sulfinyl compounds and

[1326]

[1327] (S)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetane-3-yl)-λ 6 -sulfinyl compounds

[1328] The synthesis was similar to that described for Example 17. A mixture of diastereomers (300 mg, 0.691 mmol) was separated by chiral SFC (mobile phase: CO2, MeOH / CH3CN (1:1) (0.25% i-PrNH2 solution) = 65:35; flow rate: 80 g / min; 5 min; column temperature: 25 °C; back pressure: 100 bar; column: Chiral Technologies Chiralcel OX-H, 21 × 250 mm) to give two diastereomers at the sulfur atom with absolutely unknown stereochemistry, namely title compound 45a (94 mg, 31% yield, 95% ee), as a brown solid, and title compound 45b (125 mg, 42% yield, 96% ee), as a brown solid.

[1329] 45a((R)-methyl(oxecyclobutane-3-yl)-λ 6 ...

Claims

1. A compound with structural formula (I): (I) Or its salt, wherein: R 1 and R 2 Independently selected from methyl, cyclopropyl, and oxetane-3-yl, or R 1 and R 2 Together with sulfur attached to both of them, they form optionally one or more compounds selected from C(O)R 8 R 5 Thiomorpholine rings substituted with functional groups; R 3 Selected from methyl, fluoromethyl, difluoromethyl, and trifluoromethyl; R 4 Selected from 1 H -pyrazole-1-yl, 1 H -pyrazole-3-yl, 1 H -pyrazole-4-yl, 1 H -imidazol-1-yl, 1 H -imidazol-2-yl, 1 H -imidazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1 H -indol-1-yl, 1 H -Indole-4-yl, 1 H -Indazole-1-yl, 1 H -Indazole-4-yl, 1 H -benzo[ d Imidazol-1-yl, 1 H -benzo[ d Imidazol-4-yl, 1 H -pyrrolo[2,3- b ]pyridin-4-yl, 1 H -pyrrolo[2,3- c ]pyridin-4-yl, pyrazolo[1,5- a ]pyridin-3-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2- a ]pyridin-5-yl, 1 H -imidazo[4,5- c ]Pyridin-1-yl, 7 H -pyrrolo[2,3- d ]Pyrimidine-4-yl, 1 H -pyrazolo[3,4- b ]pyridin-4-yl, 3 H -imidazo[4,5- b ]pyridin-7-yl and 1 H -benzo[ d [1,2,3]triazol-1-yl, optionally surrounded by one or two R groups selected from amino, fluorine, methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxymethyl 6 Group substitution; and R 8 It is C 1-4 Alkyl or C 3-6 Cycloalkyl groups, optionally prefixed with hydroxyl or C 1-3 Alkyl-substituted.

2. The compound of claim 1, wherein the compound has structural formula (II): (II) or its salt, wherein R 1 R 2 R 3 and R 4 As defined in claim 1.

3. The compound or a salt thereof as described in claim 1 or 2, wherein, R 3 It is a methyl group.

4. The compound or a salt thereof as described in any one of claims 1 to 3, wherein, R 1 and R 2 Together with sulfur attached to both of them, they form on nitrogen and are selected from C(O)R 8 R 5 Thiomorpholine rings substituted with functional groups.

5. A pharmaceutical composition comprising a compound or a salt thereof as described in any one of claims 1-4 and a pharmaceutically acceptable carrier.

6. Use of the compound or a salt thereof of any one of claims 1-4 in the preparation of a medicament for treating ATR kinase-mediated diseases, the use comprising administering a therapeutically effective amount of the compound or a salt thereof to a patient in need thereof, wherein the ATR kinase-mediated disease is cancer.

7. The use as described in claim 6, wherein, This cancer is a chemotherapy-resistant cancer.

8. The use as described in claim 6, wherein, This cancer is radiation-resistant.

9. The use as described in claim 6, wherein, This cancer is an ALT-positive cancer.

10. The use as described in claim 6, wherein, The cancer is a sarcoma.

11. The use as described in claim 6, wherein, The cancer is selected from osteosarcoma and glioblastoma.

12. The use as described in claim 6, wherein, The cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, stomach cancer, and brain cancer.

13. The use as described in claim 6, wherein, The cancers selected include non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.

14. The use as described in claim 6, wherein, This cancer has a deficiency in base excision repair proteins.

15. The use as described in claim 6, wherein, This cancer has a defect in the ATM signal cascade.

16. The use as described in claim 15, wherein, The deficiency is an alteration in the expression or activity of one or more of the following: TM, p53, CHK2, MRE11, RAD50, NBS 1, 53BP1, MDC1, H2AX, MCPH1 / BRIT1, CTIP, or SMC1.

17. The use as claimed in claim 6, further comprising administering another therapeutic agent to the patient, wherein the other therapeutic agent inhibits or modulates base excision repair proteins.

18. Use of the compound of any one of claims 1-4 or a salt thereof in the preparation of a medicament for treating an ATR kinase-mediated disease, wherein the ATR kinase-mediated disease is cancer, and wherein the use comprises administration to a patient in need thereof: a. A therapeutically effective amount of the compound or a salt thereof as described in any one of claims 1-4; and b. Another treatment.

19. The use as described in claim 18, wherein, The other treatment is a CHK1 inhibitor.

20. The use as described in claim 19, wherein, The CHK1 inhibitors were selected from MK-8776, LY2603618, V158411, PF-477736, UCN-01 and AZD7762.

21. The use as described in claim 18, wherein, The other therapeutic agent is a DNA damage agent.

22. The use as described in claim 21, wherein, The DNA damaging agent is selected from ionizing radiation, radioactive neoplasms, platinum-based agents, Topo I inhibitors, Topo II inhibitors, antimetabolites, alkylating agents, alkyl sulfonates, and antibiotics.

23. The use as described in claim 22, wherein, The platinumizing agent is selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, triplatinum tetranitrate, pyrplatin, saxaplatin, ProLindac, and alroplatin.

24. The use as described in claim 22, wherein, The Topo I inhibitor is selected from camptothecin, topotecan, irinotecan / SN38, rubitecan, and belotetane.

25. The use as described in claim 22, wherein, The Topo II inhibitor is selected from etoposide, daunorubicin, doxorubicin, arubicin, epirubicin, idarubicin, amorubicin, pirarubicin, pentorubicin, zorubicin and teniposide.

26. The use as described in claim 22, wherein, The antimetabolites are selected from aminopterin, methotrexate, pemetrexed, raltitrexed, pentostatin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur, carmoflu, fluorouracil, cytarabine, gemcitabine, azacitidine, and hydroxyurea.

27. The use as described in claim 22, wherein, The alkylating agent is selected from dichloromethyldiethylamine, cyclophosphamide, ifosfamide, trefophosphamide, chlorambucil, melphalan, prenimustine, bendamustine, uramustine, estrustine, carmustine, lomustine, semustine, formustine, nimustine, ramustine, streptozotocin, busulfan, triamcinolone, carboquinone, thiotepa, triamidoquinone, tratamido, mebenzylhydrazine, dacarbazine, temozolomide, hexamethylmelamine, dibromomannitol, actinomycin, bleomycin, mitomycin, and procainoxam.

28. The use as described in claim 6, wherein, This use further includes non-chemical methods for administering cancer treatments.

29. The use as described in claim 28, wherein, This use further includes administering radiation therapy.

30. The use as described in claim 28, wherein, This use further includes surgical application, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

31. Use of the compound of any one of claims 1-4 in the preparation of a medicament for increasing the sensitivity of cancer cells to cancer therapies selected from chemotherapy or radiotherapy, said use comprising administering said compound to a patient.

32. The use as described in claim 31, wherein, The cancer cells are pancreatic cancer cells.

Images