Pyrido [4, 3-d] pyrimidine compounds

Abstract

The present invention relates to compounds of formulae (I) to (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 invention are useful for treating, preventing, inhibiting and ameliorating cancers, diseases or disorders. Formulae (V), (VI) and (VII) # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel pyrido[4,3-d]pyrimidine compound as a Kirsten rat sarcoma viral homolog (KRAS) inhibitor, the present invention also relates to the preparation of the compound and the intermediate used in the preparation, a composition containing the compound, and the use of the compound for treating KRAS-related diseases, such as cancer. Background Art

[0002] KRAS, HRAS (Harvey rat sarcoma virus) and NRAS (neuroblastoma RAS viral gene homolog; Neuroblastoma RAS Viral Oncogene Homolog) belong to a group of GTPases that are essential for cell survival and proliferation through complex signaling cascades. Mutated 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 commonly mutated RAS isoform in cancer cells (up to 85%), which causes the development of cancers including non-small cell lung cancer (NSCLC), colorectal cancer and pancreatic cancer, which has significant unmet medical needs both overall and individually for affected patients. KRAS mutations are widely seen in pancreatic ductal carcinoma (PDAC). Mutations in KRAS have been observed in 30% of NSCLC cases, which is the main (80%) form of lung cancer. KRAS mutations seen 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] Inhibitors of KRAS have been sought for decades, with recent progress in the approval of Sotolasib and subsequent KRASG12C-targeted compounds in trials (Palmer et al. 2021, NPJ Precision Oncology, 5, 98). Sotolasib specifically targets mutations in KRAS via covalent modification of mutant cysteine ​​at position 12. For this reason, when considering other major KRAS mutations, such as G12V and G12D, Sotolasib and other currently known KRAS inhibitors that rely on the same mechanism of action may have a narrow therapeutic range and limited use.

[0004] Therefore, there remains a need for new KRAS inhibitors that can be used to treat a wider range of cancers. Summary of the invention

[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 KRAS G12C, KRAS G12D, and KRAS G12V receptors, and can be used to treat, prevent, inhibit, and improve diseases mediated by any of KRAS G12C, KRAS G12D, and KRAS G12V receptors or combinations thereof, such as cancer, disorders, and conditions. A pharmaceutical composition is also provided, which comprises a compound or salt of the present invention alone or in combination with another anticancer therapeutic agent. 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 for using the foregoing. The present invention content is provided to introduce a selection of concepts further described below in a specific embodiment in a simplified form. The present invention content is not intended to identify the key features or essential features of the claimed subject matter, nor is it intended to be used alone as an aid in determining the scope of the claimed subject matter.

[0006] According to an embodiment of the present invention, there is provided a compound of formula (I)

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] R 1 C 3 -C 10 Cycloalkyl or 4-12 membered heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, O and S, wherein C 3 -C 10 The cycloalkyl or 4-12 membered heterocycloalkyl groups are each optionally substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CN, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy;

[0010] R 2 Selected from the group consisting of:

[0011]

[0012] Where R 2 Optionally substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CH 2 OH, -CN, -CH 2 CN, halogen, C 1 -C 3Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy;

[0013] R 3 C 6 -C 10 aryl or 4-12 membered heteroaryl containing one, two, three or four nitrogen atoms, wherein C 6 -C 10 The aryl or 4-12 membered heteroaryl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of: -OH, halogen, -CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, C 1 -C 3 Alkoxy and C 2 -C 3 Alkynyl;

[0014] R 4 For hydrogen, halogen, C 1 -C 3 Alkyl or C 1 -C 3 Fluoroalkyl;

[0015] L is a linker comprising one, two or three independently selected from -O-, -S-, -NR 5 -and-CR 6 R 7 - Members of the group;

[0016] R 5 , R 6 and R 7 Each independently is H or C 1 -C 3 alkyl;

[0017] X and Y are each independently selected from O, S, -SO 2 - and C 1 -C 2 A group consisting of an alkylene group; and

[0018] Z is a key, C 1 -C 2 Alkylene, O, S or -SO 2 -,

[0019] When Z is 0, R 2 is substituted by one, two or three substituents independently selected from the group consisting of: -OH, -CH 2OH, -CN, -CH 2 CN, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy,

[0020] When R 2 is a piperazinyl ring When the piperazinyl ring is substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CH 2 OH, -CN, -CH 2 CN, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy.

[0021] Embodiments of the present invention are described below, wherein for convenience, Embodiment 1 (E1) is the same as the embodiments of Formula (I) provided above.

[0022] 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 DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Mouse PK study results are provided showing unbound plasma concentrations of Example 33 in female NSG mouse plasma following oral dosing to female NSG mice at 100 mg / kg (n=3, mean + / - SD). Solutions of Example 33 were prepared using a Pluronic-based formulation [2.5% (w / v) Pluronic F-68 (Poloxamer 188)], and suspension arms of both Example 33 and Example 34 were prepared using a 0.5% (w / v) methylcellulose formulation. DETAILED DESCRIPTION

[0024] The present invention can be more easily understood by reference to the following detailed description of embodiments of the present invention and the examples included therein. It should be understood that the present invention is not limited to specific synthetic manufacturing methods, which can certainly vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be restrictive.

[0025] E1 is a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0026] E2 Compound of formula (Ia)

[0027]

[0028] or a pharmaceutically acceptable salt thereof, wherein:

[0029] R 1 C 3 -C 10 Cycloalkyl or 4-12 membered heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, O and S, wherein C 3 -C 10 The cycloalkyl or 4-12 membered heterocycloalkyl groups are each optionally substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CN, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy;

[0030] R 2 is a 4-12 membered heterocycloalkyl group comprising one, two or three heteroatoms selected from the group consisting of N, O and S, wherein the 4-12 membered heterocycloalkyl group has one and only one nitrogen as a ring member directly attached to the pyrido[4,3-d]pyrimidine core of formula (Ia), wherein the 4-12 membered heterocycloalkyl group is optionally substituted by one, two or three substituents independently selected from the group consisting of: -OH, -CH 2 OH, -CN, -CH 2 CN, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy, and when R 2 When the morpholinyl ring is a morpholinyl ring, the morpholinyl ring is substituted by one, two or three substituents independently selected from the group consisting of: -OH, -CH 2 OH, -CN, -CH 2 CN, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy;

[0031] R 3 C 6 -C 10aryl, or a 4-12 membered heteroaryl containing one, two, three or four nitrogen atoms, wherein C 6 -C 10 The aryl or 4-12 membered heteroaryl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of: -OH, halogen, -CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, C 1 -C 3 Alkoxy and C 2 -C 3 Alkynyl;

[0032] R 4 is hydrogen, halogen or C 1 -C 3 alkyl;

[0033] L is a linker comprising one, two or three independently selected from -O-, -S-, -NR 5 -and-CR 6 R 7 - members of the group; and

[0034] R 5 , R 6 and R 7 Each independently is H or C 1 -C 3 alkyl.

[0035] E3 A compound of Embodiment E1 or Embodiment E2 or a pharmaceutically acceptable salt thereof, wherein L is -O-CH 2 -.

[0036] E4 A compound according to any one of Embodiments E1 to E3, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-8 membered heterocycloalkyl containing one N as the only heteroatom, and the 5-8 membered heterocycloalkyl is optionally substituted by one, two or three independently selected from halogen and C 1 -C 3 The alkyl group is substituted with a substituent.

[0037] E5 A compound according to any one of Embodiments E1 to E4, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0038]

[0039] E6 A compound of embodiment E5 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0040]

[0041] E7 A compound according to any one of Embodiments E1 to E6, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

[0042]

[0043] Wherein X and Y are each independently O or -CH 2 -, and R 2 Optionally substituted with one, two or three substituents independently selected from the group consisting of -OH and -CN.

[0044] E8 A compound of embodiment E7 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

[0045]

[0046] E9 A compound of embodiment E8 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

[0047]

[0048] E10 A compound according to any one of Embodiments E1 to E6, or a pharmaceutically acceptable salt thereof, wherein R 2 for

[0049]

[0050] Where Z is a bond, -CH 2 - or O, where R 2 Optionally substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CH 2 OH, -CN, -CH 2 CN, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 alkoxy, and when Z is O, R 2 is substituted by one, two or three substituents independently selected from the group consisting of: -OH, -CH 2 OH, -CN, -CH 2 CN, halogen, C 1 -C 3 Alkyl, C 1 -C3 Fluoroalkyl and C 1 -C 3 Alkoxy.

[0051] E11 A compound of Embodiment E10 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

[0052]

[0053] E12 A compound according to any one of Embodiments E1 to E6, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the group consisting of:

[0054]

[0055] E13 A compound according to any one of Embodiments E1 to E12, or a pharmaceutically acceptable salt thereof, wherein R 3 C 6 -C 10 bicyclic aryl or 4-12 membered bicyclic heteroaryl, and wherein R 3 Optionally substituted with one, two, three or four substituents independently selected from the group consisting of: -OH, halogen, -CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 2 -C 3 Alkynyl.

[0056] E14 A compound of Embodiment E13 or a pharmaceutically acceptable salt thereof, wherein R 3 is naphthyl optionally substituted by one, two, three or four substituents independently selected from the group consisting of: -OH, halogen, -CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 2 -C 3 Alkynyl.

[0057] E15 A compound of Embodiment E14 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of:

[0058]

[0059] E16 A compound according to any one of Embodiments E1 to E15, or a pharmaceutically acceptable salt thereof, wherein R 4 It is Cl or F.

[0060] E17 The compound of any one of Embodiments E1 to E16, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0061]

[0062]

[0063]

[0064] E18 The compound of embodiment E17, wherein the compound is selected from the group consisting of:

[0065]

[0066]

[0067] E19 A pharmaceutical composition comprising a compound according to any one of embodiments E1 to E18 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0068] E20 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments E1 to E18 or a pharmaceutically acceptable salt thereof.

[0069] E21 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments E1 to E18 or a pharmaceutically acceptable salt thereof as a single agent.

[0070] E22 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to 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.

[0071] E23 The method for treating cancer according to any one of embodiments E20 to E22, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0072] E24 A compound according to any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0073] E25 A compound according to any one of Embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

[0074] E26 A compound for use in the treatment of cancer according to embodiment E25, wherein the cancer is non-small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0075] E27 Use of a compound according to any one of Embodiments E1 to E18 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating cancer.

[0076] E28 Use of a compound of embodiment E27 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0077] E29 is for use in a method of treating a disorder mediated by inhibition of KRAS G12C, KRAS G12D and KRAS G12V receptors in a subject, comprising administering to a subject in need thereof an amount of a compound of any one of Embodiments E1 to E18 or a pharmaceutically acceptable salt thereof effective to treat the disorder.

[0078] E30 A pharmaceutical combination comprising a compound according to 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.

[0079] E31 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E30 and at least one excipient.

[0080] E32 Compound of formula (II):

[0081]

[0082] or a pharmaceutically acceptable salt thereof, wherein:

[0083] R 1 C 3 -C 10 Cycloalkyl or 4-12 membered heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, O and S, each of which is optionally substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CN, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy;

[0084] R 2 H or selected from the group consisting of: -(C 1 -C 6 Alkylene)-OH, -(C 1 -C 6 Alkylene)-CN, -(C 1 -C 6 Alkylene)-SH, -(C 1 -C 3Alkylene)-S-(C 1 -C 3 Alkyl), -(C 1 -C 3 alkylene)-(S=O)-(C 1 -C 3 Alkyl), -(C 1 -C 3 Alkylene)-(SO 2 )-(C 1 -C 3 Alkyl), C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Fluoroalkyl, C 3 -C 6 Fluorinated cycloalkyl and C 1 -C 6 alkoxy, each of which is optionally substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CN, -NH 2 ,-SH,-(C 1 -C 4 Alkylene)-CN, -(C 1 -C 4 Alkylene)-OH, halogen, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy;

[0085] R 3 C 6 -C 10 aryl or 4-12 membered heteroaryl containing one, two, three or four N atoms, each of which is optionally substituted by one, two, three or four substituents independently selected from the group consisting of: -OH, halogen, -CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, C 1 -C 3 Alkoxy and C 2 -C 3 Alkynyl, when R 3 By two C 1 -C 3 When alkyl is substituted, the two C 1 -C3 Alkyl groups may be attached to form a fused 6 -C 10 3-6 membered ring of aryl or 4-12 membered heteroaryl;

[0086] R 4 H, halogen, C 1 -C 3 Alkyl or C 1 -C 3 Fluoroalkyl;

[0087] R 5 H, -OH, halogen, -NH 2 , CN or selected from the group consisting of: -(C 1 -C 6 Alkylene)-OH, -(C 1 -C 6 Alkylene)-CN, -(C 1 -C 6 Alkylene)-SH, -(C 1 -C 3 Alkylene)-S-(C 1 -C 3 Alkyl), -(C 1 -C 3 alkylene)-(S=O)-(C 1 -C 3 Alkyl), -(C 1 -C 3 Alkylene)-(SO 2 )-(C 1 -C 3 Alkyl), C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Fluoroalkyl, C 3 -C 6 Fluorinated cycloalkyl and C 1 -C 6 alkoxy, each of which is optionally substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CN, -NH 2 ,-SH,-(C 1 -C 4 Alkylene)-CN, halogen, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Fluoroalkyl and C 1 -C3 alkoxy; or alternatively, R 5 With R 5 Connected carbon, and R 2 With R 2 The nitrogen atoms are joined together to form a 4-8 membered heterocycloalkyl group containing one, two or three heteroatoms selected from the group consisting of N, O and S, or selected from N(C 1 -C 6 alkyl), -(S=O)- and -(SO 2 )-containing heteroatom group, wherein the 4-8 membered heterocycloalkyl group is optionally substituted by one, two or three substituents selected from the group consisting of: -OH, -CN, halogen, C 1 -C 3 Alkyl, -(C 1 -C 6 Alkylene)-CN and -(C 1 -C 6 Alkylene)-OH;

[0088] R 6 is independently at each occurrence H, -OH, halogen, CN or selected from the group consisting of: -(C 1 -C 6 Alkylene)-OH, -(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 Fluorinated cycloalkyl and C 1 -C 6 Alkoxy groups, each of which is optionally substituted with one, two or three substituents independently selected from the group consisting of: -OH, -CN, -(C 1 -C 4 Alkylene)-CN, halogen, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 3 Fluoroalkyl and C 1 -C 3 Alkoxy;

[0089] L is a linker comprising one, two or three independently selected from -O-, -S-, -NR 7 -and-CR 8 R9 - Members of the group;

[0090] R 7 , R 8 and R 9 Each independently is H or C 1 -C 3 alkyl;

[0091] X is O, N or S;

[0092] l is 1 or 2; and

[0093] x is 1 or 2.

[0094] E33 A compound of embodiment E32 or a pharmaceutically acceptable salt thereof, wherein the linker L is -(O-CH 2 )-.

[0095] E34 A compound of Embodiment E32 or Embodiment E33, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-8 membered heterocycloalkyl group containing one N as the only heteroatom, and the 5-8 membered heterocycloalkyl group is optionally substituted by one, two or three independently selected from halogen and C 1 -C 3 The alkyl group is substituted with a substituent.

[0096] E35 A compound of embodiment E34 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0097]

[0098] E36 A compound of embodiment E35 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0099]

[0100] E37 A compound according to any one of embodiments E32 to E36, or a pharmaceutically acceptable salt thereof, wherein R 2 H or selected from -(C 1 -C 5 Alkylene)-OH and C 1 -C 5 The group consisting of alkyl, each of which is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN and halogen.

[0101] E38 A compound according to any one of embodiments E32 to E37, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6Each is H, -OH, -CN, halogen, or independently selected from -(C 1 -C 5 Alkylene)-OH and C 1 -C 5 The group consisting of alkyl groups, each optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN and halogen.

[0102] E39 A compound according to any one of embodiments E32 to E38, wherein the compound has formula (III):

[0103]

[0104] Wherein Y is selected from the group consisting of: CH 2 、O、N(C 1 -C 6 alkyl), S, (S=O) and (SO 2 );

[0105] R 10 is independently selected at each occurrence from the group consisting of: -OH, -CN, halogen, C 1 -C 3 Alkyl, -(C 1 -C 6 Alkylene)-CN and -(C 1 -C 6 alkylene)-OH; and

[0106] m and n are each independently 0, 1, 2 or 3, y is 1, 2 or 3, and m plus n is 1, 2, 3, 4 or 5.

[0107] E40 A compound of Embodiment E39 wherein Y is -CH 2 -or O.

[0108] E41 A compound according to any one of embodiments E32 to E40, or a pharmaceutically acceptable salt thereof, wherein R 3 is a bicyclic aryl or bicyclic heteroaryl, each of which is optionally substituted by one to four substituents independently selected from the group consisting of: -OH, halogen, -CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 2 -C 3 Alkynyl, when R 3 By two C 1 -C 3 When alkyl is substituted, the two C 1 -C 3 The alkyl groups may be linked to form a 3-6 membered ring.

[0109] E42 A compound of Embodiment E41 or a pharmaceutically acceptable salt thereof, wherein R 3 is naphthyl optionally substituted by one to four substituents independently selected from the group consisting of: -OH, halogen, -CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 2 -C 3 Alkynyl.

[0110] E43 A compound of Embodiment E42 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of:

[0111]

[0112] E44 A compound according to any one of embodiments E32 to E43, or a pharmaceutically acceptable salt thereof, wherein R 4 It is Cl or F.

[0113] E45 A compound of Embodiment E32 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (IV):

[0114]

[0115] Where R 3 is naphthyl optionally substituted by one to four substituents independently selected from the group consisting of: -OH, halogen, -CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl and C 2 -C 3 Alkynyl; l is 1 or 2.

[0116] E46 The compound of embodiment E32 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0117]

[0118] E47 compound which is:

[0119]

[0120] or a pharmaceutically acceptable salt thereof.

[0121] E48 compound which is:

[0122]

[0123] A pharmaceutically acceptable salt of E49 compound, wherein the compound is:

[0124]

[0125] E50 A pharmaceutical composition comprising a compound according to any one of embodiments E32 to E47 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0126] E51 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments E32 to E47 or a pharmaceutically acceptable salt thereof.

[0127] E52 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments E32 to E47 or a pharmaceutically acceptable salt thereof as a single agent.

[0128] E53 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a 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.

[0129] E54 The method for treating cancer according to any one of embodiments E51 to E53, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0130] E55 A compound according to any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0131] E56 A compound according to any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

[0132] E57 A compound for use in the treatment of cancer according to embodiment E56, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0133] E58 Use of a compound according to any one of embodiments E32 to E47, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer.

[0134] E59 Use of a compound of embodiment E58 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0135] E60 A method for treating a disorder mediated by inhibition of 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.

[0136] E61 A pharmaceutical combination comprising a compound according to 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, wherein the pharmaceutical combination is a fixed or non-fixed combination.

[0137] E62 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E61 and at least one excipient.

[0138] E63 Compound of formula (V):

[0139]

[0140] or a pharmaceutically acceptable salt thereof, wherein:

[0141] R 1 Selected from the group consisting of:

[0142]

[0143] R 2 C 1 Alkyl, C 3 Alkyl, -(C 1 Alkylene)-OH or -(C 3 Alkylene)-OH;

[0144] R 3 Selected from the group consisting of:

[0145]

[0146] R 4 Cl or F;

[0147] R 5 For-(C 1 Alkylene)-OH or C 1 Alkyl, where R 2 and R 5 optionally together form a 7-membered heterocycloalkyl group containing one heteroatom O;

[0148] R 6 represents one or two substituents selected from the group consisting of: H, -OH, halogen, -(C 1 -C 6 Alkylene)-OH, -CN, -(C1 -C 6 Alkylene)-CN, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Fluoroalkyl, C 3 -C 6 Fluorinated cycloalkyl and C 1 -C 6 Alkoxy;

[0149] L is a linker comprising one, two or three independently selected from -O-, -S-, -NR 7 -and-CR 8 R 9 - Members of the group;

[0150] R 7 , R 8 and R 9 Each independently is H or C 1 -C 3 alkyl;

[0151] X is O, N or S; and

[0152] l is 1 or 2.

[0153] E64 A compound of Embodiment E63 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0154]

[0155] E65 A compound of embodiment E64 or a pharmaceutically acceptable salt thereof, wherein R 1 for:

[0156]

[0157] E66 A compound according to any one of embodiments E63 to E65, or a pharmaceutically acceptable salt thereof, wherein R 2 C 3 Alkyl, and R 5 For-(C 1 Alkylene)-OH.

[0158] E67 A compound according to any one of embodiments E63 to E65, or a pharmaceutically acceptable salt thereof, wherein R 2 For-(C 3 Alkylene)-OH, and R 5 C 1 alkyl.

[0159] E68 A compound of Embodiment E66 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 are linked together to form a 7-membered heterocycloalkyl group containing one heteroatom O.

[0160] E69 A compound of Embodiment E67 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 are linked together to form a 7-membered heterocycloalkyl group containing one heteroatom O.

[0161] E70 A compound according to any one of embodiments E63 to E69, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

[0162]

[0163] E71 A compound according to any one of embodiments E63 to E70, or a pharmaceutically acceptable salt thereof, wherein R 4 For F.

[0164] E72 A compound according to any one of Embodiments E63 to E71, or a pharmaceutically acceptable salt thereof, wherein X is O and l is 1.

[0165] E73 A compound of Embodiment E63 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (VI):

[0166]

[0167] E74 A compound of embodiment E73 or a pharmaceutically acceptable salt thereof, wherein R 2 C 3 Alkyl, and R 5 For-(C 1 Alkylene)-OH.

[0168] E75 A compound of Embodiment E73 or a pharmaceutically acceptable salt thereof, wherein R 2 For-(C 3 Alkylene)-OH, and R 5 C 1 alkyl.

[0169] E76 A compound of embodiment E74 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 Together they form a 7-membered heterocycloalkyl group containing one heteroatom O.

[0170] E77 A compound of embodiment E75 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5Together they form a 7-membered heterocycloalkyl group containing one heteroatom O.

[0171] E78 Compound of formula (VII)

[0172]

[0173] or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 and R 14 Each independently is H or C 1 -C 3 alkyl.

[0174] E79 A compound of Embodiment E78 or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 and R 14 Each is independently H or methyl.

[0175] E80 A compound according to embodiment E78 or E79, or a pharmaceutically acceptable salt thereof, wherein the compound is

[0176]

[0177] E81 compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0178]

[0179] E82 A pharmaceutical composition comprising a compound according to any one of embodiments E63 to E81 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0180] E83 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments E63 to E81 or a pharmaceutically acceptable salt thereof.

[0181] E84 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments E63 to E81 or a pharmaceutically acceptable salt thereof as a single agent.

[0182] E85 A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a 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.

[0183] E86 The method for treating cancer according to any one of embodiments E83 to E85, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0184] E87 A compound according to any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0185] E88 A compound according to any one of embodiments E63 to E81, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

[0186] E89 The compound for use in the treatment of cancer according to embodiment E88, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0187] E90 Use of a compound according to any one of embodiments E63 to E81 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer.

[0188] E91 Use of a compound of embodiment E90 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

[0189] E92 A method for treating a disorder mediated by inhibition of KRAS G12C, KRAS G12D and KRAS G12V receptors in a subject, comprising administering to a subject in need thereof an amount of a compound of any one of embodiments E63 to E81 or a pharmaceutically acceptable salt thereof effective to treat the disorder.

[0190] E93 A pharmaceutical combination comprising a compound according to 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, wherein the pharmaceutical combination is a fixed or non-fixed combination.

[0191] E94 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E93 and at least one excipient.

[0192] Each of the embodiments described herein can be combined with any other (one or more) embodiment described herein, and any (one or more) other embodiment is consistent with the (one or more) embodiment with which it is combined. In addition, any one of the compounds described in the examples or a pharmaceutically acceptable salt thereof can be claimed separately or grouped together with one or more other compounds of the examples or a pharmaceutically acceptable salt thereof.

[0193] Additionally, each of the embodiments described herein contemplates within its scope pharmaceutically acceptable salts of the compounds described herein, stereoisomers of the compounds, and pharmaceutically acceptable salts of stereoisomers.

[0194] definition

[0195] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by one of ordinary skill in the art.

[0196] The invention described herein may suitably be practiced in the absence of any element(s) not specifically disclosed herein.

[0197] "Compounds of the present invention" include compounds of formula (I) and novel intermediates used in their preparation. Those of ordinary skill in the art will appreciate that compounds of the present invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers, and other mixtures of such isomers, tautomers. Those of ordinary skill in the art will also appreciate that compounds of the present invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotope-labeled forms that they may form.

[0198] As used herein, the singular forms "a", "an", and "the" include plural references unless otherwise indicated. By way of example, "a" or "an" substituent includes one or more substituents.

[0199] As used herein, when used to modify a numerically defined parameter (e.g., a dosage of 5 mg), the term "about" means that the variation of the parameter can be as much as 10% lower or higher than the specified value of the parameter. For example, a dosage of about 5 mg means 5% ± 10%, i.e., it can vary between 4.5 mg and 5.5 mg.

[0200] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the others. Thus, each substituent may be the same as or different from the other substituent(s).

[0201] "Optional" or "optionally" means that the subsequently described event or circumstance may or need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0202] The terms "optionally substituted with" and "substituted or unsubstituted" are used interchangeably to indicate that the particular group being described may not have a non-hydrogen substituent (i.e., unsubstituted), or that the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present in the unsubstituted form of the described group. When the optional substituent is connected via a double bond, such as an oxy-substituent (=O), the group occupies two available valences, so the total number of other substituents included is reduced by two. In the case where the optional substituents are independently selected from a list of alternatives, the selected groups may be the same or different. Throughout this disclosure, it will be understood that the number and nature of the optional substituents will be limited to the extent that such substitution is chemically reasonable for a person of ordinary skill in the art.

[0203] "Halogen" refers to fluorine, chlorine, bromine and iodine (F, Cl, Br, I).

[0204] "Cyano" refers to a substituent in which a carbon atom is connected to a nitrogen atom by a triple bond, ie, -C≡N (also depicted herein as "-CN").

[0205] "Hydroxy" refers to an -OH group.

[0206] "Oxylidene" refers to a double-bonded oxygen (=0).

[0207] "Alkyl" refers to a saturated monovalent aliphatic hydrocarbon radical having a specified number of carbon atoms, including straight or branched chain radicals. Alkyl groups may contain, but are not limited to, 1 to 6 carbon atoms ("C 1 -C 6 alkyl”), 1 to 3 carbon atoms (“C 1 -C 3 alkyl") or 1 to 2 carbon atoms ("C 1 -C 2 Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.

[0208] "Fluoroalkyl" refers to an alkyl group as defined herein in which from one to all of the hydrogen atoms of the alkyl group 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 (-CF 3 ) and pentafluoroethyl (-C 2 F 5 ).

[0209] "Alkylene" refers to a divalent aliphatic hydrocarbon radical having a specified number of carbon atoms. An alkylene radical may contain, but is not limited to, 1 to 6 carbon atoms ("C 1 -C 6alkylene”) or 1 to 2 carbon atoms (“C 1 -C 2 Examples include -(CH 2 )-(methylene) and -(CH 2 -CH 2 )-(ethylene).

[0210] "Alkoxy" refers to an alkyl group, as defined herein, that is singly bonded to an oxygen atom. The point of attachment of the alkoxy group to the molecule is through the oxygen atom. The alkoxy group may be depicted as alkyl-O-. The alkoxy group may contain, but is not limited to, 1 to 6 carbon atoms ("C 1 -C 6 alkoxy”) or 1 to 3 carbon atoms (“C 1 -C 3 Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, and the like.

[0211] "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 groups may contain 2 to 3 carbon atoms ("C 2 -C 3 Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0212] "Cycloalkyl" refers to a fully saturated hydrocarbon ring system having the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring system attached to the base molecule through the carbon atoms of the cycloalkyl ring. Cycloalkyl may contain, but is not limited to, 3 to 10 carbon atoms ("C 3 -C 10 cycloalkyl”), 3 to 8 carbon atoms (“C 3 -C 8 cycloalkyl”), 3 to 6 carbon atoms (“C 3 -C 6 cycloalkyl”), 3 to 5 carbon atoms (“C 3 -C 5 cycloalkyl”) or 3 to 4 carbon atoms (“C 3 -C 4 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted as otherwise defined herein.

[0213] "Fluorocycloalkyl" refers to a cycloalkyl group as defined herein in which from one to all of the hydrogen atoms of the alkyl group are replaced by fluorine atoms. Examples include, but are not limited to, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, and fluorocyclohexyl.

[0214] "Heterocycloalkyl" refers to a fully saturated ring system 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 atoms are optionally substituted with one or two oxy groups (i.e., S(O) q , wherein q is 0, 1 or 2) and wherein the heterocycloalkyl ring is connected to the base molecule through a ring atom which may be C or N. The heterocycloalkyl ring includes a monocyclic or polycyclic ring, such as a bicyclic ring. The heterocycloalkyl ring also includes a spirocyclic ring, a bridged ring or a ring fused to one or more other heterocycloalkyl rings or carbocyclic rings, wherein such a spirocyclic ring, a bridged ring or a fused ring itself may be saturated, partially unsaturated or aromatic, and the degree of unsaturation or aromaticity is chemically reasonable provided that the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. The heterocycloalkyl ring may contain 1 to 4 atoms selected from N, O and S(O) q as ring members, or 1 to 3 ring heteroatoms or 1 to 2 ring heteroatoms, provided that such a heterocycloalkyl ring does not contain two adjacent oxygen atoms or sulfur atoms.

[0215] As further defined herein, the heterocycloalkyl ring may be optionally substituted, unsubstituted or substituted. Such substituents may be present on the heterocycle attached to the base molecule, or on the monocyclic, bicyclic, tricyclic, spirocyclic, bridged or fused ring to which it is attached.

[0216] According to the definition herein, heterocycloalkyl ring can include, but is not limited to, 4-12 membered heterocyclyl, such as 5-8 membered or 4-6 membered heterocycloalkyl.Examples of heterocycloalkyl ring groups of the present invention can include, but are not limited to, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl, thiazepanyl, hexahydro-1H-pyrrolizine (pyrrolizine) ring group, 8-oxa-3-azabicyclo [3.2.1] octane ring group, 3-azabicyclo [3.2.1] octane ring group, 6-azabicyclo [3.2.1] octane ring group or 3-azabicyclo [3.2.0] heptane ring group.

[0217] "Aryl" or "aromatic" refers to a monocyclic, bicyclic (eg, biaryl, fused), or polycyclic ring system containing the specified number of ring atoms, wherein all carbon atoms in the ring(s) have sp 2 The aryl group may contain, but is not limited to, 6 to 10 carbon atoms (“C 6 -C 10 Fused aryl groups may include an aromatic ring (e.g., a benzene ring) fused to another aromatic ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted, or substituted as otherwise defined herein.

[0218] Similarly, "heteroaryl" or "heteroaromatic" refers to a monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring system containing the specified number of ring atoms and including at least one heteroatom selected from N, O and S as a ring member in the ring, wherein all carbon atoms in the ring have sp 2 The heteroaryl group is a group of 5-14 ring atoms, 5-12 ring atoms, 5-10 ring atoms, 5-9 ring atoms, or 5-6 ring atoms. The heteroaryl ring is connected to the base molecule via the ring atoms of the heteroaryl ring. Therefore, a 5- or 6-membered heteroaryl ring (alone or in a fused structure) can be connected to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrazolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[3,2-b]pyridyl, quinolyl, isoquinolyl, purinyl, triazine, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, carbazolyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[4,3-d]pyridyl pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, purinyl, indolyl, 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, azaquinazole

[0063] In some embodiments, the heteroaryl groups are pyrrolyl, 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, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl rings. As further defined herein, heteroaryl groups may be optionally substituted, unsubstituted or substituted.

[0219] "Amino" refers to the unsubstituted radical -NH 2Where an amino group is described as being substituted or optionally substituted, the term includes groups of the form -NRxRy, wherein each of Rx and Ry is defined as otherwise described herein. For example, "alkylamino" refers to the group -NRxRy, wherein one of Rx and Ry is an alkyl moiety and the other is H, and "dialkylamino" refers to -NRxRy, wherein both Rx and Ry are alkyl moieties, wherein the alkyl moiety has a specified number of carbon atoms (e.g., -NH(C 1 -C 4 Alkyl) or -N(C 1 -C 4 alkyl) 2 ).

[0220] Wavy lines used in chemical structures in this disclosure refers to the point of attachment of a substituent.

[0221] The term "pharmaceutically acceptable" means that a substance (eg, a compound described herein) and any salt thereof, or a composition containing the substance or salt of the invention is suitable for administration to a subject or patient.

[0222] As used herein, "deuterium enrichment factor" means the ratio between the abundance of deuterium and the natural abundance of deuterium, each relative to the abundance of hydrogen. In particular embodiments, the deuterium enrichment factor for atomic positions designated as having deuterium is typically at least 1000 (15% deuterium incorporated), at least 2000 (30% deuterium incorporated), at least 3000 (45% deuterium incorporated), at least 3500 (52.5% deuterium incorporated), at least 3500 (52.5% deuterium incorporated at each designated deuterium atom), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated).

[0223] Salt

[0224] Salts encompassed within the term "pharmaceutically acceptable salts" refer to compounds of the invention which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid or base, respectively, to provide salts of the compounds of the invention suitable for administration to a subject or patient.

[0225] In addition, compounds of formula (I) may also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, which can be used 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 diastereomers of compounds of formula (I).

[0226] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclaminate, edisylate, ethanesulfonate, formate, fumarate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzylbenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene dicarboxylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, 1,5-naphthalene disulfonic acid, and xinafoate.

[0227] Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, N,N'-dibenzylethylenediamine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0228] Hemisalts of acids and bases can also be formed, for example hemisulphate and hemicalcium salts.

[0229] 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.

[0230] The 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 steps:

[0231] (i) reacting a compound of the present invention with a desired acid or base;

[0232] (ii) by removing an acid-labile or base-labile protecting group from a suitable precursor of the compound of the invention, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using the desired acid or base; or

[0233] (iii) by converting one salt of a compound of the invention into another salt. This can be achieved by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure.

[0234] These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.

[0235] Solvate

[0236] The compounds of the present invention or their pharmaceutically acceptable salts may exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the present invention or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used.

[0237] In addition, the compounds of formula (I) may also include other solvates of such compounds that are not necessarily pharmaceutically acceptable solvates, which can be used as intermediates for one or more of the following: 1) preparing the compounds of formula (I); 2) purifying the compounds of formula (I); 3) separating the enantiomers of the compounds of formula (I); or 4) separating the diastereomers of the compounds of formula (I).

[0238] The currently accepted classification system for organic hydrates is a system that defines isolated site hydrates, channel hydrates or metal ion coordinated hydrates - see KR Morris's Polymorphism in Pharmaceuti calSolids (HG Brittain, ed., Marcel Dekker, 1995). Isolated site hydrates are hydrates in which the water molecules are separated from each other by intervening organic molecules and are not in direct contact. In channel hydrates, the water molecules are in the lattice channels in close proximity to other water molecules. In metal-ion coordinated hydrates, the water molecules are bound to the metal ions.

[0239] When the solvent or water is tightly bound, the complex can have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound (as in channel solvates and hygroscopic compounds), the water / solvent content can depend on humidity and drying conditions. In such cases, non-stoichiometry will become the norm.

[0240] Compound

[0241] Also included within the scope of the present invention are multi-component complexes (except salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include inclusion compounds (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular components bound together via non-covalent interactions, such as complexes (co-crystals) that can form hydrogen bonds with neutral molecules or with salts. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together - see O. Almarsson and MJ Zaworotko, Chem Commun, 17, 1889-1896 (2004). For a general review of multi-component complexes, see Haleblian, J Pharm Sci, 64 (8), 1269-1288 (August 1975).

[0242] Solid form

[0243] The compounds of the present invention can exist in a continuous solid state form ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or liquid depending on the temperature. Typically, such a material does not produce a unique X-ray diffraction pattern, and while exhibiting the properties of a solid, is more formally described as a liquid. Upon heating, a change in the properties of a solid to the properties of a liquid occurs, characterized by a change in state, typically secondary ("glass transition"). The term "crystalline" refers to a solid phase in which a material has a regularly ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with a specified peak. Such a material will exhibit the properties of a liquid when fully heated, but the solid becomes a liquid characterized by a phase transition, typically primary ("melting point").

[0244] The compounds of the present invention may also exist in a mesomorphic state (intermediate phase or liquid crystal) when subjected to appropriate conditions. The mesomorphic state is an intermediate state between a true crystalline state and a true liquid state (melt or solution) and consists of two-dimensional order at the molecular level. Mesomorphisms that occur due to temperature changes are described as "thermotropic", and mesomorphisms that occur due to 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 are composed of molecules with ionic polar head groups (such as -COO - Na + 、-COO - K + or -SO 3 - Na + ) or nonionic polar head groups (such as -N - N + (CH3 ) 3 ) molecular composition. For more information, see NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope, 4th edition (Edward Arnold, 1970).

[0245] Stereoisomers

[0246] The compounds of the present invention may exist in the form of 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, diastereomers, rotational isomers, atropisomers and conformational isomers. For example, compounds of the present invention containing one or more asymmetric carbon atoms may exist in the form of two or more stereoisomers.

[0247] The pharmaceutically acceptable salts of the compounds of the present invention may also contain an optically active counter ion (eg, d-lactate or L-lysine) or a racemic counter ion (eg, dl-tartrate or dl-arginine).

[0248] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example chromatography and fractional crystallization.

[0249] Conventional techniques for preparing / isolating single enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g., alcohol, or a base or acid, such as 1-phenylethylamine or tartaric acid, in the case where the compounds of the present invention contain an acidic or basic moiety). The resulting diastereomeric mixture can be separated by chromatography, fractional crystallization, or by using both of the techniques, and one or both of the diastereomers can be converted into the corresponding pure enantiomers in a manner well known to the technician. The chiral compounds of the present invention (and their chiral precursors) can be obtained in an enantiomerically enriched form using chromatography (usually HPLC). Concentrating the eluent provides an enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be used. Methods for chiral chromatography suitable for use 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).

[0250] When any racemate is crystallized, there may be two different types of crystals. The first type is the racemic compound (real racemate) mentioned above, which wherein produces a crystal of a homogeneous form containing two enantiomers of equimolar amount. The second type is a racemic mixture or an agglomerate, which wherein produces two crystalline forms each comprising a single enantiomer in equimolar amount. Although the two crystalline forms present in the racemic mixture can have the same physical properties, it can be different from the real racemate in physical properties. The racemic mixture can be separated by conventional techniques known to those skilled in the art-see, for example, ELEiel and SH Wilen's Stereochemistry of Organic Compounds (Wiley, 1994).

[0251] Tautomerism

[0252] When structural isomers can be interconverted via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can occur as proton tautomerism in compounds of the invention containing, for example, imino / amino, keto / enol or oxime / nitroso, lactam / lactim groups, or as so-called valence tautomerism in compounds containing aromatic moieties. It can be seen that a single compound can exhibit more than one type of isomerism.

[0253] It must be emphasized that, although the compounds of the present invention have been drawn herein in a single tautomeric form for the sake of brevity, all possible tautomeric forms are encompassed within the scope of the present invention.

[0254] isotope

[0255] The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the present invention wherein 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 predominantly found in nature.

[0256] Examples of isotopes suitable for inclusion in the compounds of the present invention may include isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of phosphorus, such as 32 P; and sulfur isotopes, such as 35 S.

[0257] Certain isotopically labeled compounds of the invention (e.g., compounds into which a radioactive isotope has been incorporated) are useful in either or both drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) is particularly suitable for this purpose due to its easy introduction and ready means of detection.

[0258] Deuterium (i.e. 2 H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability.

[0259] Using positron emitting isotopes (such as11 C. 18 F. 15 O and 13 Substitution of N) can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0260] In some embodiments, the present invention provides deuterium-labeled (or deuterated) compounds and salts, wherein the chemical formulas and variables of such compounds and salts are each and independently described herein. "Deuterated" means that at least one of the atoms in the compound is deuterium, and its abundance is greater than the natural abundance of deuterium (usually about 0.015%). The skilled person recognizes that in a compound with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, of which about 0.015% is D. The concentration of deuterium introduced into the deuterium-labeled compounds and salts of the present invention can be defined by the deuterium enrichment factor. It should be understood that one or more deuteriums can be exchanged with hydrogen under physiological conditions.

[0261] In some embodiments, the deuterium compound is selected from any one of the compounds set forth in Table 2 shown in the Examples section.

[0262] In some embodiments, one or more hydrogen atoms at certain metabolic sites on the compounds of the invention are deuterated.

[0263] Isotopically-labeled compounds of the 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 non-labeled reagent previously employed.

[0264] Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, for example D 2 O、d 6 -acetone, d 6 -DMSO.

[0265] Prodrug

[0266] The compounds of the present invention can be administered in the form of prodrugs. Therefore, some derivatives of the compounds of the present invention that may have little or no pharmacological activity in themselves can be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage, especially by hydrolytic cleavage promoted by esterases or peptidases, when applied to the body or body. Such derivatives are referred to as "prodrugs". Other information about 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.)".

[0267] Prodrugs according to the invention can be produced, for example, by replacing appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0268] Thus, the prodrugs of the present invention can be (a) ester or amide derivatives of carboxylic acids when present in the compounds of the present invention; (b) ester, carbonate, carbamate, phosphate, or ether derivatives of hydroxy groups when present in the compounds of the present invention; (c) amide, imine, carbamate, or amine derivatives of amino groups when present in the compounds of the present invention; (d) thioester, thiocarbonate, thiocarbamate, or sulfide derivatives of thiol groups when present in the compounds of the present invention; or (e) oxime or imine derivatives of carbonyl groups when present in the compounds of the present invention.

[0269] Some specific examples of prodrugs according to the present invention include:

[0270] (i) When the compounds of the present invention contain a carboxylic acid functional group (-COOH), esters thereof, such as those in which the hydrogen of the carboxylic acid functional group of the compound is replaced by C 1 -C 8 Alkyl (e.g. ethyl) or (C 1 -C 8 alkyl)C(=O)OCH 2 -(For example t BuC(=O)OCH 2 -) replaced compounds;

[0271] (ii) When the compounds of the present invention contain an alcohol functional group (-OH), their esters, such as those in which the hydrogen of the alcohol functional group of the compound is replaced by -CO(C 1 -C 8Compounds in which the alcohol is esterified with an amino acid;

[0272] (iii) When the compounds of the present invention contain an alcohol functional group (-OH), their ethers, such as those in which the hydrogen of the alcohol functional group of the compound is replaced by (C 1 -C 8 alkyl)C(=O)OCH 2 -or-CH 2 OP(=O)(OH) 2 Replaced compounds;

[0273] (iv) When the compound of the present invention contains an alcohol functional group (-OH), its phosphate ester, such as one in which the hydrogen of the alcohol functional group of the compound is replaced by -P(=O)(OH) 2 or -P(=O)(O - Na + ) 2 or -P(=O)(O - ) 2 Ca 2+ Replaced compounds;

[0274] (v) When the compounds of the present invention contain a primary or secondary amino functional group (-NH 2 or -NHR, wherein R≠H), its amide, for example, wherein, as the case may be, one or both hydrogen atoms of the amino functional group of the compound are replaced by (C 1 -C 10 )alkanoyl, -COCH 2 NH 2 Compounds in which the amino group is replaced or derivatized with amino acids;

[0275] (vi) When the compounds of the present invention contain a primary or secondary amino functional group (-NH 2 or -NHR, wherein R≠H), the amine, for example, wherein, as the case may be, one or both hydrogen atoms of the amino functional group of the compound are replaced by -CH 2 OP(=O)(OH) 2 Replacement compounds.

[0276] (vii) When the compound of the present invention contains an alcohol functional group (-OH), the hydrogen of the alcohol functional group is replaced with a group selected from the following group:

[0277]

[0278] Where R, R', R", R'' are (C 1 -C 8 ) alkyl or (C 1 -C 8 )alkoxy and may be linear, branched or cyclic.

[0279] Some preferred prodrugs can be obtained by C 6 -C 10 Some more preferred prodrugs can be prepared via -OH on a naphthyl group.

[0280] Certain compounds of the present invention themselves can serve as prodrugs of other compounds of the present invention. Two compounds of the present invention may also be joined together in prodrug form. In some cases, a prodrug of a compound of the present invention can be produced by internally connecting two functional groups in a compound of the present invention, for example by forming a lactone.

[0281] Metabolites

[0282] Also included within the scope of the present invention are active metabolites of the compounds of the present invention, i.e. compounds formed in vivo following administration of the drug, usually by oxidation or dealkylation. Some examples of metabolites according to the present invention include, but are not limited to:

[0283] (i) In the case where the compounds of the present invention contain an alkyl group, their hydroxyalkyl derivatives (-CH>-COH);

[0284] (ii) in the case where the compounds of the present invention contain an alkoxy group, the hydroxy derivatives thereof (-OR->-OH);

[0285] (iii) in the case where the compound of the present invention contains a tertiary amino group, its secondary amino group derivative (-NRR'->-NHR or -NHR');

[0286] (iv) Where the compounds of the present invention contain secondary amino groups, their primary derivatives (-NHR->-NH 2 );

[0287] (v) Where the compounds of the present invention contain a phenyl moiety, their phenol derivatives (-Ph->-PhOH);

[0288] (vi) When the compound of the present invention contains an acylamino group, its carboxylic acid derivative (-CONH 2 ->COOH); and

[0289] (vii) Where the compound contains a hydroxyl or carboxylic acid group, the compound may be metabolized by, for example, conjugation with glucuronic acid to form a glucuronide. Other conjugation metabolic pathways exist. These pathways are often referred to as phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups such as NH groups may also undergo conjugation.

[0290] Pharmaceutical composition

[0291] In another embodiment, the present invention includes pharmaceutical compositions. For the purpose of pharmaceutical compositions, the compound itself or a pharmaceutically acceptable salt thereof will be referred to simply as a compound of the present invention.

[0292] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof as active ingredients and at least one pharmaceutically acceptable excipient.

[0293] The term "excipient" is used herein to describe any ingredient other than a compound of the invention. The choice of excipient will to a large extent 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.

[0294] As used herein, "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, carriers, diluents, etc. that are compatible physiologically. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc. and combinations thereof, and may include isotonic agents in the composition, such as sugar, sodium chloride or polyols, such as mannitol or sorbitol. Examples of excipients also include various organic solvents (such as hydrates and solvates). If necessary, the pharmaceutical composition may contain additional excipients, such as flavorings, binders / binding agents, lubricants, disintegrants, sweeteners or flavorings, colorants or dyes, etc. For example, for oral administration, tablets containing various excipients (such as citric acid) can be used together with various disintegrants (such as starch, alginic acid and some composite silicates) and binders (such as sucrose, gelatin and gum arabic). Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. In addition, lubricants (such as magnesium stearate, sodium lauryl sulfate and talc) are generally suitable for tableting purposes. Similar types of solid compositions can also be used in soft and hard filled gelatin capsules. Therefore, non-limiting examples of excipients also include lactose or milk sugar and high molecular weight polyethylene glycol. When it is necessary to orally administer an aqueous suspension or elixir, the active compound therein can be combined with various sweeteners or flavorings, coloring agents or dyes and emulsifiers or suspending agents when necessary, and with other excipients (such as water, ethanol, propylene glycol, glycerol or a combination thereof).

[0295] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the compound.

[0296] The compositions of the present invention can be in various forms. These forms include, for example, liquid, semisolid 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.

[0297] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those commonly used to passively immunize 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.

[0298] Oral administration of solid dosage forms can be presented, for example, in the form of discrete units, such as hard or soft capsules, pills, cachets, lozenges or tablets, each of which contains a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration can be carried out in the form of a powder or granules. In another embodiment, the oral dosage form is sublingual, such as a lozenge. In such solid dosage forms, the compounds of the present invention are generally combined with one or more adjuvants. Such capsules or tablets may contain controlled release formulations. In the case of capsules, tablets and pills, the dosage form may also contain a buffer or may be prepared with an enteric coating.

[0299] In another embodiment, oral administration can be carried out in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents (e.g., water) commonly used in the art. Such compositions may also include adjuvants, such as one or more of wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), and / or aromatics.

[0300] 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 prepared according to known techniques using one or more of suitable dispersants, wetting agents and / or suspending agents.

[0301] In another embodiment, the present invention includes topical dosage forms. "Topical application" includes, for example, transdermal and transdermal application (such as via transdermal patch or iontophoresis device), intraocular application, or intranasal or inhalation application. Compositions for topical application also include, for example, topical gels, sprays, ointments and creams. Topical preparations can include compounds that enhance the absorption or penetration of active ingredients through the skin or other affected areas. When the compound of the present invention is applied by a transdermal device, the patch of a reservoir and porous membrane type or a patch of a solid matrix type is used to achieve. Typical preparations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical excipients include alcohol, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol and propylene glycol. Permeation enhancers may be incorporated - see, for example, BC Finnin and TM Morgan, J. Pharm. Sci., Vol. 88, pp. 955-958, 1999.

[0302] Preparations suitable for topical application to eyes include, for example, eye drops, in which the compounds of the present invention are dissolved or suspended in suitable excipients. Typical preparations suitable for eye or ear administration can be in the form of drops of micronized suspensions or solutions in pH-adjusted isotonic sterile saline. Other preparations suitable for eye and ear administration include ointments, biodegradable implants (i.e., absorbable gel sponges, collagen) and biodegradable implants (i.e., silicones), sticky rice paper, lenses and granular or vesicle systems, such as vesicles (niosomes) or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum) can be introduced together with preservatives such as benzalkonium chloride. Such preparations can also be delivered by iontophoresis.

[0303] For intranasal administration, the compounds of the present invention are preferably delivered in the form of a solution or suspension from a pump spray container squeezed or pumped by the patient, or delivered in the form of an aerosol spray presentation from a pressurized container or a nebulizer using a suitable propellant. Preparations suitable for intranasal administration are usually administered in the form of a dry powder from a dry powder inhaler (alone, as a mixture, for example, dry blended with lactose, or as mixed component particles, for example, mixed with phospholipids (such as phosphatidylcholine)), or in the form of an aerosol spray from a pressurized container, a pump, a nebulizer, an atomizer (preferably an atomizer using electrohydrodynamics to generate a fine mist) or a 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, such as chitosan or cyclodextrin.

[0304] In another embodiment, the present invention includes a rectal dosage form. Such a rectal dosage form can be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various substitutes can be used when appropriate.

[0305] Other excipients and modes of administration known in the pharmaceutical field can also be used. The pharmaceutical compositions of the present invention can be prepared by any of the well-known pharmaceutical techniques, such as effective formulation and administration procedures. The above considerations on effective formulation and administration procedures are well known in the art and described in standard textbooks. The formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., ed., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.

[0306] Acceptable excipients are nontoxic to the subject at the dosages and concentrations employed, and may include one or more of the following: 1) buffers, such as phosphate, citrate or other organic acids; 2) salts, such as sodium chloride; 3) antioxidants, such as ascorbic acid or methionine; 4) preservatives, such as octadecyldimethylbenzyl ammonium chloride, hexahydroxyquaternium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol or benzyl alcohol; 5) alkyl parabens, such as methyl paraben, propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins, such as serum albumin, gelatin or immunoglobulin; 8) hydrophilic polymers such as polyvinyl pyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; 10) monosaccharides, disaccharides or 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).

[0307] For oral administration, the composition can be provided to the patient 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 mg of active ingredient for symptomatic adjustment of dosage. The medicament generally contains about 0.01 mg to about 500 mg of active ingredient, or in another embodiment, contains about 1 mg to about 100 mg of active ingredient. In the case of intravenous administration, during constant rate infusion, the dosage can be in the range of about 0.01 to about 10 mg / kg / minute.

[0308] 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 suitable liposomes can be produced by reverse phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through a filter of defined pore size to produce liposomes having a desired diameter.

[0309] The compounds of the invention may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions, respectively. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0310] Sustained release preparations can be used.Sustained release preparations suitable examples include semipermeable matrixes of solid hydrophobic polymers containing compounds of the present invention, and the matrix is ​​in the form of formed articles, such as films or microcapsules.Examples of sustained release matrixes include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as copolymers in leuprolide acetate for reservoir suspensions) (injectable microspheres consisting of lactic acid-glycolic acid copolymers and leuprolide acetate), sucrose acetate isobutyrate and poly-D-(-)-3-hydroxybutyric acid.

[0311] Preparations for intravenous administration must be sterile. This is easily achieved, for example, by filtration through a sterile filtration membrane. The compounds of the present invention are typically placed in a container with a sterile access port, such as an intravenous solution bag or vial with a stopper pierceable by a hypodermic injection needle.

[0312] Suitable emulsions can be prepared using commercially available fat emulsions, such as lipid emulsions comprising soybean oil, fat emulsions for intravenous administration (e.g., safflower oil, soybean oil, lecithin and glycerol contained 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, it can be dissolved in oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and in an emulsion formed after mixing with phospholipids (e.g., lecithin, soybean lecithin or soybean lecithin) and water. It should be understood that other ingredients, such as glycerol or glucose, can be added to adjust the emulsion tension. Suitable emulsions will generally contain up to 20% oil, such as between 5% and 20%. Fat emulsions can include fat 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.

[0313] For example, the emulsion composition may be one prepared by mixing the compound of the present invention with a lipid emulsion containing soybean oil or its components (soybean oil, lecithin, glycerin and water).

[0314] 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 excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory routes for local or systemic effects. Compositions in preferably sterile pharmaceutically acceptable solvents can be atomized by using gases. Atomized solutions can be directly inhaled from a nebulizer, or a nebulizer can be connected to a mask, curtain or intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions can be preferably administered orally or nasally from a device that delivers the preparation in an appropriate manner.

[0315] Drug intermediate (DPI) is a partially processed material that must undergo other processing steps before it becomes a raw drug. The compound of the present invention can be formulated into a drug intermediate DPI, which contains an active ingredient in a higher free energy form compared to a crystalline form. One reason for using DPI is to improve oral absorption characteristics, which is due to lower solubility, slow dissolution, improved mass transport via the mucus layer adjacent to the epithelial cells, and in some cases, due to limitations caused by biological barriers such as metabolism and transport proteins. Other reasons may include improved solid-state stability and downstream manufacturability. In one embodiment, the drug intermediate contains a compound of the present invention (e.g., amorphous solid dispersion (ASD)) separated and stable in an amorphous form. There are many techniques known in the art for manufacturing ASD, which produces materials suitable for integration into raw drug materials, such as spray-dried dispersions (SDD), melt extrudates (commonly referred to as HME), coprecipitates, amorphous drug nanoparticles and nanoadsorbates. In one embodiment, an amorphous solid dispersion comprises a compound of the present invention and a polymer excipient. Other excipients and the concentrations of the excipient and the compound of the present invention are well known in the art and described in standard textbooks. See, for example, Navnit Shah et al., "Amorphous Solid Dispersions Theory and Practice."

[0316] Administration and dosing

[0317] As used herein, the terms "treating," "treat," or "treatment" encompass both preventive (i.e., prophylactic) and palliative (i.e., alleviating, relieving or slowing the progression of a patient's disease (or condition) or any tissue damage associated with the disease) treatments.

[0318] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals. Mammals according to the present invention include dogs, cats, cattle, goats, horses, sheep, pigs, rodents, lagomorphs, primates, humans, and the like, and encompass unborn mammals. In one embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0319] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual or human being that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following:

[0320] (1) preventing a disease; for example, preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who does not yet experience or display the pathology or symptomology of the disease;

[0321] (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying pathology or symptomology of the disease, condition, or disorder (i.e., arresting (or slowing) further development of the pathology or symptomology, or both); and

[0322] (3) ameliorating a disease; e.g., ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology or symptomology or both).

[0323] Typically, the compounds of the present invention are administered in an amount effective to treat the conditions described herein. The compounds of the present invention can be administered as the compounds themselves or alternatively as pharmaceutically acceptable salts. For the purposes of administration and dosing, the compounds themselves or their pharmaceutically acceptable salts will be referred to as compounds of the present invention.

[0324] The compounds of the invention are administered by any suitable route, in the form of pharmaceutical compositions suitable for such routes and in doses effective to achieve the desired treatment. The compounds of the invention may be administered orally, rectally, vaginally, parenterally, topically, intranasally or by inhalation.

[0325] The compounds of the present invention may be administered orally. Oral administration may include swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, thereby allowing the compound to enter the bloodstream directly from the oral cavity.

[0326] In another embodiment, the compounds of the invention can also be administered parenterally, for example, directly into the bloodstream, into a muscle, or into an internal organ. Suitable modes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

[0327] In another embodiment, the compounds of the present invention may also be topically applied to the skin or mucous membranes, i.e., transdermally or transdermally. In another embodiment, the compounds of the present invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may also be administered rectally or vaginally. In another embodiment, the compounds of the present invention may also be administered directly to the eye or ear.

[0328] The dosing regimen of the compound of the present invention or the composition containing the compound is based on various factors, including: the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the dosing regimen can vary widely. In one embodiment, the total daily dose of the compound of the present invention is generally about 0.01 to about 100 mg / kg (i.e., mg compound of the present invention / kg body weight) for the treatment of the specified condition discussed herein. In another embodiment, the total daily dose of the 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 for the compound of the present invention to be repeatedly administered multiple times (typically no more than 4 times) in a day. If necessary, multiple doses can usually be used every day to increase the total daily dose.

[0329] Treatments and uses

[0330] The compounds of the present invention can inhibit the activity of all KRAS G12C, KRAS G12D and KRAS G12V receptors, and can be used to treat, prevent, inhibit and improve diseases mediated by any one of KRAS G12C, KRAS G12D and KRAS G12V receptors or a combination thereof, such as cancer, disorders and conditions.

[0331] 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 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 cancer, stomach cancer, uterine cancer, bladder cancer (including non-muscle invasive bladder cancer), liver tumors, breast cancer and head and neck cancer.

[0332] Preferably, the compounds of the present invention are suitable for treating lung cancer, such as non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer, breast cancer, blood cancer, gynecological cancer, prostate cancer or skin cancer. See Mustachio, L., Targeting KRAS in Cancer: Promising Therapeutic Strategies, Cancers, 2021, 13, 1204.

[0333] More preferably, the compounds of the present invention may be useful in the treatment of non-small cell lung cancer (NSCLC), pancreatic cancer and colorectal cancer.

[0334] Co-administration

[0335] The compounds of the invention may be used alone or in combination with one or more other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein, wherein a compound of the invention or a pharmaceutically acceptable salt thereof is used in combination with one or more other anti-cancer therapeutic agents discussed herein.

[0336] The "combination (in combination)" administration of two or more compounds refers to the administration of all compounds close enough in time to affect the treatment of the subject. Depending on the treatment regimen, two or more compounds may be administered simultaneously or sequentially via the same or different routes of administration on the same or different administration schedules and in the presence or absence of specific time limits. In addition, simultaneous administration may be performed by mixing the compounds before administration, or by administering the compounds as separate dosage forms at the same time point but at the same or different administration sites. Examples of "combination" include, but are not limited to, "parallel administration", "co-administration", "simultaneous administration", "sequential administration" and "simultaneous administration".

[0337] The compounds of the invention and one or more other therapeutic agents may be administered in the form of a fixed or non-fixed combination of active ingredients. The term "fixed combination" means that the compounds of the invention or pharmaceutically acceptable salts thereof and one or more therapeutic agents are administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that the compounds of the invention or pharmaceutically acceptable salts thereof and one or more therapeutic agents are formulated as separate compositions or dosage forms so that they can be administered to a subject in need thereof simultaneously or at different times with variable time intervals, wherein such administration provides an effective amount of two or more compounds in the subject.

[0338] Classes of additional chemotherapeutic agents that can be administered in combination with the compounds of the invention include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogestins, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists; IL-2 receptor agonists (recombinant cytokines or agonists directed against cytokine receptors); and antisense oligonucleotides or oligonucleotide derivatives that inhibit the expression of genes involved in abnormal cell proliferation or tumor growth.

[0339] Other additional chemotherapeutic agents include not only taxanes or platinum-based agents, but also HER2-targeted agents, such as trastuzumab.

[0340] In another embodiment, such additional anticancer therapeutics include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, spindle toxin plant alkaloids, MCT4 inhibitors; MAT2a inhibitors; alk / c-Met / ROS inhibitors (including crizotinib or lorlatinib); mTOR inhibitors (including temsirolimus ) or gedatolisib); 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.

[0341] In another embodiment, such additional anti-cancer therapeutics include compounds derived from anti-angiogenic agents, including, for example, tyrosine kinase / vascular endothelial growth factor (VEGF) receptor (VEGFR) inhibitors (including sunitinib, axitinib, sorafenib and tivozanib), TIE-2 inhibitors, PDGFR inhibitors, angiogenin inhibitors, PKCβ inhibitors, cyclooxygenase II (COX-2) inhibitors, integrins (α-v / β-3), matrix-metalloproteinase 2 (MMP-2) inhibitors and matrix-metalloproteinase 9 (MMP-9) inhibitors. Preferred anti-angiogenic agents include sunitinib (Sutent TM ), bevacizumab (Avastin TM ), axitinib (Inlyta TM ), SU 14813 (Pfizer), and AG 13958 (Pfizer). Additional anti-angiogenic agents include vatalanib (CGP 79787), pegaptanib octasodium (Macugen TM ), vandetanib (ZactimaTM )、PF-0337210(Pfizer), SU 14843(Pfizer), AZD 2171(AstraZeneca), ranibizumab(Lucentis TM ), Neovastat TM (AE 941), tetrathiomolybdata (Coprexa TM ), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352) and CP-868,596 (Pfizer). Other anti-angiogenic agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex TM ) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenic agents include celecoxib (Celebrex TM ), parecoxib (Dynastat TM ), deracoxib (SC 59046), lumiracoxib (Preige TM ), valdecoxib (Bextra TM ), rofecoxib (Vioxx TM ), iguratimod (Careram TM ), IP 751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia TM Other anti-angiogenic agents include exisulind (Aptosyn TM ), salsalate (Amigesic TM ), diflunisal (Dolobid TM ), ibuprofen (Motrin TM ), ketoprofen (OrudisTM ), nabumetone (Relafen TM )、piroxicam (Feldene TM ), naproxen (Aleve TM 、Naprosyn TM ), diclofenac (Voltaren TM ), indomethacin TM ), sulindac (Clinoril TM ), tolmetin (Tolectin TM ), etodolac (Lodine TM ), ketorolac (Toradol TM ) and oxaprozin (Daypro TM Other anti-angiogenic agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat TM ) and PCK 3145 (Procyon). Still other anti-angiogenic agents include acitretin (Neotigason TM ), plitidepsin (aplidine TM ), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin TM )、Pazem TM (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS275291), catumaxomab (Removab TM ), lenalidomide (Revlimid TM )、squalamine (EVIZON TM ), thalidomide TM), Ukrain TM (NSC 631570), Vitaxin TM (MEDI522) and zoledronic acid (Zometa TM ).

[0342] In another embodiment, such additional anticancer therapeutics include compounds derived from hormone agents and antagonists. Where antihormonal agents are used to regulate or inhibit hormonal activity on tumors, examples include antiestrogens and selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs), including tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifene (Fareston) and fulvestrant. Examples also include aromatase inhibitors, which inhibit the aromatase enzyme, 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.

[0343] 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: a signal transduction inhibitor (e.g., inhibiting the way in which regulatory molecules control the fundamental processes of cell growth, differentiation, and survival communicated within cells). 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 TM )), c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, BRAF (including encorafenib (Braftovi TM )), Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors and multi-targeted kinase inhibitors.

[0344] In another embodiment, such additional anti-cancer therapeutics include docetaxel, paclitaxel, paclitaxel protein-bound particles, cisplatin, carboplatin, oxaliplatin, capecitabine, gemcitabine, or vinorelbine.

[0345] In another embodiment, such additional anti-cancer therapeutics include compounds derived from epigenetic regulators, examples of which 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.

[0346] In another embodiment, such additional anti-cancer therapeutics include compounds that are immuno-oncology agents, including immunomodulatory agents.

[0347] In another embodiment, combinations with pattern recognition receptors (PRRs) are contemplated. PRRs are receptors expressed by cells of the immune system and recognize various molecules associated with pathogens and / or cell damage or death. PRRs participate in both innate and acquired immune responses. PRR agonists can be used to stimulate the immune response of a subject. There are various classes 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.

[0348] The STING protein acts as both a cyrosolic DNA sensor and an adaptor protein in type 1 interferon signaling. The terms "STING" and "stimulator of interferon genes" refer to any form of the STING protein, as well as variants, isomers, and species homologs that retain at least a portion of the STING activity. Unless otherwise indicated, such as by specific reference to human STING, STING includes all mammalian species of native sequence STING, such as humans, monkeys, and mouse STING is also referred to as TMEM173.

[0349] 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 suitable for use in any of the methods, agents and uses of the present invention include, for example, nucleic acid ligands that bind to STING.

[0350] Examples of STING agonists suitable for the treatment methods, drugs and uses of the present invention include various immunostimulatory nucleic acids, such as synthetic double-stranded DNA, cyclic di-GMP, cyclic-GMP-AMP (cGAMP); synthetic cyclic dinucleotides (CDNs), such as MK-1454 and ADU-S100 (MIW815); and small molecules, such as WO2019027858, WO20180093964, WO2017175156, WO2017175147.

[0351] Therapeutic antibodies may have specificity for various different antigens. For example, therapeutic antibodies may be directed to tumor-associated antigens, so that the combination of the antibody and the antigen promotes the death of cells expressing the antigen. In another example, therapeutic antibodies may be directed to antigens on immune cells, so that the combination of the antibody prevents the activity of cells expressing the antigen from being downregulated (and thereby promotes the activity of cells expressing the antigen). In some cases, therapeutic antibodies may work by a variety of different mechanisms (for example, they may simultaneously i) promote cell death of the antigen, and ii) prevent the antigen from causing the activity of immune cells in contact with cells expressing the antigen to be downregulated).

[0352] In another embodiment, such additional anti-cancer therapeutics include antibodies that would 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.

[0353] In another embodiment, such additional anti-cancer therapeutic comprises an antibody that is a 4-1BB, OX40, GITR, ICOS or CD40 agonist.

[0354] In another embodiment, the anti-cancer therapy may be CAR-T cell therapy.

[0355] 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-placental cadherin (P-cadherin) / anti-CD3 antibodies. Examples of cytotoxic agents that can be incorporated into ADCs include anthracyclines, auristatins, dolastatins, combretastatins, duocarmycins, pyrrolobenzodiazepines, and styrene. Dimer, indolin-benzodiazepine dimer, enediyne, geldanamycin, maytansine, puromycin, taxane, vinca alkaloid, camptothecin, tubulysin, hemiasterlin, spliceostatin, pladienolide and stereoisomers, isosteres, analogs or derivatives thereof. Examples of exemplary immunomodulators that can be incorporated into ADCs include gancyclovier, etanercept, tacrolimus, sirolimus, voclosporin, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, , glucocorticoids and their analogs, cytokines, stem cell growth factors, lymphotoxins, tumor necrosis factor (TNF), hematopoietic factors, interleukins (e.g., interleukin-1 (IL-1), 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-α, interferon-β and interferon-γ), a stem cell growth factor known as "S1 factor", erythropoietin and thrombopoietin, or a combination thereof.

[0356] Other examples of therapeutic antibodies may include the following antigens, wherein the following also includes exemplary antibodies against the antigen (in brackets / parentheses after the antigen). The following antigens may also be referred to herein as "target antigens" or their analogs. 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., abagovomab); carbonic anhydrase IX; CCR2; CCR4 (e.g., mogamulizumab); CCR5 (e.g., leronlimab); CCR8; CD3 [e.g., blinatumomab (CD3 / CD19 bispecific), C [D3 / P-cadherin bispecific, CD3 / BCMA bispecific]; CD19 (e.g., blinatumomab, MOR208); CD20 (e.g., ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, ublituximab); CD22 (inotuzumab ozogamicin, moxetumomab pasudotox); CD25; CD28; CD30 (e.g., brentuximab vedotin); CD33 (e.g., gemtuzumab ozogamicin); CD38 (e.g., daratumumab, isatuximab), CD40; CD-40L; CD44v6; CD47 (e.g., Hu5F9-G4, CC-90002, SRF231, B6H12); CD52 (e.g., alemtuzumab); CD56; CD63; CD79 (e.g., polatuzumab vedotin); 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 tesirine); DLL4; E-cadherin; EDA; EDB; EFNA4; EGFR (e.g., cetuximab, depatuxizumab mafodotin, necitumumab, panitumumab); EGFRvIII; Endosialin; EpCAM (e.g., oportuzumab monatox); FAP; Fetal Acetylcholine Receptor Receptor); FLT3 (e.g., see WO2018 / 220584); GD2 (e.g., dinutuximab, 3F8); GD3; GITR; GloboH; GM1; GM2; HER2 / neu [e.g., margetuximab, pertuzumab, trastuzumab; ado-trastuzumab emtansine), trastuzumabduocarmazine, [see US8828401]; HER3; HER4; ICOS; IL-10; ITG-AvB6; LAG-3 (e.g., relatlimab); Lewis-Y; LG; Ly-6; M-CSF [see US7326414]; MCSP; mesothelin; MUC1; MUC2; MUC3; MUC4; MUC5AC; MUC5B; MUC7; MUC16; Notch1; Notch3; adhesion molecule-4 (e.g., enfortumab vedotin)); OX40 [see US7960515]; placental cadherin (P-Cadherein) [see WO2016 / 001810]; PCDHB2; PDGFRA (e.g., olaratumab); plasma cell antigen (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-β; TIGIT; TIM-3; TMPRSS3;TNF-α precursor; TROP-2 (e.g., sacituzumab govitecan); TSPAN8; VEGF (e.g., bevacizumab, brolucizumab); VEGFR1 (e.g., ranibizumab); VEGFR2 (e.g., ramucirumab, ranibizumab); Wue-1. ;

[0357] Exemplary imaging agents that can be included in the ADC include fluorescein, rhodamine, lanthanide phosphors and their derivatives, or radioisotopes conjugated to chelating agents. Examples of fluorophores include, but are not limited to, fluorescent isothiocyanate (FITC) (e.g., 5-FITC), fluorescein phosphoramidite (FAM) (e.g., 5-FAM), eosin, carboxyfluorescein, erythrosine, Alexa Fluor, fluorescein ... (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 sulfonylrhodamine (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-pentanedioic acid-4,7-acetic acid (deferoxamine), diethylenetriaminepentaacetic acid (DTPA), and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA).

[0358] Exemplary therapeutic proteins that may be included in an ADC include toxins, hormones, enzymes, and growth factors.

[0359] Exemplary biocompatible polymers that can be incorporated into ADCs include water-soluble polymers, such as polyethylene glycol (PEG) or its derivatives, and biocompatible polymers containing zwitterions (eg, phosphorylcholine-containing polymers).

[0360] Exemplary biocompatible polymers that can be incorporated into ADCs include antisense oligonucleotides.

[0361] 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 may be administered in combination with additional therapies, such as radiation therapy and / or chemotherapy.

[0362] These agents and compounds of the invention may be combined with pharmaceutically acceptable vehicles such as saline, Ringer's solution, dextrose solution, etc. The specific dosing regimen, ie, dose, timing and repetition, will depend on the particular individual and that individual's medical history.

[0363] Reagent test kit

[0364] 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. In addition to the compound of the present invention or its pharmaceutical composition, the kit may also include a diagnostic agent or a therapeutic agent. The kit may also include instructions for use of a diagnostic or therapeutic method. In some embodiments, the kit includes a compound or its pharmaceutical composition and a diagnostic agent. In other embodiments, the kit includes a compound or its pharmaceutical composition and one or more therapeutic agents.

[0365] In yet another embodiment, the present invention includes a kit suitable for carrying out the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more compounds of the present invention in an amount sufficient to carry out the methods 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 methods of the present invention and a container for the dosage form.

[0366] Synthesis method

[0367] The compounds of the present invention can be synthesized by synthetic routes including methods similar to those well known in the chemical arts, particularly according to the descriptions contained herein. Starting materials are generally available from commercial sources 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 in which one or more of scientific interest or commercial needs have emerged. Thus, such compounds can be one or more of the following: 1) commercially available; 2) reported in the literature or 3) prepared by those skilled in the art using materials reported in the literature, based on other generally available substances.

[0368] For the purpose of illustration, the reaction scheme described below provides a potential approach to synthesizing compounds of the present invention and key intermediates. For a more detailed description of individual reaction steps, see the following examples section. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize compounds of the present invention. Although specific starting materials and reagents are discussed below, other starting materials and reagents can be substituted to provide one or more of various derivatives or reaction conditions. In addition, many compounds prepared by the method described below can be modified in addition according to the present invention using conventional chemical methods well known to those skilled in the art.

[0369] The skilled artisan will appreciate that the experimental conditions set forth in the schemes below illustrate suitable conditions for achieving the transformations shown, and may require or need to change the precise conditions for preparing the compounds of the present invention. It will also be appreciated that it may be necessary or necessary to transform in an order different from that described in the schemes, or to modify one or more of the transformations to provide desired compounds of the present invention.

[0370] It should be noted that some preparation methods suitable for preparing the compounds described herein may require protection of distal functional groups (e.g., primary amines, secondary amines, carboxyl groups, etc. in the precursors of the compounds of the present invention). The need for such protection will vary depending on the nature of the distal functional group and the conditions of the preparation method. The need for such protection is easily determined by those skilled in the art. The use of such protection / deprotection methods is also within the technical scope of the art. For a general description of protecting groups and their uses, see March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th edition.

[0371] For example, if the compound contains an amine or carboxylic acid functional group, such functional group may interfere with the reaction at other sites of the molecule if it is not protected. Therefore, such functional groups can be protected by an appropriate protecting group (PG), which can be removed in subsequent steps. Suitable protecting groups for protecting amines and carboxylic acids include those commonly used in peptide synthesis (such as N-tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines and lower alkyl groups, or benzyl esters for carboxylic acids), which are generally not chemically reactive under the described reaction conditions and can generally be removed without chemically changing other functional groups in the compounds of the present invention.

[0372] Overall experimental details

[0373] Recorded on a Bruker XWIN-NMR (400 or 700 MHz) spectrometer 1 H and 19 F nuclear magnetic resonance (NMR) spectroscopy. 1 H and 19 F resonances are reported in parts per million (ppm) downfield from tetramethylsilane. 1 H NMR data are reported in multiplicity format (e.g., s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; dd, doublet of doublets; dt, doublet of triplets; br s, broad singlet). 3 DMSO-d 6 and CD 3Spectra obtained in OD, 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 were not always observed.

[0374] Optical rotations were determined on a Jasco P-2000 or Rudolph Autopol IV polarimeter. Unless otherwise stated, all final compounds were purified to ≥ 95% purity. (R, S) notation was used when the absolute stereochemistry was known. When the absolute stereochemistry was unknown, the software-generated names were modified to include (+)- and (-)- prefixes, and (R* / S*) notation was used to show relative configuration, depending on the optical rotation.

[0375] Mass spectra MS (m / z) were recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Where relevant and unless otherwise stated, the m / z data provided are for isotopes 19 F. 35 Cl, 79 Br and 127 I.

[0376] Nomenclature is written as described by IUPAC (International Union of Pure and Applied Chemistry produced in Perkin Elmers Chemdraw 18.0.0.231. 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 consistent with the recommendations of the International Union of Pure and Applied Chemistry for organic chemical nomenclature and CAS indexing rules.

[0377] abbreviation

[0378] aq is water (solution);

[0379] Bn is benzyl;

[0380] Boc is tert-butoxycarbonyl;

[0381] Boc 2 O is di-tert-butyl dicarbonate;

[0382] br is width;

[0383] tBu is tert-butyl;

[0384] ℃ is Celsius;

[0385] CDCl 3 is deuterated chloroform;

[0386] δ is the chemical shift;

[0387] d is a doublet;

[0388] dd is a doublet;

[0389] ddd is a doublet of doublets;

[0390] dt is a double triplet;

[0391] DCM is dichloromethane; methylene chloride;

[0392] DIPEA is N-ethyldiisopropylamine, also known as N,N-diisopropylethylamine;

[0393] DMAP is 4-dimethylaminopyridine;

[0394] DMF is N,N-dimethylformamide;

[0395] DMSO is dimethyl sulfoxide;

[0396] DMSO-d 6 is deuterated dimethyl sulfoxide;

[0397] ee is the enantiomeric excess;

[0398] ESI is electrospray ionization;

[0399] Et 2 O is ether;

[0400] EtOAc is ethyl acetate;

[0401] EtOH is ethanol;

[0402] Et 3 N is triethylamine;

[0403] g is grams;

[0404] HPLC is high pressure liquid chromatography;

[0405] hr is hours;

[0406] L is liter;

[0407] LCMS is liquid chromatography mass spectrometry;

[0408] m is the multiplet;

[0409] M is mole;

[0410] m-CPBA is 3-chloroperbenzoic acid;

[0411] MeOD_d 4 is deuterated methanol;

[0412] MeOH is methanol;

[0413] 2-MeTHF is 2-methyltetrahydrofuran;

[0414] mg is milligram;

[0415] MHz is megahertz;

[0416] min is minutes;

[0417] mL is milliliter;

[0418] mmol is millimole;

[0419] Mol is mole;

[0420] MOM is a methoxymethyl ether group;

[0421] MS (m / z) is the mass spectrum peak;

[0422] NMR is nuclear magnetic resonance;

[0423] Pd / C is palladium / carbon;

[0424] Pd(dppf)Cl 2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II);

[0425] pH is the hydrogen concentration;

[0426] ppm is parts per million;

[0427] Psi is pounds per square inch;

[0428] q is a quartet;

[0429] rpm is revolutions per minute;

[0430] rt is room temperature;

[0431] RT is the residence time;

[0432] RuPhos Pd G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (CAS No.: 1445085-77-7);

[0433] s is a single peak;

[0434] SEMCl is 2-(trimethylsilyl)ethoxymethyl chloride;

[0435] SEM is 2-(trimethylsilyl)ethoxymethyl;

[0436] SFC is supercritical fluid chromatography;

[0437] t is a triplet peak;

[0438] TBAF is tert-butylammonium fluoride;

[0439] TFA is trifluoroacetic acid;

[0440] THF is tetrahydrofuran;

[0441] TLC is thin layer chromatography;

[0442] TMSCN is trimethylsilyl cyanide;

[0443] TsCl is p-toluenesulfonyl chloride;

[0444] μL is microliter; and

[0445] μmol is micromole.

[0446] The scheme described below is intended to provide a general description of the methodology for preparing the compounds of the present invention. Some of the compounds of the present invention contain a single chiral center. In the following schemes, the general method for preparing the compounds is to show in racemic or enantiomerically enriched form. It will be apparent to those skilled in the art that all synthetic transformations can be carried out in a very similar manner, whether the material is enantiomerically enriched or racemic. In addition, the desired optically active material can be split at any desired point in the sequence using well-known methods as described herein and in the chemical literature.

[0447] General method:

[0448] Unless otherwise indicated, the variables in Schemes I to III have the same meanings as defined herein.

[0449] Scheme I: General Method A

[0450]

[0451] As exemplified in Scheme I, 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (CAS No. 2454396-80-4) can be treated with an amine in the presence of an effective base such as DIPEA in a suitable solvent such as DCM to provide an adduct at the 4-chloro position via a SnAr reaction. The adduct is prepared using a palladium catalyst such as CataCXiumA Pd G3 and a base such as K in a suitable solvent such as dioxane / water. 2 CO 3 or K 3 PO 4), Suzuki reaction is carried out at 7-chloro position to produce naphthol group. 2-thiomethyl can be oxidized to sulfone using an oxidant (such as mCPBA) in a solvent (such as DCM). Sulfone group obtained by replacement of a suitable base (such as LHMDS) in a suitable solvent (such as DCM) can be obtained by alcohol nucleophile (such as ((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl) methanol, CAS No. 2097518-76-6). In some cases, the penultimate intermediate can contain a protecting group, which can be removed by other steps in the synthesis sequence using conditions known in the art (March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition or Protecting Groups, 10Georg Thieme Verlag, 1994). Compounds at each step can be purified by standard techniques such as column chromatography, crystallization, reversed-phase HPLC or SFC.

[0452] Scheme II: General Method B

[0453]

[0454] As illustrated in Scheme II, 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (CAS No. 2454396-80-4) can be treated with an amine in the presence of an effective base (such as DIPEA) in a suitable solvent (such as DCM) to provide an adduct at the 4-chloro position via a SnAr reaction. A second SnAr reaction at the 2-chloro position in the presence of a base (such as DIPEA) in a suitable solvent (such as 1,4-dioxane) at an elevated temperature (such as 90° C.) produces an alcohol nucleophile (such as ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol, CAS No. 2097518-76-6). Using a palladium catalyst (such as Pd(OAc) 2 / dppf) and a base (such as NaOH) in a suitable solvent (such as CH 3 CN / water), a Suzuki reaction was carried out at the 7-chloro position to generate a naphthol group.

[0455] Scheme III: General Method C

[0456]

[0457] As exemplified in Scheme III, 4,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (CAS No. 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 an appropriate solvent such as DCM to provide an adduct at the 4-chloro position via a SnAr reaction. The adduct can be prepared using a palladium catalyst such as CataCXium Pd G3 and a base such as K 3 PO 4 ) in a suitable solvent (such as THF / water), a Suzuki reaction at the 7-chloro position generates a naphthol group. The thiomethyl group can be oxidized to the sulfone using an oxidizing agent (such as buffered potassium persulfate (Oxone)) in a solvent (such as acetone / water). The thiomethyl group is reacted in a suitable solvent (such as CH 3 CN), a second SnAr reaction at the 2-sulfonyl position produces an alcohol nucleophile (such as ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol) at an elevated temperature (such as 80°C). The occupier amine can be removed using a base (such as NaOH) in the presence of a fluoride source (such as TBAF) at an elevated temperature (such as 60°C). Subsequently, the desired C4 amine is added in the presence of 2-chloro-1-methylpyridinium iodide and an effective base (such as DIPEA) in an appropriate solvent (such as 2-MeTHF) to provide an adduct at the 4-oxy subunit position via a SnAr reaction.

[0458] Scheme IV: General Method D

[0459]

[0460] As exemplified in Scheme IV, 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine can be treated with an amino alcohol (cyclic or acyclic) in the presence of an effective base (such as DIPEA) in an appropriate solvent (such as DCM) to provide an adduct at the 4-chloro position via a SnAr reaction. 2 CO 3 or K 3 PO 4 ) in a suitable solvent (such as dioxane / water), a Suzuki reaction at the 7-chloro position produces a naphthol group or a naphthyl group. An oxidizing agent (such as potassium persulfate) can be used in a buffered aqueous solvent (containing NaHCO 3and acetone or methyl ethyl ketone), 2-thiomethyl is oxidized to sulfone. This can be accomplished by using an alcohol nucleophile (e.g., ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, CAS No. 2097518-76-6) and a suitable base (e.g., LHMDS or LiOTMS) in a suitable solvent (e.g., CH 3 CN) to replace the obtained sulfone group. In some cases, the penultimate intermediate may contain a protecting group, which can be removed by other steps in the synthesis 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). Standard techniques such as column chromatography, crystallization, reversed-phase HPLC or SFC purification of the compound at each step can be used.

[0461] Variable R in Schemes I to III 1 Same as defined in Embodiments E1 to E31 herein.

[0462] The variable R in Schemes I to III represents one to four substituents selected from the group consisting of: -OH, halogen, CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, C 1 -C 3 Alkoxy and C 2 -C 3 Alkynyl is as defined in the embodiments and claims herein.

[0463] The variable R' in Schemes I to III may be, but is not limited to, H or C 1 -C 5 Alkyl, wherein two R' may be linked to form a ring, R' is not part of the definition in the claims herein.

[0464] Amines as provided in Schemes I to III is a general structure corresponding to R defined in Embodiments E1 to E31 2 The definition of R 2 for:

[0465]

[0466] Variable R in Scheme IV 1 As defined herein in Embodiments E32 to E60.

[0467] The variable R in Scheme IV represents one to four substituents selected from the group consisting of: -OH, halogen, CN, C 1 -C 3 Alkyl, C 1 -C 3 Fluoroalkyl, C 1 -C 3 Alkoxy and C 2 -C 3 Alkynyl is as defined in the embodiments and claims herein.

[0468] The variable R' in Scheme IV may be, but is not limited to, H or C 1 -C 5 Alkyl, wherein two R' may be linked to form a ring, R' is not part of the definition in the claims herein.

[0469] The amino alcohols in Scheme IV are representative general moieties that can form the desired tetracyclic structures defined in the embodiments such as E32 (where R 2 and R 5 Optionally together to form a 4-8 membered heterocycloalkyl) and E39. The amino alcohol may be a non-cyclic moiety, which may be derived from the desired tricyclic structure defined in the embodiment, such as E32 (when R 2 and R 5 not together to form a 4-8 membered heterocycloalkyl).

[0470] The synthetic intermediates generally defined in the above schemes are useful in preparing the compounds of the invention, and the synthesis of such non-commercial intermediates is provided as a further aspect of the invention.

[0471] preparation:

[0472] Preparation 1: (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol

[0473]

[0474] Chiral SFC (AS-H column, 95 / 5CO 2 / EtOH mobile phase, 2 mL injection volume, 2.5 mL / min flow rate, 35 ° C), for the chiral separation of 1a (700g, 3.2mol) prepared as described in J. Med. Chem. 2012, 55 (10), 4605. The retention time of the preparative AS-H column with baseline resolution was: 3.01min for peak 1 and 3.70min for peak 2. The er ratio of peak 1 material was 100 / 0. The peak 1 material (1b, 294g, 1.37mol) from the chiral separation was dissolved in EtOH (3.2L) and Boc 2 O (486 g, 2.23 mol), followed by 10% Pd / C (10 g). At 25 °C in H 2 The reaction was stirred under an atmosphere of (60 psi) for 18 h. Subsequently, fresh Pd / C (5 g) was added and the mixture was stirred under an atmosphere of H 2 (60psi) and continued stirring for 30min. HPLC showed that all benzyl groups had been removed. Filter out the catalyst and remove most of the EtOH in vacuo to provide a yellow oil. Add heptane (500mL) and co-evaporate the mixture to remove as much EtOH as possible. The yellow residue was dissolved in 2-MeTHF (1.8L) and cooled in an ice-water bath. When the internal temperature was below 5°C, N,N-dimethylethylenediamine (105mL, 0.956mol) was added to quench excess Boc 2 O. After the addition, the reaction was allowed to warm to room temperature and stirred for 45 minutes. The reaction was recooled in an ice bath and 1N HCl (800 mL) was added to bring the pH to 2 while keeping the internal temperature below 20°C. The layers were separated and the aqueous layer was extracted with 2-MeTHF (1×300 mL). The reaction was concentrated with saturated NaHCO 3 The combined organic extracts were washed with brine and purified by MgSO 4 Dry. Remove the solvent to produce a yellow oil. Co-evaporate with heptane (250mL) to obtain 286g of a crude oil with an HPLC purity of 89%. Heptane (1.1L) is added to the oil and the mixture is cooled in an ice-water bath. When the internal temperature reaches 9 ° C, the mixture becomes turbid. Add a small amount of seed crystals, and allow the mixture to slowly warm to room temperature overnight. The solid formed is collected by filtration and washed with a small amount of cold heptane. After suction drying, (1R, 5R)-6-oxygen-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester (1c, 237g, 77%, HPLC purity is 97.4%) is obtained as a white solid. A solution of 1c (5.0g, 22mmol) in MeOH (100mL) is cooled in an ice bath. Add NaBH 4(924 mg, 24.4 mmol) and stirred the reaction at 0 °C for 10 min. Remove the ice bath and stir the reaction at rt for 1 hour. Remove the methanol under vacuum and partition the resulting residue with saturated NaHCO 3 The aqueous layer was further extracted with EtOAc and the combined organic extracts were purified by Na 2 SO 4 Drying and concentration gave 5.5 g of the Boc-protected alcohol as a white solid. The yield was slightly higher than 100% due to residual EtOAc in the sample. 1 H NMR (400MHz, chloroform-d) δ = 4.30-4.18 (m, 2H), 3.81 (br d, J = 12.2Hz, 1H), 2.93 (br d,J=12.5Hz,1H),2.87(dd,J=1.2,13.2Hz,1H),2.29(ddd,J=7.0,10.6,13.9Hz,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=2.8,14.0Hz,1H). To a solution of Boc protected alcohol (5.0 g, 22 mmol) in DCM (5 mL) was added HCl (25 mL of 4N, 100 mmol) in dioxane. The gas was immediately released. The reaction was stirred at rt for 5 min and a white precipitate was formed. After an additional 1 h, the reaction was diluted with heptane and the white solid was collected by filtration. The solid was dried overnight under high vacuum to give (1R, 5R, 6R)-3-azabicyclo [3.2.1] octan-6-ol HCl salt as a white powder, preparing 1 (3.5 g, 97%). 1 H NMR (400 MHz, D 2 O)δ=4.63-4.54(m,1H),3.48(dd,J=2.6,12.6Hz,1H),3.24(s,2H),3.16(br d,J=12.7Hz,1H),2.50-2.38(m,3H),1.77(d,J=2.2Hz,2H),1.53-1.45(m,1H); MS:[M+H] + 128.1.

[0475] Preparation 2-(+) and Preparation 2-(-): (1R*,5R*,6R*)-6-hydroxy-8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester and (1S*,5S*,6S*)-6-hydroxy-8-oxa-3-azabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0476]

[0477] A racemic mixture of (+ / -) 2a was prepared as described in U.S. Pat. No. 2013 / 0079321. The mixture was stirred at 50 °C under 30 psi H 2 Use Boc 2 O (5.7 g, 26 mmol) and Pd(OH) 2 The optical mixture of (+ / -) 2a (3.80 g, 16.6 mmol) was treated with 1% ethyl acetate (4 g) and 1% ethyl acetate (4 g) in EtOH (40 mL) overnight. The reaction mixture was filtered through a celite pad and the filtrate was concentrated. The residue was suspended and stirred in petroleum ether (30 mL) for 1 hr and filtered. The filter cake was dried in vacuo to give a racemic mixture of (+ / -) 2b (3.4 g, 87%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ=4.32(ddd,J=4.1,6.0,10.6Hz,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=12.9Hz,1H),2.38(ddd,J=7.9,10.8,12.4Hz,1H),1.36(s,9H),1.21-1.13(m,1H),MS:130[M+H-Boc] + .

[0478] The racemic mixture of (+ / -) 2b was resolved using chiral SFC as follows: chiral SFC (Chiralpak IG SFC 5 μm 21×250 mm column, 90 / 10 CO 2 850 mg (+ / -) 2b was separated into its enantiomers using an isocratic mobile phase of 1H / MeOH, 120 bar, a flow rate of 70 mL / min.

[0479] Peak 1 = Preparation 2-(+): [α] D 22 +10.7 (c 0.3, MeOH), 392 mg, >99.0%ee.

[0480] Peak 2 = Preparation 2-(-): [α] D 22 -27.1 (c 0.1, MeOH), 294 mg, 98% ee.

[0481] Preparation 3: (S)-2-(1-acetylpiperazin-2-yl)acetonitrile

[0482]

[0483] Compound 3a was prepared as described in J. Med. Chem. 2020, 63(13), 6679. Compound 3a (4.9 g, 22 mmol) and Et 3 N (3.3 g, 33 mmol) was added with acetic anhydride (2.44 g, 23.9 mmol). After stirring at 20 °C for 1 h, LCMS showed product formation. 3 The mixture was washed with aqueous solution (100 mL×2), and the organic phase was washed with saturated aqueous citric acid solution (100 mL×2), brine (100 mL) and then purified by Na 2 SO 4 After drying, filtration and concentration, 3b (6.2 g) was obtained as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ4.66(s,1H),3.87(d,J=13.8Hz,2H),3.47(d,J=195.2Hz,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 at 25 °C for 5 hours. LCMS showed product formation and a white solid precipitated from the 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-d 6 )δ9.72(d,J=67.0Hz,2H),4.83(d,J=149.1Hz,1H),4.20(dd,J=226.7,14.2Hz, 1H),3.66-3.45(m,1H),3.40-2.74(m,6H),2.11(d,J=26.4Hz,3H),MS:168[M+H] + .

[0484] Preparation 4: (S)-2-(3-methylpyrrolidin-3-yl)acetonitrile

[0485]

[0486] (R)-1-((Benzyloxy)carbonyl)-3-methylpyrrolidine-3-carboxylic acid (4a, 0.700 g, 2.66 mmol) was dissolved in THF (10 mL). BH3 THF (7.98 mL of 1 M, 7.98 mmol). The reaction was then warmed to 25 °C and stirred at 25 °C for 2 hours. LCMS analysis showed 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 to 40% EtOAc / petroleum ether to give 4b (600 mg, 90%) as a colorless oil. 1 H NMR (DMSO-d 6 ,400MHz)δ7.41-7.21(m,5H),5.05(d,2H,J=3.5Hz),3.59(br d,1H,J=5.5Hz),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 showed 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 1N HCl (50 mL). The organic layer was purified by anhydrous Na 2 SO 4 Drying, filtration and concentration gave (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] + (R)-3-methyl-3-((tosyloxy)methyl)pyrrolidine-1-carboxylate from above (2.41 mmol) was dissolved in CH 3 CN (30 mL). TMSCN (836 mg, 8.43 mmol) and TBAF (8.43 mL of 1.0 M in THF, 8.43 mmol) were added. The resulting solution was heated at 100 °C for 16 h. LCMS analysis showed that the tosylate salt was consumed and the desired product was observed. 2 The reaction mixture was diluted with 1% O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were purified by anhydrous Na 2 SO 4 Dried, filtered and concentrated.The residue was purified using flash chromatography eluting with a 0 to 60% EtOAc / petroleum ether gradient to afford 4c (620 mg, 100%) as a colorless oil. 1H NMR (DMSO-d 6 , 400MHz)δ7.46-7.25(m,5H),5.06(d,2H,J=2.9Hz),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=2.2Hz). NMR showed evidence of restricted rotation around 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 mixture was stirred at 25 °C under H 2 The reaction was stirred at 4°C (1 atm) for 4 h. LCMS analysis showed that 4c was consumed and the product was observed. The reaction mixture was filtered and the filtrate was concentrated to give (S)-2-(3-methylpyrrolidin-3-yl)acetonitrile as a colorless oil to prepare 4 (120 mg). 1 H NMR (CDCl 3 ,400MHz)d 3.83(br s,1H),3.07(t,1H,J=7.2Hz),2.86(d,1H,J=11.0Hz),2.75(d,1H,J=11.0Hz),2.43(s,2H),1.6-1.8(m,2H),1.26(s,3H),MS:125.2[M+H] + .

[0487] Preparation 5: (S)-2-(3-methylpiperidin-3-yl)acetonitrile

[0488]

[0489] Compound 5a (tert-butyl (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 showed 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 x 30 mL). The organic phase was purified by anhydrous Na 2 SO 4 Drying, filtration and concentration gave 5b (550 mg, 37%) as a gum. 1 H NMR (CDCl 3, 400MHz)d 7.78(d,2H,J=8.2Hz),7.35(d,2H,J=8.1Hz),3.92-3.65(m,2H),3.36(br s,1H),3.31-3.18(m,2H),3.04(br d,1H,J=13.2Hz,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] + 5b (450 mg, 1.17 mmol) was added to CH 3 To a solution of 5b in CN (20 mL) was added TMSCN (233 mg, 2.35 mmol) and TBAF (1.17 mL of 1 M in THF, 1.17 mmol). The solution was heated at 100 °C for 24 h. LCMS analysis showed that 5b was consumed and 5c was observed. CH 3 CN and the residue was purified using flash chromatography using a gradient of 0 to 15% EtOAc / petroleum ether to afford (S)-tert-butyl 3-(cyanomethyl)-3-methylpiperidine-1-carboxylate, 5c (240 mg, 70%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δ3.64 (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 (1.0 mL of 4N, 4.0 mmol) in dioxane. The reaction was then stirred at 25 °C for 2 hours. LCMS analysis showed that 5c was consumed and Preparation 5 was observed. The reaction was concentrated to give (S)-2-(3-methylpiperidin-3-yl)acetonitrile HCl salt as a colorless oil, Preparation 5 (116 mg, 79%), which was used in the next step without further purification. 1 H NMR (400MHz, 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=4.7Hz,1H),1.73-1.64(m,1H),1.58-1.47(m,1H),1.11(s,3H),MS:139[M+H] + .

[0490] Preparation 6: rac-(4-fluoropyrrolidin-3-yl)acetonitrile

[0491]

[0492] 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. Subsequently, the reaction mixture was 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 1N aqueous HCl (2×30 mL). The combined organic phase was purified by anhydrous Na 2 SO 4 Drying, filtration and concentration gave 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] + 6b (670 mg, 1.79 mmol) was added to CH 3 To a solution in CN (10 mL) was added TMSCN (356 mg, 3.59 mmol) and TBAF (1.79 mL of 1 M in THF, 1.79 mmol). The solution was heated at 100 °C for 3 hours. 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 with a gradient elution of 0 to 30% EtOAc / petroleum ether. After concentration of the pure fractions, 6c (330 mg, 69%) was obtained as a colorless gum. 1 H NMR (400 MHz, CDCl 3 )δ4.95(dd,J=52.0,17.4Hz,1H),3.70-3.51(m,3H),3.29(s,1H),2.68(d,J=7.7Hz,1H),2.38(dd,J=26.2,11.9Hz,2H),1.40(s,9H),MS:173.1[M+H-56tert-butyl] +To a solution of 6c (300 mg, 1.13 mmol) in DCM (25 mL) was added HCl in dioxane (6.57 mL of 4N, 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. Removal of the solvent gave rac-(4-fluoropyrrolidin-3-yl)acetonitrile hydrochloride as a colorless oil, Preparation 6 (185 mg, 100%). 1 HNMR(400MHz,DMSO)δ10.27-9.66(m,2H),5.31-5.10(m,1H),3.60-3.36(m,3H ),3.08(d,J=5.7Hz,1H),2.96-2.70(m,2H),2.34-2.16(m,1H).MS:129.1[M+H] + .

[0493] 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.

[0494]

[0495] 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 h. The reactant was concentrated and the residue was eluted with 5% EtOAc / petroleum ether and purified by flash chromatography to obtain a SEM-protected intermediate (21.5 g, 51%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ9.24(s,1H),7.71-7.66(m,1H),7.48(dd,J=7.1,1.1Hz,1H),7.30(dd,J=8.2,7.3Hz,1H),6.98(d,J=2.4Hz,1H),6.7 6(d,J=2.4Hz,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. Tf 2 O (19.3 g, 68.5 mmol) and the reaction was stirred at -45 °C for 1 h. TLC (5% EtOAc / petroleum ether) analysis indicated the reaction was complete. The reaction mixture was poured into H 2 The product was added to 4% 4-nitropropene (2% ethyl acetate, 1% sodium sulfate, 2% sodium pyrochlore) and the mixture was added to 4% 4-nitropropene (2% ethyl acetate, 1% sodium pyrochlore) 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 / petroleum ether to give 7b (26.8 g, 97%) as an orange oil. 1 H NMR (400 MHz, CDCl 3 )δ7.73(t, J=6.9Hz,2H),7.45-7.40(m,2H),7.30(d, J=2.2Hz,1H),5.33(s,2H),3.86-3.74(m,2H),1.16(d, J=5.9Hz,21H),1.01-0.93(m,2H),0.00(s,9H). To a mixture of 7b (6.00 g, 9.95 mmol) was added dioxane (100 mL) containing pinacol diboron (5.05 g, 19.9 mmol) and cesium pivalate (4.66 g, 19.9 mmol). Pd(dppf)Cl was added 2 (728 mg, 0.995 mmol) and heated at 110 °C under N 2 The mixture was stirred for 48 hours under 4% saturation. LCMS analysis showed that the product was formed. The mixture was cooled and concentrated. The residue was eluted with a gradient of 10% to 30% DCM / petroleum ether, purified by flash chromatography, and trimethyl [2-({[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-{[tri(propyl-2-yl)silyl]ethynyl}naphthalene-2-yl]oxy}methoxy)ethyl]silane was obtained as an orange oil, preparation 7 (2.58g, 45%). 1 H NMR (400 MHz, CDCl 3 )δ7.71-7.66(m,2H),7.46(d,J=2.5Hz,1H),7.39(d,J=2.5Hz,1H),7.35(d,J=7.5Hz,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]+ .

[0496] Preparation 8: (7,8-Difluoro-3-hydroxynaphthalen-1-yl)boronic acid.

[0497]

[0498] 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) was added 2 (706 mg, 3.14 mmol), (tert-butyl) 3 P-HBF 4 (1.82 g, 6.29 mmol) and LiF (4.89 mg, 189 mmol), followed by tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (18.4 g, 97.5 mmol). 2 Bubble through the mixture for 10 min and heat the reaction at 70 °C for 30 min. Cool the reaction to rt and add H 2 O (50 mL) and EtOAc (100 mL). 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 x 50 mL) and concentrated. The residue was dissolved in EtOAc. 2 O (100 mL) and heptane (200 mL) was added followed by azeotropic removal of heptane to remove residual DMF. The resulting residue was purified using flash chromatography eluting with a 0 to 100% EtOAc / heptane gradient to afford 8b (6.24 g, 87%) as an oil. 1 H NMR (400 MHz, CDCl 3)δ7.18 (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) was added LHMDS (49.2 mL of 1 M in THF, 49.2 mmol) dropwise at -78 °C. The reaction turned red and 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 adding 2M HCl (100 mL). EtOAc (100 mL) was added and stirring continued for several min. 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 obtain 8c (4.91 g, 91%) as a red solid, which was used in the next step without further purification. The solution of MeOH (125 mL) was cooled to 0 ° C and acetyl chloride (37.3 g, 476 mmol) was added dropwise. After a slight heat release, the reactant was brought to 0 ° C. Subsequently, a solution of 8c (4.91 g, 25.0 mmol) in MeOH (50 mL) was added. The reaction was equipped with a reflux condenser and heated at 60 ° C for 6.5 hours. The reactant was concentrated and the gradient of 0 to 50% EtOAc / heptane was used to purify by flash chromatography to obtain 8d (3.78 g, 72%) as a beige solid. 1 H NMR (400 MHz, CDCl 3 )δ7.43 (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 Et 3 N (3.64 g, 36.0 mmol), N, N-bis (trifluoromethanesulfonyl) aniline (7.71 g, 21.6 mmol) and DMAP (110 mg, 0.899 mmol). The reaction was stirred at rt for 8 hours. N, N-bis (trifluoromethanesulfonyl) aniline (1.29 g, 3.60 mmol) was added again and the reaction was stirred for another 11 hours. The mixture was transferred to a separatory funnel and washed with 1N NaOH (50 mL). The DCM layer was separated by Na 2 SO 4Dried, filtered and purified by flash chromatography eluting with a gradient of 0 to 30% EtOAc / heptane to give 8e (6.7 g) as a solid, which exceeded theoretical yield. Due to low purity shown by NMR, the material was repurified using a 220 g Gold Isco column and eluting with a gradient of 0 to 30% EtOAc / heptane to give 8e (5.18 g, 84%) as a beige solid. 1 H NMR (400 MHz, CDCl 3 )δ7.53(ddd,J=9.2,4.6,1.9Hz,1H),7.39(td,J=9.4,7.3Hz,1H),7.20(d,J=2.3Hz,1H),7.14(t,J=2.1Hz,1H),3.94(s,3H),MS:210[M+H-SO 2 CF 3 ] + . 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 min. The reaction was heated to 50 °C for 17 h. LCMS showed a new peak that was more polar but not ionized. The mixture was diluted with EtOAc and the product was extracted with 1N NaOH (2×75 mL). The aqueous layer was acidified to pH=1 with 6N HCl and extracted with EtOAc (2×200 mL). EtOAc was purified by Na 2 SO 4 Drying and concentration gave (7,8-difluoro-3-hydroxynaphthalen-1-yl)boronic acid, Preparation 8 (3.6 g, 99%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ=7.50(ddd,J=1.7,4.7,9.0Hz,1H),7.42(d,J=2.3Hz,1H),7.32(dt,J=7.9,9.4Hz,1H),7.14(t,J=2.1Hz,1H),3.93(s,3H), among which B(OH) 2 Protons appear as very broad peaks between 2 and 3 ppm, depending on concentration. 19 F NMR (376 MHz, CDCl 3 )δ=-141.77(d,J=18Hz,1F),-144.32(d,J=20Hz,1F).

[0499] Preparation 9: 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0500]

[0501] Diisopropylamine (44.1 mL, 314 mmol) was dissolved in THF (300 mL) and the solution was cooled to -78 °C. n-BuLi (114 mL of 2.5 M in hexanes, 286 mmol) was added over 15 min. The mixture was stirred for 45 min, and CAS: 82671-06-5 (30 g, 143 mmol) was added as a solution in THF (75 mL) over 6 min. The mixture was stirred at -78 °C for 30 min. CAS: 630-25-1 (69.8 g, 214 mmol) was added as a solution in THF (120 mL) over 10 min. The reaction was kept at -78 °C for 2 h and the reaction was checked by LCMS. A 3-hydroxy-1-nitropropene with MH=242 (product-CO) was observed. 2 H) (negative ion mode). The mixture was quenched by adding water (120 mL). After stirring at -78 °C for 10 min, the cold bath was removed and 6N HCl (90 mL) was added. The aqueous layer at pH = 1 was extracted with EtOAc (×3). The combined organic extracts were washed with brine (×2) and purified by MgSO 4 Dried. Removal of solvent gave a solid which was stirred in heptane (250 mL) for 1 hour to remove tetrachloroethylene byproduct. After filtration, the solid was washed with heptane (3 x 100 mL) and dried to give 9a as a cream solid, 30.3 g (73%). 19 FNMR (376MHz, DMSO) d-114.17. A solution of 9a (30.2g, 104mmol) was suspended in DCM (420mL). Oxalyl chloride (25.0mL, 300mmol) was added, followed by DMF (40mg). After stirring for 2 hours, solids were still present and bubble formation could still be found. Therefore, the mixture was stirred overnight (16 hours). After stirring for 16 hours at RT, the solids had dissolved and the mixture became a yellow solution. The solvent was removed in vacuo to give 33.3g of the acid chloride as a tan solid. In a separate 500mL round-bottom flask, methyliminothiocarbamate sulfate (33.2g, 177mmol) was mixed with half-saturated Na 2 CO 3 (80 mL) was stirred together to obtain a clear solution. 2O (60mL) was added to the solution cooled to 10°C. Subsequently, the acid chloride of 9a was slowly added as a solution in EtOAc (120mL), and the temperature was monitored with an internal thermometer. A very slight exotherm was observed and the ice bath was removed after the addition was complete. After warming to RT, the mixture was stirred for 30min while the consumption of the acid chloride was monitored using negative ion mode ionization and 9a was observed to no longer exist (hydrolysis occurred during LCMS to give acid). After the reaction was completed, complete product formation was observed and a new peak with a polyhalogen pattern of M+H=360 was observed. The mixture was distributed between water (100mL) and EtOAc (150mL) and the aqueous layer was extracted with EtOAc (×2). The combined organic extracts were washed with saturated NaHCO 3 (×1) washed with MgSO 4 Drying and concentration afforded 35 g of 9b (93%) as a tan solid which was used in the next reaction without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (br s, 1H), 9.53 (br s, 1H), 2.40 (s, 3H). 9b (14.7 g, 40.7 mmol) was dissolved in DMF (45 mL) and DIEA (14.2 mL, 81.4 mmol) was added. 2 The reaction was heated to 95° C. for 3 hours at 4 ° C., at which time LCMS analysis showed complete conversion to the cyclized product (9c), with M+H=282, 284. After cooling to RT, the mixture solution was poured into a pH 5 buffer solution and 100 g of ice, and the resulting solution was adjusted to pH 3 using 6N HCl. After addition to the cold aqueous solution, a creamy yellow solid precipitated from the solution. The precipitate was collected in a Buchner funnel and washed with water (×3) to give 9.6 g of 9c (84%) after drying. 19 F NMR (376 MHz, DMSO) d 135.4. DIEA (7.1 mL, 28.6 mmol) was added to a flask containing 9c (5.6 g, 20 mmol) and stirred at N 2 The suspension was cooled to 0°C. POCl was added in one portion. 3 (30 mL, 320 mmol) and the ice bath was removed. The mixture was then heated to 90°C for 4 hours. LCMS analysis (sample dissolved in MeOH) showed two monomethanol adducts with M+H=294, with Cl 2 Isotope pattern. Removal of POCl in vacuum 3 , chase the excess POCl with a mixture of toluene and DCM (×2) 3After all volatiles were removed, the resulting orange solid was dry loaded onto an 80 g ISCO silica gel column and purified using a gradient of 0 to 100% EtOAc / heptane, maintaining 100% EtOAc for 7 column volumes as the product slowly eluted from the column. The fractions were concentrated to give 5.7 g (95%) of Preparation 9 as an orange solid. 13 C NMR (101MHz, DMSO-d6) δppm165.5,157.2,148.6,146.7,146.0,143.2,137.4,137.3,114.8,12.9; 19 F NMR (376 MHz, DMSO) d -135.5.

[0502] Preparation 10: (8aS)-5-chloro-4-fluoro-2-(methylthio)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0503]

[0504] Preparation 9 (1.25 g, 3.70 mmol) was suspended in CH 3 CN (24mL) and DIEA (0.668mL, 3.83mmol) was added. The mixture was cooled to 0°C and (S)-piperidin-2-ylmethanol (421mg, 3.65mmol) was added as a solution in THF (18mL). After 8min, the first nitrogen-carbon bond was formed as observed by LCMS. LiOtBu (877mg, 11.0mmol) was added as a solution in THF (22mL) and the mixture was warmed to 50°C. After 4 hours at 50°C, LCMS analysis showed conversion to Preparation 9. Subsequently, the reaction mixture was diluted with 200mL of water and the product was extracted with DCM (50mL×4). The combined organic extracts were purified by Na 2 SO 4 Drying, filtration and evaporation gave Preparation 10 as a crude solid. Purification was achieved via flash chromatography eluting with a gradient of 0 to 10% MeOH / DCM to give 1.13 g of Preparation 10 (91%). 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]+ .

[0505] Preparation 11: (8aS)-4-fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-(methylthio)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0506]

[0507] Preparation 10 (1.13 g, 3.32 mmol) and CAS: 2621932-37-2 were dissolved in THF (33 mL). Aqueous K3PO4 (7.3 mL of 1.5 M, 11 mmol) was added and the mixture was stirred for 2 h with N 2 The mixture was purged for 5 min. cataCXiumA Pd G3 (241 mg, 0.332 mmol) was added and N 2 The mixture was purged for another 5 min. The reaction was heated at 60 °C for 16 h. LCMS analysis of the mixture showed that CAS: 2621932-37-2 was consumed and some Preparation 10 remained. The mixture was cooled to RT and diluted with water (40 mL). The mixture was extracted into EtOAc (20 mL x 3). The combined organic extracts were purified by Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography eluting with a gradient of 0 to 55% EtOAc / heptane. Preparation 11 was eluted with 55% EtOAc to afford 1.09 g (48%) as a solid. 1 H NMR (400MHz, DMSO) δ8.12-8.03(m,1H),7.72(t,J=2.1Hz,1H),7.55(td,J=8.9,2.6Hz,1H),7.36(dd ,J=6.0,2.6Hz,1H),5.36(s,2H),5.09(dd,J=88.0,13.1Hz,1H),4.54-4.31(m,2H),4.04-3.79(m,1 H),3.43(s,3H),3.01(t,J=12.8Hz,1H),2.52(d,J=3.7Hz,3H),1.85(ddd,J=36.1,23.2,11.5Hz,4H ),1.72-1.47(m,1H),1.45-1.33(m,1H),0.86(dd,J=7.5,3.9Hz,18H),0.57(dq,J=15.0,7.4Hz,3H), 19F NMR(377MHz,DMSO)δ-107.27,-143.30,MS:691.3[M+H] + .

[0508] Preparation 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-pyrrolizin-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

[0509]

[0510] Preparation 11 (944 mg, 1.37 mmol) was dissolved in methyl ethyl ketone (47 mL) and saturated NaHCO3 (24 mL) was added before potassium persulfate (1.89 g, 3.07 mmol). The reaction was allowed to stir for 40 min, at which time a mixture of sulfone and sulfoxide was observed. The reaction mixture was stirred for 2 hours with saturated Na 2 SO 3 Excess potassium persulfate was quenched and the product was extracted into EtOAc (15 mL x 3). The organic extract was washed with brine (x 1) and purified by Na 2 SO 4 Drying, filtration and evaporation gave 966 mg (100%) of a sulfone / sulfoxide mixture as a solid. MS: 707, 723 [M+H] + The solid was dissolved in CH 3 CN (10mL), and before LiOTMS (435mg, 4.52mmol), ((2R, 7AS) -2- fluorohexahydro -1H- pyrrolizine -7A- base) methanol (288mg, 1.81mmol) was added. The reactant was heated and stirred at 80 ° C for 20min. LCMS analysis showed the consumption of sulfone and sulfoxide starting materials. The mixture was cooled to RT and diluted with MeOH (5mL). HCl (4.8mL of 4M in dioxane, 19mmol) was added. The mixture was stirred at RT for 90min, and the MOM deprotection group was observed to be complete. The mixture was evaporated to dryness and EtOAc (80mL) was added. With saturated NaHCO 3 The EtOAc layer was washed with aqueous solution (×3), and the organic layer was collected and purified by Na 2 SO 4The purified diatomaceous earth supported product was dried and loaded on a 40 g Gold ISCO column and purified by flash chromatography using a gradient elution of 0 to 100% EtOAc / heptane followed by 50% MeOH / DCM. Both the desired product and by-product appeared during the 50% MeOH / DCM gradient, and the fractions were concentrated and purified a second time using a 24 g Gold ISCO column and a gradient elution of 0 to 20% MeOH / DCM. The pure fractions were collected and concentrated to give 910 mg (80%) of Preparation 12 as a solid. 1 H NMR (400MHz, DMSO) δ10.07(d,J=3.2Hz,1H),8.00-7.92(m,1H),7.46(td,J=9.0,1.9Hz,1H),7.36(s,1H),7.19(dd ,J=16.8,2.5Hz,1H),5.29(d,J=54.1Hz,1H),5.07(dd,J=81.2,12.8Hz,1H),4.51-4.31(m,2H),4.13(dd,J=16.6,1 0.4Hz,1H),4.08-3.97(m,2H),3.89(dd,J=43.2,9.7Hz,1H),3.17(d,J=4.7Hz,4H),3.12(d,J=7.5Hz,1H),3.07-2 .79(m,3H),2.18-1.97(m,3H),1.89-1.77(m,5H),0.85(td,J=6.8,6.3,1.8Hz,18H),0.57(dq,J=14.8,7.3Hz,3H), 19 FNMR(377MHz,DMSO)δ-109.05,-143.64,-172.29,MS:758.4[M+H] + .

[0511] 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

[0512]

[0513] In N 2 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) was added [(t-Bu) 3 P]HBF4 (4.94 g, 17.0 mmol), LiF (15.5 g, 596 mmol) and Pd(OAc) 2 (1.91 g, 8.51 mmol). The mixture was then stirred at 70 °C for 1 hour, at which time LCMS analysis showed that the starting methyl ketone had been consumed. After cooling to rt, the mixture was filtered through a celite pad, and the filtrate was diluted with water (500 mL). The product was extracted with EtOAc (4 × 250 mL) and the combined organic phases were washed with brine (3 × 200 mL) and purified by Na 2 SO 4 Dried and concentrated.The residue was purified by flash chromatography using a gradient of 0 to 35% EtOAc / petroleum ether to afford 8.08 g of 13a (83%) as a white solid. 1 H NMR(400MHz, DMSO)δδ8.10(dd,J=11.5,8.3Hz,1H),7.52(dd,J=11.6,8.0Hz,1H),3.88(s,2H),3.58(s,3H),2.54(s,3H),MS:229[M+H] + Subsequently, 13a (6.98 mg, 30.6 mmol) was dissolved in anhydrous THF (306 mL) and stirred at N 2 The mixture was cooled to -78 °C at 4 °C. LHMDS (55 mL of 1.0 M in THF, 55 mmol) was added and the mixture was stirred at 0 °C for 2 hours. LCMS analysis showed that the starting ketoester had been consumed and 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 purified by Na 2 SO 4 After concentration of the extract, the crude product 13b (6.42 g) was obtained as a red solid. 1 H NMR (400MHz, MeOD) δ7.81-7.71(m,1H),7.39-7.29(m,1H),6.59(d,J=2.1Hz,1H),6.47(d,J=2.0Hz,1H),MS:197[M+H] + The crude material was used in the next step without further purification. 2To a solution of 13b (6.42 g, 32.7 mmol) and CAS111409-79-1 (10.3 g, 39.3 mmol) in anhydrous 1,4-dioxane (113 mL) was added dichloro(p-isopropyltoluene)ruthenium(II) dimer (2.01 g, 3.27 mmol) and KOAc (6.43 g, 65.5 mmol). The mixture was then stirred at 110 °C for 16 hours. LCMS analysis showed that the starting material was consumed. After cooling to rt, the mixture was filtered through a celite pad 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) and purified by Na 2 SO 4 Dry and concentrate. The crude product was purified by flash chromatography using a gradient of 0 to 30% EtOAc / petroleum ether to afford 7.19 g of 13c (58%) 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) was added SEMCl (3.19 g, 19.1 mmol) and the reaction was stirred at 20 ° C for 24 hours. LCMS analysis showed that the starting material was consumed, and the desired product was detected. The mixture was concentrated and the residue was subsequently purified by silica gel column chromatography using a gradient of 0 to 5% EtOAc / petroleum ether to give 7.64 g of 13d (79%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ8.99(s,1H),7.40(dd,J=10.8,7.9Hz,1H),6.89(d,J=2.4Hz,1H),6.75(d,J=2.3Hz,1H),5.28(d,J=3.3Hz,2H),3.80-3.75(m,2H),1.27(d,J=7.9Hz,2H),1.18(d,J=5.4Hz,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), and Tf was added dropwise. 2 O (6.38 g, 22.6 mmol) was added before the solution was cooled to -30 °C. The resulting mixture was stirred at -30 °C for 1 hour, at which time TLC analysis showed a new light 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 purified by anhydrous Na 2 SO4 The mixture was concentrated and the residue was purified by flash chromatography eluting with a gradient of 0 to 2% EtOAc / petroleum ether to afford 5.69 g of 13e (59%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ7.46(dd,J=10.1,7.7Hz,1H),7.35(d,J=2.3Hz,1H),7.30(d,J=2.2Hz,1H),5.31(s,2H),3.78(dd,J =9.7, 4.3Hz, 2H), 1.24 (dd, J = 5.0, 3.3Hz, 2H), 1.17 (t, J = 5.0Hz, 18H), 1.02-0.90 (m, 3H), 0.00 (s, 9H). in N 2 13e (5.69 g, 8.90 mmol) and B 2 Pin 2 To a solution of (4.52 g, 17.8 mmol) in 1,4-dioxane (45 mL) was added Pd(dppf)Cl 2 (651 mg, 0.890 mmol) and KOAc (2.62 g, 26.7 mmol). The reaction was then stirred at 110 °C for 16 hours. LCMS analysis showed that the starting material was consumed and the mixture was filtered through a celite pad. The filtrate was concentrated to give a crude material, which was purified by flash chromatography with a gradient elution of 0 to 5% EtOAc / petroleum ether. The fractions containing the desired product were concentrated to give 2.24 g of Preparation 13 (41%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.44(m,1H),7.43-7.38(m,1H),7.31(d,J=2.6Hz,1H),5.30(s,2H),3.80-3.74(m,2H),1.42(s, 12H),1.17(d,J=3.3Hz,18H),0.98-0.94(m,2H),0.87(dd,J=6.0,2.7Hz,2H),0.00(s,9H),MS:617[M+H] + Using General Procedure D, the boronate ester Preparation 13 was coupled with Preparation 10 to give Example 32 in 5 steps.

[0514] Example

[0515] In order to better understand the present invention, the following examples are described. The examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0516] Example 1: {(3S)-1-[7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetra

[0063]

[0064] 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-yl}acetonitrile.

[0517]

[0518] Example 1 was prepared according to the scheme representing General Method A above.

[0519] To a solution of CAS No. 2454396-80-4 (215 mg, 0.814 mmol) and CAS No. 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 allowed to warm to rt 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) and purified by Na 2 SO 4 Dried, filtered and concentrated.The residue was purified by flash chromatography using a gradient of 0 to 60% EtOAc / petroleum ether to afford 1A (160 mg, 56%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.88(s,1H),4.48(d,J=11.6Hz,1H),4.38(d,J=13.4Hz,1H),3.38(t,J=10.9Hz,1H),3.27-3.20(m,1H),2.63(dd,J=6.7,4.0Hz,2H ),2.59-2.52(m,3H),2.14-2.05(m,1H),1.94(d,J=9.8Hz,1H),1.87-1.79(m,1H),1.71-1.62(m,1H),1.49-1.40(m,1H),MS:352[M+H] + In N 2 1A (160 mg, 0.455 mmol) and Preparation 7 (343 mg, 0.591 mmol) were dissolved in dioxane (10 mL) and H 2 To the solution in O (1 mL) were added CataCXium A Pd G3 (33.1 mg, 0.0455 mmol) and K 2 CO 3 (189 mg, 1.36 mmol). 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 / petroleum ether to give 1B (207 mg, 59%) as a yellow solid. 1H NMR (400MHz, DMSO) δ9.10(d,J=4.6Hz,1H),8.04(d,J=8.3Hz,1H),7.72(s,1H),7.69-7.63(m,1H),7.58(t,J=7. 7Hz,1H),7.33(d,J=2.3Hz,1H),5.46(s,2H),4.57(d,J=11.8Hz,1H),4.48(s,1H),3.88-3.76(m,2H),3.20(d,J= 10.8Hz,1H),2.71(d,J=6.8Hz,2H),2.60(d,J=2.2Hz,3H),2.10-1.92(m,3H),1.51(d,J=11.7Hz,1H),1.28(s,1H ),1.00-0.94(m,2H),0.93-0.80(m,18H),0.53(dq,J=14.4,7.1Hz,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 hour. 2 SO 3 The reaction mixture was diluted with aqueous solution (20 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with saturated NaHCO 3 (100 mL), brine (100 mL) and washed with anhydrous Na 2 SO 4 After drying, crude 1C (211 mg, 99%) was obtained as a yellow solid. 1 H NMR (400MHz, DMSO) δ9.31(s,1H),8.07(d,J=8.2Hz,1H),7.76(s,1H),7.67(s,1H),7.60(t,J =8.0Hz,1H),7.36(s,1H),5.47(s,2H),4.67(s,2H),3.81(t,J=7.8Hz,2H),2.98(dd,J=11.1, 6.6Hz,3H),2.76(s,2H),2.04(d,J=7.8Hz,2H),1.28(s,3H),0.96(t,J=8.2Hz,2H),0.86(dd ,J=12.3,5.1Hz,18H),0.54(dt,J=14.9,7.4Hz,3H),0.05(s,3H),-0.00(s,9H),MS:786[M+H] + At 0℃ in N 2To a solution of 1C (211 mg, 0.263 mmol) and CAS No. 2097518-76-6 (50.3 mg, 0.316 mmol) in dry DCM (10 mL) was added LHMDS (0.289 mL of 1 M in THF, 0.289 mmol) dropwise. The reaction was stirred at 0°C for 1 hour. The mixture was heated to 40°C with H 2 The reaction mixture was diluted with 4% CO (15 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4 After concentration under reduced pressure, the resulting residue was purified by flash chromatography eluting with a gradient of 0 to 10% MeOH / DCM to afford ID (161 mg, 69%) as a yellow solid. 1 H NMR (400MHz, DMSO) δ9.09(d,J=3.8Hz,1H),8.04(d,J=8.2Hz,1H),7.72(d,J=2.5Hz,1H),7.69-7.63(m,1H),7.62-7.54(m,1H),7.32(d,J=1.9Hz ,1H),5.46(s,2H),5.27(s,1H),4.48(dd,J=42.3,11.5Hz,3H),4.18(dd ,J=23.5,10.5Hz,1H),4.09-3.97(m,1H),3.90-3.67(m,2H),3.19(dd,J= 25.0,11.6Hz,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=13.2Hz,2H),1.80(d,J=11.7Hz,2H),1.52(d,J=13 .4Hz,2H),0.97(dd,J=18.9,10.0Hz,3H),0.91-0.82(m,18H),0.54(tt, J=15.0,6.0Hz,3H),0.11-0.02(m,3H),0.02--0.04(m,9H),MS:881[M+H] + To a solution of ID (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 hour. 2 The reaction mixture was diluted with 1% O (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4After concentration under reduced pressure, the crude terminal alkyne (132 mg, 99%) was obtained as a yellow solid and used in 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 (0.20 mL of 4 M in dioxane, 0.80 mmol). The reaction was stirred at 25 °C for 0.5 h. The reaction was concentrated and purified by preparative HPLC (column: Xbridge 5m C18 150×19 mm; mobile phase: CH 3 The crude product was purified by evaporation of 4% paraformyl alcohol (5% ethanol, 1% ethanol, 2% ethanol, 4% ethanol, 0.1% ethanol, 0.2% ethanol, 0.4% ethanol, 0.6% ethanol, 0.7% ethanol, 0.8% ethanol, 1% ethanol, 0.9% ethanol, 2% ethanol, 0.1% ethanol, 0.2% ethanol, 0.8% ethanol, 0.9% ethanol, 1% ethanol, 0.8% ethanol, 0.9% ethanol, 0.8% ethanol, 0.8% ethanol, 0.8% ethanol, 0.9% ethanol, 1% ethanol, 0.8 ... 1 H NMR (400 MHz, DMSO-d 6 )δ9.00(d,J=10.0Hz,1H),7.88(d,J=8.0Hz,1H),7.50-7.39(m,2H),7.34(d,J=2.4Hz,1H),7.14 (d,J=2.3Hz,1H),5.48-5.15(m,1H),4.45(dd,J=25.6,13.0Hz,3H),4.25-4.10(m,1H),4.10-4. 00(m,1H),3.62(d,J=3.7Hz,1H),3.20-2.97(m,5H),2.83(d,J=6.6Hz,1H),2.66(d,J=7.5Hz,2H ),2.13(d,J=4.7Hz,2H),2.05(s,1H),2.01(s,2H),1.92-1.71(m,4H),1.47(s,1H),MS:595[M+H] + .

[0520] Examples 2 to 9 reported in Table 1 were prepared according to Scheme I / General Procedure A with noncritical modifications that would be apparent to one skilled in the art.

[0521] Example 10: (1R, 5R, 6R)-3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3-azabicyclo [3.2.1] Octan-6-ol.

[0522]

[0523] Example 10 was prepared according to the scheme representing General Method B above.

[0524] A solution of CAS No. 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 hour and the cold bath was removed. The reaction was allowed to warm to rt over 1 hour. The solvent was removed and the residue was purified via flash chromatography using a gradient elution of 0 to 100% EtOAc / heptane. After concentrating the pure fractions, 10A (1.09 g, 88%) was obtained as a yellow solid. 1 HNMR (400 MHz, DMSO-d 6 )δppm 1.17-1.24(m,1H)1.69(s,1H)1.79(s,1H)2.05-2.15(m,1H)2.16-2.22(m,1H)2.33-2.38(m,1H)3.45(br d,J=12.6Hz,1H)3.74(br d,J=12.5Hz,1H)4.15-4.22(m,1H)4.46(br s,1H)4.58(br d,J=13.3Hz,1H)4.66-4.73(m,1H)9.21(s,1H),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-pyrrolizine-7A-yl)methanol (1.13 g, 7.11 mmol), and the mixture was heated to 90 ° C for 48 hours. The reactant 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 via SFC to give 10B (890 mg, 54%). 1 H NMR (400 MHz, DMSO-d 6)δppm 9.08(s,1H)5.16-5.41(m,1H)4.62-4.75(m,2H)4.47(br d,J=12.1Hz,1H)4.08-4.19(m,2H)4.00(d,J=10.3Hz,1H)3.63-3.74(m,1H)3.33(s,1H)2.98-3.14(m,3H)2.73-2.91(m,1H)2.31(br s,1H)1.93-2.20(m,5H)1.72-1.91(m,4H)1.57-1.69(m,1H)1.11-1.26(m,1H),MS 466[M+H] + To a mixture of 10B (100 mg, 0.215 mmol) and CAS No. 2621932-37-2 (132 mg, 0.258 mmol) in THF (2.5 mL) was added K 3 PO 4 The mixture was concentrated under vacuum and the resulting residue was eluted with a gradient of 0 to 20% iPrOH / DCM and purified by flash chromatography. After concentrating the pure fractions, 10C (130 mg, 74%) was obtained as a yellow powder. 1 H NMR (400 MHz, DMSO-d 6)δ=9.62,9.26(2s,1H, major and minor rotamers, respectively),8.10(dd,J=5.9,9.3Hz,1H),7.73(d,J=2.4Hz,1H),7.56(t,J=8.9Hz,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=3.4Hz,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 buried under 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] + 10C (126 mg, 0.154 mmol) was added to CH 3 CsF (235 mg, 1.55 mmol) was added to the solution in CN (5 mL). The reaction was stirred at rt for 4 hours. The mixture was neutralized with acetic acid (22 mL, 0.386 mmol) and concentrated under vacuum. The residue was dissolved in EtOAc and the salt was removed by filtration. The filtrate was concentrated to give a peach-colored powder of terminal alkyne (102 mg), which was used in the next step without further purification. The terminal alkyne (102 mg, 0.154 mmol) from the previous step was cooled in an ice bath in CH 3 CN (2 mL). 4N HCl (2 mL of 4N in dioxane, 8.0 mmol) was added. The reaction was stirred at 0 °C for 1 hour. The solvent was evaporated to give an orange solid. This residue was dissolved in MeOH (1 mL) and purified by preparative HPLC using acetic acid as CH 3CN / water eluent additive purification. The 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-pyrrolizine-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 light orange powder. 1 H NMR (400MHz, methanol-d4) δ = 9.28-9.04 (m, 1H), 7.90-7.81 (m, 1H), 7.35 (d, J = 2. 4Hz,1H),7.34-7.28(m,1H),7.27-7.19(m,1H),5.49-5.30(m,1H),5.21(br d,J=11.9Hz,1H),4.67(br d,J=12.1Hz,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] + .

[0525] Examples 11 to 17 reported in Table 1 were prepared according to General Procedure B / Example 10 with noncritical modifications that would be apparent to one skilled in the art.

[0526] Example 18: (1R*, 5R*, 6R*)-3-[7-(8-ethynyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-8-oxa-3- Azabicyclo[3.2.1]octan-6-ol.

[0527]

[0528] Example 18 was prepared according to the scheme representing General Method C above.

[0529] Compound CAS No. 2454491-14-4 (3.66 g, 13.8 mmol) was combined with DCM (69 mL) containing CAS No. 135938-63-5 (3.18 g, 13.9 mmol). 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 rt over 3.5 hours. The mixture was partitioned between water and DCM and the DCM layer was washed with water (3×). The organic layer was dried over sodium sulfate and re-subjected to the reaction conditions, adding fresh CAS No. 135938-63-5 (1.6 g, 6.9 mmol) and fresh DIPEA (7.0 mL, 42 mmol). After stirring for 1 hour, a third portion of CAS No. 135938-63-5 (1.6 g, 6.9 mmol) was added and the reaction was stirred at rt 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 via flash chromatography using a gradient of 0 to 100% EtOAc / heptane afforded 18A (4.26 g, 67%) as a glass. 1 HNMR (400MHz, CDCl 3 )δ8.94(s,1H),4.84(s,1H),4.46(d,J=13.5Hz,1H),4.12(dd,J=10.5,8.6Hz,1H),3.76(dd,J=10.5,5 .7Hz,1H),3.34(t,J=12.3Hz,1H),2.60(s,3H),1.88-1.64(m,9H),0.79(s,8H),0.02(d,J=2.3Hz,6H), 19 F NMR (376 MHz, CDCl 3 )δ-134.84,MS:457.1[M+H] + 18A (197 mg, 0.430 mmol) was mixed with THF (4.3 mL) containing Preparation 7 (500 mg, 0.861 mmol) and K 3 PO 4Aqueous solution (1.43mL of 1.5M, 2.15mmol) was combined. The mixture was purged with nitrogen for 3min. Subsequently, CataCXium A Pd G3 (31.3mg, 0.0430mmol) was added and the mixture was purged with nitrogen for another 3min. The reactants were heated at 70°C for 4.5 hours and product formation was observed by TLC. The mixture was then directly evaporated on diatomaceous earth. The diatomaceous earth was encapsulated in an Isco cartridge and the product was eluted with a gradient of 0 to 100% EtOAc / heptane and purified by flash chromatography. The fractions were analyzed using a non-polar / high quality LCMS method that picked up the target mass as a late elution peak. The pure fractions were concentrated to give compound 18B (367mg, 49%) as a glassy orange solid. 1 H NMR (400 MHz, CDCl 3 )δ9.11(d,J=20.0Hz,1H),7.81(dt,J=8.3,1.5Hz,1H),7.68(dd,J=7.2,1.2Hz,1H),7.54(t,J=3.0Hz,1H),7.42-7.38(m,1H),7.30(dd,J =4.3,2.6Hz,1H),5.37(d,J=7.0Hz,1H),5.35-5.31(m,1H),4.87(s,1H),4.38(dd,J=38.0,13.8Hz,1H),4.05-3.96(m,1H),3.84-3.74(m ,3H),3.51-3.32(m,1H),2.61(d,J=1.3Hz,3H),1.27(q,J=2.2Hz,4H),1.19-1.16(m,4H),1.05(d,J=1.1Hz,3H),1.00-0.95(m,3H),0.90 (d,J=1.6Hz,9H),0.88(t,J=1.8Hz,9H),0.77(s,6H),0.58-0.49(m,3H),-0.00(t,J=1.2Hz,9H),-0.03(d,J=2.5Hz,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 solution (10 mL). Potassium persulfate (322 mg, 0.524 mmol) was added and the mixture was stirred at rt for 45 min. The pH value was tested with pH test paper and observed to be between 7 and 8. The reactant was quenched by adding saturated aqueous sodium sulfite solution (20 mL) and the reaction mixture was stirred for 5 min. The reaction mixture was extracted with 50 / 50 heptane: EtOAc (1×40 mL) and the organic extract was washed with brine (1×25 mL) and dried over sodium sulfate. After filtration and concentration, 18C (341 mg, 90%) was obtained. Note: Both sulfoxide and sulfone masses were observed under a single broad peak. MS: sulfoxide: 891.4, sulfone: 907.4 [M+H] + This material was used in the next step without further purification. Compound 18C (341 mg, 0.376 mmol) was mixed with CH 2 O containing CAS No. 2097518-76-6 (89.7 mg, 0.564 mmol) and lithium trimethylsilanol (108 mg, 1.13 mmol). 3 CN (4.18mL) was combined. The mixture was heated at 80°C for 30min. After cooling, the solid was removed by filtration. The filtrate was diluted with water (40mL) and extracted with a solvent mixture of 10% EtOAc / heptane (3×10mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography by dissolving in 5mL heptane and directly loaded on a silica gel column. Elution was performed using a gradient of 0 to 100% EtOAc / heptane to give 18D (236mg, 64%). MS: 986.5[M+H] + Compound 18D (236 mg, 0.239 mmol) was dissolved in THF (2.39 mL), and aqueous NaOH solution (1.20 mL of 1 M, 1.20 mmol) was added, followed by TBAF (1.20 mL of 1 M in THF, 1.20 mmol), and the mixture was heated to 60 ° C under stirring. After 2.3 hours, the reaction mixture was cooled to rt 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 with a gradient elution of 0 to 100% EtOAc (containing 10% by volume, 7N ammonia / methanol) / heptane. Pure fractions were collected to obtain (50 mg, 27%), and the column was further rinsed with DCM containing 75% methanol to elute the residual target substance retained on the column to obtain another 100 mg of product. The total yield of the C4 deprotection step was 150 mg, 81%, MS: 775.3 [M+H] +. Half of this material was used directly in the amine coupling step. The material from the TBAF / NaOH treatment (50 mg, 0.065 mmol) was combined with DCM (1.0 mL) containing CMPI (26.4 mg, 0.103 mmol) and DIPEA (57.4 μL, 0.323 mmol). The mixture was stirred at rt for 1 hour. Subsequently, Prepared 2-(-) (17.1 mg, 0.103 mmol) was added and the mixture was stirred at rt for 3 hours. The reaction mixture was diluted with EtOAc (30 mL) and the organic layer was washed with brine (3×10 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 CH 3 CN (1.0 mL) and CsF (89.1 mg, 0.587 mmol) was added. The reaction mixture was stirred at rt for 6 hours to complete the removal of the TiPS group. Subsequently, HCl (0.293 mL of 4.0 M in dioxane, 1.17 mmol) was 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 NaOH aqueous solution (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-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-8-oxa-3-azabicyclo[3.2.1]octan-6-ol, Example 18, 1 H NMR (400 MHz, DMSO) δ 9.07 and 9.31 (2s, 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 (2d, J = 2.6 Hz, 1H, major and minor rotamers, respectively), 5.26 (d, J = 54.3 Hz, 1H), 4. 42(d,J=7.3Hz,1H),4.33-4.19(m,2H),4.16-3.98(m,4H),3.44(d,J=11.9Hz,1H),3.07(d,J=9.5Hz, 2H),2.99(s,1H),2.81(t,J=7.9Hz,1H),2.34-2.25(m,1H),2.11-2.02(m,2H),1.77(d,J=8.2Hz,8H),19 F NMR (376 MHz, DMSO) δ -141.48, -172.18 (only the major rotamer is reported), MS: 600.2 [M+H] + .

[0530] Examples 19 to 22 reported in Table 1 were prepared according to General Procedure C / Example 18 with noncritical modifications that would be appreciated by one skilled in the art.

[0531] Other compounds of the present invention are prepared by the modified methods exemplified herein. Unless otherwise indicated, all compounds with chiral centers are prepared and / or isolated as single enantiomers with known relative configuration. Compounds labeled as "absolute stereochemistry unknown" are usually prepared from racemic intermediates and are separated into single enantiomers by appropriate chiral preparative SFC methods prior to characterization and testing.

[0532] Examples 1 to 22 and their corresponding characterization data are all presented in Table 1 below.

[0533] Table 1: Examples 1 to 22

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546] a. The symbol "*" found in the chemical names (1R*, 5R*, 6R*) and (1S*, 5S*, 6S*) of Example 18 and Example 19 only indicates that the relative stereochemistry of the two compounds is known, but the absolute chemistry is unknown. Therefore, (1R*, 5R*, 6R*) and (1S*, 5S*, 6S*) should not be considered as the actual (1R, 5R, 6R) and (1S, 5S, 6S) found in Example 20, which have a definite absolute stereochemistry (1R, 5R, 6R).

[0547] Example 23: 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cycloheptyl[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol

[0548]

[0549] Preparation 12 (910 mg, 1.2 mmol) was dissolved in CH 3 CN (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 x 3) and the combined organic extracts were purified by Na 2 SO 4 Dry, filter and concentrate. The product was purified by SFC in CO using a ZymorSPHER HADP 150×21.2 column and a gradient of 15% to 40% MeOH. 2 The resulting solid was purified at 400 mL / min, 110 bar to afford 493 mg (68%) of Example 23 as a yellow solid. 1 H NMR observed 29 / 30 protons (no exchangeable phenol observed) 1H NMR (400MHz, DMSO) δ7.89 (dd, J=8.8, 6.4Hz, 1H), 7.40 (t, J=9.6Hz, 1H), 7.30 (d, J=2.6Hz, 1H), 7.13 (dd,J=14.8,2.5Hz,1H),5.28(d,J=52.9Hz,1H),5.20-5.06(m,1H),4.53-4.36(m,2H),4.12(dd,J= 10.4,3.2Hz,1H),4.05-3.97(m,2H),3.92(dd,J=9.5,5.1Hz,1H),3.13-3.06(m,2H),3.01(d,J=9.2 Hz,2H),2.83(q,J=8.6Hz,1H),2.20-2.09(m,1H),2.03(dd,J=20.6,3.4Hz,2H),1.92-1.47(m,9H), 19 F NMR (377MHz, DMSO) δ-111.58,-145.15,-172.11.

[0550] The procedures and reaction conditions outlined above for Example 23 are defined herein as General Method D.

[0551] Examples 24 to 31 reported in Table 1A were prepared according to General Procedure D / Example 23 with noncritical modifications that would be appreciated by one skilled in the art.

[0552] Table 1A: Examples 24 to 31

[0553]

[0554]

[0555]

[0556]

[0557]

[0558] Example 32: 5-ethynyl-6,7-difluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cycloheptyl[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol

[0559]

[0560] Boronate Preparation 13 was coupled with Preparation 10 using General Procedure D / Example 23 and non-critical modifications that would be apparent to one skilled in the art to provide Example 32 in 5 steps, the final SEM deprotection step of which is provided below.

[0561] The SEM protected intermediate leading to Example 32 (90 mg, 0.12 mmol) was dissolved in DCM (5 mL). To the DCM solution was added HCl in dioxane (0.45 mL of 4 M, 1.8 mmol) at 15 °C. The mixture was stirred at 15 °C under N 2 The reaction mixture was stirred for 30 min at 4 °C. LCMS analysis showed that the starting material was almost consumed. The mixture was concentrated under vacuum to give a crude product which was purified by preparative HPLC (Waters MS-triggered preparative LC and SQD2 detector; column: Welch 10m C18 250×21.2 mm; flow rate: 25 mL / min; wavelength: 214 nm; 50% to 70% ACN in H 2 O(0.1% NH 3 ) to afford Example 32 (24 mg, 30%) as a yellow solid. 1 H NMR(methanol-d4,400MHz)d 7.6-7.7(m,1H),7.25(d,1H,J=2.6Hz),7.15(dd,1H,J=2.5,16.7Hz),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=9.8Hz),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 FNMR (Methanol-d4, 376MHz)d - 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] + .

[0562] Example 33: 5-ethynyl-6,7-difluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cycloheptyl[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol

[0563]

[0564] Preparation 9 (450 mg, 1.51 mmol) was suspended in CH 3 CN (10 mL). DIPEA (276 μL, 1.59 mmol) was added and stirred under N 2 The suspension was cooled to 0 ° C. In a separate vial, CAS1262409-55-1-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 to give a milky mixture. This solution was added to a flask containing a cold solution of Preparation 9. After about 45 min at 0 ° C, LCMS analysis showed that the initial reaction was complete. LiOtBu (4.5 mL of 1 M in THF, 4.5 mmol) was added dropwise and the ice bath was removed. The ice bath was replaced with an oil bath and the reactants were heated at 50 ° C for 30 min. LCMS analysis showed that the cyclization step was complete. The solution was cooled to rt and evaporated. Saturated NaHCO was added. 3 The combined organic extracts were purified by Na 2 SO 4 The above-described process was repeated for the second time on the same scale to obtain the same observations and results. The crude material from the two reactions was combined and purified using flash chromatography with a gradient elution of 0 to 100% EtOAc / heptane, and the crude material was loaded on a silica cartridge using DCM. The fractions containing the desired product were combined and concentrated to give 483 mg of 14a (70%) as a tan solid. 1H 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 (CAS1262409-55-1-HCl salt) was not optically pure. In a subsequent sequence, preparative chiral SFC (see below) was used to remove the minor enantiomer. 14a (400 mg, 1.12 mmol), CAS2621932-37-2 (689 mg, 1.35 mmol), 1,4-dioxane (5.6 mL) and K were added to a vial with a stir bar. 2 CO 3 (465 mg, 3.4 mmol) (added in the form of aqueous solution (0.6 mL)). 2 The mixture was purged for 3 min and RuPhos Pd G3 (94 mg, 0.11 mmol) was added. The vial was capped 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 purified by Na 2 SO 4 Dried, filtered, evaporated and submitted for chiral SFC purification to remove the minor enantiomer.After chiral SFC, 480 mg (62%) of 14b were obtained with 90% ee. 1H NMR (400MHz, methanol-d4) δ = 7.95 (dd, J = 5.8, 9.1Hz, 1H), 7.64 (d, J = 2.5Hz, 1H), 7.40 (t, J = 8.9Hz, 1H), 7.34 (d d,J=2.3,19.4Hz,1H),5.39-5.30(m,2H),5.26-5.14(m,1H),4.71(ddd,J=4.7,13.6,18.6Hz,1H),4.57- 4.48(m,1H),4.31(tt,J=4.9,9.4Hz,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 x 20 mL). The combined organic extracts were purified by Na 2 SO 4 Drying, filtration and evaporation gave a crude material which was subjected to chiral SFC to further enrich the desired enantiomer.After chiral SFC, 257 mg of 14c was obtained as a tan solid (82%). 1H 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=9.1,12.6Hz,1H),3.52(d,J=2.8Hz,3H),3.47-3.23(m,2H),2 .92(d,J=19.6Hz,1H),2.64(s,3H),2.36-2.17(m,1H),2.13-1.93(m,1H),1.50(s,1H), 19 F NMR (376 MHz, chloroform-d) δ = -106.89--109.75 (m, 1F), -143.05 (d, J = 363.4 Hz, 1F). Solid potassium persulfate (646 mg, 1.03 mmol) and saturated NaHCO were added to a mixture of 14c (252 mg, 0.46 mmol) in MEK (7 mL). 3 Aqueous solution (7 mL). The mixture was stirred at 1500 rpm for 20 min at rt. The reaction was diluted with EtOAc (20 mL) and the aqueous layer was extracted twice with EtOAc (2×20 mL). 2 S 2 O 3 The combined organic extracts were washed with aqueous solution (10 mL) and brine (10 mL). 2 SO 4 After drying, the mixture was filtered and evaporated to give 301 mg of sulfone as a light yellow gum. MS: 583 [M+H] + This material was used in the next step without further purification. Sulfone (267 mg, 0.458 mmol) and CAS 2097518-76-6 (100 mg, 0.64 mmol) were dissolved in CH 3 CN (0.9 mL). Lithium trimethylsilanol (130 mg, 1.4 mmol) was added and the vial was capped, stirred and heated to 50 ° C for 30 min to give 14d, which was subjected to the MOM deprotection step in the same tank. After cooling to rt, MeOH (2 mL) was added to the 14d solution, followed by addition of HCl (3.5 mL of 4 M in 1,4-dioxane, 14 mmol) and the reaction was stirred at rt for 30 min. The solvent was removed under vacuum and saturated NaHCO was added. 3Aqueous solution (10 mL) and water (10 mL). From this mixture a solid precipitated which was insoluble in EtOAc but soluble in DCM. The aqueous mixture was extracted with DCM 1×150 mL and then 2×50 mL. The combined organic extracts were purified by Na 2 SO 4 Dried, filtered, evaporated and provided for purification. Purification was achieved using SFC with Princeton HA-morpholine 5 μm 21.2×150 mm column at 5.0 min, 120 bar, 100 mL / min, eluting with CO 2 / MeOH 10% to 50% to afford 193 mg (68%) of Example 33 as a white solid. 1 H 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), 4.22-4.1 1 (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 2 chemical shifts, two doublets, where 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 (377MHz, methanol-d4) δ= - 111.68(qd,J=4.6,61.0Hz,1F), - 143.97- - 147.51(m,1F), - 173.14- - 174.37(m,1F),MS:618[M+H] + .

[0565] Example 34: dihydrogen phosphate ({5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]hepten-5-yl]naphthalen-2-yl}oxy)methyl ester.

[0566]

[0567] 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 hours. LCMS analysis showed 90% conversion to 34a and another portion of di-tert-butyl chloromethyl phosphate (72 mg, 0.14 mmol) was added. The mixture was stirred for another 5 hours at 20 ° C. Water (44 mL) was added and the mixture was stirred at 20 ° C for 40 min. Multiple stirring bars were used to adjust to a smaller particle size. The solid was filtered out, collected and placed in a 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 hours, at which time LCMS analysis showed hydrolysis of the tert-butyl group. The mixture was evaporated and redissolved in 50 / 50 CHCl. 3 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 acetic acid. 1 H NMR (400MHz, DMSO) δ8.03(ddd,J=8.6,5.9,2.4Hz,1H),7.75(t,J=2.7Hz,1H),7.51(t,J=9.0Hz,1H),7.3 7(dd,J=41.4,2.6Hz,1H),5.60(d,J=10.5Hz,2H),5.40(d,J=53.5Hz,1H),5.04-4.94(m,1H),4.66(dt,J= 13.4,4.9Hz,1H),4.52-4.47(m,1H),4.34(p,J=10.8,10.3Hz,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] + .

[0568] Example 34 was developed as a prodrug of Example 33 to improve the unbound exposure of Example 33 in plasma.

[0569] The solution of Example 33 was prepared as a 2.5% (w / v) solution of Pluronic F-68 (Poloxamer 188) in water. The amorphous suspension formulations of Examples 33 and 34 were prepared using 0.5% (w / v) methylcellulose / water.

[0570] like Figure 1 As demonstrated in Table 1-A, following oral administration of a single dose of 100 mg (active substance) / kg in female NSG mice, the mean systemic exposure of Example 33 (as assessed by AUC and / or Cav) was approximately 10 to 17 times higher following administration of Example 34 relative to administration of an oral suspension dose of Example 33 (free base).

[0571] Table 1-A

[0572]

[0573] Prophetic Deuterated Analog (PDA) of Example 33

[0574] The compounds provided in Table 2 are prophetic deuterated analogs (PDAs) of Example 33. Formula (V) is the general formula of deuterated Example 33, wherein Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4 and Y 5 Each independently is H or D. The deuterated analogs of Example 33 in Table 2 were analyzed based on the metabolic properties of Example 33 using MetaSite ( moldiscovery.com / software / metasite / ) to make predictions. Based on MetaSite predictions, Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4 and Y 5 The most likely location for metabolism.

[0575]

[0576] Table 2

[0577]

[0578]

[0579] General methods / reviews for obtaining metabolite profiles and identifying compound metabolites are described 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", Chapter 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., "ChapterFifteen-Metabolite Annotation and Identification."

[0580] Many publicly and commercially available software tools can be used to help predict metabolic pathways and compound metabolites. 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 series of machine learning models to provide predictions of metabolic pathways and metabolite structures covering both Phase I and Phase II biotransformations of small molecules.

[0581] The predicted deuterated analogs V-1 to V-18 of Example 33 in Table 2 may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time-dependent), or improved therapeutic index or tolerability.

[0582] A person skilled in the art can prepare 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4 and Y 5 Other deuterated analogs of Example 33 in different combinations of. Such other deuterated analogs may provide similar therapeutic benefits that can be achieved by deuterated analogs V-1 to V-18 of Example 33 in Table 2.

[0583] KRAS surface plasmon resonance (SPR) binding assay

[0584] SPR assay was used to measure the kinetic binding constant (K) of the present invention. D ).

[0585] By surface plasmon resonance (SPR), using Biacore 8K or 8K+ (Cytiva, Marlborough, MA) instrument to measure the binding affinity and kinetics of the present invention embodiment. In this experiment, recombinant wild-type (WT) KRAS (aa1-185), G12D KRAS (aa1-185), G12C KRAS (aa2-184), G12VKRAS (aa2-184), WT HRAS (aa2-184) and WT NRAS (aa2-185) proteins with C-terminal site-specific biotinylation were used, and the protein was purified in the presence of 1 μM GDP. Binding measurements were performed in parallel for WT / G12D / G12C / G12V KRAS or WT K / H / N RAS protein groups.

[0586] The Biacore instrument was removed and docked to a S-series sensor chip SA. Proteins were quantified with assay buffer (50 mM HEPES, 150 mM NaCl, 10 μM GDP, 5 mM MgCl 2 , 0.5mM TCEP, 5% glycerol, 0.02% Tween-20, 2% DMSO, pH 7.2) was diluted to 50 μg / mL and fixed at a flow rate of 3 μL / min at 10°C with a contact time of 15 min to capture about 3000 to 4000 RU of protein on the surface. The functionalized surface was then balanced with analysis buffer for about 1 h. The unfunctionalized SA surface without protein was used as a reference for binding kinetic analysis. Compound binding kinetics were measured in multi-cycle or single-cycle kinetic form.

[0587] Multi-cycle kinetic analysis (MCK)

[0588] Two-fold, 10-point serial dilutions of test compounds were prepared in 96-well microtiter plates (Greiner; catalog number 650101) with the highest concentration being 10 μM or 100 μM. Binding kinetics were measured at 10°C by injecting serial dilutions of compounds over the reference channel and the RAS immobilized channel at a flow rate of 100 μL / min and an association time of 90 seconds. Compound dissociation was monitored for at least 400 seconds during each cycle. No additional regeneration was used. A DMSO calibration curve was obtained by injecting assay buffer containing 0 to 4% DMSO before and after compound analysis. Appropriate compounds with known affinity and kinetics were tested once in each experiment as positive controls to assess the activity of proteins captured on the surface.

[0589] Single Cycle Kinetics (SCK)

[0590] Three-fold, six-point serial dilutions of compounds were prepared in deep 96-well microplates (Greiner Bio; catalog number 780201) with the highest concentration being 1 μM (concentration range: 0.004 to 1 μM). Binding kinetics were measured at 10°C by injecting serial dilutions of compounds in ascending order over the reference channel as well as the RAS immobilized channel at a flow rate of 100 μL / min and an association time of 120 seconds. Compound dissociation was monitored for at least 3600 seconds. Two blank buffers were also run in a single cycle kinetic format as a double reference before compound action. No additional regeneration was used. DMSO calibration curves were obtained by injecting assay buffer containing 0 to 4% DMSO before and after compound analysis. Suitable compounds with known affinity and kinetics were tested once in each experiment as positive controls to assess the activity of proteins captured on the surface.

[0591] 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 measure the kinetic binding constant (K D ), association rate (k on ) and dissociation rate (k off ). Using the standard equation (t 1 / 2 =0.693 / k off ) from the measured k off Calculate the dissociation half-life (t 1 / 2 ). The adequacy of the fit is determined by c 2 The randomness of the values ​​and residual distribution is determined.

[0592] The results of the SPR binding assays for Examples 1 to 31 are provided in Table 3. When more than one example was tested, the binding constant K is provided. D The geometric mean (n is the number of test replicates). Blank cells in Table 3 indicate that no data for this example were obtained in this particular analysis.

[0593] Binding constant K D It was demonstrated that the exemplary compounds have potent binding ability to all KRAS G12C, KRAS G12D and KRAS G12V receptors and may have selectivity for HRAS and NRAS receptors.

[0594] Table 3: SPR binding assay results

[0595]

[0596]

[0597] KRAS Cell Titer Glo (CTG) analysis

[0598] The (CTG) luminescent cell viability assay is a homogenous method for determining the number of viable cells in culture based on the quantification of the ATP present, an indicator of metabolically active cells. CTG is designed for use with multiwell formats, making it suitable for automated high-throughput screening (HTS), cell proliferation, and cytotoxicity assays. The homogenous assay procedure involves the addition of a single reagent ( The reagents were added directly to cells cultured in serum-supplemented medium. Cell washing, medium removal, and multiple pipetting steps were not required. Within 10 minutes of adding the reagents and mixing, the system detected only 15 cells per well in a 384-well format.

[0599] Using the culture conditions outlined below, cells were grown at 37°C in a humidified atmosphere with 5% CO. 2Grow in an incubator. All cell culture medium reagents were purchased from Gibco. Cell lines were purchased from ATCC: H358 (non-small cell lung cancer cell line), SW620 (colorectal cancer cell line), PANC08.13 (RPMI1640 + 10% FBS + 10 units / ml insulin, pancreatic cancer cell line). Before cell inoculation, the test and control compounds were dispensed in 0.1% DMSO in the form of nanoliter droplets on a 384 analysis plate (Corning, catalog number 3764) according to the desired final concentration using an Echo Acoustic Dispenser. The cells were inoculated at the following cell density (cells / well) in a volume of 40 μL / well: H358 (300), SW620 (750), PANC08.13 (600). The cells were incubated in the presence of the compound for 7 days. On the 7th day, the test and control compounds were dispensed in the form of nanoliter droplets in 0.1% DMSO according to the desired final concentration. (CTG) luminescent cell viability analysis (Promega) measures viability.Add CTG until the final volume of 20 μ l per well and incubate at room temperature for 15 min, then use EnVision reader and LUM384 US scheme to capture luminescence.Use Activity Base analysis data to measure compound reaction, and with effect percentage (PCTEFF) or control percentage (PCTOCTL) as described below to represent: zero effect control percentage (ZPE) (negative control)-100% DMSO.Hundred percent effect (HPE) (positive control)-1 μ M trametinib (Trametinib) (GSK1120212, MEK inhibitor) (10mM of 4nl per well and 36nl of DMSO). The following equation / nomenclature ((Effect %; PCTEFF) and (Control %; PCTOCTL)) was used: PCTEFF: 100*(Raw_Data_Value-HPE / ZPE-HPE), PCTOCTL: 100*(Raw_Data_Value / User_Defined_Array), where User_Defined_Array is the summarized HPE or ZPE.

[0600] The CTG assay results for some illustrative examples are provided in Table 4. When more than one example was tested, the IC 50 The geometric mean (nM) is shown in Table 1 (n is the number of test repetitions).

[0601] Selective exemplary compounds of the present invention have been demonstrated to have anticancer activity against pancreatic cancer, non-small cell lung cancer and colorectal cancer as shown by CTG assay.

[0602] Table 4: CTG determination results

[0603]

[0604] It will be apparent to those skilled in the art that various modifications and variations may be made in the present invention without departing from the spirit or scope of the present invention. Other embodiments of the present invention will be apparent to those skilled in the art in view of the specification and practice of the present invention disclosed herein. It is intended that this specification and examples be considered merely exemplary, with the true scope and spirit of the present invention being indicated by the following claims.

[0605] All references cited herein (including patents, patent applications, papers, textbooks, and the like), and the references cited therein (to the extent they have not already been cited), are hereby incorporated by reference in their entirety. In the event that one or more of the incorporated literature and similar materials (including, but not limited to, defined terms, term usage, described techniques, or the like) differs from or contradicts this application, this application shall prevail.

Claims

1. Compounds of formula (V) or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from the group consisting of: R 2 is C1 alkyl, C3 alkyl, -(C1 alkylene)-OH or -(C3 alkylene)-OH; R 3 Selected from the group consisting of: R 4 Cl or F; R 5 is -(C1 alkylene)-OH or C1 alkyl, wherein R 2 and R 5 optionally together form a 7-membered heterocycloalkyl group 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 a linker comprising one, two or three independently selected from -O-, -S-, -NR 7 -and-CR 8 R 9 - Members of the group; R 7 , R 8 and R 9 Each independently is H or C1-C3 alkyl; X is O, N or S; and l is 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 for:

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is a C3 alkyl group, and R 5 It is -(C1 alkylene)-OH.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is -(C3 alkylene)-OH, and R 5 It is a C1 alkyl group.

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 Together they form a 7-membered heterocycloalkyl group containing one heteroatom O.

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 Together they form a 7-membered heterocycloalkyl group containing one heteroatom O.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 3 for:

9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 4 For F. 10 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is O and l is 1.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (VI):

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 2 is a C3 alkyl group, and R 5 It is -(C1 alkylene)-OH.

13. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 2 is -(C3 alkylene)-OH, and R 5 It is a C1 alkyl group.

14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 Together they form a 7-membered heterocycloalkyl group containing one heteroatom O.

15. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 Together they form a 7-membered heterocycloalkyl group containing one heteroatom O.

16. A compound of formula (VII), or a pharmaceutically acceptable salt thereof, Where R 11 , R 12 , R 13 and R 14 Each is independently H or C1-C3 alkyl.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 , R 13 and R 14 Each is independently H or methyl.

18. The compound according to claim 16 or 17 or a pharmaceutically acceptable salt thereof, wherein the compound is 19. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

21. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

22. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof as a single agent.

23. A method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and further comprising administering a therapeutically effective amount of an additional anti-cancer therapeutic.

24. The method of any one of claims 21 to 23, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer, or colorectal cancer.

25. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use as a medicament.

26. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

27. The compound for use in treating cancer according to claim 26, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

28. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer.

29. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 28 for preparing a medicament for treating cancer, wherein the cancer is small cell lung cancer (NSCLC), pancreatic cancer or colorectal cancer.

30. A method for treating a disorder mediated by inhibition of KRAS G12C, KRAS G12D and KRAS G12V receptors in a subject, comprising administering to a subject in need thereof an amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof effective to treat the disorder.

31. A pharmaceutical combination comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, or a pharmaceutically acceptable salt thereof.

32. Pharmaceutical composition comprising the pharmaceutical combination according to claim 31 and at least one excipient.

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