Pyrido[4,3-d]pyrimidine compounds

Abstract

The present invention relates to compounds of formula (I)-(VII), or pharmaceutically acceptable salts thereof, their use in medicine; compositions containing them; processes for their preparation; and intermediates used in such processes. The compounds of the present invention may be useful in the treatment, prevention, suppression, and amelioration of cancer, diseases, or disorders. Formulas (V), (VI) & (VII) [Formula 1] TIFF2025525406000096.tif59163

Description

[Technical Field]

[0001] The present invention relates to novel pyrido[4,3-d]pyrimidine compounds as inhibitors of Kirsten rat sarcoma viral oncogene homolog (KRAS). The present invention also relates to the preparation of the compounds, intermediates used in the preparation, compositions containing the compounds, and the use of the compounds to treat KRAS-related diseases, such as cancer. [Background technology]

[0002] KRAS, HRAS (Harvey rat sarcoma virus), and NRAS (neuroblastoma RAS viral oncogene homolog) belong to a group of GTPases crucial for cell survival and proliferation through complex signaling cascades. Mutant RAS genes are found in approximately 30% of all cancers (Hyun et al., 2021 Int. J. Mol. Sci. 22(22), 12142). KRAS is the most frequently mutated RAS isoform in cancer cells (up to 85%), leading to the development of cancers including non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic cancer, which represent a significant unmet medical need for affected patients, both individually and collectively. KRAS mutations are prevalent in pancreatic ductal adenocarcinoma (PDAC). Mutations in KRAS have been observed in 30% of cases of NSCLC, the predominant form of lung cancer (80%). KRAS mutations found in NSCLC include G12C in 39%, G12V in 18-21%, and G12D in 17-18%. KRAS mutations occur in 35-45% of colon cancers and lead to drug resistance.

[0003] KRAS inhibitors have been sought for decades, with recent advances seeing the approval of sotorasib and subsequent KRAS G12C-targeting compounds in clinical trials (Palmer et al., 2021 NPJ Precision Oncology, 5, 98). Sotorasib specifically targets KRAS mutations through covalent modification of the mutant cysteine at position 12. Therefore, sotorasib and other currently known KRAS inhibitors that rely on the same mechanism of action may have a narrow therapeutic window and limited use when considering other major KRAS mutations, such as G12V and G12D. Summary of the Invention [Problem to be solved by the invention]

[0004] Therefore, there remains a need for new KRAS inhibitors that can be used to treat a broader range of cancers. [Means for solving the problem]

[0005] The present invention provides, in part, compounds of Formula (I) to Formula (VII), and pharmaceutically acceptable salts thereof. The compounds of the present invention can inhibit the activity of all of the KRAS G12C, KRAS G12D, and KRAS G12V receptors and may be useful in the treatment, prevention, suppression, and amelioration of diseases, such as cancers, disorders, and conditions mediated by any of the KRAS G12C, KRAS G12D, and KRAS G12V receptors, or a combination thereof. Pharmaceutical compositions containing the compounds or salts of the present invention, alone or in combination with an additional anti-cancer therapeutic agent, are also provided. The present invention also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts, and compositions of the present invention, as well as methods of using the foregoing. This Summary is provided to introduce, in a simplified form, selected concepts that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

[0006] According to one embodiment of the present invention, a compound of formula (I)

[0007] [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C3~C 10 cycloalkyl or 4-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, and S; 10 each cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; R 2 teeth,

[0008] [ka] is selected from the group consisting of R 2 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CHOH, -CN, -CHCN, halogen, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; R 3 is C6~C 10 aryl or 4-12 membered heteroaryl containing 1, 2, 3, or 4 N atoms, C6-C 10 the aryl or 4- to 12-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, and C2-C3 alkynyl; R 4 is hydrogen, halogen, C1-C3 alkyl, or C1-C3 fluoroalkyl; L is -O-, -S-, -NR 5 -, and -CR 6 R 7 - a linker comprising 1, 2 or 3 members independently selected from the group consisting of: R 5 , R 6 , and R 7 are each independently H or C1-C3 alkyl, X and Y are each independently selected from the group consisting of O, S, —SO—, and C-C alkylene; Z is a bond, C1-C2 alkylene, O, S, or -SO2-; When Z is O, R 2 is substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CHOH, -CN, -CHCN, halogen, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; R 2 contains a piperazinyl ring

[0009] [ka] wherein the piperazinyl ring is substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OH, -CHOH, -CN, -CHCN, halogen, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy.

[0010] Embodiments of the invention are described below, but for convenience, embodiment 1 (E1) is identical to the embodiment of formula (I) presented above.

[0011] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief explanation of the drawings]

[0012] [Figure 1] 1 is a graph of mouse PK study results showing the unbound plasma concentration of Example 33 in female NSG mouse plasma after oral dosing at 100 mg / kg to female NSG mice (n=3, mean + / - SD). The solution of Example 33 was prepared using a Pluronic-based formulation [2.5% (w / v) Pluronic F-68 (Poloxamer 188)], and the suspension arms of both Example 33 and Example 34 were prepared using a 0.5% (w / v) methylcellulose formulation. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention may be more readily understood by reference to the following detailed description of embodiments and examples of the present invention contained herein. It should be understood that the present invention is not limited to specific synthetic methods of making, which may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting.

[0014] E1 A compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0015] E2 Compounds of formula (Ia)

[0016] [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C3~C 10 cycloalkyl or 4-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O, and S; 10 each cycloalkyl or 4- to 12-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; R 2 is a 4- to 12-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, wherein the 4- to 12-membered heterocycloalkyl has only one nitrogen as a ring member directly attached to the pyrido[4,3-d]pyrimidine nucleus of Formula (Ia), and the 4- to 12-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CHOH, -CN, -CHCN, halogen, C-C alkyl, C-C fluoroalkyl, and C-C alkoxy; R2 is a morpholinyl ring, the morpholinyl ring is substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CHOH, -CN, -CHCN, halogen, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; R 3 is C6~C 10 aryl or 4-12 membered heteroaryl containing 1, 2, 3, or 4 N atoms, C6-C 10 the aryl or 4- to 12-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, and C2-C3 alkynyl; R 4 is hydrogen, halogen, or C1-C3 alkyl, L is -O-, -S-, -NR 5 -, and -CR 6 R 7 - a linker comprising 1, 2 or 3 members independently selected from the group consisting of: R 5 , R 6 , and R 7 are each independently H or C1-C3 alkyl.

[0017] E3 The compound of Embodiment E1 or Embodiment E2, or a pharmaceutically acceptable salt thereof, wherein L is -O-CH2-.

[0018] E4 R 1 is a 5-8 membered heterocycloalkyl containing one N as the only heteroatom, wherein the 5-8 membered heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen and C1-C3 alkyl, or a pharmaceutically acceptable salt thereof.

[0019] E5 R 1but,

[0020] [ka] The compound of any one of embodiments E1 to E4, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0021] E6 R 1 but,

[0022] [ka] A compound of embodiment E5 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0023] E7 R 2 but,

[0024] [ka] [wherein X and Y are each independently O or —CH—; R 2 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OH and -CN, or a pharmaceutically acceptable salt thereof.

[0025] E8 R 2 but,

[0026] [ka] The compound of embodiment E7 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0027] E9 R 2 but,

[0028] [ka] The compound of embodiment E8, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0029] E10 R 2 but,

[0030] [ka] wherein Z is a bond, —CH—, or O; and R 2 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CHOH, -CN, -CHCN, halogen, C-C alkyl, C-C fluoroalkyl, and C-C alkoxy; when Z is O, R 2 is substituted with 1, 2 or 3 substituents independently selected from the group consisting of: -OH, -CHOH, -CN, -CHCN, halogen, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0031] E11 R 2 but,

[0032] [ka] The compound of embodiment E10 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0033] E12 R 2 but,

[0034] [ka] The compound of any one of embodiments E1 to E6, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0035] E13 R 3 But C6~C 10 bicyclic aryl or 4- to 12-membered bicyclic heteroaryl, R 3 is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of: -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, and C2-C3 alkynyl, or a pharmaceutically acceptable salt thereof.

[0036] E14 R 3 is naphthyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of: -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, and C2-C3 alkynyl, or a pharmaceutically acceptable salt thereof.

[0037] E15 R 3 but,

[0038] [ka] The compound of embodiment E14 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0039] E16 R 4 The compound of any one of embodiments E1 to E15, wherein is Cl or F, or a pharmaceutically acceptable salt thereof.

[0040] E17

[0041] [ka]

[0042] [ka] The compound of any one of embodiments E1 to E16, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0043] E18

[0044] [ka]

[0045] [ka] The compound of embodiment E17 selected from the group consisting of:

[0046] E19 A pharmaceutical composition comprising a compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0047] E20 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof.

[0048] E21 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, as a single agent.

[0049] E22 A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, and further comprising administering a therapeutically effective amount of an additional anti-cancer therapeutic agent.

[0050] E23 The method for treating cancer of any one of embodiments E20 to E22, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0051] E24 A compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0052] E25 The compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0053] E26 The compound for use in the treatment of cancer according to embodiment E25, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0054] E27 The use of a compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer.

[0055] E28 The use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer according to embodiment E27, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0056] E29 A method for treating a disorder mediated by inhibition of the KRAS G12C, KRAS G12D, and KRAS G12V receptors in a subject, comprising administering to a subject in need thereof a compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disorder.

[0057] E30 A pharmaceutical combination comprising a compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof.

[0058] E31 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E30 and at least one excipient.

[0059] E32 Compounds of formula (II):

[0060] [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 each of which is a C3-C alkyl group optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; 10 cycloalkyl or a 4- to 12-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S; R 2 is H, or -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-, each of which is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CN, -NH2, -SH, -(C1-C4 alkylene)-CN, -(C1-C4 alkylene)-OH, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy. selected from the group consisting of CN, -(C1-C6 alkylene)-SH, -(C1-C3 alkylene)-S-(C1-C3 alkyl), -(C1-C3 alkylene)-(S=O)-(C1-C3 alkyl), -(C1-C3 alkylene)-(SO2)-(C1-C3 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 fluoroalkyl, C3-C6 fluorocycloalkyl, and C1-C6 alkoxy; R 3 each of which is a C6-C alkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, and C2-C3 alkynyl; 10aryl or 4-12 membered heteroaryl containing 1, 2, 3 or 4 N atoms, R 3 is substituted with two C1-C3 alkyl groups, the two C1-C3 alkyl groups together form the C6-C 10 may form a 3- to 6-membered ring fused to an aryl or a 4- to 12-membered heteroaryl; R 4 is H, halogen, C1-C3 alkyl, or C1-C3 fluoroalkyl; R 5 is H, -OH, halogen, -NH, CN, or -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-CN ... or alternatively, R is selected from the group consisting of -(C1-C6 alkylene)-SH, -(C1-C3 alkylene)-S-(C1-C3 alkyl), -(C1-C3 alkylene)-(S═O)-(C1-C3 alkyl), -(C1-C3 alkylene)-(SO2)-(C1-C3 alkyl), C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 fluoroalkyl, C3-C6 fluorocycloalkyl, and C1-C6 alkoxy; 5 and R 5 The carbon to which R is attached 2 and R 2 are bonded together to form a 4- to 8-membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, or a heteroatom-containing group selected from the group consisting of N(C1-C6 alkyl), -(S=O)-, and -(SO2)-, wherein the 4- to 8-membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, -(C1-C6 alkylene)-CN, and -(C1-C6 alkylene)-OH; R 6is independently at each occurrence H, -OH, halogen, CN, or is selected from the group consisting of -(C1-C6 alkylene)-OH, -(C1-C6 alkylene)-CN, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 fluoroalkyl, C3-C6 fluorocycloalkyl, and C1-C6 alkoxy, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OH, -CN, -(C1-C4 alkylene)-CN, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 fluoroalkyl, and C1-C3 alkoxy; L is -O-, -S-, -NR 7 -, and -CR 8 R 9 - a linker comprising 1, 2 or 3 members independently selected from the group consisting of: R 7 , R 8 , and R 9 are each independently H or C1-C3 alkyl, X is O, N, or S; l is 1 or 2, x is 1 or 2].

[0061] E33 The compound of embodiment E32, wherein the linker L is -(O-CH2)-, or a pharmaceutically acceptable salt thereof.

[0062] E34 R 1 is a 5-8 membered heterocycloalkyl containing one N as a single heteroatom, said 5-8 membered heterocycloalkyl being optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, and C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

[0063] E35 R 1 but,

[0064] [ka] The compound of embodiment E34 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0065] E36 R 1 but,

[0066] [ka] The compound of embodiment E35 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0067] E37 R 2 is H or selected from the group consisting of -(C1-C5 alkylene)-OH and C1-C5 alkyl, each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -CN, and halogen; or a pharmaceutically acceptable salt thereof.

[0068] E38 R 5 and R 6 are each independently selected from the group consisting of H, —OH, —CN, halogen, or —(C1-C5 alkylene)-OH] and C1-C5 alkyl, each optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of —OH, —CN, and halogen; or a pharmaceutically acceptable salt thereof.

[0069] E39 Formula (III):

[0070] [ka] wherein Y is selected from the group consisting of CH, O, N(C-C alkyl), S, (S=O), and (SO); R 10is independently selected at each occurrence from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, -(C1-C6 alkylene)-CN, and -(C1-C6 alkylene)-OH; m and n are each independently 0, 1, 2, or 3; y is 1, 2, or 3; and m+n is 1, 2, 3, 4, or 5. The compound of any one of embodiments E32 to E38, having

[0071] E40 The compound of embodiment E39, wherein Y is -CH2- or O.

[0072] E41 R 3 is a bicyclic aryl or bicyclic heteroaryl, each optionally substituted with 1 to 4 substituents independently selected from the group consisting of -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, and C2-C3 alkynyl; R 3 The compound of any one of embodiments E32 to E40, or a pharmaceutically acceptable salt thereof, wherein when is substituted with two C1-C3 alkyl groups, the two C1-C3 alkyl groups may together form a 3- to 6-membered ring.

[0073] E42 R 3 is naphthyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of: -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, and C2-C3 alkynyl; or a pharmaceutically acceptable salt thereof.

[0074] E43 R 3 but,

[0075] [ka] A compound of embodiment E42 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0076] E44 R 4 The compound of any one of embodiments E32 to E43, or a pharmaceutically acceptable salt thereof, wherein is Cl or F.

[0077] E45 Formula (IV):

[0078] [ka] [In the formula, R 3 is naphthyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of -OH, halogen, -CN, C1-C3 alkyl, C1-C3 fluoroalkyl, and C2-C3 alkynyl, and 1 is 1 or 2. The compound of embodiment E32, or a pharmaceutically acceptable salt thereof, having the following structure:

[0079] E46

[0080] [ka] The compound of embodiment E32 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0081] E47

[0082] [ka] or a pharmaceutically acceptable salt thereof.

[0083] E48

[0084] [ka] A compound.

[0085] E49

[0086] [ka] A pharmaceutically acceptable salt of the compound,

[0087] E50 A pharmaceutical composition comprising a compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0088] E51 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof.

[0089] E52 A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, as a single agent.

[0090] E53 A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, and further comprising administering a therapeutically effective amount of an additional anti-cancer therapeutic agent.

[0091] E54 The method for treating cancer of any one of embodiments E51 to E53, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0092] E55 A compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0093] E56 The compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0094] E57 The compound for use in the treatment of cancer according to embodiment E56, wherein said cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0095] E58 The use of a compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer.

[0096] E59 The use of the compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer according to embodiment E58, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0097] E60 A method for treating a disorder mediated by inhibition of the KRAS G12C, KRAS G12D, and KRAS G12V receptors in a subject, comprising administering to a subject in need thereof a compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disorder.

[0098] E61 A pharmaceutical combination comprising a compound of any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof, which may be a fixed or non-fixed combination.

[0099] E62 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E61 and at least one excipient.

[0100] E63 Compounds of formula (V):

[0101] [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 teeth,

[0102] [ka] is selected from the group consisting of R 2 is a C1 alkyl, a C3 alkyl, -(C1 alkylene)-OH, or -(C3 alkylene)-OH; R 3 teeth,

[0103] [ka] is selected from the group consisting of R 4 is Cl or F, R 5 is -(C1 alkylene)-OH, or C1 alkyl, and R 2 and R 5 may be taken together to form a 7-membered heterocycloalkyl containing one heteroatom O; R 6 represents one or two substituents selected from the group consisting of H, -OH, halogen, -(C1-C6 alkylene)-OH, -CN, -(C1-C6 alkylene)-CN, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 fluoroalkyl, C3-C6 fluorocycloalkyl, and C1-C6 alkoxy; L is -O-, -S-, -NR 7 -, and -CR 8 R 9 - a linker comprising 1, 2 or 3 members independently selected from the group consisting of: R 7 , R 8 , and R 9 are each independently H or C1-C3 alkyl, X is O, N, or S; l is 1 or 2].

[0104] E64 R 1 but,

[0105] [ka] or a pharmaceutically acceptable salt thereof.

[0106] E65 R 1 but,

[0107] [ka] The compound of embodiment E64, wherein:

[0108] E66 R 2 is a C3 alkyl, and R 5 The compound of any one of embodiments E63 to E65, or a pharmaceutically acceptable salt thereof, wherein is -(C1 alkylene)-OH.

[0109] E67 R 2 is -(C3 alkylene)-OH, and R 5 The compound of any one of embodiments E63 to E65, or a pharmaceutically acceptable salt thereof, wherein is C1 alkyl.

[0110] E68 R 2 and R 5 The compound of embodiment E66, wherein are taken together to form a 7-membered heterocycloalkyl containing one heteroatom O, or a pharmaceutically acceptable salt thereof.

[0111] E69 R 2 and R 5 The compound of embodiment E67, wherein are taken together to form a 7-membered heterocycloalkyl containing one heteroatom O, or a pharmaceutically acceptable salt thereof.

[0112] E70 R 3 but,

[0113] [ka] The compound of any one of embodiments E63 to E69, wherein:

[0114] E71 R 4 The compound of any one of embodiments E63 to E70, wherein is F, or a pharmaceutically acceptable salt thereof.

[0115] E72 The compound of any one of embodiments E63 to E71, wherein X is O and 1 is 1, or a pharmaceutically acceptable salt thereof.

[0116] E73 Formula (VI):

[0117] [ka] The compound of embodiment E63, or a pharmaceutically acceptable salt thereof, having

[0118] E74 R 2 is a C3 alkyl, and R 5 The compound of embodiment E73, wherein is -(C1 alkylene)-OH, or a pharmaceutically acceptable salt thereof.

[0119] E75 R 2 is -(C3 alkylene)-OH, and R 5 The compound of embodiment E73, or a pharmaceutically acceptable salt thereof, wherein is C1 alkyl.

[0120] E76 R 2 and R 5The compound of embodiment E74, wherein combined to form a 7-membered heterocycloalkyl containing one heteroatom O, or a pharmaceutically acceptable salt thereof.

[0121] E77 R 2 and R 5 The compound of embodiment E75, wherein are taken together to form a 7-membered heterocycloalkyl containing one heteroatom O, or a pharmaceutically acceptable salt thereof.

[0122] E78 Compound of formula (VII)

[0123] [ka] or a pharmaceutically acceptable salt thereof [wherein R 11 , R 12 , R 13 , and R 14 are each independently H or C1-C3 alkyl.

[0124] E79 R 11 , R 12 , R 13 , and R 14 is each independently H or methyl, or a pharmaceutically acceptable salt thereof.

[0125] E80

[0126] [ka] The compound of embodiment E78 or E79, wherein:

[0127] E81

[0128] [ka] or a pharmaceutically acceptable salt thereof.

[0129] E82 A pharmaceutical composition comprising the compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0130] E83 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof.

[0131] E84 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, as a single agent.

[0132] E85 A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, and further comprising administering a therapeutically effective amount of an additional anti-cancer therapeutic agent.

[0133] E86 The method for treating cancer of any one of embodiments E83 to E85, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0134] E87 The compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0135] E88 The compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0136] E89 The compound for use in the treatment of cancer according to embodiment E88, wherein said cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0137] E90 The use of a compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer.

[0138] E91 The use of the compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer according to embodiment E90, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

[0139] E92 A method for treating a disorder mediated by inhibition of the KRAS G12C, KRAS G12D, and KRAS G12V receptors in a subject, comprising administering to a subject in need thereof a compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disorder.

[0140] E93 A pharmaceutical combination comprising the compound of any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof, which may be a fixed or non-fixed combination.

[0141] E94 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E93 and at least one excipient.

[0142] Each of the embodiments described herein can be combined with any other embodiment described herein that is not inconsistent with the combined embodiment. In addition, any of the compounds described in the examples, or a pharmaceutically acceptable salt thereof, may be claimed individually or as a group together with one or more other compounds of the examples, or a pharmaceutically acceptable salt thereof.

[0143] Additionally, each of the embodiments described herein contemplates within its scope pharmaceutically acceptable salts of the compounds, stereoisomers of the compounds, and pharmaceutically acceptable salts of the stereoisomers described herein.

[0144] definition Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have meanings that are commonly understood by those of ordinary skill in the art.

[0145] The invention described herein may suitably be practiced in the absence of any element not specifically disclosed herein.

[0146] "Compounds of the invention" include compounds of formula (I) and novel intermediates used in their preparation. Those skilled in the art will recognize that compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereoisomers), if they exist, as well as racemates, diastereoisomers, and other mixtures of such isomers, and tautomers thereof. Those skilled in the art will also recognize that compounds of the invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labeled versions thereof, if they may be formed.

[0147] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" substituent includes one or more substituents.

[0148] As used herein, the term "about," when used to modify a parameter defined by a numerical value (e.g., a 5 mg dose), means that the parameter may vary 10% above or below the numerical value stated for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0149] When substituents are described as being "independently selected" from a group, each substituent is selected independently of the others. Thus, each substituent can be the same or different from the other substituents.

[0150] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

[0151] The terms "optionally substituted" and "substituted or unsubstituted" are used interchangeably to indicate that a particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or that the group may have one or more non-hydrogen substituents (i.e., substituted). Unless otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. When an optional substituent is attached through a double bond, such as an oxo (=O) substituent, the group occupies two available valencies, and thus the total number of other substituents included is reduced by two. When optional substituents are independently selected from a list of alternatives, the selected groups may be the same or different. It will be understood that throughout this disclosure, the number and nature of optional substituents will be limited to the extent that such substitution makes chemical sense to one of ordinary skill in the art.

[0152] "Halogen" refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

[0153] "Cyano" refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, ie, --C.ident.N (also designated herein as "--CN").

[0154] "Hydroxy" refers to the group --OH.

[0155] "Oxo" refers to a double-bonded oxygen (=O).

[0156] "Alkyl" refers to a saturated monovalent aliphatic hydrocarbon radical having the specified number of carbon atoms, including straight-chain or branched-chain groups. The alkyl group may contain, but is not limited to, 1 to 6 carbon atoms ("C1-C6 alkyl"), 1 to 3 carbon atoms ("C1-C3 alkyl"), or 1 to 2 carbon atoms ("C1-C2 alkyl"). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.

[0157] "Fluoroalkyl" refers to an alkyl group as defined herein, in which one to all of the alkyl group's hydrogen atoms are replaced by fluorine atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-CF5).

[0158] "Alkylene" refers to a divalent aliphatic hydrocarbon radical having the specified number of carbon atoms. Alkylene groups can contain, but are not limited to, 1 to 6 carbon atoms ("C1-C6 alkylene"), or 1 to 2 carbon atoms ("C1-C2 alkylene"). Examples include -(CH2)-(methylene) and -(CH2-CH2)-(ethylene).

[0159] "Alkoxy" refers to an alkyl group, as defined herein, single-bonded to an oxygen atom. The point of attachment of the alkoxy radical to the molecule is through the oxygen atom. The alkoxy radical is sometimes depicted as alkyl-O-. Alkoxy groups can contain, but are not limited to, 1 to 6 carbon atoms ("C1-C6 alkoxy"), or 1 to 3 carbon atoms ("C1-C3 alkoxy"). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and the like.

[0160] "Alkynyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl can contain 2 to 3 carbon atoms ("C2-C3 alkynyl"). Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0161] "Cycloalkyl" refers to a fully saturated hydrocarbon ring system which may be a monocyclic bridged or fused bicyclic or polycyclic ring system having the specified number of carbon atoms and which is connected to the base molecule through a carbon atom of the cycloalkyl ring. Cycloalkyl groups include, but are not limited to, cycloalkyl groups containing 3 to 10 carbon atoms ("C3-C4"). 10 The cycloalkyl group may contain 3 to 8 carbon atoms ("C-C cycloalkyl"), 3 to 6 carbon atoms ("C-C cycloalkyl"), 3 to 5 carbon atoms ("C-C cycloalkyl"), or 3 to 4 carbon atoms ("C-C cycloalkyl"). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantanyl, and the like. Cycloalkyl groups may be substituted, unsubstituted, or substituted as further defined herein.

[0162] "Fluorocycloalkyl" refers to a cycloalkyl group, as defined herein, in which one to all of the alkyl group's hydrogen atoms have been replaced by fluoro atoms. Examples include, but are not limited to, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, and fluorocyclohexyl.

[0163] "Heterocycloalkyl" refers to a group containing the specified number of ring atoms and containing at least one heteroatom selected from N, O, and S as a ring member, wherein the ring S atom is optionally substituted by one or two oxo groups (i.e., S(O) q , where q is 0, 1, or 2), heterocycloalkyl rings refer to fully saturated ring systems linked to the base molecule through a ring atom, which may be C or N. Heterocycloalkyl rings include monocyclic or polycyclic, such as bicyclic rings. Heterocycloalkyl rings include spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, and such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated, or aromatic to the extent that unsaturation or aromaticity makes chemical sense, provided that the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. Heterocycloalkyl rings include N, O, and S(O) as ring members. q and optionally contain 1 to 4 heteroatoms, or 1 to 3 ring heteroatoms, or 1 to 2 ring heteroatoms selected from, provided that such heterocycloalkyl ring does not contain two adjacent oxygen or sulfur atoms.

[0164] Heterocycloalkyl rings can be substituted, unsubstituted, or substituted as further defined herein, and such substituents can be present on the heterocyclic ring attached to the base molecule or on any monocyclic, bicyclic, tricyclic, spirocyclic, bridged, or fused ring attached thereto.

[0165] Heterocycloalkyl rings can include, but are not limited to, 4- to 12-membered heterocyclyl groups, such as 5- to 8- or 4- to 6-membered heterocycloalkyl groups, as defined herein. Examples of heterocycloalkyl ring groups of the present invention can include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl, thieazepanyl, a hexahydro-1H-pyrrolidine ring radical, an 8-oxa-3-azabicyclo[3.2.1]octane ring radical, a 3-azabicyclo[3.2.1]octane ring radical, a 6-azabicyclo[3.2.1]octane ring radical, or a 3-azabicyclo[3.2.0]heptane ring radical.

[0166] "Aryl" or "aromatic" refers to an aromatic ring containing a specified number of ring atoms, where all carbon atoms in the ring are sp 2 Aryl groups refer to hybridized, pi-electron conjugated, monocyclic, bicyclic (e.g., biaryl, fused), or polycyclic ring systems. Aryl groups include, but are not limited to, groups containing 6 to 10 carbon atoms ("C6-C6"). 10 A fused aryl group may contain an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be substituted, unsubstituted, or substituted as further defined herein.

[0167] Similarly, a "heteroaryl" or "heteroaromatic" refers to a heteroaryl containing a specified number of ring atoms and including at least one heteroatom selected from N, O, and S as a ring member in the ring, and all carbon atoms in the ring are sp 2Heteroaryl refers to a hybridized, pi-electron conjugated, monocyclic, bicyclic (e.g., heterobiaryl, fused), or polycyclic ring system. Heteroaryl groups may contain, but are not limited to, 5 to 14 ring atoms ("5-14-membered heteroaryl"), 5 to 12 ring atoms ("5-12-membered heteroaryl"), 5 to 10 ring atoms ("5-10-membered heteroaryl"), 5 to 9 ring atoms ("5-9-membered heteroaryl"), or 5 to 6 ring atoms ("5-6-membered heteroaryl"). The heteroaryl ring is attached to the base molecule through a ring atom of the heteroaromatic ring. Thus, either a 5- or 6-membered heteroaryl ring, alone or in a fused configuration, may be attached to the base molecule through a ring C or N atom.Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, and the like. Risinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, carbazolyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl (pyidinyl), pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, purinyl, indolininyl , imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, azaquinazolinyl, phthalazinyl, (pyrido[3,2-d]pyrimidinyl, (pyrido[4,3-d]pyrimidinyl, (pyrido[3,4-d]pyrimidinyl, (pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2, [3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl rings. Heteroaryl groups may be substituted, unsubstituted, or substituted, as further defined herein.

[0168] "Amino" refers to the unsubstituted -NH group. Where amino is described as substituted or optionally substituted, the term includes groups of the form -NRxRy, where each of Rx and Ry is defined as further described herein. For example, "alkylamino" refers to the group -NRxRy, where one of Rx and Ry is an alkyl moiety and the other is H, and "dialkylamino" refers to -NRxRy, where both Rx and Ry are alkyl moieties, with the alkyl moieties having the specified number of carbon atoms (e.g., -NH(C1-C4 alkyl) or -N(C1-C4 alkyl)2).

[0169] The wavy line "" used in the chemical structures in this disclosure

[0170] [ka] " refers to the point of attachment of the substituent.

[0171] The term "pharmaceutically acceptable" means that a substance (e.g., a compound described herein) and any salt thereof, or a composition containing a substance or salt of the invention, is suitable for administration to a subject or patient.

[0172] "Deuterium enrichment factor" as used herein means the ratio between the deuterium abundance relative to the hydrogen abundance and the natural abundance of deuterium, respectively. Atomic configurations designated as having deuterium typically have a deuterium enrichment factor of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation), in certain embodiments.

[0173] salt Salts included within the term "pharmaceutically acceptable salts" generally refer to compounds of the present invention prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to obtain a salt of a compound of the present invention that is suitable for administration to a subject or patient.

[0174] In addition, compounds of formula (I) may include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, but which may be useful as intermediates for one or more of the following: 1) preparing compounds of formula (I); 2) purifying compounds of formula (I); 3) separating enantiomers of compounds of formula (I); or 4) separating diastereoisomers of compounds of formula (I).

[0175] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, These include lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphthalenedisulfonate and xinofoate.

[0176] Suitable base salts are formed from bases which form non-toxic salts, examples include, but are not limited to, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0177] Hemisalts of acids and bases, such as hemisulfates and hemicalcium salts, may also be formed.

[0178] For a review of suitable salts, see Paulekun, GS et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007;50(26), 6665-6672.

[0179] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by methods well known to those skilled in the art, including, but not limited to, the following procedures: (i) by reacting a compound of the present invention with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, with a desired acid or base; or (iii) by converting one salt of a compound of the invention into another salt, which can be achieved by reaction with the appropriate acid or base, or by using suitable ion exchange procedures.

[0180] These procedures are typically carried out in solution, and the resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent.

[0181] solvate The compound of the present invention and its pharmaceutically acceptable salt can exist in non-solvated and solvated form.The term "solvate" is used herein to describe the molecular complex that comprises the compound of the present invention or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.The term "hydrate" is used when the solvent is water.

[0182] In addition, compounds of formula (I) may include other solvates of such compounds, which are not necessarily pharmaceutically acceptable solvates, and may be useful as intermediates for one or more of the following: 1) preparing compounds of formula (I); 2) purifying compounds of formula (I); 3) separating enantiomers of compounds of formula (I); or 4) separating diastereoisomers of compounds of formula (I).

[0183] The currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal ion coordinated hydrates. See Polymorphism in Pharmaceutical Solids by KR Morris (HGBrittain, ed., Marcel Dekker, 1995). Isolated site hydrates are hydrates in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules reside in lattice channels where they are adjacent to other water molecules. In metal ion coordinated hydrates, the water molecules are bound to the metal ion.

[0184] When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry becomes the norm.

[0185] Complex Multicomponent complexes (other than salts and solvates) in which a drug and at least one other component are present in stoichiometric or non-stoichiometric amounts are also included within the scope of the present invention. This type of complex includes clathrates (drug-host inclusion complexes) and cocrystals. The latter are typically defined as crystalline complexes of neutral molecular components bound together by non-covalent interactions; for example, hydrogen-bonded complexes (cocrystals) can be formed with neutral molecules or with salts. Cocrystals can be prepared by melt crystallization, recrystallization from solvents, or physical grinding of the components together. See O. Almarsson and MJ Zaworotko (2004), Chem Commun, 17; 1889-1896. For a general review of multicomponent complexes, see Haleblian (August 1975), J Pharm Sci, 64(8), 1269-1288.

[0186] solid form The compounds of the present invention can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid, depending on temperature. Typically, such materials do not exhibit a distinctive X-ray diffraction pattern and are more formally described as liquids, while exhibiting the properties of a solid. Upon heating, a change from solid to liquid properties occurs, which is typically characterized by a second-order change of state ("glass transition"). The term "crystalline" refers to a solid phase in which the material has an internal structure that is regularly ordered at the molecular level and exhibits a distinctive X-ray diffraction pattern with defined peaks. When such materials are heated sufficiently, they also exhibit the properties of a liquid, but the change from solid to liquid is typically characterized by a first-order phase change ("melting point").

[0187] The compounds of the present invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two-dimensional order at the molecular level. Mesomorphic states that arise as a result of a change in temperature are described as "thermotropic," while those that arise upon the addition of a second component, such as water or another solvent, are described as "lyotropic." Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic," and may be ionic (-COO - Na + , -COO - K + , or -SO3 - Na + ) or non-ionic (-N - N + They consist of molecules with polar head groups (e.g., (CH3)3). For more information, see Crystals and the Polarizing Microscope, N.H. Hartshorne and A. Stuart, 4th ed. (Edward Arnold, 1970).

[0188] stereoisomer The compounds of the present invention may exist as two or more stereoisomers. The stereoisomers of the compounds may include cis and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereoisomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the present invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers.

[0189] Pharmaceutically acceptable salts of the compounds of the invention may also contain counterions that are optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine).

[0190] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0191] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, if the compound of the present invention contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting mixture of diastereoisomers can be separated by chromatography, fractional crystallization, or both of the aforementioned techniques, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer by means well known to those skilled in the art. Chromatography can be used to obtain the chiral compounds of the present invention (and their chiral precursors) in enantiomerically enriched form, typically by HPLC concentration of the eluent to yield the enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be used. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, e.g., Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein).

[0192] When any racemate crystallizes, two different types of crystals can occur. The first type is the racemate (true racemate) mentioned above, which produces a single uniform crystal form containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate, which produces two crystalline forms in equimolar amounts, each containing a single enantiomer. Both crystalline forms present in a racemic mixture have the same physical properties, but they may have different physical properties compared to a true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art. For example, see Stereochemistry of Organic Compounds by EL Eliel and SH Wilen (Wiley, New York, 1994).

[0193] Tautomerism Tautomeric isomerism ("tautomerism") can occur where structural isomers are interconvertible via a low energy barrier. This can take the form of proton tautomerism in compounds of the invention that contain, for example, imino / amino, keto / enol, or oxime / nitroso groups, lactam / lactim, or so-called valence tautomerism in compounds that contain aromatic moieties. It follows that a single compound may exhibit more than one type of isomerism.

[0194] For simplicity, the compounds of the invention are depicted herein in a single tautomeric form, however, it should be emphasized that all possible tautomeric forms are included within the scope of the invention.

[0195] Isotopes The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0196] Examples of isotopes suitable for inclusion in the compounds of the invention include:2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 chlorine such as Cl, 18 Fluorine such as F, 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus, such as P, 35 Isotopes of sulfur such as S may be included.

[0197] Certain isotopically labeled compounds of the present invention, for example, those incorporating a radioactive isotope, are useful in drug or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and rapid means of detection.

[0198] Deuterium, i.e., 2 Substitution with H may confer certain therapeutic advantages resulting from greater metabolic stability.

[0199] Positron-emitting isotopes, e.g. 11 C. 18 F, 15 O and 13 Substitution at N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0200] In some embodiments, the present disclosure provides deuterium-labeled (or deuterated) compounds and salts, wherein the formulas and variables of such compounds and salts are each and independently as described herein. "Deuterated" means that at least one of the atoms in the compound is deuterium, at an abundance higher than the natural abundance of deuterium (typically approximately 0.015%). Skilled practitioners recognize that in chemical compounds containing hydrogen atoms, the hydrogen atoms actually exist as a mixture of H and D, with approximately 0.015% being D. The concentration of deuterium incorporated in the deuterium-labeled compounds and salts of the present invention can be defined by the deuterium enrichment factor. It is understood that one or more deuterium atoms can be exchanged for hydrogen under physiological conditions.

[0201] In some embodiments, the deuterated compound is selected from any one of the compounds set forth in Table 2 shown in the Examples section.

[0202] In some embodiments, one or more hydrogen atoms at certain metabolic sites on the compounds of the invention are deuterated.

[0203] Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples and Preparations, using an appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0204] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, d6-acetone, d6-DMSO.

[0205] Prodrug The compounds of the present invention can be administered in the form of prodrugs. Thus, certain derivatives of the compounds of the present invention, which may themselves have little or no pharmacological activity, can be converted into compounds of the present invention having the desired activity when administered into or onto the body, for example, by hydrolytic cleavage, particularly hydrolytic cleavage facilitated by esterase or peptidase enzymes. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs can be found in "The Expanding Role of Prodrugs in Contemporary Drug Design and Development," Nature Reviews Drug Discovery, 17, 559-587 (2018) (J. Rautio et al.).

[0206] Prodrugs according to the present invention can be generated, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "promoieties," as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0207] Thus, a prodrug according to the present invention may be (a) an ester or amide derivative of a carboxylic acid, when present in a compound of the invention; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group, when present in a compound of the invention; (c) an amide, imine, carbamate or amine derivative of an amino group, when present in a compound of the invention; (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivative of a thiol group, when present in a compound of the invention; or (e) an oxime or imine derivative of a carbonyl group, when present in a compound of the invention.

[0208] Some specific examples of prodrugs according to the present invention include: (i) When the compound of the present invention contains a carboxylic acid functional group (—COOH), its ester, for example, when the hydrogen of the carboxylic acid functional group of the compound is replaced with a C1-C8 alkyl (e.g., ethyl) or (C1-C8 alkyl)C(═O)OCH2— (e.g., t BuC(=O)OCH2-); (ii) When the compound of the present invention contains an alcohol functional group (—OH), its ester, for example, a compound in which the hydrogen of the alcohol functional group of the compound is replaced by —CO(C1-C8 alkyl) (e.g., methylcarbonyl) or the alcohol is esterified with an amino acid; (iii) When the compound of the present invention contains an alcohol functional group (—OH), its ether, for example, a compound in which the hydrogen of the alcohol functional group of the compound is replaced by (C1-C8 alkyl)C(═O)OCH2— or —CH2OP(═O)(OH)2; (iv) When a compound of the invention contains an alcohol functional group (—OH), its phosphate, e.g., when the hydrogen of the alcohol functional group of the compound is —P(═O)(OH) or —P(═O)(O - Na + )2 or -P(=O)(O - )2Ca 2+ Compounds that are replaced by; (v) When a compound of the invention contains a primary or secondary amino functional group (—NH or —NHR, where R≠H), its amide, e.g., optionally, when one or both of the hydrogens of the amino functional group of the compound is (C1-C 10 ) alkanoyl, -COCH2NH2 replaced by or the amino group is derivatized with an amino acid; (vi) When a compound of the invention contains a primary or secondary amino functional group (-NH or -NHR, where R ≠ H), the amine, e.g., optionally, compounds in which one or both hydrogens of the amino functional group of the compound are replaced by -CHOP(=O)(OH); (vii) When the compound of the invention contains an alcohol functional group (—OH), replacement of the hydrogen of the alcohol functional group with a group selected from the set below:

[0209] [ka] wherein R, R', R", and R"' are (C1-C8) alkyl or (C1-C8) alkoxy, and may be linear, branched, or cyclic. Includes:

[0210] Some preferred prodrugs are C6-C 10 They can be prepared via an -OH on the bicyclic aryl or 4- to 12-membered bicyclic heteroaryl. Some more preferred prodrugs can be prepared via an -OH on the naphthyl.

[0211] Certain compounds of the present invention can act as prodrugs of other compounds of the present invention.Two compounds of the present invention can be in the form of prodrugs together.In certain circumstances, prodrugs of compounds of the present invention can be prepared by connecting two functional groups in the compounds of the present invention internally, for example, by forming lactones.

[0212] Metabolites Active metabolites of the compounds of the invention, i.e., compounds formed in vivo upon drug administration, often by oxidation or dealkylation, are also included within the scope of the invention. Some examples of metabolites according to the invention include, but are not limited to: (i) When the compound of the present invention contains an alkyl group, its hydroxyalkyl derivative (-CH > -COH): (ii) when the compound of the invention contains an alkoxy group, its hydroxy derivative (-OR → -OH); (iii) if the compound of the invention contains a tertiary amino group, its secondary amino derivative (-NRR' → -NHR or -NHR'); (iv) If the compound of the invention contains a secondary amino group, its primary derivative (-NHR → -NH2); (v) When the compound of the invention contains a phenyl moiety, its phenol derivative (-Ph → -PhOH); (vi) When the compound of the invention contains an amide group, its carboxylic acid derivative (-CONH2 → COOH); and (vii) If the compound contains a hydroxy or carboxylic acid group, the compound may be metabolized, for example, by conjugation with glucuronic acid to form a glucuronide. Other pathways of conjugation metabolism exist. These pathways are often known as phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, can also undergo conjugation.

[0213] Pharmaceutical Composition In another embodiment, the invention comprises a pharmaceutical composition, for the purposes of which the compound per se or a pharmaceutically acceptable salt thereof will simply be referred to as the compound of the invention.

[0214] A "pharmaceutical composition" refers to a mixture of one or more compounds of the invention, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, as the active ingredient, and at least one pharmaceutically acceptable excipient.

[0215] The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will largely depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0216] As used herein, "additives" include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity and absorption retarding agents, carriers, diluents, and the like. Examples of additives include one or more of water, saline, phosphate buffer solution, dextrose, glycerol, ethanol, and the like, as well as combinations thereof, and isotonicity adjusting agents, such as sugars, sodium chloride, or polyalcohols, such as mannitol or sorbitol, may also be included in the composition. Examples of additives also include various organic solvents (such as hydrates and solvates). If desired, pharmaceutical compositions may contain additional additives, such as flavoring agents, binders / binding agents, lubricants, disintegrants, sweeteners or flavoring agents, coloring agents or pigments, and the like. For example, for oral administration, tablets containing various additives such as citric acid can be used with various disintegrating agents such as starch, alginic acid, and certain complex silicates, and binders such as sucrose, gelatin, and gum arabic. Non-limiting examples of additives include calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting. Similar types of solid compositions can also be used in filled soft and hard gelatin capsules. Non-limiting examples of additives include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein can be combined with various sweeteners or flavoring agents, colorings or pigments, and, if desired, emulsifying or suspending agents, along with additional additives such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0217] Examples of additives also include pharmaceutically acceptable substances which enhance the shelf life or effectiveness of the compound, such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers.

[0218] The compositions of the present invention may be in a variety of forms, including, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0219] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those generally used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[0220] Oral administration of solid dosage forms can be provided in separate units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention.In another embodiment, oral administration can be in the form of powder or granules.In another embodiment, oral dosage forms are sublingual, such as lozenges.In such solid dosage forms, the compound of the present invention is usually combined with one or more adjuvants.Such capsules or tablets can contain controlled-release formulations.In the case of capsules, tablets, and pills, dosage forms can contain buffering agents or be prepared with enteric coatings.

[0221] In another embodiment, oral administration may be in liquid dosage form.Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (e.g., water).Such compositions may also contain one or more auxiliary agents, such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners) or aromatic agents.

[0222] In another embodiment, the present invention includes parenteral dosage forms. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using one or more suitable dispersing agents, wetting agents, or suspending agents.

[0223] In another embodiment, the present invention encompasses topical dosage forms. "Topical administration" includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoretic devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When administering the compounds of the present invention via a transdermal device, administration will be achieved using a patch, either of the reservoir and porous membrane type or of the solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical additives include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Permeation enhancers can be incorporated. See, e.g., B.C. Finnin and T.M. Morgan, J. Pharm. Sci., vol. 88, pp. 955-958, 1999.

[0224] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compounds of the present invention are dissolved or suspended in a suitable excipient. Typical formulations suitable for ocular or aural administration may be in the form of drops of micronized suspensions or solutions in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and microparticle or vesicle systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum, together with preservatives such as benzalkonium chloride, can also be incorporated. Such formulations can also be delivered by iontophoresis.

[0225] For intranasal administration, the compounds of the present invention are conveniently delivered in the form of a solution or suspension from a pump-type spray container that the patient squeezes or pumps, or as an aerosol spray delivery from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder from a dry powder inhaler (either alone or as a mixture, for example, in a dry blend with lactose, or as mixed component particles, for example, mixed with a phospholipid such as phosphatidylcholine), or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or nebulizer with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive, for example, chitosan or cyclodextrin.

[0226] In another embodiment, the present invention includes a rectal dosage form. Such a rectal dosage form may be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, although various alternatives can be used where appropriate.

[0227] Other additives and modes of administration known in the pharmaceutical art can also be used.The pharmaceutical compositions of the present invention can be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.The above discussion of effective formulation and administration procedures is well known in the art and is described in standard textbooks.Drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington, 1999.

[0228] Acceptable additives are non-toxic to subjects at the dosages and concentrations used and may include one or more of the following: 1) buffers such as phosphates, citrates, and other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid and methionine; 4) preservatives such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkylparabens such as methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) serum albumin, 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose, or sorbitol; 13) salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers, or polyethylene glycol (PEG).

[0229] For oral administration, the compositions can be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, 500, or 1000 milligrams of the active ingredient for symptomatic adjustment of dosage to the patient. Medicaments typically contain from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of the active ingredient. Intravenously, doses can range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0230] Liposomes containing the compounds of the present invention can be prepared by methods known in the art (see, for example, Chang, HI; Yeh, MK; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012;7;49-60). Particularly useful liposomes can be generated by the reverse-phase evaporation method using a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0231] The compound of the present invention can also be encapsulated in microcapsules, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, prepared by coacervation technology or by interfacial polymerization, respectively, in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or in macroemulsions.Such technology is disclosed in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0232] Sustained-release preparations can be used.The preferred example of sustained-release preparation comprises the semipermeable matrix of solid hydrophobic polymer containing the compound of the present invention, and this matrix is in the form of shaped article, for example, film or microcapsule.The example of sustained-release matrix comprises polyester, hydrogel (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide, L-glutamic acid and 7-ethyl-L-glutamate copolymer, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer (such as that used in leuprolide acetate for depot suspensions (injectable microspheres made of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate and poly-D-(-)-3-hydroxybutyric acid.

[0233] Preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. The compound of the present invention is generally placed into a container with a sterile access port, for example, an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic injection needle.

[0234] Suitable emulsions can be prepared using commercially available lipid emulsions, such as lipid emulsions containing soybean oil, lipid emulsions for intravenous administration (e.g., containing safflower oil, soybean oil, egg phospholipids, and glycerin in water), emulsions containing soybean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient can be dissolved in a premixed emulsion composition, or alternatively, can be dissolved in an emulsion formed by mixing oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) with water. It will be appreciated that other ingredients, such as glycerol or glucose, can be added to adjust the tonicity of the emulsion. Suitable emulsions typically contain up to 20% oil, for example, between 5 and 20%. The lipid emulsion may contain lipid droplets between 0.1 and 1.0 μm, especially between 0.1 and 0.5 μm, and have a pH in the range of 5.5 to 8.0.

[0235] For example, an emulsion composition can be prepared by mixing a compound of the present invention with a lipid emulsion comprising soybean oil or its components (soybean oil, egg phospholipids, glycerol, and water).

[0236] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.Liquid or solid compositions may contain suitable pharmaceutically acceptable additives as described above.In some embodiments, compositions are administered by oral or nasal respiratory route for local or systemic effect.Preferably, compositions in sterile pharmaceutically acceptable solvents can be nebulized by using gas.Nebulized solutions can be directly breathed from the nebulizing device, or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure respirator.Solution, suspension, or powder compositions can be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0237] A drug formulation intermediate (DPI) is a partially processed material that requires further processing steps before becoming a bulk formulation. The compounds of the present invention can be formulated into a drug formulation intermediate DPI that contains the active ingredient in a form with a higher free energy than the crystalline form. One reason for using a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved transport of substances through the mucin layer adjacent to epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid-state stability and downstream manufacturability. In one embodiment, the drug formulation intermediate contains a compound of the present invention isolated and stabilized in an amorphous state (e.g., an amorphous solid dispersion (ASD)). Many techniques are known in the art for producing ASDs that produce materials suitable for incorporation into bulk formulations, such as spray-dried dispersions (SDDs), melt extrudates (often referred to as HMEs), co-precipitates, amorphous drug nanoparticles, and nanoadsorbates. In one embodiment, the amorphous solid dispersion contains a compound of the present invention and a polymeric additive. Other additives, as well as the concentrations of said additives and compounds of the present invention, are well known in the art and are described in standard textbooks, see, for example, "Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0238] Administration and Dosage The terms "treating," "treat," or "treatment" as used herein encompass both preventative, i.e., protective, and palliative, treatment, i.e., reducing, alleviating, or slowing the progression of a patient's disease (or condition) or any tissue damage associated with the disease.

[0239] As used herein, the terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including mammals. Mammals according to the present invention include dogs, cats, cows, goats, horses, sheep, pigs, rodents, rabbits, primates, humans, and the like, including mammals in utero. In one embodiment, humans are the preferred subject. Human subjects may be of any gender and at any stage of development.

[0240] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician, which includes one or more of the following: (1) Preventing disease; e.g., preventing a disease, condition, or disorder in an individual who is susceptible to the disease, condition, or disorder but who has not yet experienced or exhibited any pathology or symptomology; (2) inhibiting a disease; for example, inhibiting a disease, condition, or disorder (i.e., arresting (or slowing) the further development of the pathology or symptomology, or both) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder; and (3) Ameliorating a disease; for example, ameliorating a disease, condition, or disorder (i.e., reversing the pathology or symptomology, or both) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder.

[0241] Typically, the compound of the present invention is administered in an amount that is effective for treating the disease states as described herein.The compound of the present invention can be administered as compound itself or alternatively as pharmaceutically acceptable salt.For the purpose of administration and dosage, compound itself or its pharmaceutically acceptable salt will simply be referred to as the compound of the present invention.

[0242] The compounds of the present invention are administered by any suitable route, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the intended treatment. The compounds of the present invention can be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.

[0243] The compounds of the present invention can be administered orally, either by swallowing, so that the compound enters the gastrointestinal tract, or by using buccal or sublingual administration, by which the compound enters the blood stream directly from the mouth.

[0244] In another embodiment, the compound of the present invention can be administered parenterally, for example, directly into the bloodstream, muscle, or internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous.Suitable devices for parenteral administration include needle (including fine needle) injectors, needle-free injectors, and infusion techniques.

[0245] In another embodiment, the compounds of the present invention can be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the present invention can be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention can be administered rectally or vaginally. In another embodiment, the compounds of the present invention can be administered directly to the eye or ear.

[0246] Dosing regimens for compounds of the present invention or compositions containing the compounds are based on a variety of factors, including the species, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound used. Accordingly, dosing regimens can vary widely. In one embodiment, the total daily dose of a compound of the present invention is typically about 0.01 to about 100 mg / kg (i.e., mg of compound of the present invention per kg of body weight) for treatment of the indicated conditions discussed herein. In another embodiment, the total daily dose of a compound of the present invention is about 0.1 to about 50 mg / kg, and in another embodiment, about 0.5 to about 30 mg / kg. It is not uncommon to repeat the administration of a compound of the present invention multiple times per day (typically up to four times). Multiple doses per day can typically be used to increase the total daily dose, if desired.

[0247] Treatment Methods and Uses The compounds of the present invention can inhibit the activity of all of the KRAS G12C, KRAS G12D, and KRAS G12V receptors and may be useful in the treatment, prevention, suppression, and amelioration of diseases such as cancers, disorders, and conditions mediated by any of the KRAS G12C, KRAS G12D, and KRAS G12V receptors, or combinations thereof.

[0248] Cancers to be treated include squamous cell carcinoma, basal cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal (tract) cancer, kidney cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain tumor, gastric cancer, uterine cancer, bladder cancer including non-muscle invasive bladder cancer, hepatocellular carcinoma, breast cancer, and head and neck cancer.

[0249] Preferably, the compounds of the present invention may be useful for treating lung cancer, such as non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer, breast cancer, hematological cancer, gynecological cancer, prostate cancer, or skin cancer. See Mustachio, L., Targeting KRAS in Cancer: Promising Therapeutic Strategies, Cancers, 2021, 13, 1204.

[0250] More preferably, the compounds of the present invention may be useful for treating non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer.

[0251] Coadministration The compounds of the present invention can be used alone or in combination with one or more other therapeutic agents. The present invention provides any of the uses, methods or compositions as defined herein, in which the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used in combination with one or more other therapeutic anti-cancer agents discussed herein.

[0252] Administration of two or more compounds "in combination" means that all of the compounds are administered close enough in time to affect the treatment of the subject.Two or more compounds can be administered synchronously or sequentially, via the same or different administration routes, with the same or different administration schedules, with or without specific time limits, depending on the treatment regimen.In addition, synchronous administration can be achieved by mixing the compounds before administration, or by administering the compounds in separate dosage forms at the same time but at the same or different administration sites.Examples of "in combination" include, but are not limited to, "simultaneous administration," "co-administration," "synchronous administration," "sequential administration," and "administered synchronously."

[0253] The compound of the present invention and one or more other therapeutic agents can be administered as a fixed or non-fixed combination of active ingredients. The term "fixed combination" means that the compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents are both administered to a subject synchronously in a single composition or dosage. The term "non-fixed combination" means that the compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents are formulated as separate compositions or dosages so that they can be administered to a subject in need thereof synchronously or at different times with varying intervening time periods, such that such administration can result in effective levels of the two or more compounds in the subject's body.

[0254] Additional classes of chemotherapeutic agents that may be administered in combination with the compounds of the present invention include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle-inhibiting plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogesterones, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists; IL-2 receptor agonists (recombinant cytokines or agonists for cytokine receptors); and antisense oligonucleotides or oligonucleotide derivatives that inhibit the expression of genes involved in abnormal cell proliferation or tumor growth.

[0255] Other additional chemotherapy agents include taxanes or platinum agents as well as HER2-targeted agents, such as trastuzumab.

[0256] In another embodiment, such additional anticancer therapeutic agents include compounds derived from the following groups: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, spindle-inhibiting plant alkaloids, MCT4 inhibitors; MAT2a inhibitors; alk / c-Met / ROS inhibitors (including crizotinib or lorlatinib); mTOR inhibitors (including temsirolimus or gedatricisib); src / abl inhibitors (including bosutinib); cyclin-dependent kinase (CDK) inhibitors (including palbociclib, PF-06873600); erb inhibitors (including dacomitinib); PARP inhibitors (including talazoparib); SMO inhibitors (including glasdegib); EGFR T790M inhibitors; PRMT5 inhibitors; TGFβR1 inhibitors; growth factor inhibitors; cell cycle inhibitors, biological response modifiers; enzyme inhibitors; and cytotoxic agents.

[0257] In another embodiment, such additional anticancer therapeutic agents include, for example, antiangiogenic agents, including tyrosine kinase / vascular endothelial growth factor (VEGF) receptor (VEGFR) inhibitors (including sunitinib, axitinib, sorafenib, and tivozanib), TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (alpha-v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors. Preferred antiangiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (Inlyta™), SU14813 (Pfizer), and AG13958 (Pfizer). Additional antiangiogenic agents include vatalanib (CGP79787), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU14843 (Pfizer), AZD2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE941), tetrathiomolybdate (Coprexa™), AMG706 (Amgen), and VEGF inhibitors. Other antiangiogenic agents include Trap (AVE0005), CEP7055 (Sanofi-Aventis), XL880 (Exelixis), telatinib (BAY57-9352), and CP-868,596 (Pfizer). Other antiangiogenic agents include enzastaurin (LY317615), midostaurin (CGP41251), perifosine (KRX0401), teprenone (Selbex™), and UCN 01 (Kyowa Hakko).Other examples of anti-angiogenic agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™). Still further antiangiogenic agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Still further anti-angiogenic drugs include ABT510 (Abbott), aplatastat (TMI005), AZD8955 (AstraZeneca), incyclinide (Metastat™), and PCK3145 (Procyon).Still further anti-angiogenic agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengutide (EMD121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfi zer), Revimastat (BMS275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukraine™ (NSC631570), Vitaxin™ (MEDI522), and zoledronic acid (Zometa™).

[0258] In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from hormone drugs and antagonists.Examples include, for example, anti-estrogens and selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs), where anti-hormonal drugs act to regulate or inhibit hormone action on tumors, including tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifene (Fareston), and fulvestrant. Examples also include aromatase inhibitors, which inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, and include compounds such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, fluridil, apalutamide, enzalutamide, cimetidine, and goserelin.

[0259] In another embodiment, such additional anticancer therapeutic agents include compounds derived from signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases: signal transduction inhibitors (e.g., inhibiting the means by which regulatory molecules govern fundamental processes of cell proliferation, differentiation, and survival transmitted intracellularly). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK (including binimetinib (Mektovi™)), c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, BRAF (including encorafenib (Braftovi™)), Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, inhibitors of the WNT pathway, and multi-targeted kinase inhibitors.

[0260] In another embodiment, such additional anticancer therapeutic agents include docetaxel, paclitaxel, paclitaxel protein-bound particles, cisplatin, carboplatin, oxaliplatin, capecitabine, gemcitabine, or vinorelbine.

[0261] In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from epigenetic modulators, where examples include inhibitors of EZH2 (including PF-06821497), SMARCA4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2 or BCL6.

[0262] In another embodiment, such additional anti-cancer therapeutic agents include compounds that are immuno-oncology agents, including immunomodulatory agents.

[0263] In another embodiment, it is contemplated to combine with pattern recognition receptors (PRRs). PRRs are receptors that are expressed by cells of the immune system and recognize various molecules associated with pathogens and / or cell damage or death. PRRs are involved in both innate and adaptive immune responses. PRR agonists can be used to stimulate immune responses in subjects. There are several groups of PRR molecules, including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), and stimulator of interferon genes (STING) proteins.

[0264] The STING protein functions as both a cytosolic DNA sensor and an adaptor protein in type 1 interferon signal transduction. The terms "STING" and "stimulator of interferon genes" refer to any form of the STING protein, as well as variants, isoforms, and species homologs that maintain at least some of the activity of STING. Unless otherwise indicated, such as by specific reference to human STING, STING includes all mammalian species of native sequence STING, for example, human, monkey, and mouse STING are also known as -TMEM173.

[0265] As used herein, "STING agonist" refers to any molecule that, upon binding to STING, (1) stimulates or activates STING, (2) enhances, increases, promotes, induces, or prolongs the activity, function, or presence of STING, or (3) enhances, increases, promotes, or induces the expression of STING. STING agonists useful in any of the treatment methods, medicaments, and uses of the invention include, for example, nucleic acid ligands that bind to STING.

[0266] Examples of STING agonists useful in the treatment methods, medicaments, and uses of the invention include various immunostimulatory nucleic acids such as synthetic double-stranded DNA, synthetic cyclic dinucleotides (CDNs) such as cyclic di-GMP, cyclic-GMP-AMP (cGAMP), MK-1454, and ADU-S100 (MIW815), and small molecules such as WO2019027858, WO20180093964, WO2017175156, WO2017175147.

[0267] Therapeutic antibodies can have specificity for a variety of different antigens. For example, a therapeutic antibody can be directed against a tumor-associated antigen, and binding of the antibody to the antigen promotes the death of cells expressing the antigen. In another example, a therapeutic antibody can be directed against an antigen on an immune cell, and binding of the antibody prevents downregulation of the activity of the cells expressing the antigen (and thereby promotes the activity of the cells expressing the antigen). In some situations, a therapeutic antibody can function through multiple different mechanisms (e.g., it can both i) promote the death of cells expressing the antigen and ii) prevent the antigen from causing downregulation of the activity of immune cells in contact with the cells expressing the antigen).

[0268] In another embodiment, such additional anti-cancer therapeutics include antibodies that may be blocking or inhibitory at the target: CTLA-4 (including ipilimumab or tremelimumab), PD-1 or PD-L1 (including atezolizumab, avelumab, cemiplimab, durvalumab, nivolumab, sasanlimab, or pembrolizumab), LAG-3, TIM-3, or TIGIT.

[0269] In another embodiment, such additional anti-cancer therapeutic agents include antibodies that are agonists of 4-1BB, OX40, GITR, ICOS, or CD40.

[0270] In another embodiment, the anti-cancer treatment may be a CAR-T-cell therapy.

[0271] Examples of therapeutic antibodies include anti-OX40 antibodies, anti-4-1BB antibodies, anti-HER2 antibodies (including anti-HER2 antibody-drug conjugates (ADCs)), bispecific anti-CD47 / anti-PD-L1 antibodies, and bispecific anti-P-cadherin / anti-CD3 antibodies. Examples of cytotoxic drugs that can be incorporated into ADCs include anthracyclines, auristatins, dolastatins, combretastatins, duocarmycins, pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, enediynes, geldanamycin, maytansine, puromycin, taxanes, vinca alkaloids, camptothecin, tubulysin, hemiasterlin, spliceostatin, pladienolide, and stereoisomers, isosteres, analogs, or derivatives thereof. Exemplary immunomodulatory agents that can be incorporated into ADCs include ganciclovir, etanercept, tacrolimus, sirolimus, voclosporin, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, glucocorticoids and analogs thereof, cytokines, stem cell growth factors, lymphotoxins, tumor necrosis factors (TNF), hematopoietic factors, interleukins (e.g., interleukin-1 (IL-1), IL-2), and the like. IL-2, IL-3, IL-6, IL-10, IL-12, IL-15, IL-18, and IL-21), colony stimulating factors (e.g., granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF)), interferons (e.g., interferon-alpha, -beta, and -gamma), stem cell growth factors known as "S1 factors," erythropoietin, and thrombopoietin, or combinations thereof.

[0272] Additional examples of therapeutic antibodies can include the following antigens, with exemplary antibodies directed to those antigens also included below (in brackets / parenthesis after the antigen). The following antigens may also be referred to herein as "target antigens" or the like. Target antigens for therapeutic antibodies herein include, for example: 4-1BB (e.g., utomilumab); 5T4; A33; alpha-folate receptor 1 (e.g., mirvetuximab soravtansine); Alk-1; BCMA [see, e.g., US9969809]; BTN1A1 (see, e.g., WO2018222689); CA-125 (e.g., abagomomab); carboanhydrase IX; CCR2; CCR CCR4 (e.g., mogamulizumab); CCR5 (e.g., leronlimab); CCR8; CD3 [e.g., blinatumomab (CD3 / CD19 bispecific), CD3 / P-cadherin bispecific, CD3 / BCMA bispecific], CD19 (e.g., blinatumomab, MOR208); CD20 (e.g., ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, ublituximab); CD22 (inotuzumab CD25; CD28; CD30 (e.g., brentuximab vedotin); CD33 (e.g., gemtuzumab ozogamicin); CD38 (e.g., daratumumab, isatuximab); CD40; CD40L; CD44v6; CD47 (e.g., Hu5F9-G4, CC-90002, SRF231, B6H12); CD52 (e.g., alemtuzumab); CD56; C D63; CD79 (e.g., polatuzumab vedotin); CD80; CD123; CD276 / B7-H3 (e.g., omburtamab); CDH17; CEA; ClhCG; CTLA-4 (e.g., ipilimumab, tremelimumab), CXCR4; desmoglein 4; DLL3 (e.g., rovalpituzumab tesirin); DLL4; E-cadherin; EDA; EDB; EFNA4; EGFR (e.g., cetuximab, depatuxizumab mafodotin, necitumumab, panitumumab); EGFRvIII; endosialin; EpCAM (e.g., oportuzumab monatoxin); FAP; fetal acetylcholine receptor;FLT3 (see, e.g., WO2018 / 220584); GD2 (e.g., dinutuximab, 3F8); GD3; GITR; GloboH; GM1; GM2; HER2 / neu [e.g., margetuximab, pertuzumab, trastuzumab; ado-trastuzumab emtansine, trastuzumab duocarmazine, [see US8828401]; HER3; HER4; ICOS; IL-10; ITG-AvB6; LAG-3 (e.g., leratolimab); Lewis-Y; LG; Ly-6; M-CSF [see US7326414]; MCSP; mesothelin; MUC1; MUC2; MUC3; MUC4; MUC5AC; MUC5B; MUC7; MUC16; Notch1; Notch3; Nectin-4 (e.g., enfortumab vedotin) OX40 [see US7960515]; P-cadherin [see WO2016 / 001810]; PCDHB2; PDGFRA (e.g., olaratumab); plasma cell antigen; polySA; PSCA; PSMA; PTK7 [see US9409995]; Ror1; SAS; SCRx6; SLAMF7 (e.g., elotuzumab); SHH; SIRPa (e.g., , ED9, Effi-DEM); STEAP; TGF-beta; TIGIT; TIM-3; TMPRSS3; TNF-alpha precursor; TROP-2 (e.g., sacituzumab govitecan); TSPAN8; VEGF (e.g., bevacizumab, brolucizumab); VEGFR1 (e.g., ranibizumab); VEGFR2 (e.g., ramucirumab, ranibizumab); Wue-1;

[0273] Exemplary imaging agents that may be included in ADCs include fluorescein, rhodamine, lanthanide fluorophores, and their derivatives or radioisotopes bound to chelators. Examples of fluorophores include, but are not limited to, fluorescein isothiocyanate (FITC) (e.g., 5-FITC), fluorescein amidite (FAM) (e.g., 5-FAM), eosin, carboxyfluorescein, erythrosine, Alexa Fluor® (e.g., Alexa 350, 405, 430, 488, 500, 514, 532, 546, 555, 568, 594, 610, 633, 647, 660, 680, 700, or 750), carboxytetramethylrhodamine (TAMRA) (e.g., 5,-TAMRA), tetramethylrhodamine (TMR), and sulforhodamine (SR) (e.g., SR101). Examples of chelating agents include, but are not limited to, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid (deferoxamine), diethylenetriaminepentaacetic acid (DTPA), and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) (BAPTA).

[0274] Exemplary therapeutic proteins that may be included in an ADC include toxins, hormones, enzymes, and growth factors.

[0275] Exemplary biocompatible polymers that may be incorporated into ADCs include water-soluble polymers such as polyethylene glycol (PEG) or its derivatives, and zwitterion-containing biocompatible polymers (e.g., phosphorylcholine-containing polymers).

[0276] Exemplary biocompatible polymers that may be incorporated into ADCs include antisense oligonucleotides.

[0277] The present invention also relates to the use of radiation in combination with any of the anti-cancer therapeutic agents administered herein. More specifically, the compounds of the present invention can be administered in combination with additional treatments such as radiation therapy and / or chemotherapy.

[0278] These agents and compounds of the present invention can be combined with a pharmaceutically acceptable vehicle such as saline, Ringer's solution, dextrose solution, and the like. The particular administration regimen, i.e., dosage, timing, and repetition, will depend on the particular individual and their medical history.

[0279] kit Another aspect of the present invention provides a kit comprising a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. The kit may include a diagnostic or therapeutic agent in addition to the compound of the present invention or a pharmaceutical composition thereof. The kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes a compound or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes a compound or a pharmaceutical composition thereof and one or more therapeutic agents.

[0280] In another embodiment, the present invention comprises a kit suitable for use in carrying out the treatment methods described herein.In one embodiment, the kit contains a first dosage form containing one or more compounds of the present invention in an amount sufficient to carry out the method of the present invention.In another embodiment, the kit comprises one or more compounds of the present invention in an amount sufficient to carry out the method of the present invention, and a container for dosage amounts and a container for dosage amounts.

[0281] Synthesis method The compounds of the present invention can be synthesized by synthetic routes, including processes similar to those well known in the chemical arts, particularly in light of the description contained herein.Starting materials are generally available from commercial suppliers or can be prepared using methods well known to those skilled in the art.Many of the compounds used herein are related to or can be derived from compounds that have one or more scientific importance or commercial needs.Therefore, such compounds can be one or more of: 1) commercially available; 2) reported in literature; or 3) prepared by those skilled in the art from other commercially available materials using materials reported in literature.

[0282] For illustrative purposes, the reaction schemes shown below provide potential routes for synthesizing the compounds of the present invention, as well as key intermediates. For more detailed descriptions of the individual reaction steps, see the Examples section below. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compounds of the present invention. While specific starting materials and reagents are discussed below, other starting materials and reagents can be substituted to obtain one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0283] Those skilled in the art will recognize that the experimental conditions depicted in the following schemes are illustrative of conditions suitable for carrying out the transformations shown, and that it may be necessary or desirable to vary the exact conditions used to prepare the compounds of the invention. Furthermore, it will be recognized that it may be necessary or desirable to carry out the transformations in a different order than that depicted in the schemes, or to modify one or more of the transformations to obtain the desired compounds of the invention.

[0284] In preparing the compounds of the present invention, it is noted that some of the preparative methods useful for preparing the compounds described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls, etc. in precursors of the compounds of the present invention). The need for such protection will vary depending on the nature of the remote functional group and the conditions of its preparation method. One skilled in the art will readily determine the need for such protection. The use of such protection / deprotection methods is also within the skill in the art. For a review of protecting groups and their uses, see March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Edition.

[0285] For example, if a compound contains an amine or carboxylic acid functional group, such a functional group, if left unprotected, may interfere with reactions at other sites of the molecule. Therefore, such functional groups can be protected with a suitable protecting group (PG) that can be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include protecting groups commonly used in peptide synthesis (such as N-tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids), which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functional groups in the compounds of the present invention.

[0286] General Experimental Details 1 H and 19 F nuclear magnetic resonance (NMR) spectra were recorded on a Bruker XWIN-NMR (400 or 700 MHz) spectrometer. 1 H and 19 F resonances are reported in parts per million (ppm) downfield from tetramethylsilane. 1H NMR data are reported as multiplets (e.g., s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; dd, double doublet; dt, triple doublet; br s, broad singlet). For spectra obtained in CDCl3, DMSO-d6, and CD3OD, residual protons (7.27, 2.50, and 3.31 ppm, respectively) were used as internal references. All observed coupling constants, J, are reported in hertz (Hz). Exchangeable protons are not always observed.

[0287] Optical rotations were determined on a Jasco P-2000 or Rudolph Autopol IV polarimeter. All final compounds were purified to ≥95% purity unless otherwise specified. When the absolute stereochemistry was known, the (R,S) label was used. When the absolute stereochemistry was not known, the software-generated name was modified to include the prefixes (+)- and (-)- according to the optical rotation, and (R) to indicate the relative configuration. * / S * ) signs are used.

[0288] Mass spectra, MS (m / z), were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Where relevant, and unless otherwise stated, the m / z data presented are isotopic. 19 F, 35 Cl, 79 Br and 127 It's about I.

[0289] The names are generated and written in Perkin Elmers Chemdraw 18.0.0.231 as specified by IUPAC (International Union of Pure and Applied Chemistry). The naming conventions provided by Perkin Elmers Chemdraw 18.0.0.231 are well known to those skilled in the art, and are believed to be generally compatible with the IUPAC (International Union for Pure and Applied Chemistry) recommendations for organic chemical nomenclature and the CAS Index rules.

[0290] Abbreviation aq is aqueous; Bn is benzyl; Boc is tert-butoxycarbonyl; BocO is di-tert-butyl dicarbonate; br is broad; tBu is tert-butyl; °C is the temperature in degrees Celsius; CDCl3 is deuterated chloroform; δ is the chemical shift; d is a double line; dd is double doublet; ddd is a double double of a double line; dt is the triplet doublet; DCM is dichloromethane; DCM is methylene chloride; DIPEA is N-ethyldiisopropylamine, also known as N,N-diisopropylethylamine; DMAP is 4-dimethylaminopyridine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; DMSO-d6 is deuterated dimethyl sulfoxide; ee is the enantiomeric excess; ESI is electrospray ionization; Et2O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Et3N is triethylamine; g is grams; HPLC is high pressure liquid chromatography; hr is time; L is liters; LCMS is liquid chromatography mass spectrometry; m is a multiplet; M is moles; m-CPBA is 3-chloroperbenzoic acid; MeOD_d4 is deuterated methanol; MeOH is methanol; 2-MeTHF is 2-methyltetrahydrofuran; mg is milligrams; MHz is megahertz; min is minutes; mL is milliliters; mmol is millimole; mol is moles; MOM is a methoxymethyl ether group; MS(m / z) is the mass spectrum peak; NMR is nuclear magnetic resonance; Pd / C is palladium on carbon; Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); pH is the hydrogen ion potential; ppm is parts per million; psi is pounds per square inch; q is a quartet; rpm is revolutions per minute; rt is room temperature; RT is retention time; RuPhos Pd G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS Number: 1445085-77-7); s is a singlet; SEMCl is 2-(trimethylsilyl)ethoxymethyl chloride; SEM is 2-(trimethylsilyl)ethoxymethyl; SFC is supercritical fluid chromatography; t is the triple line; TBAF is tert-butylammonium fluoride; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin layer chromatography; TMSCN is trimethylsilyl cyanide; TsCl is p-toluenesulfonyl chloride; μL is microliter; μmol is micromole.

[0291] The schemes set forth below are intended to provide an overview of the methods used in the preparation of compounds of the present invention. Some of the compounds of the present invention contain a single chiral center. In the following schemes, general methods for preparing compounds are shown in either racemic or enantiomerically enriched form. It will be apparent to those skilled in the art that all synthetic transformations can be carried out in exactly the same manner regardless of whether the material is enantiomerically enriched or racemic. Furthermore, resolution into the desired optically active material can be carried out at any desired point in the sequence using well-known methods, such as those described herein and in the chemical literature.

[0292] General method: Unless otherwise stated, the variables in Schemes I-III have the same meanings as defined herein.

[0293] [ka]

[0294] As illustrated in Scheme I, 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (CAS#: 2454396-80-4) can be treated with an amine in the presence of an effective base (e.g., DIPEA) in a suitable solvent (e.g., DCM) to afford an adduct via a SnAr reaction at the 4-chloro position. A Suzuki reaction at the 7-chloro position incorporates a naphthol group using a palladium catalyst (e.g., CataCXium A Pd G3) and a base (e.g., KCO or KPO) in a suitable solvent, such as dioxane / water. Oxidation of the 2-thiomethyl group to a sulfone can be achieved using an oxidizing agent (e.g., mCPBA) in a solvent (e.g., DCM). The resulting sulfone group can be displaced with an alcohol nucleophile (e.g., ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, CAS#2097518-76-6) using a suitable base (e.g., LHMDS) in a suitable solvent (e.g., DCM). In some cases, the penultimate intermediate may contain a protecting group, which can be removed by an additional step in the synthetic sequence using conditions known in the art (March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition or Protecting Groups, 10 Georg Thieme Verlag, 1994). Compounds at each step can be purified by standard techniques, such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0295] [ka]

[0296] As illustrated in Scheme II, 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (CAS# 2454396-80-4) can be treated with an amine in a suitable solvent (e.g., DCM) in the presence of an effective base (e.g., DIPEA) to afford an adduct via a SnAr reaction at the 4-chloro position. A second SnAr reaction at the 2-chloro position incorporates an alcohol nucleophile (e.g., ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, CAS# 2097518-76-6) in a suitable solvent (e.g., 1,4-dioxane) in the presence of a base (e.g., DIPEA) at elevated temperatures (e.g., 90°C). A Suzuki reaction at the 7-chloro position incorporates the naphthol group using a palladium catalyst (such as Pd(OAc)2 / dppf) and a base (such as NaOH) in a suitable solvent such as CH3CN / water.

[0297] [ka]

[0298] As illustrated in Scheme III, 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (CAS# 2454491-14-4) can be treated with a placeholder amine (such as 2-(((tert-butyldimethylsilyl)oxy)methyl)piperidine) in the presence of an effective base (such as DIPEA) in a suitable solvent (such as DCM) to afford the adduct via a SnAr reaction at the 4-chloro position. A Suzuki reaction at the 7-chloro position incorporates a naphthol group using a palladium catalyst (such as CataCXium Pd G3) and a base (such as K3PO4) in a suitable solvent (such as THF / water). Oxidation of the thiomethyl group to the sulfone can be achieved using an oxidizing agent (such as buffered Oxone) in a solvent (such as acetone / water). A second SnAr reaction at the 2-sulfonyl position incorporates an alcohol nucleophile (such as ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol) in the presence of a base (such as LiOTMS) in a suitable solvent (such as CHCN) at elevated temperatures (such as 80 °C). The placeholder amine can be removed using a base (such as NaOH) in the presence of a fluoride source (such as TBAF) at elevated temperatures (such as 60 °C). The desired C4 amine is then added in the presence of 2-chloro-1-methylpyridinium iodide and an effective base (such as DIPEA) in a suitable solvent (such as 2-MeTHF) to afford the adduct via a SnAr reaction at the 4-oxo position.

[0299] [ka]

[0300] As illustrated in Scheme IV, 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine can be treated with an aminoalcohol (cyclic or acyclic) in the presence of an effective base (e.g., DIPEA) in a suitable solvent (e.g., DCM) to afford an adduct via a SnAr reaction at the 4-chloro position. Suzuki reaction at the 7-chloro position incorporates a naphthol or naphthyl group using a palladium catalyst (e.g., RuPhos Pd G3) and a base (e.g., KCO3 or K3PO4) in a suitable solvent such as dioxane / water. Oxidation of the 2-thiomethyl group to a sulfone can be achieved using an oxidizing agent (e.g., Oxone) in a buffered aqueous solvent containing NaHCO3 and either acetone or methyl ethyl ketone. The resulting sulfone group can be displaced with an alcohol nucleophile (such as ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol, CAS# 2097518-76-6) using a suitable base (such as LHMDS or LiOTMS) in a suitable solvent (such as CHCN). In some cases, the penultimate intermediate may contain a protecting group, which can be removed by an additional step in the synthetic sequence using conditions known in the art (March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition or Protecting Groups, 10 Georg Thieme Verlag, 1994). Compounds at each step can be purified by standard techniques, such as column chromatography, crystallization, reverse-phase HPLC, or SFC.

[0301] Variable R in Schemes I-III 1 is the same as defined in embodiments E1 to E31 herein.

[0302] The variable R in Schemes I-III represents one to four substituents selected from the group consisting of —OH, halogen, CN, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, and C2-C3 alkynyl, as defined in the embodiments and claims herein.

[0303] The variable R' in Schemes I-III can be, but is not limited to, H or C1-C5 alkyl, and two R's together can form a ring, and R's are not part of the definition of the claims herein.

[0304] Amines as presented in Schemes I-III

[0305] [ka] is R as defined in embodiments E1 to E31. 2 is a general structure corresponding to the definition of R 2 teeth,:

[0306] [ka] is.

[0307] Variable R in Scheme IV 1 is the same as defined in embodiments E32 to E60 herein.

[0308] The variable R in Scheme IV represents one to four substituents selected from the group consisting of —OH, halogen, CN, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, and C2-C3 alkynyl, as defined in the embodiments and claims herein.

[0309] The variable R' in Scheme IV can be, but is not limited to, H or C1-C5 alkyl, two R's can be joined to form a ring, and R's are not part of the claims herein.

[0310] The amino alcohol in Scheme IV is E32, where R 2 and R 5 are representative generic moieties that can form the desired tetracyclic ring structure as defined in embodiments such as E39, (which may be taken together to form a 4-8 membered heterocycloalkyl) and E39. Amino alcohols are represented by R 2 and R 5 may be acyclic moieties that can form the desired tricyclic ring structure as defined in embodiments such as E32, where E is not taken together to form a 4-8 membered heterocycloalkyl.

[0311] The synthetic intermediates generally defined in the above schemes are useful for preparing compounds of the invention, and the synthesis of such non-commercially available intermediates is provided as a further aspect of the invention.

[0312] Preparation example: Preparation Example 1: (1R,5R,6R)-3-Azabicyclo[3.2.1]octan-6-ol

[0313] [ka] Chiral separation of 1a (700 g, 3.2 mol), prepared as described in J. Med. Chem. 2012, 55(10), 4605, was carried out using chiral SFC (AS-H column, 95 / 5 CO2 / EtOH mobile phase, 2 mL injection volume, 2.5 mL / min flow rate, 35 °C). Retention times using the preparative AS-H column were 3.01 min for peak 1 and 3.70 min for peak 2 with baseline resolution. Peak 1 material had an er ratio of 100 / 0. Peak 1 material from the chiral separation (1b, 294 g, 1.37 mol) was dissolved in EtOH (3.2 L) and BocO (486 g, 2.23 mol) was added, followed by Pd10% / C (10 g). The reaction was stirred at 25 °C under an atmosphere of H2 (60 psi) for 18 h. Fresh Pd / C (5 g) was then added, and stirring under H2 (60 psi) was continued for 30 min. HPLC showed that all benzyl groups had been removed. The catalyst was filtered off, and most of the EtOH was removed in vacuo to give a yellow oil. Heptane (500 mL) was added, and the mixture was co-evaporated to remove as much EtOH as possible. The yellow residue was dissolved in 2-MeTHF (1.8 L) and cooled in an ice-water bath. When the internal temperature was below 5 °C, N,N-dimethylethylenediamine (105 mL, 0.956 mol) was added to quench the excess Boc2O. After the addition, the reaction was warmed to room temperature and stirred for 45 min. The reaction was re-cooled in an ice bath, and 1 N HCl (800 mL) was added to pH 2, maintaining the internal temperature below 20 °C. The layers were separated, and the aqueous layer was extracted with 2-MeTHF (1 x 300 mL). The combined organic extracts were washed with saturated NaHCO3, brine, and dried over MgSO4. The solvent was removed to give a yellow oil. Co-evaporation with heptane (250 mL) gave 286 g of crude oil with 89% purity by HPLC. Heptane (1.1 L) was added to the oil, and the mixture was cooled in an ice-water bath. When the internal temperature reached 9 °C, the mixture became cloudy. A few seed crystals were added, and the mixture was allowed to warm slowly to room temperature overnight. The solid that formed was collected by filtration and washed with a small amount of cold heptane.After drying under vacuum, tert-butyl (1R,5R)-6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (1c, 237 g, 77%, 97.4% pure by HPLC) was obtained as a white solid. A solution of 1c (5.0 g, 22 mmol) in MeOH (100 mL) was cooled in an ice bath. NaBH (924 mg, 24.4 mmol) was added, and the reaction was stirred at 0 °C for 10 min. The ice bath was removed, and the reaction was stirred at room temperature for 1 h. Methanol was removed in vacuo, and the resulting residue was partitioned between saturated aqueous NaHCO and EtOAc. The aqueous layer was further extracted with EtOAc, and the combined organic extracts were dried over NaSO and concentrated to give 5.5 g of the Boc-protected alcohol as a white solid. The yield was slightly greater than 100% due to the presence of residual EtOAc in the sample. 1 H NMR (400 MHz, chloroform-d) δ = 4.30 - 4.18 (m, 2H), 3.81 (br d, J = 12.2 Hz, 1H), 2.93 (br d, J = 12.5 Hz, 1H), 2.87 (dd, J = 1.2, 13.2 Hz, 1H), 2.29 (ddd, J = 7.0, 10.6, 13.9 Hz, 1H), 2.14 (br s, 2H), 1.69 - 1.62 (m, 1H), 1.59 - 1.53 (m, 1H), 1.48 (s, 9H), 1.46 - 1.41 (m, 1H), 1.15 (td, J = 2.8, 14.0 Hz, 1H). To a solution of the Boc-protected alcohol (5.0 g, 22 mmol) in DCM (5 mL) was added HCl in dioxane (4N 25 mL, 100 mmol). Gas evolution occurred immediately. The reaction was stirred at room temperature for 5 minutes, and a white precipitate formed. After an additional hour, the reaction was diluted with heptane and the white solid was collected by filtration. The solid was dried under high vacuum overnight to give (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol HCl salt, Preparation 1 (3.5 g, 97%) as a white powder. 1H NMR (400 MHz, D2O) δ = 4.63 - 4.54 (m, 1H), 3.48 (dd, J = 2.6, 12.6 Hz, 1H), 3.24 (s, 2H), 3.16 (br d, J = 12.7 Hz, 1H), 2.50 - 2.38 (m, 3H), 1.77 (d, J = 2.2 Hz, 2H), 1.53 - 1.45 (m, 1H); MS: [M+H] + 128.1.

[0314] Preparation Example 2-(+) and Preparation Example 2-(-): tert-butylethyl-(1R * ,5R * ,6R * )-6-hydroxy-8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate and tert-butylthyl-(1S * ,5S * ,6S * )-6-Hydroxy-8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylate

[0315] [ka] The racemic mixture of (+ / -) 2a was prepared as described in US Patent No. 2013 / 0079321. The optical mixture of (+ / -) 2a (3.80 g, 16.6 mmol) was treated with BocO (5.7 g, 26 mmol) and Pd(OH) on carbon (4 g) in EtOH (40 mL) at 50 °C under 30 psi H2 overnight. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was suspended in petroleum ether (30 mL), stirred for 1 h, and filtered. The filter cake was dried in vacuo to give the racemic mixture of (+ / -) 2b (3.4 g, 87%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 4.32 (ddd, J = 4.1, 6.0, 10.6 Hz, 1H), 4.14 (br s, 1H), 4.05 - 3.87 (m, 2H), 3.56 (br s, 1H), 3.08 (br s, 2H), 2.96 (br d, J = 12.9 Hz, 1H), 2.38 (ddd, J = 7.9, 10.8, 12.4 Hz, 1H), 1.36 (s, 9H), 1.21 - 1.13 (m, 1H), MS: 130 [M+H-Boc] + .

[0316] The racemic mixture of (+ / -)2b was resolved using chiral SFC as follows: 850 mg of (+ / -)2b was separated into its enantiomers using chiral SFC (Chiralpak IG SFC 5 um 21 x 250 mm column, 90 / 10 CO2 / MeOH isocratic mobile phase, 120 bar, flow rate 70 mL / min). Peak 1 = Preparation Example 2-(+): [α] D 22 +10.7(c 0.3, MeOH), 392 mg, >99.0%ee. Peak 2 = Preparation Example 2-(-): [α] D 22 -27.1(c 0.1, MeOH), 294mg, 98%ee.

[0317] Preparation Example 3: (S)-2-(1-acetylpiperazin-2-yl)acetonitrile

[0318] [ka] Compound 3a was prepared as described in J. Med. Chem. 2020, 63(13), 6679. To compound 3a (4.9 g, 22 mmol) and EtN (3.3 g, 33 mmol) in DCM (50 mL) was added acetic anhydride (2.44 g, 23.9 mmol) at 0 °C. After stirring at 20 °C for 1 h, LCMS showed the formation of the product. The mixture was washed with saturated aqueous NaHCO (100 mL × 2), and the organic phase was washed with saturated aqueous citric acid (100 mL × 2), brine (100 mL), and dried over NaSO. After filtration and concentration, 3b (6.2 g) was obtained as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 4.66 (s, 1H), 3.87 (d, J = 13.8 Hz, 2H), 3.47 (d, J = 195.2 Hz, 1H), 3.11 - 3.02 (m, 2H), 2.75 (s, 3H), 2.05 (s, 3H), 1.43 (s, 9H); MS: [M+H+Na] + 290. To a solution of 3b (5.80 g, 21.7 mmol) in DCM (40 mL) was added HCl in dioxane (15 mL, 4 M) and the mixture was stirred for 5 h at 25 °C. LCMS showed the formation of the product and a white solid precipitated from solution. The solid was filtered and dried to give (S)-2-(1-acetylpiperazin-2-yl)acetonitrile HCl salt, Preparation 3 (5 g, crude yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (d, J = 67.0 Hz, 2H), 4.83 (d, J = 149.1 Hz, 1H), 4.20 (dd, J = 226.7, 14.2 Hz, 1H), 3.66 - 3.45 (m, 1H), 3.40 - 2.74 (m, 6H), 2.11 (d, J = 26.4 Hz, 3H), MS: 168 [M+H] + .

[0319] Preparation Example 4: (S)-2-(3-methylpyrrolidin-3-yl)acetonitrile

[0320] [ka] (R)-1-((benzyloxy)carbonyl)-3-methylpyrrolidine-3-carboxylic acid (4a, 0.700 g, 2.66 mmol) was dissolved in THF (10 mL). BH3·THF (1 M, 7.98 mL, 7.98 mmol) was added dropwise at 0 °C. The reaction was then warmed to 25 °C and stirred at 25 °C for 2 h. LCMS analysis indicated that 4a was consumed, and the desired alcohol 4b was observed. The reaction was quenched by the dropwise addition of MeOH (10 mL). The resulting solution was concentrated and purified using flash chromatography eluting with a gradient of 0–40% EtOAc in petroleum ether to afford 4b (600 mg, 90%) as a colorless oil. 1 H NMR (DMSO-d6, 400 MHz) δ 7.41-7.21 (m, 5H), 5.05 (d, 2H, J = 3.5 Hz), 3.59 (br d, 1H, J = 5.5 Hz), 3.2-3.4 (m, 4H), 3.12-2.93 (m, 1H), 1.94-1.73 (m, 1H), 1.65-1.44 (m, 2H), 0.98 (s, 3H), MS: 250.1 [M+H] + To a solution of 4b (600 mg, 2.41 mmol) in pyridine (20 mL) was added TsCl (551 mg, 2.89 mmol) portionwise at 0 °C. The solution was then warmed to 25 °C and stirred for 24 h. LCMS analysis indicated that 4b was consumed, and the desired product was observed. Pyridine was removed in vacuo, and the resulting residue was diluted with EtOAc (50 mL). The organic layer was washed with 1 N HCl (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give (R)-3-methyl-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.9 g) as a crude yellow solid, which was used directly in the next step. MS: 404.1 [M+H-56] +The crude (R)-3-methyl-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.41 mmol) from above was dissolved in CHCN (30 mL). TMSCN (836 mg, 8.43 mmol) and TBAF (1.0 M in THF, 8.43 mL, 8.43 mmol) were added. The resulting solution was heated at 100 °C for 16 h. LCMS analysis indicated that the tosylate was consumed, and the desired product was observed. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified using flash chromatography eluting with a gradient of 0–60% EtOAc in petroleum ether to give 4c (620 mg, 100%) as a colorless oil. 1 H NMR (DMSO-d6, 400 MHz) δ 7.46-7.25 (m, 5H), 5.06 (d, 2H, J = 2.9 Hz), 3.55-3.34 (m, 2H), 3.37-3.12 (m, 2H), 2.76-2.64 (m, 2H), 1.98-1.67 (m, 2H), 1.14 (d, 3H, J = 2.2 Hz). NMR shows evidence of restricted rotation about the N-Cbz bond, MS: 281.1 [M+H+Na] + To a solution of 4c (200 mg, 0.774 mmol) in MeOH (10 mL) was added 10% Pd / C (41 mg). The reaction was stirred at 25 °C under H (1 atm) for 4 h. LCMS analysis indicated that 4c was consumed and product was observed. The reaction mixture was filtered and the filtrate was concentrated to give (S)-2-(3-methylpyrrolidin-3-yl)acetonitrile, Preparation 4 (120 mg) as a colorless oil. 1 H NMR (CDCl3, 400 MHz) 3.83 (br s, 1H), 3.07 (t, 1H, J = 7.2 Hz), 2.86 (d, 1H, J = 11.0 Hz), 2.75 (d, 1H, J = 11.0 Hz), 2.43 (s, 2H), 1.6-1.8 (m, 2H), 1.26 (s, 3H), MS: 125.2 [M+H] + .

[0321] Preparation Example 5: (S)-2-(3-methylpiperidin-3-yl)acetonitrile

[0322] [ka] Compound 5a tert-Butylethyl (R)-3-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (900 mg, 3.92 mmol) was dissolved in pyridine (30 mL), cooled to 0 °C, and TsCl (1.5 g, 7.8 mmol) was added. The reaction mixture was warmed to 25 °C and stirred for 24 h. LCMS analysis indicated that 5a was consumed, and 5b was observed. Pyridine was removed in vacuo, and the residue was dissolved in EtOAc (50 mL). The organic layer was washed with 1 N aqueous HCl (2 × 30 mL). The organic phase was dried over anhydrous NaSO, filtered, and concentrated to give 5b (550 mg, 37%) as a gum. 1 H NMR (CDCl3, 400 MHz) 7.78 (d, 2H, J = 8.2 Hz), 7.35 (d, 2H, J = 8.1 Hz), 3.92 - 3.65 (m, 2H), 3.36 (br s, 1H), 3.31 - 3.18 (m, 2H), 3.04 (br d, 1H, J = 13.2 Hz, 2H), 2.46 (s, 3H), 1.70 - 1.54 (m, 1H), 1.52 - 1.46 (m, 1H), 1.44 (s, 9H), 1.33 - 1.23 (m, 2H), 0.86 (s, 3H), MS: 328.1 [M+H-56 tert-butyl] +To a solution of 5b (450 mg, 1.17 mmol) in CH3CN (20 mL) was added TMSCN (233 mg, 2.35 mmol) and TBAF (1 M in THF, 1.17 mL, 1.17 mmol). The solution was heated at 100 °C for 24 h. LCMS analysis indicated that 5b was consumed, and 5c was observed. CH3CN was removed in vacuo, and the residue was purified using flash chromatography using a gradient of 0 to 15% EtOAc in petroleum ether to give tert-butylethyl (S)-3-(cyanomethyl)-3-methylpiperidine-1-carboxylate, 5c (240 mg, 70%), as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 3.64 (s, 1H), 3.45 (s, 1H), 3.11 (s, 1H), 2.99 (d, J = 13.4 Hz, 1H), 2.31 (s, 2H), 1.76 - 1.51 (m, 4H), 1.46 (s, 9H), 1.10 (s, 3H). To a solution of 5c (200 mg, 0.839 mmol) in DCM (5 mL) was added HCl in dioxane (4N 1.0 mL, 4.0 mmol). The reaction was then stirred at 25 °C for 2 h. LCMS analysis indicated that 5c was consumed, and Preparation 5 was observed. The reaction was concentrated to afford (S)-2-(3-methylpiperidin-3-yl)acetonitrile HCl salt, Preparation 5 (116 mg, 79%) as a colorless oil, which was used for the next step without further purification. 1 H NMR (400 MHz, DMSO) δ = 9.11 (br s, 1H), 8.81 (br s, 1H), 3.57 (s, 3H), 3.38 (s, 2H), 2.91 (s, 2H), 2.75 (d, J = 4.7 Hz, 1H), 1.73 - 1.64 (m, 1H), 1.58 - 1.47 (m, 1H), 1.11 (s, 3H), MS: 139 [M+H] + .

[0323] Preparation Example 6: rac-(4-fluoropyrrolidin-3-yl)acetonitrile

[0324] [ka] To a solution of 6a (750 mg, 3.42 mmol) in pyridine (30 mL) was added TsCl (1.30 g, 6.84 mmol) at 0 °C. The reaction mixture was then warmed to 25 °C and stirred for 24 h. LCMS analysis showed that 6a was consumed, and 6b was observed. Pyridine was removed in vacuo, and the residue was diluted with EtOAc (50 mL). The organic layer was washed with 1 N aqueous HCl (2 × 30 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated to give 6b (670 mg, 52%) as a colorless gum. 1 H NMR (400 MHz, DMSO) δ 7.81 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 5.05 (d, J = 51.8 Hz, 1H), 4.03 (d, J = 7.1 Hz, 2H), 3.50 - 3.38 (m, 3H), 3.10 (dd, J = 11.4, 2.6 Hz, 1H), 2.71 - 3.38 (m, 1H), 2.43 (s, 3H), 1.38 (s, 9H). MS: 318.1 [M+H-56 tert-butyl] + To a solution of 6b (670 mg, 1.79 mmol) in CH3CN (10 mL) was added TMSCN (356 mg, 3.59 mmol) and TBAF (1 M in THF, 1.79 mL, 1.79 mmol). The solution was heated at 100 °C for 3 h. LCMS analysis showed that 6b was consumed, and 6c was observed. The solvent was removed in vacuo, and the residue was purified using flash chromatography eluting with a gradient of 0 to 30% EtOAc in petroleum ether. After concentration of pure fractions, 6c (330 mg, 69%) was obtained as a colorless gum. 1H NMR (400 MHz, CDCl3) δ 4.95 (dd, J = 52.0, 17.4 Hz, 1H), 3.70 - 3.51 (m, 3H), 3.29 (s, 1H), 2.68 (d, J = 7.7 Hz, 1H), 2.38 (dd, J = 26.2, 11.9 Hz, 2H), 1.40 (s, 9H), MS: 173.1 [M+H-56 tert-butyl] + To a solution of 6c (300 mg, 1.13 mmol) in DCM (25 mL) was added HCl in dioxane (4N 6.57 mL, 26.3 mmol). The mixture was stirred at 25° C. for 24 h. LCMS analysis showed that 6c had been consumed and Preparation 6 was detected. The solvent was removed to give rac-(4-fluoropyrrolidin-3-yl)acetonitrile hydrochloride, Preparation 6 (185 mg, 100%) as a colorless oil. 1 H NMR (400 MHz, DMSO) δ 10.27 - 9.66 (m, 2H), 5.31 - 5.10 (m, 1H), 3.60 - 3.36 (m, 3H), 3.08 (d, J = 5.7 Hz, 1H), 2.96 - 2.70 (m, 2H), 2.34 - 2.16 (m, 1H). MS: 129.1 [M+H] + .

[0325] Preparation 7: Trimethyl[2-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-yl]oxy}methoxy)ethyl]silane.

[0326] [ka] Compound 7a was prepared as described in WO2021041671. To a mixture of 7a (30.2 g, 88.7 mmol) and DIPEA (17.2 g, 133 mmol) in DCM / THF (500 mL / 50 mL) was added SEMCl (14.8 mg, 88.7 mmol). The mixture was stirred at 20° C. for 16 hours. The reaction was concentrated, and the residue was purified by flash chromatography eluting with 5% EtOAc in petroleum ether to give the SEM-protected intermediate as a yellow oil (21.5 g, 51%). 1 H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 7.71 - 7.66 (m, 1H), 7.48 (dd, J = 7.1, 1.1 Hz, 1H), 7.30 (dd, J = 8.2, 7.3 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 5.31 (s, 2H), 3.84 - 3.71 (m, 2H), 1.21 - 1.15 (m, 21H), 1.00 - 0.94 (m, 2H), -0.00 (s, 9H), MS: 471 [M+H] + The SEM-protected intermediate (21.5 g, 45.7 mmol) was dissolved in DCM (300 mL). DIPEA (11.8 g, 91.3 mmol) was added, and the reaction was cooled to −45° C. TfO (19.3 g, 68.5 mmol) was added dropwise, and the reaction was stirred at −45° C. for 1 h. Analysis by TLC (5% EtOAc in petroleum ether) indicated completion of the reaction. The reaction mixture was poured into H2O (200 mL), and the aqueous layer was extracted with DCM (2 × 200 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography eluting with 5% EtOAc in petroleum ether to give 7b (26.8 g, 97%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (t, J = 6.9 Hz, 2H), 7.45 - 7.40 (m, 2H), 7.30 (d, J = 2.2 Hz, 1H), 5.33 (s, 2H), 3.86 - 3.74 (m, 2H), 1.16 (d, J = 5.9 Hz, 21H), 1.01 - 0.93 (m, 2H), 0.00 (s, 9H). To a mixture of 7b (6.00 g, 9.95 mmol) was added bis(pinacolato)diboron (5.05 g, 19.9 mmol) and cesium pivalate (4.66 g, 19.9 mmol) in dioxane (100 mL). Pd(dppf)Cl2 (728 mg, 0.995 mmol) was added, and the mixture was stirred at 110 °C under N2 for 48 h. LCMS analysis indicated the formation of the product. The mixture was cooled and concentrated. The residue was purified by flash chromatography eluting with a gradient of 10-30% DCM in petroleum ether to give trimethyl[2-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-yl]oxy}methoxy)ethyl]silane, Preparation 7 (2.58 g, 45%) as an orange oil. 1 H NMR (400 MHz, CDCl3) δ 7.71 - 7.66 (m, 2H), 7.46 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 5.32 (s, 2H), 3.87 - 3.69 (m, 2H), 1.43 (s, 12H), 1.15 (s, 21H), 1.01 - 0.95 (m, 2H), 0.00 (s, 9H), MS: 581 [M+H] + .

[0327] Preparation 8: (7,8-Difluoro-3-hydroxynaphthalen-1-yl)boronic acid.

[0328] [ka] The compound 1-(6-bromo-2,3-difluorophenyl)ethan-1-one (8a) (7.39 g, 31.4 mmol) was dissolved in DMF (79 mL). Pd(OAc) (706 mg, 3.14 mmol), (tert-Bu)P-HBF (1.82 g, 6.29 mmol), and LiF (4.89 mg, 189 mmol) were added, followed by tert-butyltyl((1-methoxyvinyl)oxy)dimethylsilane (18.4 g, 97.5 mmol). N was bubbled through the mixture for 10 minutes, and the reaction was heated at 70 °C for 30 minutes. The reaction was cooled to room temperature, and HO (50 mL) and EtOAc (100 mL) were added. The layers were separated, and the aqueous layer was extracted with another portion of EtOAc (100 mL). The combined organic extracts were washed with brine (5 × 50 mL) and concentrated. The residue was dissolved in EtO (100 mL), and heptane (200 mL) was added, followed by removal of heptane to azeotropically remove residual DMF. The resulting residue was purified using flash chromatography eluting with a gradient of 0 to 100% EtOAc in heptane to afford 8b (6.24 g, 87%) as an oil. 1 H NMR (400 MHz, CDCl3) δ 7.18 (dt, J = 9.5, 8.3 Hz, 1H), 6.97 (ddd, J = 8.4, 4.4, 1.7 Hz, 1H), 3.77 (s, 2H), 3.68 (s, 3H), 2.62 (d, J = 3.8 Hz, 3H). To a solution of 8b (6.24 g, 27.3 mmol) in THF (273 mL) at −78° C. was added LHMDS (1 M in THF 49.2 mL, 49.2 mmol) dropwise. The reaction turned red and was stirred for 5 min, after which the −78° C. bath was replaced with an ice bath. After 15 min, the reaction was complete based on LCMS analysis and was quenched by the addition of 2 M HCl (100 mL). EtOAc (100 mL) was added and stirring continued for several minutes. The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (50 mL) and dried over sodium sulfate to give 8c (4.91 g, 91%) as a red solid, which was used in the next step without further purification. A solution of MeOH (125 mL) was cooled to 0 °C, and acetyl chloride (37.3 g, 476 mmol) was added dropwise. After a slight exotherm, the reaction reached 0 °C again. A solution of 8c (4.91 g, 25.0 mmol) in MeOH (50 mL) was then added. The reaction was charged to a reflux condenser and heated at 60 °C for 6.5 h. The reaction was concentrated and purified by flash chromatography using a gradient of 0 to 50% EtOAc in heptane to give 8d (3.78 g, 72%) as a beige solid. 1 H NMR (400 MHz, CDCl3) δ 7.43 (ddd, J = 9.2, 4.7, 1.8 Hz, 1H), 7.29 - 7.21 (m, 1H), 6.74 - 6.69 (m, 2H), 6.63 (d, J = 22.8 Hz, 1H), 3.88 (s, 3H). To a solution of 8d (3.78 g, 40.2 mmol) in DCM (90 mL) was added EtN (3.64 g, 36.0 mmol), N,N-Bis(trifluoromethylsulfonyl)aniline (7.71 g, 21.6 mmol), and DMAP (110 mg, 0.899 mmol). The reaction was stirred at room temperature for 8 h. Additional N,N-bis(trifluoromethylsulfonyl)aniline (1.29 g, 3.60 mmol) was added, and the reaction was stirred for an additional 11 h. The mixture was transferred to a separatory funnel and washed with 1 N NaOH (50 mL). The DCM layer was dried over Na2SO4, filtered, and purified by flash chromatography eluting with a gradient of 0 to 30% EtOAc in heptane to give 8e (6.7 g) as a solid in greater than theoretical yield. NMR indicated low purity, so the material was repurified using a 220 g Gold Isco column eluting with a gradient of 0 to 30% EtOAc in heptane to give 8e (5.18 g, 84%) as a beige solid. 1 H NMR (400 MHz, CDCl3) δ 7.53 (ddd, J = 9.2, 4.6, 1.9 Hz, 1H), 7.39 (td, J = 9.4, 7.3 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.14 (t, J = 2.1 Hz, 1H), 3.94 (s, 3H), MS: 210 [M+H-SO2CF3] +Ethanol (56 mL) and DIPEA (7.91 mL, 45.4 mmol) were added to a flask containing 8e (5.18 g, 15.1 mmol). Tetrahydroxydiborane (2.04 g, 22.7 mmol), 1,3-bis(diphenylphosphino)propanenickel(II) chloride (410 mg, 0.757 mmol), and triphenylphosphine (397 mg, 1.51 mmol) were added. Nitrogen was bubbled through the mixture for 5 minutes. The reaction was heated to 50 °C for 17 hours. LCMS showed one new peak that was more polar but not ionized. The mixture was diluted with EtOAc, and the product was extracted with 1 N NaOH (2 × 75 mL). The aqueous layer was acidified to pH = 1 with 6 N HCl and extracted with EtOAc (2 × 200 mL). The EtOAc was dried over Na2SO4 and concentrated to give (7,8-difluoro-3-hydroxynaphthalen-1-yl)boronic acid, Preparation 8 (3.6 g, 99%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 7.50 (ddd, J = 1.7, 4.7, 9.0 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), The B(OH)2 protons appeared as very broad peaks at 7.32 (dt, J = 7.9, 9.4 Hz, 1H), 7.14 (t, J = 2.1 Hz, 1H), and 3.93 (s, 3H) between 2 and 3 ppm depending on the concentration. 19 F NMR (376 MHz, CDCl3) δ = -141.77 (d, J = 18 Hz, 1F), -144.32 (d, J = 20 Hz, 1F).

[0329] Preparation 9: 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0330] [ka] Diisopropylamine (44.1 mL, 314 mmol) was dissolved in THF (300 mL) and the solution was cooled to −78° C. n-BuLi (2.5 M in hexanes, 114 mL, 286 mmol) was added over 15 minutes. The mixture was stirred for 45 minutes, and CAS: 82671-06-5 (30 g, 143 mmol) was added as a solution in THF (75 mL) over 6 minutes. The mixture was stirred at −78° C. for 30 minutes. CAS: 630-25-1 (69.8 g, 214 mmol) was added as a solution in THF (120 mL) over 10 minutes. The reaction was maintained at −78° C. for 2 hours, and the reaction was monitored by LCMS. A new peak with MH=242 (product − COH) was observed (negative ion mode). The mixture was quenched by adding water (120 mL). After stirring for 10 min at −78° C., the cooling bath was removed and 6 N HCl (90 mL) was added. The pH=1 aqueous layer was extracted with EtOAc (×3). The combined organic extracts were washed with brine (×2) and dried over MgSO4. Removal of the solvent gave a solid, which was stirred in heptane (250 mL) for 1 h to remove the tetrachloroethylene by-product. After filtration, the solid was washed with heptane (3×100 mL) and dried to give 9a, 30.3 g (73%) as a cream-colored solid. 19F NMR (376 MHz, DMSO) A solution of d-114.17.9a (30.2 g, 104 mmol) was suspended in DCM (420 mL). Oxalyl chloride (25.0 mL, 300 mmol) was added, followed by DMF (40 mg). After stirring for 2 hours, solids were still present and bubbles were still visible. The mixture was then stirred overnight (16 hours). After stirring for 16 hours at room temperature, the solids had dissolved and the mixture became a yellow solution. The solvent was removed in vacuo to give 33.3 g of the acid chloride as a light brown solid. In a separate 500 mL round-bottom flask, methylimidothiocarbamate sulfate (33.2 g, 177 mmol) was stirred with half-saturated Na2CO3 (80 mL) to give a clear solution. Et2O (60 mL) was added to the solution, which was then cooled to 10 °C. The acid chloride of 9a was then added slowly as a solution in EtOAc (120 mL), monitoring the temperature with an internal thermometer. A very slight exotherm was observed, and the ice bath was removed after the addition was complete. After warming to room temperature, the mixture was stirred for 30 minutes while monitoring the consumption of the acid chloride using negative mode ionization and waiting for the absence of additional 9a (hydrolysis occurred during LCMS to give the acid). After the reaction was complete, clean product formation was observed, and a new peak at M+H=360 was observed with a multiple halogen pattern. The mixture was partitioned between water (100 mL) and EtOAc (150 mL), and the aqueous layer was extracted with EtOAc (×2). The combined organic extracts were washed with saturated NaHCO3 (×1), dried over MgSO4, and concentrated to give 35 g (93%) of 9b as a light brown solid, which was used in the next reaction without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (br s, 1 H), 9.53 (br s, 1 H), 2.40 (s, 3 H). 9b (14.7 g, 40.7 9c (9.6 mmol) was dissolved in DMF (45 mL) and DIEA (14.2 mL, 81.4 mmol) was added. The reaction was heated to 95° C. under N for 3 h, at which point LCMS analysis showed clean conversion to the cyclized product (9c) with M+H=282, 284. After cooling to room temperature, the mixture solution was poured into aqueous pH 5 buffer and 100 g of ice, and the resulting solution was adjusted to pH 3 using 6 N HCl. After addition to the cold aqueous solution, a pale yellow solid precipitated from the solution. The precipitate was collected in a Buchner funnel and washed with water (×3), affording 9.6 g (84%) of 9c after drying. 19 F NMR (376 MHz, DMSO): To a flask containing 135.4.9c (5.6 g, 20 mmol), DIEA (7.1 mL, 28.6 mmol) was added, and the suspension was cooled to 0 °C under N. POCl (30 mL, 320 mmol) was added in one portion, and the ice bath was removed. The mixture was then heated to 90 °C for 4 h. LCMS analysis (sample dissolved in MeOH) showed two monomethanol adducts with a Cl isotope pattern of M+H = 294. Excess POCl was chased with a mixture of toluene and DCM (×2), and the POCl was removed in vacuo. After removing all volatiles, the resulting orange solid was dry-loaded onto an 80 g ISCO silica column and purified using a gradient of 0–100% EtOAc in heptane, maintaining 100% EtOAc over 7 column volumes as the product slowly washed off the column. Concentration of the fractions gave 5.7 g (95%) of Preparation 9 as an orange solid. 13 C NMR (101 MHz, DMSO-d6) δ ppm 165.5, 157.2, 148.6, 146.7, 146.0, 143.2, 137.4, 137.3, 114.8, 12.9; 19 F NMR (376 MHz, DMSO) d -135.5.

[0331] Preparation Example 10: (8aS)-5-chloro-4-fluoro-2-(methylsulfanyl)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0332] [ka] Preparation 9 (1.25 g, 3.70 mmol) was suspended in CHCN (24 mL) and DIEA (0.668 mL, 3.83 mmol) was added. The mixture was cooled to 0 °C, and (S)-piperidin-2-ylmethanol (421 mg, 3.65 mmol) was added as a solution in THF (18 mL). After 8 minutes, the first nitrogen-carbon bond was formed, as observed by LCMS. LiOtBu (877 mg, 11.0 mmol) was added as a solution in THF (22 mL), and the mixture was warmed to 50 °C. After 4 hours at 50 °C, LCMS analysis showed conversion to Preparation 9. The reaction mixture was then diluted with 200 mL of water, and the product was extracted with DCM (50 mL × 4). The combined organic extracts were dried over NaSO, filtered, and evaporated to give Preparation 10 as a crude solid. Purification was achieved by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to afford 1.13 g (91%) of Preparation 10. 1 H NMR (chloroform-d, 400 MHz) d 4.8-4.9 (m, 1H), 4.4-4.5 (m, 2H), 3.7-3.8 (m, 1H), 2.97 (dt, 1H, J=2.5, 12.8 Hz), 2.7-2.7 (m, 1H), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.7-1.8 (m, 3H), 1.5-1.7 (m, 2H), MS: 341.1 [M+H] + .

[0333] Preparation Example 11: (8aS)-4-Fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-(methylsulfanyl)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0334] [ka] Preparation 10 (1.13 g, 3.32 mmol) and CAS: 2621932-37-2 were dissolved in THF (33 mL). Aqueous K3PO4 (1.5 M, 7.3 mL, 11 mmol) was added, and the mixture was purged with N2 for 5 minutes. cataCXiumA Pd G3 (241 mg, 0.332 mmol) was added, and the mixture was purged with N2 for another 5 minutes. The reaction was heated at 60 °C for 16 hours. LCMS analysis of the mixture indicated that CAS: 2621932-37-2 had been consumed, with some Preparation 10 remaining. The mixture was cooled to room temperature and diluted with water (40 mL). The mixture was extracted with EtOAc (20 mL × 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography eluting with a gradient of 0 to 55% EtOAc in heptane. Elute Preparation 11 with 55% EtOAc to give 1.09 g (48%) as a solid. 1 H NMR (400 MHz, DMSO) δ 8.12 - 8.03 (m, 1H), 7.72 (t, J = 2.1 Hz, 1H), 7.55 (td, J = 8.9, 2.6 Hz, 1H), 7.36 (dd, J = 6.0, 2.6 Hz, 1H), 5.36 (s, 2H), 5.09 (dd, J = 88.0, 13.1 Hz, 1H), 4.54 - 4.31 (m, 2H), 4.04 - 3.79 (m, 1H), 3.43 (s, 3H), 3.01 (t, J = 12.8 Hz, 1H), 2.52 (d, J = 3.7 Hz, 3H), 1.85 (ddd, J = 36.1, 23.2, 11.5 Hz, 4H), 1.72 - 1.47 (m, 1H), 1.45 - 1.33 (m, 1H), 0.86 (dd, J = 7.5, 3.9 Hz, 18H), 0.57 (dq, J = 15.0, 7.4 Hz, 3H), 19 F NMR (377 MHz, DMSO) δ -107.27, -143.30, MS: 691.3 [M+H] + .

[0335] Preparation Example 12: (8aS)-4-Fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0336] [ka] Preparation 11 (944 mg, 1.37 mmol) was dissolved in methyl ethyl ketone (47 mL) and saturated NaHCO3 (24 mL) was added, followed by oxone (1.89 g, 3.07 mmol). The reaction was stirred for 40 minutes, at which point a mixture of sulfone and sulfoxide was observed. Excess oxone was quenched with saturated Na2SO3, and the product was extracted into EtOAc (15 mL x 3). The organic extract was washed with brine (x 1), dried over Na2SO4, filtered, and evaporated to give 966 mg (100%) of the sulfone / sulfoxide mixture as a solid. MS: 707, 723 [M+H] +This solid was dissolved in CH3CN (10 mL) and ((2R,7AS)-2-fluorohexahydro-1H-pyrrolidin-7A-yl)methanol (288 mg, 1.81 mmol) was added, followed by LiOTMS (435 mg, 4.52 mmol). The reaction was heated and stirred at 80 °C for 20 min. LCMS analysis indicated consumption of both the sulfone and sulfoxide starting materials. The mixture was cooled to room temperature and diluted with MeOH (5 mL). HCl (4 M in dioxane, 4.8 mL, 19 mmol) was added. The mixture was stirred at room temperature for 90 min, at which point MOM deprotection was observed to be complete. The mixture was evaporated to dryness and EtOAc (80 mL) was added. The EtOAc layer was washed with saturated aqueous NaHCO3 (x3), and the organic layer was collected, dried over Na2SO4, filtered, and evaporated onto Celite. Purification was achieved. The Celite-supported product was dry-loaded onto a 40 g Gold ISCO column and purified by flash chromatography eluting with a gradient of 0-100% EtOAc in heptane, followed by 50% MeOH in DCM. Both the desired product and a by-product appeared in the 50% MeOH DCM gradient; the fractions were concentrated and purified again using a 24 g Gold ISCO column eluting with a gradient of 0-20% MeOH in DCM. Pure fractions were pooled and concentrated to give 910 mg (80%) of Preparation 12 as a solid. 1 H NMR (400 MHz, DMSO) δ 10.07 (d, J = 3.2 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.46 (td, J = 9.0, 1.9 Hz, 1H), 7.36 (s, 1H), 7.19 (dd, J = 16.8, 2.5 Hz, 1H), 5.29 (d, J = 54.1 Hz, 1H), 5.07 (dd, J = 81.2, 12.8 Hz, 1H), 4.51 - 4.31 (m, 2H), 4.13 (dd, J = 16.6, 10.4 Hz, 1H), 4.08 - 3.97 (m, 2H), 3.89 (dd, J = 43.2, 9.7 Hz, 1H), 3.17 (d, J = 4.7 Hz, 4H), 3.12 (d, J = 7.5 Hz, 1H), 3.07 - 2.79 (m, 3H), 2.18 - 1.97 (m, 3H), 1.89 - 1.77 (m, 5H), 0.85 (td, J = 6.8, 6.3, 1.8 Hz, 18H), 0.57 (dq, J = 14.8, 7.3 Hz, 3H), 19 F NMR (377 MHz, DMSO) δ -109.05, -143.64, -172.29, MS: 758.4 [M+H] + .

[0337] Preparation 13: {[2,3-difluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-{[2-(trimethylsilyl)ethoxy]methoxy}naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane

[0338] [ka] To a solution of CAS 127371-55-5 (10.0 g, 42.5 mmol) and CAS 77086-38-5 (32.1 g, 170 mmol) in anhydrous DMF (100 mL) were added [(t-Bu)P]HBF (4.94 g, 17.0 mmol), LiF (15.5 g, 596 mmol), and Pd(OAc) (1.91 g, 8.51 mmol) sequentially under N. The mixture was then stirred at 70 °C for 1 h, at which time LCMS analysis indicated that the starting methyl ketone had been consumed. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was diluted with water (500 mL). The product was extracted using EtOAc (4 × 250 mL), and the combined organic phase was washed with brine (3 × 200 mL), dried over NaSO, and concentrated. The residue was purified by flash chromatography using a gradient of 0-35% EtOAc in petroleum ether to give 8.08 g (83%) of 13a as a white solid. 1H NMR (400 MHz, DMSO) δ δ 8.10 (dd, J = 11.5, 8.3 Hz, 1H), 7.52 (dd, J = 11.6, 8.0 Hz, 1H), 3.88 (s, 2H), 3.58 (s, 3H), 2.54 (s, 3H), MS: 229 [M+H] + 13a (6.98 mg, 30.6 mmol) was then dissolved in anhydrous THF (306 mL) and cooled to −78 °C under N. LHMDS (1.0 M in THF 55 mL, 55 mmol) was added, and the mixture was stirred at 0 °C for 2 h. Analysis by LCMS indicated that the starting ketoester had been consumed, so the mixture was quenched with 1 M HCl (55 mL) and diluted with water (200 mL). The aqueous layer was extracted with EtOAc (4 × 200 mL), and the combined organic extracts were washed with brine and dried over NaSO. After concentration of the extracts, crude 13b (6.42 g) was obtained as a red solid. 1 H NMR (400 MHz, MeOD) δ 7.81 - 7.71 (m, 1H), 7.39 - 7.29 (m, 1H), 6.59 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), MS: 197 [M+H] +This crude product was carried on to the next step without further purification. To a solution of 13b (6.42 g, 32.7 mmol) and CAS 111409-79-1 (10.3 g, 39.3 mmol) in anhydrous 1,4-dioxane (113 mL), dichloro(p-cymene)ruthenium(II) dimer (2.01 g, 3.27 mmol) and KOAc (6.43 g, 65.5 mmol) were added under N2. The mixture was then stirred at 110 °C for 16 h. Analysis by LCMS indicated that the starting material had been consumed. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was diluted with water (200 mL). The organic product was extracted into EtOAc (4 × 200 mL), and the combined organic extracts were washed with brine (3 × 20 mL), dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in petroleum ether to give 7.19 g (58%) of 13c as a brown solid. MS: 377 [M+H] + To a mixture of 13c (7.19 g, 19.1 mmol) and DIPEA (3.7 g, 28.7 mmol) in DCM (100 mL) and THF (10 mL), SEMCl (3.19 g, 19.1 mmol) was added, and the reaction was stirred at 20 °C for 24 h. Analysis by LCMS indicated that the starting material had been consumed, and the desired product was detected. The mixture was then concentrated, and the residue was purified by silica gel column chromatography using a gradient of 0 to 5% EtOAc in petroleum ether to give 7.64 g (79%) of 13d as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.40 (dd, J = 10.8, 7.9 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 5.28 (d, J = 3.3 Hz, 2H), 3.80 - 3.75 (m, 2H),1.27 (d, J = 7.9 Hz, 2H), 1.18 (d, J = 5.4 Hz, 18H), 1.00 - 0.94 (m, 3H), 0.00 (s, 9H). To a mixture of 13d (7.64 g, 15.1 mmol) in DCM (84 mL) was added DIPEA (3.9 g, 30.2 mmol), the solution was cooled to −30 °C, and then TfO (6.38 g, 22.6 mmol) was added dropwise. The resulting mixture was stirred at −30 °C for 1 h, at which point TLC analysis showed a new spot. The resulting mixture was then poured into water (200 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous NaSO. The mixture was concentrated, and the residue was purified by flash chromatography eluting with a gradient of 0–2% EtOAc in petroleum ether to afford 5.69 g (59%) of 13e as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 10.1, 7.7 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 5.31 (s, 2H), 3.78 (dd, J = 9.7, 4.3 Hz, 2H), 1.24 (dd, J = 5.0, 3.3 Hz, 2H), 1.17 (t, J = 5.0 Hz, 18H), 1.02 - 0.90 (m, 3H), 0.00 (s, 9H). To a solution of 13e (5.69 g, 8.90 mmol) and B2Pin2 (4.52 g, 17.8 mmol) in 1,4-dioxane (45 mL) was added Pd(dppf)Cl2 (651 mg, 0.890 mmol) and KOAc (2.62 g, 26.7 mmol) under N2. The reaction was then stirred at 110 °C for 16 h. LCMS analysis indicated that the starting material had been consumed, and the mixture was filtered through a pad of Celite. The filtrate was concentrated to give the crude product, which was purified by flash chromatography eluting with a gradient of 0 to 5% EtOAc in petroleum ether. The fractions containing the desired product were concentrated to give 2.24 g (41%) of Preparation 13 as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.45 - 7.44 (m, 1H), 7.43 - 7.38 (m, 1H), 7.31 (d, J = 2.6 Hz, 1H), 5.30 (s, 2H), 3.80 - 3.74 (m, 2H), 1.42 (s, 12H), 1.17 (d, J = 3.3 Hz, 18H), 0.98 - 0.94 (m, 2H), 0.87 (dd, J = 6.0, 2.7 Hz, 2H), 0.00 (s, 9H), MS: 617 [M+H] + Using general procedure D, boronic ester Preparation 13 was coupled to Preparation 10 in five steps to give Example 32. [Example]

[0339] In order that this invention may be better understood, the following examples are set forth. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0340] Example 1 {(3S)-1-[7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-yl}acetonitrile.

[0341] [ka] Example 1 was prepared according to the above scheme and is representative of General Method A.

[0342] To a solution of CAS# 2454396-80-4 (215 mg, 0.814 mmol) and CAS# 1693757-39-9 (131 mg, 0.819 mmol) in DCM (10 mL) was added DIPEA (316 mg, 2.44 mmol) at -40 °C under argon. The mixture was stirred at 25 °C for 2 h. The mixture was warmed to room temperature and diluted with water (30 mL). The aqueous layer was extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography using a gradient of 0–60% EtOAc in petroleum ether to give 1A (160 mg, 56%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 4.48 (d, J = 11.6 Hz, 1H), 4.38 (d, J = 13.4 Hz, 1H), 3.38 (t, J = 10.9 Hz, 1H), 3.27 - 3.20 (m, 1H), 2.63 (dd, J = 6.7, 4.0 Hz, 2H), 2.59 - 2.52 (m, 3H), 2.14 - 2.05 (m, 1H), 1.94 (d, J = 9.8 Hz, 1H), 1.87 - 1.79 (m, 1H), 1.71 - 1.62 (m, 1H), 1.49 - 1.40 (m, 1H), MS: 352 [M+H] + To a solution of 1A (160 mg, 0.455 mmol) and Preparation 7 (343 mg, 0.591 mmol) in dioxane (10 mL) and HO (1 mL) was added CataCXium A Pd G3 (33.1 mg, 0.0455 mmol) and K2CO3 (189 mg, 1.36 mmol) in a tube under N2. The reaction was stirred at 80 °C for 6 h. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography using a gradient of 0 to 50% EtOAc in petroleum ether to give 1B (207 mg, 59%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 9.10 (d, J = 4.6 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.72 (s, 1H), 7.69 - 7.63 (m, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 5.46 (s, 2H), 4.57 (d, J = 11.8 Hz, 1H), 4.48 (s, 1H), 3.88 - 3.76 (m, 2H), 3.20 (d, J = 10.8 Hz, 1H), 2.71 (d, J = 6.8 Hz, 2H), 2.60 (d, J = 2.2 Hz, 3H), 2.10 - 1.92 (m, 3H), 1.51 (d, J = 11.7 Hz, 1H), 1.28 (s, 1H), 1.00 - 0.94 (m, 2H), 0.93 - 0.80 (m, 18H), 0.53 (dq, J = 14.4, 7.1 Hz, 3H), 0.05 (s, 1H), -0.00 (s, 9H), MS: 770 [M+H] + To a solution of 1B (207 mg, 0.269 mmol) in DCM (10 mL) was added mCBPA (69.6 mg, 0.403 mmol). The reaction was stirred at 20 °C for 1 h. The reaction mixture was diluted with saturated aqueous NaSO (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with saturated NaHCO (100 mL), brine (100 mL), and dried over anhydrous NaSO. After concentration, crude 1C (211 mg, 99%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.36 (s, 1H), 5.47 (s, 2H), 4.67 (s, 2H), 3.81 (t, J = 7.8 Hz, 2H), 2.98 (dd, J = 11.1, 6.6 Hz, 3H), 2.76 (s, 2H), 2.04 (d, J = 7.8 Hz, 2H), 1.28 (s, 3H), 0.96 (t, J = 8.2 Hz, 2H), 0.86 (dd, J = 12.3, 5.1 Hz, 18H), 0.54 (dt, J = 14.9, 7.4 Hz, 3H), 0.05 (s, 3H), -0.00 (s, 9H), MS: 786 [M+H] + To a solution of 1C (211 mg, 0.263 mmol) and CAS# 2097518-76-6 (50.3 mg, 0.316 mmol) in anhydrous DCM (10 mL) was added LHMDS (1 M in THF 0.289 mL, 0.289 mmol) dropwise at 0 °C under N. The reaction was stirred at 0 °C for 1 h. The reaction mixture was diluted with HO (15 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After concentration under reduced pressure, the resulting residue was purified by flash chromatography eluting with a gradient of 0–10% MeOH in DCM to afford 1D (161 mg, 69%) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 9.09 (d, J = 3.8 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.69 - 7.63 (m, 1H), 7.62 - 7.54 (m, 1H), 7.32 (d, J = 1.9 Hz, 1H), 5.46 (s, 2H), 5.27 (s, 1H), 4.48 (dd, J = 42.3, 11.5 Hz, 3H), 4.18 (dd, J = 23.5, 10.5 Hz, 1H), 4.09 - 3.97 (m, 1H), 3.90 - 3.67 (m, 2H), 3.19 (dd, J = 25.0, 11.6 Hz, 3H), 3.07 (s, 1H), 2.89 (s, 1H), 2.77 - 2.67 (m, 2H), 2.11 - 2.01 (m, 2H), 1.96 (d, J = 13.2 Hz, 2H), 1.80 (d, J = 11.7 Hz, 2H), 1.52 (d, J = 13.4 Hz, 2H), 0.97 (dd, J = 18.9, 10.0 Hz, 3H), 0.91 - 0.82 (m, 18H), 0.54 (tt, J = 15.0, 6.0 Hz, 3H), 0.11 - 0.02 (m, 3H), 0.02 - -0.04 (m, 9H), MS: 881 [M+H] + To a solution of 1D (160 mg, 0.182 mmol) in DMF (5 mL) was added CsF (276 mg, 1.82 mmol). The reaction was then stirred at 25 °C for 1 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After concentration under reduced pressure, the crude terminal alkyne (132 mg, 99%) was obtained as a yellow solid, which was used for the next step without further purification. MS: 725 [M+H] + To a solution of the crude terminal alkyne (120 mg, 0.166 mmol) in DCM (10 mL) was added HCl (4 M in dioxane, 0.20 mL, 0.80 mmol). The reaction was stirred at 25° C. for 0.5 h. The reaction was concentrated and the crude product was purified by preparative HPLC (Column: Xbridge 5m C18 150 × 19 mm; Mobile phase: CHCN-water (0.1% formic acid); Gradient: 23% to 100%; Flow rate: 20 mL / min) to give {(3S)-1-[7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-yl}acetonitrile, Example 1 (25.2 mg, 24%) as a yellow solid.1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 10.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 5.48 - 5.15 (m, 1H), 4.45 (dd, J = 25.6, 13.0 Hz, 3H), 4.25 - 4.10 (m, 1H), 4.10 - 4.00 (m, 1H), 3.62 (d, J = 3.7 Hz, 1H), 3.20 - 2.97 (m, 5H), 2.83 (d, J = 6.6 Hz, 1H), 2.66 (d, J = 7.5 Hz, 2H), 2.13 (d, J = 4.7 Hz, 2H), 2.05 (s, 1H), 2.01 (s, 2H), 1.92 - 1.71 (m, 4H), 1.47 (s, 1H), MS: 595 [M+H] + .

[0343] Examples 2-9 reported in Table 1 were prepared according to Scheme I / General Method A with minor variations that would be recognized by one skilled in the art.

[0344] Example 10 (1R,5R,6R)-3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-6-ol.

[0345] [ka] Example 10 was prepared according to the above scheme and is representative of General Method B.

[0346] A solution of CAS# 2454396-80-4 (913 mg, 3.61) and Preparation 1 (591 mg, 3.61 mmol) was dissolved in DCM (72 mL). The solution was cooled to -78 °C and DIPEA (1.57 mL, 9.04 mmol) was added. The reaction was stirred at -78 °C for 1 h and the cold bath was removed. The reaction was allowed to warm to room temperature over 1 h. The solvent was removed and the residue was purified by flash chromatography eluting with a gradient of 0 to 100% EtOAc in heptane. After concentration of the pure fractions, 10A (1.09 g, 88%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.17 - 1.24 (m, 1 H) 1.69 (s, 1 H) 1.79 (s, 1 H) 2.05 - 2.15 (m, 1 H) 2.16 - 2.22 (m, 1 H) 2.33 - 2.38 (m, 1 H) 3.45 (br d, J = 12.6 Hz, 1 H) 3.74 (br d, J = 12.5 Hz, 1 H) 4.15 - 4.22 (m, 1 H) 4.46 (br s, 1 H) 4.58 (br d, J = 13.3 Hz, 1 H) 4.66 - 4.73 (m, 1 H) 9.21 (s, 1 H), MS: 343, 345 [M+H] + A solution of 10A (1.22 g, 3.55 mmol) in dioxane (20 mL) was treated with DIPEA (1.24 mL, 7.11 mmol) and ((2R,7AS)-2-fluorohexahydro-1H-pyrrolidin-7A-yl)methanol (1.13 g, 7.11 mmol), and the mixture was heated to 90° C. for 48 h. The reaction was diluted with EtOAc (100 mL) and washed with water and brine. The organic extract was dried over sodium sulfate and concentrated to give an orange oil. The crude orange oil was purified by SFC to give 10B (890 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (s, 1 H) 5.16 - 5.41 (m, 1 H) 4.62 - 4.75 (m, 2 H) 4.47 (br d, J = 12.1 Hz, 1 H) 4.08 - 4.19 (m, 2 H) 4.00 (d, J = 10.3 Hz, 1 H) 3.63 - 3.74 (m, 1 H) 3.33 (s, 1 H) 2.98 - 3.14 (m, 3 H) 2.73 - 2.91 (m, 1 H) 2.31 (br s, 1 H) 1.93 - 2.20 (m, 5 H) 1.72 - 1.91 (m, 4 H) 1.57 - 1.69 (m, 1 H) 1.11 - 1.26 (m, 1H), MS 466 [M+H] + To a mixture of 10B (100 mg, 0.215 mmol) and CAS# 2621932-37-2 (132 mg, 0.258 mmol) in THF (2.5 mL) was added KPO (150 mg, 0.708 mmol) and water (0.25 mL). Nitrogen was bubbled through the solution for 10 min, and CataCXium A Pd G3 (15.6 mg, 0.0215 mmol) was added. The vial was sealed and heated to 60 °C for 2 h. LCMS indicated a clean reaction and approximately 50% conversion to the Suzuki product. Heating was continued at 60 °C for an additional 18 h. The mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography eluting with a gradient of 0–20% iPrOH in DCM. After concentration of pure fractions, 10C (130 mg, 74%) was obtained as a yellow powder. 1 H NMR (400 MHz, DMSO-d6) δ = 9.62, 9.26 (2s, 1H, major and minor rotamers, respectively), 8.10 (dd, J = 5.9, 9.3 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 8.9 Hz, 1H), 7.39 - 7.31 (m, 1H), 5.40 - 5.34 (m, 2H), 5.23 (br s, 1H), 4.97 - 4.84 (m, 1H), 4.68, 4.50 (2d, J = 3.4 Hz, br d, J = 11.5 Hz, 1H, major and minor rotamers, respectively), 4.32 - 4.05 (m, 3H), 4.01 - 3.91 (m, 1H), 3.82 - 3.73 and 3.60 - 3.53 (2m, 1H, major and minor rotamers, respectively), 3.44 (s, 2H), 3.16 - 2.99 (m, 2H), 2.91 - 2.79 (m, 1H), 2.52 - 2.35 (m, 4H is hidden by the DMSO peak), 2.40 - 2.30 (m, 1H), 2.26 - 1.96 (m, 4H), 1.91 - 1.61 (m, 4H), 1.36 - 1.22 (m, 1H), 0.87 - 0.78 (m, 18H), 0.56 - 0.42 (m, 3H); MS: 816 [M+H] +To a solution of 10C (126 mg, 0.154 mmol) in CH3CN (5 mL) was added CsF (235 mg, 1.55 mmol). The reaction was stirred at room temperature for 4 h. The mixture was neutralized with acetic acid (22 mL, 0.386 mmol) and concentrated in vacuo. The residue was taken up in EtOAc and the salts were removed by filtration. The filtrate was concentrated to give the terminal alkyne as a pink colored powder (102 mg), which was carried on to the next step without further purification. A suspension of the terminal alkyne from the previous step (102 mg, 0.154 mmol) in CH3CN (2 mL) was cooled in an ice bath. 4 N HCl (2 mL of 4 N in dioxane, 8.0 mmol) was added. The reaction was stirred at 0 °C for 1 h. The solvent was evaporated to give an orange solid. The residue was dissolved in MeOH (1 mL) and purified by preparative HPLC using acetic acid as an additive to a CHCN / water eluent. Pure fractions were combined and concentrated to 15 mL of water. The aqueous solution was frozen at −78° C. and lyophilized overnight to give (1R,5R,6R)-3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo[3.2.1]octan-6-ol (Example 10) (104 mg, 64%) as a pale orange powder. 1 H NMR (400 MHz, methanol-d4) δ = 9.28 - 9.04 (m, 1H), 7.90 - 7.81 (m, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.27 - 7.19 (m, 1H), 5.49 - 5.30 (m, 1H), 5.21 (br d, J = 11.9 Hz, 1H), 4.67 (br d, J = 12.1 Hz, 1H), 4.50 - 4.42 (m, 1H), 4.38 - 4.26 (m, 2H), 3.98 - 3.72 (m, 1H), 3.58 - 3.34 (m, 5H), 3.21 - 3.11 (m, 1H), 2.51 - 2.05 (m, 9H), 2.03 - 1.89 (m, 5H), 1.86 - 1.75 (m, 1H), 1.46 - 1.36 (m, 1H), HRMS: 616.25385 [M+H] + .

[0347] Examples 11-17 reported in Table 1 were prepared according to General Method B / Example 10 with minor variations that would be recognized by one skilled in the art.

[0348] Example 18 (1R * ,5R * ,6R * )-3-[7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-8-oxa-3-azabicyclo[3.2.1]octan-6-ol.

[0349] [ka]

[0350] Example 18 was prepared according to the above scheme and is representative of general method C.

[0351] Compound CAS# 2454491-14-4 (3.66 g, 13.8 mmol) was combined with CAS# 135938-63-5 (3.18 g, 13.9 mmol) in DCM (69 mL). The resulting solution was cooled to -40 °C and DIPEA (7.0 mL, 42 mmol) was added. The mixture was gradually warmed from -40 °C to room temperature over 3.5 hours. The mixture was partitioned between water and DCM, and the DCM layer was washed with water (3x). The organic layer was dried over sodium sulfate, and fresh CAS# 135938-63-5 (1.6 g, 6.9 mmol) was added, followed by fresh DIPEA (7.0 mL, 42 mmol), and the reaction was resubmitted to reaction conditions. After stirring for 1 hour, a third portion of CAS# 135938-63-5 (1.6 g, 6.9 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was partitioned between water and DCM, and the DCM layer was washed with water (3x). The organic layer was dried over sodium sulfate and evaporated. Purification by flash chromatography using a gradient of 0-100% EtOAc in heptane gave 18A (4.26 g, 67%) as a glass. 1 H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 4.84 (s, 1H), 4.46 (d, J = 13.5 Hz, 1H), 4.12 (dd, J = 10.5, 8.6 Hz, 1H), 3.76 (dd, J = 10.5, 5.7 Hz, 1H), 3.34 (t, J = 12.3 Hz, 1H), 2.60 (s, 3H), 1.88 - 1.64 (m, 9H), 0.79 (s, 8H), 0.02 (d, J = 2.3 Hz, 6H), 19 F NMR (376 MHz, CDCl3) δ -134.84, MS: 457.1 [M+H] +18A (197 mg, 0.430 mmol) was combined with Preparation 7 (500 mg, 0.861 mmol) in THF (4.3 mL) and aqueous KPO (1.5 M, 1.43 mL, 2.15 mmol). The mixture was purged with nitrogen for 3 minutes. CataCXium A Pd G3 (31.3 mg, 0.0430 mmol) was then added, and the mixture was purged with nitrogen for an additional 3 minutes. The reaction was heated at 70°C for 4.5 hours, and product formation was monitored by TLC. The mixture was then evaporated directly onto Celite. The Celite was loaded onto an Isco cartridge, and the product was purified by flash chromatography, eluting with a gradient of 0 to 100% EtOAc in heptane. Fractions were analyzed using a nonpolar / high mass LCMS method, which picked up the target mass as a late-eluting peak. The pure fractions were concentrated to give compound 18B (367 mg, 49%) as a glassy orange solid. 1 H NMR (400 MHz, CDCl3) δ 9.11 (d, J = 20.0 Hz, 1H), 7.81 (dt, J = 8.3, 1.5 Hz, 1H), 7.68 (dd, J = 7.2, 1.2 Hz, 1H), 7.54 (t, J = 3.0 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.30 (dd, J = 4.3, 2.6 Hz, 1H), 5.37 (d, J = 7.0 Hz, 1H), 5.35 - 5.31 (m, 1H), 4.87 (s, 1H), 4.38 (dd, J = 38.0, 13.8 Hz, 1H), 4.05 - 3.96 (m, 1H), 3.84 - 3.74 (m, 3H), 3.51 - 3.32 (m, 1H), 2.61 (d, J = 1.3 Hz, 3H), 1.27 (q, J = 2.2 Hz, 4H), 1.19 - 1.16 (m, 4H), 1.05 (d, J = 1.1 Hz, 3H), 1.00 - 0.95 (m, 3H), 0.90 (d, J = 1.6 Hz, 9H), 0.88 (t, J = 1.8 Hz, 9H), 0.77 (s, 6H), 0.58 - 0.49 (m, 3H), -0.00 (t, J = 1.2 Hz, 9H), -0.03 (d, J = 2.5 Hz, 3H), MS: 875.4 [M+H] + Compound 18B (367 mg, 0.419 mmol) was dissolved in a mixture of acetone (20 mL) and saturated aqueous sodium bicarbonate (10 mL). Oxone (322 mg, 0.524 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. The pH was checked with pH paper and observed to be between 7 and 8. The reaction was quenched by the addition of saturated aqueous sodium sulfite (20 mL), and the reaction mixture was stirred for 5 minutes. The reaction mixture was extracted with 50 / 50 heptane:EtOAc (1 x 40 mL), and the organic extract was washed with brine (1 x 25 mL) and dried over sodium sulfate. After filtration and concentration, 18C (341 mg, 90%) was obtained. Note: The masses of the sulfoxide and sulfone were both observed under a single broad peak. MS: sulfoxide: 891.4, sulfone: 907.4 [M+H] + This material was taken on to the next step without further purification. Compound 18C (341 mg, 0.376 mmol) was combined with CAS# 2097518-76-6 (89.7 mg, 0.564 mmol) and lithium trimethylsilanolate (108 mg, 1.13 mmol) in CH3CN (4.18 mL). The mixture was heated at 80 °C for 30 minutes. After cooling, the solid was removed by filtration. The filtrate was diluted with water (40 mL) and extracted with a solvent mixture of 10% EtOAc in heptane (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography by dissolving in 5 mL of heptane and loading directly onto a silica column. Gradient elution using 0-100% EtOAc in heptane gave 18D (236 mg, 64%). MS: 986.5 [M+H] +Compound 18D (236 mg, 0.239 mmol) was dissolved in THF (2.39 mL), and aqueous NaOH (1.20 mL, 1.20 mmol) was added, followed by TBAF (1.20 mL, 1.20 mmol) of 1M in THF. The mixture was heated to 60 °C with stirring. After 2.3 h, the reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The organic layer was washed with brine (6 × 25 mL) to remove excess TBAF. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography eluting with a gradient of 0 to 100% EtOAc (containing 10% by volume of 7N ammonia in methanol) in heptane. Pure fractions were collected to give 18D (50 mg, 27%), and the column was further flushed with 75% methanol in DCM to elute the remaining target material remaining on the column, yielding an additional 100 mg of product. The overall yield for the C4 deprotection step was 150 mg, 81%, MS: 775.3 [M+H]. + HCl. Half of this material was carried on directly to the amine coupling step. The material from the TBAF / NaOH treatment (50 mg, 0.065 mmol) was combined with CMPI (26.4 mg, 0.103 mmol) and DIPEA (57.4 uL, 0.323 mmol) in DCM (1.0 mL). The mixture was stirred at room temperature for 1 hour. Preparation 2-(-) (17.1 mg, 0.103 mmol) was then added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (30 mL) and the organic layer was washed with brine (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to give 18E (52.0 mg, 91%). MS 886.4 [M+H] +18E (52 mg, 0.059 mmol) was dissolved in CHCN (1.0 mL) and CsF (89.1 mg, 0.587 mmol) was added. The reaction mixture was stirred at room temperature for 6 hours to complete the removal of the TiPS groups. HCl (0.293 mL of 4.0 M in dioxane, 1.17 mmol) was then added. The reaction was stirred for 8 hours. The reaction mixture was diluted with EtOAc (30 mL) and the organic layer was washed with a 50 / 50 solution of brine and 1 M aqueous NaOH (3×20 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated to give 46 mg of crude Example 18. Purification by reverse-phase HPLC gave (1R * ,5R * ,6R * )-3-[7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-8-oxa-3-azabicyclo[3.2.1]octan-6-ol, Example 18, was obtained. 1 H NMR (400 MHz, DMSO) δ 9.07 and 9.31 (2 s, 1H, major and minor rotamers, respectively), 7.87 (dt, J = 8.0, 2.3 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.34 (t, J = 2.5 Hz, 1H), 7.17 and 7.11 (2 d, J = 2.6 Hz, 1H, major and minor rotamers, respectively), 5.26 (d, J = 54.3 Hz, 1H), 4.42 (d, J = 7.3 Hz, 1H), 4.33 - 4.19 (m, 2H), 4.16 - 3.98 (m, 4H), 3.44 (d, J = 11.9 Hz, 1H), 3.07 (d, J = 9.5 Hz, 2H), 2.99 (s, 1H), 2.81 (t, J = 7.9 Hz, 1H), 2.34 - 2.25 (m, 1H), 2.11 - 2.02 (m, 2H), 1.77 (d, J = 8.2 Hz, 8H),19 F NMR (376 MHz, DMSO) δ -141.48, -172.18 (only the major rotamer is reported), MS: 600.2 [M+H] + .

[0352] Examples 19-22 reported in Table 1 were prepared according to General Method C / Example 18 with minor variations that would be recognized by one skilled in the art.

[0353] Additional compounds of the present invention were prepared by modifying the methods exemplified herein. Unless otherwise indicated, all compounds with chiral centers were prepared and / or isolated as single enantiomers of known relative configuration. Compounds labeled "absolute stereochemistry unknown" were typically prepared from racemic intermediates and resolved into single enantiomers by appropriate chiral preparative SFC methods prior to characterization and testing.

[0354] Examples 1-22 and their corresponding characterization data are all presented in Table 1 below.

[0355] [Table 1-1]

[0356] [Table 1-2]

[0357] [Table 1-3]

[0358] [Table 1-4]

[0359] [Table 1-5]

[0360] [Table 1-6]

[0361] [Table 1-7]

[0362] [Table 1-8]

[0363] [Table 1-9]

[0364] [Table 1-10]

[0365] Example 23 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol

[0366] [ka] Preparation 12 (910 mg, 1.2 mmol) was dissolved in CHCN (12 mL) and CsF (1.1 g, 7.2 mmol) was added. The reaction was stirred at 35 °C for 16 h, and the reaction was partitioned between water (15 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (20 mL × 3), and the combined organic extracts were dried over NaSO, filtered, and concentrated. The resulting solid was purified by SFC using a ZymorSPHER HADP 150 × 21.2 column and a gradient of 15–40% MeOH in CO at 100 mL / min and 110 bar to give 493 mg (68%) of Example 23 as a yellow solid. 1 1 H NMR observed 29 / 30 protons (no exchangeable phenols observed). 1 H NMR (400 MHz, DMSO) δ 7.89 (dd, J = 8.8, 6.4 Hz, 1H), 7.40 (t, J = 9.6 Hz, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 14.8, 2.5 Hz, 1H), 5.28 (d, J = 52.9 Hz, 1H), 5.20 - 5.06 (m, 1H), 4.53 - 4.36 (m, 2H), 4.12 (dd, J = 10.4, 3.2 Hz, 1H), 4.05 - 3.97 (m, 2H), 3.92 (dd, J = 9.5, 5.1 Hz, 1H), 3.13 - 3.06 (m, 2H), 3.01 (d, J = 9.2 Hz, 2H), 2.83 (q, J = 8.6 Hz, 1H), 2.20 - 2.09 (m, 1H), 2.03 (dd, J = 20.6, 3.4 Hz, 2H), 1.92 - 1.47 (m, 9H), 19 F NMR (377 MHz, DMSO) δ -111.58, -145.15, -172.11.

[0367] The steps and reaction conditions outlined above for Example 23 are now defined as General Method D.

[0368] Examples 24-31 reported in Table 1A were prepared according to General Method D / Example 23 with minor variations that would be recognized by one skilled in the art.

[0369] [Table 2-1]

[0370] [Table 2-2]

[0371] [Table 2-3]

[0372] [Table 2-4]

[0373] Example 32 5-Ethynyl-6,7-difluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol

[0374] [ka] Using General Method D / Example 23 with minor modifications that will be appreciated by those skilled in the art, boronic ester Preparation 13 was coupled with Preparation 10 to give Example 32 in five steps, for which the final SEM deprotection step is provided below.

[0375] The SEM-protected intermediate resulting in Example 32 (90 mg, 0.12 mmol) was dissolved in DCM (5 mL). To the DCM solution was added HCl in dioxane (4 M, 0.45 mL, 1.8 mmol) at 15° C. The reaction mixture was stirred at 15° C. under N for 30 minutes. LCMS analysis indicated that the starting material was nearly consumed. The mixture was concentrated in vacuo to give the crude product, which was purified using preparative HPLC (Waters MS triggered Prep-LC equipped with an SQD2 detector; column: Welch 10 m C18 250 × 21.2 mm; flow rate: 25 mL / min; wavelength: 214 nm; 50% to 70% ACN in H2O (0.1% NH3)) to give Example 32 (24 mg, 30%) as a yellow solid. 1 H NMR (methanol-d4, 400 MHz) d 7.6-7.7 (m, 1H), 7.25 (d, 1H, J = 2.6 Hz), 7.15 (dd, 1H, J = 2.5, 16.7 Hz), 5.2-5.4 (m, 2H), 4.4-4.6 (m, 2H), 4.2-4.4 (m, 1H), 4.1-4.2 (m, 1H), 3.9-4.0 (m, 1H), 3.68 (d, 1H, J = 9.8 Hz), 3.1-3.3 (m, 3H), 3.0-3.2 (m, 1H), 3.0-3.0 (m, 1H), 2.3-2.4 (m, 1H), 2.2-2.4 (m, 1H), 2.1-2.2 (m, 1H), 1.7-2.1 (m, 8H), 19 F NMR (methanol-d4, 376 MHz) - 135.94 - - 136.00 (m, 1F), - 139.86 - - 139.91 (m, 1F), - 145.47 - - 145.64 (m, 1F), - 173.61 - - 173.67 (m, 1F), MS: 620 [M+H] + .

[0376] Example 33 5-Ethynyl-6,7-difluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol

[0377] [ka]

[0378] Preparation 9 (450 mg, 1.51 mmol) was suspended in CHCN (10 mL). DIPEA (276 μL, 1.59 mmol) was added, and the suspension was cooled to 0 °C under N. In a separate vial, CAS 1262409-55-1-HCl salt (232 mg, 1.39 mmol) was suspended in DCM (1 mL), and DIPEA (276 μL, 1.59 mmol) was added to dissolve the amine-HCl salt. THF (6 mL) was added to the resulting solution, resulting in a milky mixture. This solution was added to the flask containing the cold solution of Preparation 9. After approximately 45 minutes at 0 °C, LCMS analysis initially indicated the reaction was complete. LiOtBu (1 M in THF, 4.5 mL, 4.5 mmol) was added dropwise, and the ice bath was removed. The ice bath was replaced with an oil bath and the reaction was heated at 50 °C for 30 min. LCMS analysis indicated the cyclization step was complete. The solution was cooled to room temperature and evaporated. Saturated aqueous NaHCO3 (10 mL) was added and the mixture was extracted with DCM (3 x 30 mL). The combined organic extracts were dried over Na2SO4 and evaporated. The process described above was repeated again on the same scale with the same observations and results. The crude material from both reactions was combined and purified using flash chromatography eluting with a gradient of 0 to 100% EtOAc in heptane, using DCM to load the crude material onto a silica cartridge. Fractions containing the desired product were pooled and concentrated to give 483 mg (70%) of 14a as a light brown solid. 1 H NMR (400 MHz, chloroform-d) δ = 5.22 (ddd, J = 2.9, 6.8, 13.8 Hz, 1H), 4.65 (dd, J = 4.6, 13.4 Hz, 1H), 4.42 (d, J = 13.4 Hz, 1H), 4.22 - 4.17 (m, 1H), 4.09 - 3.98 (m, 2H), 3.72 (dd, J = 9.8, 12.6 Hz, 1H), 3.43 - 3.24 (m, 2H), 2.62 (s, 3H), 2.26 - 2.12 (m, 1H), 2.05 - 1.92 (m, 1H). 19 F NMR (376 MHz, chloroform-d) δ = -140.51 (s, 1F). Analysis of this material by chiral SFC indicated an optical purity of 50% ee, indicating that the starting amino alcohol (CAS 1262409-55-1-HCl salt) was not optically pure. In a subsequent sequence, the minor enantiomer was removed using preparative chiral SFC (see below). To a vial equipped with a stir bar was added 14a (400 mg, 1.12 mmol), CAS 2621932-37-2 (689 mg, 1.35 mmol), 1,4-dioxane (5.6 mL), and K2CO3 (465 mg, 3.4 mmol) added as a solution in water (0.6 mL). The mixture was purged with N2 for 3 min, and RuPhos Pd G3 (94 mg, 0.11 mmol) was added. The vial was sealed and heated at 90 °C for 4.5 h. LCMS showed that the starting material had been consumed, and water (5 mL) was added. The dark mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over NaSO, filtered, evaporated, and subjected to chiral SFC purification to remove the minor enantiomer. After chiral SFC, 480 mg (62%) of 14b was obtained in 90% ee. 1 H NMR (400 MHz, methanol-d4) δ = 7.95 (dd, J = 5.8, 9.1 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.40 (t, J = 8.9 Hz, 1H), 7.34 (dd, J = 2.3, 19.4 Hz, 1H), 5.39 - 5.30 (m, 2H), 5.26 - 5.14 (m, 1H), 4.71 (ddd, J = 4.7, 13.6, 18.6 Hz, 1H), 4.57 - 4.48 (m, 1H), 4.31 (tt, J = 4.9, 9.4 Hz, 1H), 4.24 - 4.14 (m, 1H), 4.06 - 3.79 (m, 2H), 3.71 - 3.52 (m, 2H), 3.51 - 3.48 (m, 3H), 2.61 (s, 3H), 2.28 - 2.12 (m, 1H), 2.07 - 1.88 (m, 1H), 0.98 - 0.90 (m, 18H), 0.77 - 0.61 (m, 3H), 19 F NMR (376 MHz, methanol-d4) δ = -108.33 (d, J = 69.4 Hz, 1F), -141.66 - -144.80 (m, 1F), MS: 707 [M+H] + 14b (402 mg, 0.57 mmol) was dissolved in DMF (9.5 mL). Anhydrous CsF (518 mg, 3.42 mmol) was added, and the reaction was heated to 35° C. for 45 min. Most of the DMF was removed in vacuo (5 mm Hg, 30° C.), and water (5 mL) was added to the resulting residue. A solid precipitated and was extracted into DCM (3×20 mL). The combined organic extracts were dried over NaSO, filtered, and evaporated to give the crude product, which was subjected to chiral SFC to further enrich the desired enantiomer. After chiral SFC, 257 mg (82%) of 14c was obtained as a light brown solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.87 - 7.74 (m, 1H), 7.55 - 7.50 (m, 1H), 7.46 - 7.35 (m, 1H), 5.37 - 5.16 (m, 3H), 4.71 - 4.59 (m, 1H), 4.54 - 4.41 (m, 1H), 4.21 (dt, J = 3.8, 12.2 Hz, 1H), 4.14 - 3.97 (m, 2H), 3.83 (td, J = 9.1, 12.6 Hz, 1H), 3.52 (d, J = 2.8 Hz, 3H), 3.47 - 3.23 (m, 2H), 2.92 (d, J = 19.6 Hz, 1H), 2.64 (s, 3H), 2.36 - 2.17 (m, 1H), 2.13 - 1.93 (m, 1H), 1.50 (s, 1H), 19F NMR (376 MHz, chloroform-d) δ = -106.89 - -109.75 (m, 1F), -143.05 (d, J = 363.4 Hz, 1F). To a mixture of 14c (252 mg, 0.46 mmol) in MEK (7 mL) was added solid oxone (646 mg, 1.03 mmol) and saturated aqueous NaHCO3 (7 mL). The mixture was stirred at 1500 rpm at room temperature for 20 min. The reaction was diluted with EtOAc (20 mL), and the aqueous layer was extracted twice more with EtOAc (2 x 20 mL). The combined organic extracts were washed with 10% aqueous Na2S2O3 (10 mL) and brine (10 mL). After drying over Na2SO4, the mixture was filtered and evaporated to give 301 mg of the sulfone as a pale yellow gum. MS: 583 [M+H] + This material was carried on to the next step without further purification. The sulfone (267 mg, 0.458 mmol) and CAS 2097518-76-6 (100 mg, 0.64 mmol) were dissolved in CHCN (0.9 mL). Lithium trimethylsilanolate (130 mg, 1.4 mmol) was added, and the vial was sealed, stirred, and heated to 50 °C for 30 min to give 14d, which was carried on to the MOM deprotection step in the same pot. After cooling to room temperature, MeOH (2 mL) was added to the 14d solution, followed by HCl (4 M in 1,4-dioxane, 3.5 mL, 14 mmol), and the reaction was stirred at room temperature for 30 min. The solvent was removed under vacuum, and saturated aqueous NaHCO (10 mL) and water (10 mL) were added. A solid precipitated from this mixture; it was insoluble in EtOAc but soluble in DCM. The aqueous mixture was extracted with 1 x 150 mL, then 2 x 50 mL, of DCM. The combined organic extracts were dried over NaSO, filtered, evaporated, and subjected to purification. Purification was achieved using SFC on a Princeton HA-Morpholine 5 um 21.2 x 150 mm column eluting with CO / MeOH 10-50% in 5.0 min, 120 bar, 100 mL / min to give 193 mg (68%) of Example 33 as a white solid. 1H NMR (400 MHz, methanol-d4) δ = 7.83 (dd, J = 5.7, 9.1 Hz, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.15 (m, 1H), 5.41 - 5.17 (m, 2H), 4.72 (td, J = 4.6, 13.5 Hz, 1H), 4.61 - 4.53 (m, 1H), 4.41 - 4.22 (m, 3H), 4.22 - 4.11 (m, 1H), 4.04 - 3.92 (m, 1H), 3.82 (ddd, J = 5.3, 9.8, 12.3 Hz, 1H), 3.71 - 3.51 (m, 1H), 3.50 and 3.36 (alkyne H has two chemical shifts, both doublets, J = 0.8 Hz, 1H), 3.49 - 3.38 (m, 1H), 3.28 - 2.95 (m, 4H), 2.42 - 2.09 (m, 4H), 2.06 - 1.81 (m, 4H); 19 F NMR (377 MHz, methanol-d4) δ = - 111.68 (qd, J = 4.6, 61.0 Hz, 1F), - 143.97 - - 147.51 (m, 1F), - 173.14 - - 174.37 (m, 1F), MS: 618 [M+H] + .

[0379] Example 34 ({5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-yl}oxy)methyl dihydrogen phosphate.

[0380] [ka] Example 33 (850 mg, 1.3 mmol) was dissolved in DMF (12.6 mL). Cesium carbonate (1.24 g, 3.79 mmol) and NaI (569 mg, 3.79 mmol) were added, followed by di-tert-butyl chloromethyl phosphate (360 mg, 1.39 mmol). The mixture was stirred at 20° C. for 22 h. LCMS analysis showed 90% conversion to 34a, and another portion of di-tert-butyl chloromethyl phosphate (72 mg, 0.14 mmol) was added to the mixture, which was then stirred for an additional 5 h at 20° C. Water (44 mL) was added, and the mixture was stirred for 40 min at 20° C. A smaller particle size was achieved using multiple stir bars. The solid was filtered, collected, and placed under high vacuum overnight to give 34a (936 mg, 88%). MS: 840.3 [M+H] + 34a (936 mg, 1.11 mmol) was dissolved in a mixture of acetic acid (9.0 mL) and deionized water (4.5 mL). The mixture was stirred at 40° C. for 16 h, at which point LCMS analysis indicated hydrolysis of the tert-butyl group. The mixture was evaporated, redissolved in 50 / 50 CH CN / water (6 mL), and purified by HPLC. The desired fractions were collected to give Example 34 (560 mg, 69%). The solid was placed under vacuum for 3 days to remove the acetic acid. 1 H NMR (400 MHz, DMSO) δ 8.03 (ddd, J = 8.6, 5.9, 2.4 Hz, 1H), 7.75 (t, J = 2.7 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.37 (dd, J = 41.4, 2.6 Hz, 1H), 5.60 (d, J = 10.5 Hz, 2H), 5.40 (d, J = 53.5 Hz, 1H), 5.04 - 4.94 (m, 1H), 4.66 (dt, J = 13.4, 4.9 Hz, 1H), 4.52 - 4.47 (m, 1H), 4.34 (p, J = 10.8, 10.3 Hz, 3H), 4.14 - 4.11 (m, 1H), 3.91 - 3.85 (m, 1H), 3.72 - 3.51 (m, 2H), 3.47 - 3.38 (m, 4H), 3.03 (s, 1H), 2.41 - 2.26 (m, 2H), 2.21 - 1.82 (m, 6H), MS: 728.2 [M+H] + .

[0381] Example 34 was developed as a prodrug of Example 33 to improve the unbound exposure of Example 33 in plasma.

[0382] The solution formulation of Example 33 was an aqueous solution containing 2.5% (w / v) Pluronic F-68 (Poloxamer 188). The amorphous suspension formulations of Examples 33 and 34 were made using 0.5% (w / v) methylcellulose in water.

[0383] As demonstrated in Figure 1 and Table 1-A, following oral administration of a single dose of 100 mg (active) / kg in female NSG mice, the mean systemic exposure of Example 33 (as assessed by AUC and / or Cav) was approximately 10-17 fold higher following administration of Example 34 compared to administration of an oral suspension dose of Example 33 (free base).

[0384] [Table 3]

[0385] Prophetic Deuterated Analogue (PDA) of Example 33 The compounds presented in Table 2 are prophetic deuterated analogs (PDAs) of Example 33. Formula (V) is the general formula for deuterated Example 33, where Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4 and Y 5 are each independently H or D. The deuterated analogs of Example 33 in Table 2 were predicted based on the metabolic profile of Example 33 using MetaSite (moldiscovery.com / software / metasite / ). 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4 and Y 5 is the most likely metabolized position based on MetaSite prediction.

[0386] [ka]

[0387] [Table 4]

[0388] General methods / overviews for obtaining metabolic profiles of compounds and identifying metabolites are given in Dalvie et al., "Assessment of Three Human in Vitro Systems in the Generation of Major Human Excretory and Circulating Metabolites," Chemical Research in Toxicology, 2009, 22, 2, 357-368, tx8004357 (acs.org); King, R., "Biotransformations in Drug Metabolism," Ch. 3, Drug Metabolism Handbook Introduction, https: / / doi.org / 10.1002 / 9781119851042.ch3; Wu, Y. et al., "Metabolite Identification in the Preclinical and Clinical Phase of Drug Development," Current Drug Metabolish, 2021, 22, 11, 838-857, 10.2174 / 1389200222666211006104502; Godzien, J. et al., "Chapter Fifteen - Metabolite Annotation and Identification."

[0389] Numerous publicly available, commercially available software tools are available to help predict metabolic pathways and metabolites of compounds. Examples of such tools include BioTransformer 3.0 (biotransformer.ca / new), which uses a database of known metabolic reactions to predict metabolic biotransformations of small molecules; MetaSite (moldiscovery.com / software / metasite / ), which predicts metabolic transformations associated with cytochrome P450 and flavin-containing monooxygenase-mediated reactions in phase I metabolism; and Lhasa Meteor Nexus (lhasalimited.org / products / meteor-nexus.htm), which uses a wide range of machine learning models to predict metabolic pathways and metabolite structures, covering phase I and phase II biotransformations of small molecules.

[0390] The predicted deuterated analogs V-1 to V-18 of Example 33 in Table 2 may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, decreased CYP450 inhibition (competitive or time-dependent), or improved therapeutic index or tolerability.

[0391] If a person has ordinary skills, Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4 and Y 5 Additional deuterated analogs of Example 33 can be made having various combinations of V-1 through V-18. Such additional deuterated analogs may provide similar therapeutic benefits that can be achieved by deuterated analogs V-1 through V-18 of Example 33 in Table 2.

[0392] KRAS surface plasma resonance (SPR) binding assay Using SPR assays, the kinetic binding constants (K D ) was measured.

[0393] The binding affinity and kinetics of the present invention were measured by surface plasmon resonance (SPR) using a Biacore 8K or 8K+ (Cytiva, Marlborough, MA) instrument. Purified recombinant C-terminal site-specifically biotinylated wild-type (WT) KRAS (aa1-185), G12D KRAS (aa1-185), G12C KRAS (aa2-184), G12V KRAS (aa2-184), WT HRAS (aa2-184), and WT NRAS (aa2-185) proteins were used in these experiments in the presence of 1 μM GDP. Binding measurements were performed in parallel for either the WT / G12D / G12C / G12V KRAS or WT K / H / N RAS protein sets.

[0394] The Biacore instrument was detached and docked with a Series S Sensor Chip SA. Protein was diluted to 50 μg / mL in assay buffer (50 mM HEPES, 150 mM NaCl, 10 μM GDP, 5 mM MgCl2, 0.5 mM TCEP, 5% glycerol, 0.02% Tween-20, 2% DMSO, pH 7.2) and immobilized at a flow rate of 3 μL / min at 10°C for a 15-minute contact time, capturing approximately 3,000–4,000 RU of protein on the surface. The functionalized surface was then equilibrated with assay buffer for approximately 1 hour. An unfunctionalized SA surface without immobilized protein served as a reference for binding kinetic analysis. Compound binding kinetics were measured in either multi-cycle or single-cycle kinetic formats.

[0395] Multi-cycle kinetic analysis (MCK) Two-fold, 10-point serial dilutions of test compounds were prepared in a 96-well microplate (Greiner; Cat # 650101) with a maximum concentration of either 10 μM or 100 μM. Binding kinetics were measured by injecting serial compound dilutions into both the reference and RAS-immobilized channels at a flow rate of 100 μL / min and an association time of 90 seconds at 10°C. Compound dissociation was monitored for at least 400 seconds during each cycle. No additional regeneration was used. DMSO calibration curves were obtained by injecting 0–4% DMSO in assay buffer before and after compound analysis. As a positive control to assess the activity of proteins captured on the surface, a suitable compound with known affinity and kinetics was tested once in each experiment.

[0396] Single-cycle kinetic analysis (SCK) Three-fold, six-point serial dilutions of compounds were prepared in a deep 96-well microplate (Greiner Bio; Cat. # 780201) with a top concentration of 1 μM (concentration range: 0.004–1 μM). Binding kinetics were measured at 10°C by injecting the serial compound dilutions in increasing order into the reference and RAS-immobilized channels at a flow rate of 100 μL / min and an association time of 120 s. Compound dissociation was monitored for at least 3600 s. Two buffer blanks were also run in a single-cycle kinetic format, followed by the compound for double referencing. No additional regeneration was used. DMSO calibration curves were obtained by injecting 0–4% DMSO in assay buffer before and after compound analysis. As a positive control to assess the activity of proteins captured on the surface, a suitable compound with known affinity and kinetics was tested once in each experiment.

[0397] Both MCK and SCK data were processed and analyzed using Biacore Insight Evaluation Software (Cytiva, Marlborough, MA). The double-referenced and solvent-corrected data were fitted to a 1:1 Langmuir model to determine the kinetic binding constant (K D ), association velocity (k on ) and dissociation rate (k off The dissociation half-life (t 1 / 2 ) to the measured k off From the standard formula (t 1 / 2 =0.693 / k off ) was calculated using the fit. 2 The values and randomness of residue distribution were used to determine the effect.

[0398] The SPR binding assay results for Examples 1-31 are presented in Table 3. When Examples were tested more than once, the binding constants K D The geometric means of the α- and β-glucans are presented (n is the number of test replicates). Blank cells in Table 3 indicate that no data was available for that example in a particular assay.

[0399] Coupling constant K D have shown that the exemplified compounds have potent binding ability to all of the KRAS G12C, KRAS G12D, and KRAS G12V receptors, and may have selectivity over the HRAS and NRAS receptors.

[0400] [Table 5]

[0401] KRAS Cell Titer Glo (CTG) assay The CellTiter-Glo® (CTG) Luminescent Cell Viability Assay is a homogeneous method for determining the number of viable cells in culture based on quantification of ATP present, an indicator of metabolically active cells. The CTG is designed for use in a multiwell format, making it ideal for automated high-throughput screening (HTS), cell proliferation, and cytotoxicity assays. The homogeneous assay procedure involves adding a single reagent (CellTiter-Glo® Reagent) directly to cells cultured in serum-supplemented medium. No cell washing, medium removal, or multiple pipetting steps are required. The system detects as few as 15 cells per well in a 384-well format in 10 minutes from reagent addition and mixing.

[0402] Cells were grown in a humidified 5% CO2 incubator at 37°C using the culture conditions outlined below. All cell culture media reagents were purchased from Gibco. Cell lines were purchased from ATCC: H358 (non-small cell lung cancer cell line), SW620 (colorectal cancer cell line), and PANC08.13 (RPMI1640 + 10% FBS + insulin 10 units / ml, pancreatic cancer cell line). Test and control compounds were dispensed as nanoliter drops at the desired final concentration in 0.1% DMSO onto a 384 assay plate (Corning, Cat#3764) using an Echo Acoustic Dispenser, followed by cell seeding. Cells were seeded in a 40 μL volume per well at the following cell densities (cells per well): H358 (300), SW620 (750), and PANC08.13 (600). Cells are incubated in the presence of compound for 7 days. Viability is determined on day 7 using CellTiter-Glo® (CTG) Luminescent Cell Viability Assay (Promega). CTG is added to a final volume of 20 μl per well and incubated at room temperature for 15 minutes, after which luminescence is captured using an EnVision Reader with the LUM384 US protocol. Data is analyzed using Activity Base to determine compound response, and is expressed as either percent effect (PCTEFF) or percent control (PCTOCTL) as described below: zero percent effect control (ZPE) (negative control) - DMSO 100%; 100 percent effect (HPE) (positive control) - 1uM trametinib (GSK1120212, MEK inhibitor) (10mM 4nl per well and DMSO 36nl). The following formula / nomenclature is used (% effect; PCTEFF) and (% of control; PCTOCTL): PCTEFF: 100 × (raw data value − HPE / ZPE − HPE), PCTOCTL: 100 × raw data value / User_Defined_Array), where User_Defined_Array is either the aggregated HPE or ZPE.

[0403] CTG assay results for some exemplified examples are presented in Table 4. If an example was tested more than once, the IC 50 Geometric means (nM) are presented (n is the number of test replicates).

[0404] The CTG assay indicates that selected exemplary compounds of the present invention have demonstrated anti-cancer activity against pancreatic cancer, non-small cell lung cancer, and colorectal cancer.

[0405] [Table 6]

[0406] It will be apparent to those skilled in the art that various modifications and variations of the present invention can be made without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0407] All references cited herein, including patents, patent applications, documents, textbooks, and the like, and the references cited therein, unless already incorporated herein, are incorporated by reference in their entirety. In the event that one or more of the incorporated documents and similar materials differs from or contradicts this application, including, but not limited to, defined terms, term usage, described techniques, or the like, this application will control.

Claims

1. Compound of formula (V): 【Chemical 1】 or a pharmaceutically acceptable salt thereof [In the formula, R １ teeth, 【Chemistry 2】 is selected from the group consisting of R ２ is C １ Alkyl, C ３ Alkyl, -(C １ alkylene)-OH, or -(C ３ alkylene)-OH, R ３ teeth, 【Chemistry 3】 is selected from the group consisting of R ４ is Cl or F, R ５ is -(C １ alkylene)-OH, or C １ alkyl, or R ２ and R ５ taken together form a 7-membered heterocycloalkyl containing one heteroatom O, R ６ is H, -OH, halogen, -(C １ ~C ６ alkylene)-OH, -CN, -(C １ ~C ６ Alkylene)-CN,C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Fluoroalkyl, C ３ ~C ６ fluorocycloalkyl, and C １ ~C ６ represents one or two substituents selected from the group consisting of alkoxy; L is —O—, —S—, or —NR ７ -, and -CR ８ R ９ - a linker comprising 1, 2 or 3 members independently selected from the group consisting of: R ７ , R ８ , and R ９ are each independently H or C １ ~C ３ is alkyl, X is O, N, or S; l is 1 or 2.

2. R １ but, 【Chemistry 4】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

3. R １ but, 【Chemistry 5】 3. The compound of claim 2, wherein:

4. R ２ But C ３ alkyl, and R ５ But -(C １ 2. The compound of claim 1, wherein R is 1 or 2; R is 2 or 3; R is 3 or 4; R is 4 or 5; R is 5 or 6; R is 6 or 7; R is 7 or 8; R is 8 or 9; R is 9 or 10; R is 10 or 11; R is 11 or 12; R is 13 or 14; R is 15 or 16; R is 16 or 17; R is 18 or 19; R is 19 or 20; R is 21 or 22; R is 23 or 24; R is 25 or 26; R is 26 or 27; R is 28 or 29; R is 29 or 30; R is 29 or 31; R is 29 or 32; R is 29 or 33; R is 29 or 34; R

5. R ２ But -(C ３ alkylene)-OH, and R ５ But C １ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

6. R ２ and R ５ and R are joined to form a 7-membered heterocycloalkyl containing one heteroatom, O, or a pharmaceutically acceptable salt thereof.

7. R ３ but, 【Chemistry 6】 2. The compound of claim 1, wherein:

8. R ４ 2. The compound of claim 1, wherein is F, or a pharmaceutically acceptable salt thereof.

9. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X is O and 1 is 1.

10. Formula (VI): 【Chemistry 7】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof.

11. R ２ But C ３ alkyl, and R ５ But -(C １ 11. The compound of claim 10, wherein R is 1 or 2; R is 2 or 3; R is 3 or 4; R is 4 or 5; R is 5 or 6; R is 6 or 7; R is 7 or 8; R is 8 or 9; R is 9 or 10; R is 10 or 1 ...

12. R ２ But -(C ３ alkylene)-OH, and R ５ But C １ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

13. R ２ and R ５ and R are joined to form a 7-membered heterocycloalkyl containing one heteroatom, O, or a pharmaceutically acceptable salt thereof.

14. Compound of formula (VII) 【Chemistry 8】 or a pharmaceutically acceptable salt thereof [In the formula, R １１ , R １２ , R １３ , and R １４ are each independently H or C １ ~C ３ alkyl].

15. R １１ , R １２ , R １３ , and R １４ 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein each is independently H or methyl.

16. The compound 【Chemistry 9】 16. The compound of claim 14 or 15, wherein:

17. 【Catalog 10】 or a pharmaceutically acceptable salt thereof.

Images